1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide derivatives as VHL inhibitors

Abstract

The present disclosure relates to 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4- hydroxypyrrolidine-2-carboxamide derivatives and structurally related compounds of formula (I) 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 injury to the cardiovascular system during ischemia, or for enhancing wound healing, reducing scarring or enhancing angiogenesis or arteriogenesis.

Description

[0001] Cross-reference of related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 112,611, filed November 11, 2020, and U.S. Provisional Patent Application No. 63 / 119,586, filed November 30, 2020, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to compounds comprising a VHL ligand moiety, and to methods of using such compounds as ligands for VHL. This disclosure further relates to the use of the compounds described herein or pharmaceutical compositions thereof for the prevention and / or treatment of a range of diseases, symptoms, and conditions. Background Technology

[0004] E3 ubiquitin ligases (more than 600 known in humans) confer substrate specificity to ubiquitination. Known ligands exist that bind to these ligases. The E3 ubiquitin ligase binding group (E3LB) is a peptide or small molecule that can bind to an E3 ubiquitin ligase.

[0005] The specific E3 ubiquitin ligase is the von Hippel-Lindau (VHL) tumor suppressor, a substrate recognition subunit of the E3 ligase complex VCB (an important target in cancer, chronic anemia, and ischemia), which is also composed of elongated proteins B and C, Cul2, and Rbxl. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-induced cytokine erythropoietin in response to hypoxia. Although HIF-1α is constitutively expressed, its intracellular levels are maintained at very low levels under normoxic conditions through hydroxylation of the prolyl hydroxylase domain (PHD) protein and subsequent VHL-mediated ubiquitination.

[0006] Crystal structures of VHLs with ligands have been obtained, demonstrating that the compounds mimic the binding pattern of the transcription factor HIF-1α (the major substrate of VHL). These compounds bind to VHLs that compete with HIF-1α substrates, thereby reducing or blocking the activity of the VHL protein. There remains a persistent need in the art for effective small-molecule VHL ligands across a wide range of disease indications. Summary of the Invention

[0007] This disclosure relates to VHL ligands, and more particularly to VHL ligands that bind to VHL E3 ubiquitin ligases.

[0008] In one aspect, this disclosure relates to a compound of formula (I):

[0009] (I),

[0010] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0011] X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0012] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0013] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0014] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-6 cycloalkyl,

[0015] Where R 2 C 1-12 Alkyl or C 3-6 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and

[0016] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20Aryl, 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 Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0017] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0018] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0019] Among them, Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0020] On the other hand, this disclosure relates to a compound of formula (I):

[0021] (I),

[0022] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0023] X 1 It is independently H or -C(O)-C each time it appears. 1-12 alkyl;

[0024] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0025] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0026] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl,

[0027] Where R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and

[0028] Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R cIndependently, and each time it appears, it is either H or C. 1-12 alkyl,

[0029] Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0030] Q 1 C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q C 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0031] Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated, C 1-6 Alkoxy group, -NHC(O)-C 1-12 Alkyl, -CN, or -NO2;

[0032] Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R aR b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0033] Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0034] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0035] Among them, Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted by one or more halogenated, cyano, or OH groups;

[0036] The condition is when Q 1 When R is cyclohexyl, biphenyl, or a 5- to 6-membered heteroaryl group, 1 C 1-3 Alkyl, C2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0037] In some embodiments, the compound of formula (I) or its pharmaceutical salt is a compound of formula (I'):

[0038] (I')

[0039] Or its medicinal salt, wherein X 1 R 1 R 2 Q 1 and Q 2 As defined in formula (I). It should be understood that X of such embodiments of the compound of formula (I') 1 R 1 R 2 Q 1 and Q 2 It may include X as described with respect to formula (I). 1 R 1 R 2 Q 1 and Q 2 .

[0040] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (IA):

[0041] (IA),

[0042] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing, wherein X 1 and R 2 As defined in formula (I). It should be understood that X of such embodiments of the compound of formula (IA) 1 and R 2 It may include X as described with respect to formula (I). 1 and R 2 .

[0043] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (IB):

[0044] (IB),

[0045] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing, wherein X 1 and R 1 As defined in formula (I). It should be understood that X of such embodiments of the compound of formula (IB) 1 and R 1 It may include X as described with respect to formula (I). 1 and R 1 .

[0046] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (IC):

[0047] (IC),

[0048] in:

[0049] R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0050] R 2 For H or C 1-12 alkyl;

[0051] Q 1 For H or C 3-15 cycloalkyl; and

[0052] Q 2 Each time it appears, it is independently H or C3-15 cycloalkyl.

[0053] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (ID):

[0054] (ID),

[0055] in:

[0056] X 1 It is independently H or -C(O)-C each time it appears. 1-12 alkyl;

[0057] R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0058] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted with one or more halogens;

[0059] Q 1 For H, C 6-20 Aryl, 5- to 6-membered heteroaryl or C 3-5 cycloalkyl, wherein Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated;

[0060] Q 2 It is independently H or C each time it appears. 3-5 cycloalkyl;

[0061] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 Aryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s It is independently halogenated or C-type each time it appears.1-6 Alkoxy;

[0062] The condition is when Q 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0063] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (IE):

[0064] (IE),

[0065] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein Q 1 and Q 2 As defined in formula (I). It should be understood that Q of such embodiments of the compound of formula (IE) 1 and Q 2 It may include Q as described for formula (I). 1 and Q 2 .

[0066] In some embodiments, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, is a compound of formula (IF):

[0067] (IF),

[0068] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein n is 0, 1, 2, 3 or 4; R s Independently, it can be OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, or -SO2C. 1-12 Alkyl group, -SO2NH2, C1-6 Alkoxy or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups; and wherein X 1 R 1 and R 2 As defined in formula (I). It should be understood that X of such embodiments of the compound of formula (IF) 1 R 1 and R 2 It may include X as described with respect to formula (I). 1 R 1 and R 2 .

[0069] In another respect, this disclosure relates to pharmaceutical compositions comprising one or more of the compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, and one or more pharmaceutical excipients.

[0070] In another aspect, this disclosure relates to methods of binding or inhibiting VHL using one or more of the compounds described herein, or their stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, or one or more of the pharmaceutical compositions described herein.

[0071] In another aspect, this disclosure relates to methods for preparing one or more of the compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, or one or more of the pharmaceutical compositions described herein.

[0072] On the other hand, this disclosure relates to a heterobifunctional compound of formula (II):

[0073] [A]-[B]-[C] (II),

[0074] in:

[0075] [A] is a portion of the VHL ligand of (I);

[0076] [B] refers to the connector portion; and

[0077] [C] represents the protein-binding portion.

[0078] In a further aspect, this disclosure relates to methods for preventing or treating diseases, symptoms, or conditions by administering to a subject in need one or more of the compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, or one or more of the pharmaceutical compositions described herein. Detailed Implementation

[0079] This disclosure relates to compounds that bind to E3 ubiquitin ligase protein complexes. In particular, compounds that bind to VonHippel-Lindau (VHL) (the substrate recognition subunit of the E3 ligase complex VCB) are described.

[0080] The subject matter disclosed herein will now be described more fully below. However, many modifications and other embodiments of the subject matter set forth herein will conceive by those skilled in the art, benefiting from the teachings set forth in the foregoing description, as applicable to the subject matter of this present disclosure. Therefore, it should be understood that the subject matter of this present disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses alternatives, modifications, and equivalents. If any or more of the incorporated documents, patents, and similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terminology, described techniques, or similar content, this application shall prevail. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, and are used in the context to describe the purpose of this disclosure. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety.

[0081] I. Definition

[0082] The terms “residue,” “part,” or “group” refer to a component that is covalently bonded or linked to another component.

[0083] The term "covalent bond" or "covalent connection" refers to a chemical bond formed by sharing one or more pairs of electrons.

[0084] "Patient," "individual," or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the patient or individual or subject is a person. In some embodiments, the patient may be a "cancer patient," that is, a patient who has one or more symptoms of cancer or is at risk of developing one or more symptoms of cancer.

[0085] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth / proliferation. A “tumor” contains one or more cancer cells. Examples of cancer are provided elsewhere in this article.

[0086] The terms "chemotherapeutic agent" or "anticancer agent" refer to chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include: alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, such as busulfan, inprossurfan, and piperossurfan; azacyclopropane derivatives, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylamelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylomelamine; and anechoic acid lactones (especially bullatacin). And bullatacinone; δ-9-tetrahydrocannabinol (drocannabinol, MARINOL®); β-lapaquinone; laparol; colchicine; betulinic acid; camptothecin (including synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogs adolaxine, calcexin, and bizexin); podophyllotoxin; podophyllic acid; teniposide; noctifluides (especially noctifluides 1 and noctifluides 8); sulphurin; duocarmycin (including the synthetic analog KW-2189) And CB1-TM1); eleutherobin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, naphthylambucil, chlorphosphamide, estradiol, ifosfamide, mechlorethamine, methoxynitrogenamine hydrochloride, melphalan, novombhichin, phenesterine, prednisamide, trofenoxam, uracil mustard; nitrosoureas, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994));CDP323, an oral α-4 integrin inhibitor; dynemicin, including dynemicin A; esperamicin; and new chromophores and related chromopyrins (enediyne antibiotic chromophores), aclacinomysins, actinomycins, autramycin, diazoserine, bleomycins, cactinomycin C, carabicin, erythromycin, carzinophilin, chromopycins, dactinomycin D, daunorubicin, detoxin, 6-diazo-5-oxo-L-leucine, doxorubicin (including ADRIAMYCIN®, morpholino-duxorubicin, cyanomorpholino-duxorubicin, 2-pyrrolino-duxorubicin, doxorubicin HCl liposomal injection (DOXIL®), liposomal doxorubicin TLC) D-99 (MYOCET®), pegylated liposome doxorubicin (CAELYX®) Deoxydoxorubicin), epirubicin, isorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, oligomycins, pepromycin, pofibromycin, puromycin, quelamycin, rodorubicin, streptomycin, streptozotocin, tuberculin, ubenmex, fenestrated statin, zorubicin; antimetabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone, and 5-fluorouracil (5-FU); folic acid analogs such as folate, methotrexate, pteroxate, trimethoprim; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidines. Analogs, such as ancitabine, azacitidine, 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens, such as capprotestone, drotaldone propionate, cyclothionol, meandranone, testrolide; antiadrenergics, such as aminoglutethimide, mitotane, trilosterone; folic acid supplements, such as frolinicacid; acetoglucan lactone; aldehyde phosphoramide glycoside; aminolevulinic acid; eniluracil; acridine; bestrabucil; bisacodyl; edatraxate; defofamine; dimethicone; diaconitine; elfornithine; elifonitrile; epothilone; etogluconate; gallium nitrate; hydroxyurea; lentinan; lonidainine;Maytansinoids, such as maytansin and anthraquinones; mitoxantrone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; loxoantrone; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); rhizoxin; cizonan; germanespiramine; tenuazonic acid; triaminoquinone; 2,2',2'-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A) And anguidine; urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; dibromomannitol; dibromoeusine; piperobromethane; gacytosine; arabinoside (“Ara-C”); thiotepa; taxanes, such as paclitaxel (TAXOL®), albumin-modified paclitaxel nanoparticle formulation (ABRAXANETM). Docetaxel (TAXOTERE®); chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum reagents such as cisplatin, oxaliplatin (e.g., ELOXATIN®), and carboplatin; vinca derivatives that prevent tubulin polymerization to form microtubules, including vinca alkaloids (VELBAN®), vincristine (ONCOVIN®), vinorelbine (ELDISINE®, FILDESIN®), and vinorelbine (NAVELBINE®); etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; mitoxantrone hydrochloride; edaraxazole; donomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid, including bexarotin (TARGRETIN®); bisphosphonates, such as clophosphonates (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronic acid (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); trisatabine (a 1,3-dioxolane cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, such as, for example, PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R);Vaccines, such as THERATOPE® and gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); rmRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); perifocin, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); bortezomib (VELCADE®); CCI-779; tepifenabil (R11577); orafenib, ABT510; Bcl-2 inhibitors, such as GENASENSE® (an antisense oligonucleotide); pickenone; EGFR Inhibitors (see definitions below); tyrosine kinase inhibitors; serine-threonine kinase inhibitors, such as rapamycin (sirolimus, RAPAMUNE®); farnesyltransferase inhibitors, such as clonafranil (SCH 6636, SARASARTM); and pharmaceutical salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone); and FOLFOX (an abbreviation for a treatment regimen using oxaliplatin (ELOXATINTM) in combination with 5-FU and leucovorin).

[0087] As defined in this article, chemotherapy agents include “anti-hormonal agents” or “endocrine therapy agents”, which work by regulating, reducing, blocking or inhibiting the effects of hormones that can promote cancer growth. These can be hormones themselves, including but not limited to: anti-estrogens with mixed agonist / antagonist properties, including tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), edoxifene, droloxifen, raloxifene (EVISTA®), trivoxifen, keoxifene, and selective estrogen receptor modulators (SERMs) (such as SERM3); pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®) and EM800 (these agents block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER conversion, and / or inhibit ER levels); aromatase inhibitors, including steroidal aromatase inhibitors (such as formestan and exemestan (AROMASIN®)) and nonsteroidal aromatase inhibitors (such as anastrozole (ARIMIDEX®) and lerazole (FEMARA®)). And aminoglutethimide) and other aromatase inhibitors (including vorcicloazole (RIVISOR®), megestrol acetate (MEGASE®), farozide and 4(5)-imidazoles); luteinizing hormone-releasing hormone agonists, including leuprorelin (LUPRON® and ELIGARD®), goserelin, busereline and tripterelin; sex steroids, including progestins (such as megestrol acetate and medroxyprogesterone acetate), estrogens (such as diethylstilbestrol and premarin) and androgens / retinoids (such as fluoromethathone, transretionic acid and fenvitamin A) Amines (fenretinide); onanasone; antiprogesterones; estrogen receptor downregulators (ERDs); antiandrogens, such as flutamide, nilumet and bicalutamide; and pharmaceutical salts, acids or derivatives of any of the above; and combinations of two or more of the above.

[0088] As used herein, “treatment” (and its grammatical variations, such as “treat” or “treating”) refers to a clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or in the course of clinicopathology. The desired effects of treatment include, but are not limited to: preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some embodiments, the compounds and compositions of the subject matter described herein are used to delay the development of disease or slow its progression. In one embodiment, treatment is performed solely for prevention. In another embodiment, treatment is performed only during the clinicopathological process (i.e., not for prevention). In yet another embodiment, treatment is performed during the clinicopathological process and for prevention.

[0089] A drug administered "concurrently" with one or more other drugs is administered on the same day of treatment with one or more other drugs within the same treatment cycle, and optionally concurrently with one or more other drugs. For example, for cancer treatment administered every 3 weeks, each concurrently administered drug is administered on day 1 of the 3-week cycle.

[0090] The term "effective" is used to describe a compound, composition, or component in an amount that, when used in the context of its intended use, achieves a desired therapeutic or preventative outcome. The term "effective" includes other effective amount or effective concentration terms (including therapeutically effective amount), which are further described or used in this application. As used herein, the term "therapeutically effective amount" means any amount that results in the treatment of a disease, condition, or side effect, or a reduction in the rate of progression of a disease or condition, compared to a corresponding subject who did not receive that amount. The term also includes, within its scope, amounts that effectively enhance normal physiological function. For use in a therapy, therapeutically effective amounts of the VHL ligand of this disclosure, as well as its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing, may be administered as raw material chemicals. Additionally, the active ingredient may be present as a pharmaceutical composition.

[0091] As used herein, unless otherwise defined in the claims, the term “optionally” means that the event described below may or may not occur, and includes both the event that occurs and the event that does not occur.

[0092] As used herein, unless otherwise defined, the phrase “optionally substituted,” “substituted,” or variations thereof means that the object is optionally substituted by one or more substituent groups (e.g., one, two, three, four, or five), including multiple degrees of substitution. This phrase should not be construed as a repetition of the substitutions described and depicted herein.

[0093] The terms “pharmaceutical formulation” or “pharmaceutical composition” refer to a formulation in which the bioactive ingredient contained herein is in a form in which it is bioactively effective and does not contain any additional components that would have unacceptable toxicity to a subject to whom the formulation will be administered.

[0094] "Pharmaceutical excipients" refer to components in pharmaceutical preparations that are non-toxic to the subjects, excluding the active ingredient. Pharmaceutical excipients include, but are not limited to, buffers, carriers, stabilizers, or preservatives.

[0095] As used herein, the phrase "medicinal salt" refers to a medicinal organic or inorganic salt of a molecule. Exemplary salts include, but are not limited to: sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylenedi-(2-hydroxy-3-naphthylcarbamate)). Medicinal salts may include another molecule, such as an acetate ion, a succinate ion, or other counterions. Counterions can be any organic or inorganic portion that stabilizes the charge on the parent compound. Furthermore, a medicinal salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of a medicinal salt may have multiple counterions. Therefore, a medicinal salt may have one or more charged atoms and / or one or more counterions.

[0096] Other non-pharmaceutical salts can be used to prepare the compounds described herein and should be considered as another aspect of forming this subject matter. These salts, such as oxalic acid or trifluoroacetate, while not pharmaceutical in themselves, can be used to prepare intermediates for obtaining the compounds described herein and their pharmaceutical salts.

[0097] "Small molecule" or "small molecule compound" generally refers to an organic molecule with a size less than about 5 kilodaltons (Kd). In some embodiments, the small molecule is less than about 4 Kd, 3 Kd, about 2 Kd, or about 1 Kd. In some embodiments, the small molecule is less than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, the small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule is non-polymerized. The small molecule is not a protein, polypeptide, oligopeptide, peptide, polynucleotide, oligonucleotide, polysaccharide, glycoprotein, proteoglycan, etc. Derivatives of small molecules refer to molecules that have the same structural core as the original small molecule but can be prepared from the original small molecule through a series of chemical reactions.

[0098] As used herein, the term "alkyl" refers to an alkyl group having one to twelve carbon atoms (C1-C2). 12Alkyl radicals of any length, consisting of a saturated straight-chain or branched monovalent hydrocarbon, wherein the alkyl radical may optionally be independently substituted by one or more substituents as described herein. In another embodiment, the alkyl radical is one to eight carbon atoms (C1-C8), one to six carbon atoms (C1-C6), one to four carbon atoms (C1-C4), or one to three carbon atoms (C1-C3). Examples of alkyl groups include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)2), and 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2). )CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl and 1-octyl, etc.

[0099] As used herein, the term "alkylene" refers to a group having one to twelve carbon atoms (C1-C2). 12The alkylene radical is a saturated straight-chain or branched divalent hydrocarbon radical of any length, wherein the alkylene group may optionally be independently substituted by one or more substituents described herein. In another embodiment, the alkylene radical is one to eight carbon atoms (C1-C8), one to six carbon atoms (C1-C6), or one to four carbon atoms (C1-C4). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), etc.

[0100] The term "alkenyl" refers to a group having two to twelve carbon atoms (C2-C4). 12 Alkenyl radicals are straight-chain or branched monovalent hydrocarbon radicals of any length, having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, wherein the alkenyl radical may optionally be independently substituted by one or more substituents described herein, and include radicals having “cis” and “trans” orientations, or alternatively “E” and “Z” orientations. Examples include, but are not limited to, vinyl (ethylenyl or vinyl) (-CH=CH2), allyl (-CH2CH=CH2), and so on.

[0101] The term "alkenyl" refers to a group having two to twelve carbon atoms (C2-C2). 12 A straight-chain or branched divalent hydrocarbon radical of any length having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, wherein the alkenyl radical may optionally be independently substituted by one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively “E” and “Z” orientations. Examples include, but are not limited to, vinylene (ethylenylene or vinylene) (-CH=CH-), allyl (-CH2CH=CH-), etc.

[0102] The term "alkynyl" refers to a group having two to twelve carbon atoms (C2-C2). 12 A straight-chain or branched monovalent hydrocarbon radical of any length having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl radical may optionally be independently substituted by one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C℃H), propynyl (propynyl, -CH2C℃H), etc.

[0103] The term "alkynylene" refers to a group having two to twelve carbon atoms (C2-C2). 12A straight-chain or branched divalent hydrocarbon radical of any length having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the ynylene group may optionally be independently substituted by one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C℃-), propargylene (propargylene, -CH2C℃-), etc.

[0104] The terms "carbocyclic", "carbocyclic group", "carbocyclic ring", and "cycloalkyl" refer to a monocyclic ring having 3 to 12 carbon atoms (C3-C4). 12 Or as a polycyclic (e.g., bicyclic) monovalent nonaromatic, saturated, or partially unsaturated ring having 7 to 12 carbon atoms. Bicyclic carbocyclic rings having 7 to 12 atoms can be arranged as, for example, bicyclic [4,5], [5,5], [5,6], or [6,6] systems, and bicyclic carbocyclic rings having 9 or 10 ring atoms can be arranged as bicyclic [5,6] or [6,6] systems, or as bridging systems, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Polycyclic (e.g., bicyclic) rings that are generally fully saturated or partially unsaturated are covered in the definitions of the terms “carbocyclic,” “carbocyclic group,” “carbon cyclic ring,” and “cycloalkyl,” including when one or more of the fused rings in the polycyclic ring are fully unsaturated (i.e., aromatic). Spirocyclic moieties are also included within the scope of this definition. Examples of monocyclic carbocyclic groups 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, indenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, etc. The carbocyclic group may optionally be independently substituted by one or more of the substituents described herein.

[0105] The term "cycloalkylene" refers to a monocyclic compound having 3 to 12 carbon atoms (C3-C4). 12Or, as a bicyclic divalent nonaromatic, saturated, or partially unsaturated ring having 7 to 12 carbon atoms. Bicyclic cycloalkylene groups having 7 to 12 atoms can be arranged, for example, as bicyclic [4,5], [5,5], [5,6], or [6,6] systems, and bicyclic cycloalkylene groups having 9 or 10 ring atoms can be arranged as bicyclic [5,6] or [6,6] systems, or can be arranged as bridging systems such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Spirocyclic moieties are also included within the scope of this definition. Examples of monocyclic cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The cycloalkyl group may optionally be independently substituted by one or more substituents described herein.

[0106] "Aryl" refers to a group of 6 to 20 carbon atoms derived by removing a hydrogen atom from a single carbon atom in the parent aromatic ring system (C6-C4). 20 A aryl radical is a monovalent aromatic hydrocarbon radical. Some aryl groups are represented as "Ar" in the exemplary structures. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, etc. The aryl group may optionally be independently substituted by one or more substituents described herein.

[0107] "Demyryl" refers to a group of 6 to 20 carbon atoms derived by removing two hydrogen atoms from two carbon atoms in the parent aromatic ring system (C6-C4). 20 A divalent aromatic hydrocarbon radical. Some arylene groups are represented as "Ar" in the exemplary structures. Alene groups include bicyclic groups comprising an aromatic ring fused to saturation, partially unsaturated rings, or aromatic carbocyclic rings. Typical arylene groups include, but are not limited to: benzene-derived (phenylene), substituted benzene, naphthalene, anthracene, biphenylene, indenyl, indenylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc. The arylene group may optionally be substituted by one or more substituents described herein.

[0108] The terms “heterocycle,” “heterocyclic group,” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double triple bonds and / or triple bonds within the ring) carbocyclic radical having 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are C, wherein one or more ring atoms are optionally independently substituted by one or more substituents described herein. The heterocycle can be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: bicyclic [4,5], [5,5], [5,6], or [6,6] systems. Heterocyclic compounds are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950–present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclic radicals” also include radicals in which a heterocyclic radical is fused with a saturated, partially unsaturated ring or an aromatic carbide ring or heterocycle.Examples of heterocycles include, but are not limited to: morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidine-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azo-1-yl, aziridine-1-yl, octahydropyridino[1,2-a]pyrazin-2-yl, [1,4]diazacyclic heptane-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran Tetrahydrothiophene, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, homopiperidinyl, oxacyclic heptyl, thiopyridinyl Heterocyclic heptyl groups, oxazepinyl groups, diazepinyl groups, thiazepinyl groups, 2-pyrrolinyl groups, 3-pyrrolinyl groups, indolinyl groups, 2H-pyranyl groups, 4H-pyranyl groups, dioxanyl groups, 1,3-dioxolaneyl groups, pyrazolinyl groups, dithianyl groups, dithiolanyl groups, dihydropyranyl groups, dihydrothienyl groups, dihydrofuranyl groups, pyrazolidinylimidazolinyl groups, imidazolidinyl groups, 3-azabicyclo[3.1.0]hexyl groups, 3-azabicyclo[4.1.0]heptyl groups, azabicyclo[2.2.2]hexyl groups, 3H-indolylquinazinyl groups, and N-pyridylurea groups. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclic groups in which two ring atoms are replaced by an oxo (= O) moiety are pyrimidinone and 1,1-dioxo-thiomorpholino. The heterocyclic groups described herein may optionally be independently substituted by one or more of the substituents described herein.

[0109] 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 having 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are carbon, wherein one or more ring atoms are optionally independently substituted by one or more substituents described herein. Heterocyclylene can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S), or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example, bicyclic [4,5], [5,5], [5,6], or [6,6] systems. Heterocyclic compounds are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950–present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Hypo-heterocyclic groups” also include divalent radicals in which the heterocyclic radical is fused with a saturated, partially unsaturated ring or aromatic carbon ring or heterocycle.Examples of heterocyclic groups include, but are not limited to: iminomorpholino-4-yl, piperidino-1-yl, piperazino, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidine-1-yl, thionomorpholino-4-yl, S-dioxothionomorpholino-4-yl, azacyclooctane-1-yl, azacyclobutane-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazacycloheptane-1-yl, pyrrolidine, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanylene, piperazino, etc. High-piperazinyl, azirrobutanediyl, azirrobutanediyl, thioheterobutanediyl, homopiperidinyl, oxacycloheptanediyl, thioheterobutanediyl, oxazonyl, diazazonyl, thiazozazonyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxaneyl, 1,3-dioxopentane The terms include pyrimidinyl, dithienyl, dithiopentanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrimidinylimidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, and N-pyridinylurea. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclic groups in which two ring atoms are partially substituted by an oxo (=O) moiety are pyrimidinylene and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups described herein may optionally be independently substituted by one or more substituents described herein.

[0110] The term "heteroaryl" refers to a monovalent aromatic radical of a 5-, 6-, or 7-membered ring, comprising a fused ring system 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 include: pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, 1-methyl-1H-benzo[d]imidazolium, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinoyl, quinoyl, pyrrolyl, quino ... The aryl group can be substituted with one or more of the substituents described herein. The substituents include linyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cenolinyl, indazolyl, indolazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purine, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazonyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furopyridinyl. The heteroaryl group may optionally be independently substituted by one or more of the substituents described herein.

[0111] The term "heteroarylene" refers to a divalent aromatic radical of a 5-, 6-, or 7-membered ring, comprising a fused ring system 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 include: pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridyl, 1-methyl-1H-benzo[d]imidazolium, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrid ... The heteroaryl group comprises pyridyl, quinolineyl, isoquinolineyl, tetrahydroisoquinolineyl, indoleyl, benzimidazolyl, benzofuranyl, terpineyl, indazoleyl, indoleazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinolineyl, quinoxalinyl, naphthidyl, and furanpyridinyl. The heteroaryl group may optionally be independently substituted by one or more of the substituents described herein.

[0112] Where possible, the heterocyclic or heteroaryl group can be carbon-linked (carbon-dependent) or nitrogen-linked (nitrogen-dependent). For example, but not limitingly, the carbon-linked heterocyclic or heteroaryl group is bonded at the following positions: 2, 3, 4, 5, or 6 of pyridine; 3, 4, 5, or 6 of pyridazine; 2, 4, 5, or 6 of pyrimidine; 2, 3, 5, or 6 of pyrazine; 2, 3, 4, or 5 of furan, tetrahydrofuran, thifuran, thiophene, pyrrole, or tetrahydropyrrole ring; 2, 4, or 5 of oxazole, imidazole, or thiazole; 3, 4, or 5 of isoxazole, pyrazole, or isothiazole; 2 or 3 of aziridine; 2, 3, or 4 of azahexacyclic butane; 2, 3, 4, 5, 6, 7, or 8 of quinoline; or 1, 3, 4, 5, 6, 7, or 8 of isoquinoline.

[0113] For example, but not limitingly, the nitrogen-bonded heterocyclic or heteroaryl group is bonded at the following positions: 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazoleidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; 2 position of isoindole or isoindolineone; 4 position of morpholine; and 9 position of carbazole or β-carbline.

[0114] The term "acyl" refers to both substituted and unsubstituted acyl groups. In some embodiments, the "acyl" can be -C(O)-R. 16 , where R 16 The group selected is from the group consisting of: substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and substituted or unsubstituted heterocyclic groups. In a particular embodiment, it is a substituted C1-C3 alkyl group.

[0115] The term "oxo" refers to "=O".

[0116] The term "chirality" refers to a molecule that does not overlap with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0117] The term "stereoisomer" refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups.

[0118] "Diabeta-isomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diabeta-isomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as electrophoresis and chromatography.

[0119] "Enantiomers" refer to two stereoisomers of a compound, which are non-overlapping mirror images of each other.

[0120] The stereochemical definitions and conventions used in this paper generally follow: SP 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 Ltd., New York. Many organic compounds exist in an optically active form, meaning they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the symbol for the rotation of a compound with respect to plane-polarized light, where (-) or 1 indicates 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. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0121] The terms "co-administration," "co-administering," or "combination therapy" refer to both simultaneous administration (the simultaneous administration of two or more therapeutic agents) and time-varying administration (the administration of one or more therapeutic agents at times different from the administration of another one or more therapeutic agents), provided that the therapeutic agents are present in the patient to a certain extent (preferably in an effective amount). In some preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one other bioactive agent (especially including anticancer agents). In particularly preferred aspects, the co-administration of the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0122] As used herein, unless otherwise indicated, the term "compound" in the context means any particular chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and stereoisomers where applicable (including optical isomers (enantiomers) and other stereoisomers (diastereomers)) and, where applicable, their pharmaceutical salts and derivatives (including prodrug forms). Within the scope of its use in the context, the term "compound" generally refers to a single compound, but may also include other compounds such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures) and specific enantiomers or enantiomer-enriched mixtures of the disclosed compounds. In the context, the term also refers to a prodrug form of the compound that has been modified to facilitate the administration and delivery of the compound to the active site. It should be noted that many substituents and associated variables are described in the description of the compounds of the present invention. Those skilled in the art will understand that the molecules described herein are stable compounds as generally described below. When bonds are shown... In the context of the compound shown, both double bonds and single bonds are represented. When a crossed double bond is shown... When ), both the E and Z configurations are represented in the context of the compound shown; and the compound may contain the E isomer, or the Z isomer, or a mixture of both the E and Z isomers.

[0123] Unless the context otherwise indicates, the terms “VCB E3 ubiquitin ligase,” “VonHippel-Lindau (or VHL) E3 ubiquitin ligase,” “VHL,” or “ubiquitin ligase” are generally used interchangeably to describe the target enzyme binding site of the ubiquitin ligase moiety, as described herein. VCB E3 is a protein that, when combined with an E2 ubiquitin conjugator, causes ubiquitin to attach to a lysine residue on a target protein; E3 ubiquitin ligases target specific protein substrates for degradation by the proteasome. Thus, either a standalone E3 ubiquitin ligase or an E3 ubiquitin ligase complexed with an E2 ubiquitin conjugator is responsible for transferring ubiquitin to the target protein. Typically, ubiquitin ligases participate in polyubiquitination, causing a second ubiquitin to attach to a first ubiquitin; a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination labels the protein for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which case the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins do not target the proteasome for degradation; instead, they can alter their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. More complexly, E3 can target different lysine residues on ubiquitin to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin, which is recognized by the proteasome.

[0124] As used in this article, the portion that binds to E3 VHL ubiquitin ligase or its components is referred to as the VHL ligand.

[0125] In some embodiments disclosed herein, certain groups (e.g., alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic) are described as “substituted.” In some such embodiments, the “substituted” group may be substituted by one, two, three, four, five, or more substituents, as indicated herein. In some embodiments, the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be substituted by one or more substituents independently selected from, but not limited to, the following: alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen (i.e., halogen), haloalkyl, oxo, OH, CN, -O-alkyl, S-alkyl, NH-alkyl, N(alkyl)2, O-cycloalkyl, S-cycloalkyl, NH-cycloalkyl, N(cycloalkyl)2, N(cycloalkyl)(alkyl), NH2, SH, SO2-alkyl, P(O)(O-alkyl)(alkyl), P(O)(O-alkyl)2, Si (OH)3, Si(alkyl)3, Si(OH)(alkyl)2, CO-alkyl, CO2H, NO2, SF5, SO2NH-alkyl, SO2N(alkyl)2, SONH-alkyl, SON(alkyl)2, CONH-alkyl, CON(alkyl)2, N(alkyl)CONH(alkyl), N(alkyl)CON(alkyl)2, NHCONH(alkyl), NHCON(alkyl)2, NHCONH2, N(alkyl)SO2NH(alkyl), N(alkyl)SO2N(alkyl)2, NHSO2NH(alkyl), NHSO2N(alkyl)2 and NHSO2NH2.

[0126] Other definitions and abbreviations are provided elsewhere in this article.

[0127] Where a range of values ​​is provided, it should be understood that each intermediate value between the upper and lower limits of the range (based on one-tenth of the lower limit unit, unless the context explicitly specifies otherwise (such as in the case of a group containing multiple carbon atoms, in which case the number of each carbon atom falling within the range is provided) and any other stated or intermediate values ​​within the range are included within the scope of this disclosure. The upper and lower limits of these smaller ranges may be independently included within that smaller range and are also included within the scope of this disclosure, based on any explicitly excluded limit value within the range. Where the range includes one or both of the limit values, the range excluding any or both of those included limit values ​​is also included within the scope of this disclosure.

[0128] As used herein and in the appended claims, unless the context clearly indicates otherwise, the articles “a” and “an” are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more elements.

[0129] In the claims and in the foregoing description, transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood as open-ended, meaning including but not limited to. As described in Section 2111.03 of the U.S. Patent and Trademark Office's Patent Examination Procedure Manual, only the transitional phrases “consisting of” and “consisting essentially of” should be closed or semi-closed transitional phrases, respectively.

[0130] As used herein in the specification and in the claims, with respect to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more of the elements in the list, but does not necessarily include every single element specifically listed in the list, nor exclude any combination of elements in the list. In addition to the specifically identified elements in the list of elements referred to by the phrase "at least one," this definition also allows elements to be optionally present, whether related to or unrelated to those specifically identified elements. Therefore, 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") in one embodiment may refer to at least one, optionally including more than one A, without the presence of B (and optionally including elements other than B); in another embodiment, it may refer to at least one, optionally including more than one B, without the presence of A (and optionally including elements other than A); in yet another embodiment, it may refer to at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0131] It should also be understood that in some methods described herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are stated, unless the context otherwise indicates.

[0132] II. Compounds

[0133] E3 ubiquitin ligases (more than 600 known in humans) confer substrate specificity to ubiquitination. Known ligands exist that bind to these ligases. The E3 ubiquitin ligase binding group (E3LB) is a peptide or small molecule that can bind to an E3 ubiquitin ligase.

[0134] The specific E3 ubiquitin ligase is von Hippel-Lindau (VHL), a tumor suppressor factor that is the substrate recognition subunit of the E3 ligase complex VCB. It is also composed of elongated proteins B and C, Cul2, and Rbxl. The primary substrate of VHL is hypoxia-inducible factor lα (HIF-lα), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-induced cytokine erythropoietin in response to hypoxia.

[0135] In one embodiment, this document provides a compound of formula (I):

[0136] (I),

[0137] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0138] X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0139] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0140] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0141] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-6 cycloalkyl,

[0142] Where R 2 C 1-12 Alkyl or C 3-6 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and

[0143] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0144] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0145] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0146] Among them, Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0147] In another embodiment, this document provides a compound of formula (I):

[0148] (I),

[0149] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0150] X 1 It is independently H or -C(O)-C each time it appears. 1-12 alkyl;

[0151] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0152] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0153] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl,

[0154] Where R 2 C 1-12 Alkyl or C 3-5The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and

[0155] Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0156] Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0157] Q 1 The C mentioned 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q The C mentioned 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0158] Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated, C 1-6Alkoxy group, -NHC(O)-C 1-12 Alkyl, -CN, or -NO2;

[0159] Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0160] Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0161] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0162] Among them, Q 1 and Q 2 The C formed 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R sEach time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein R s The C mentioned 1-12 The alkyl group is independently and optionally further substituted by one or more halogenated, cyano, or OH groups;

[0163] The condition is when Q 1 When R is cyclohexyl, biphenyl, or a 5- to 6-membered heteroaryl group, 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0164] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-6 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-6 The cycloalkyl group is optionally and independently substituted with one or more halogens or -CN. In some embodiments, R 2 It is independently H or C each time it appears. 1-12 Alkyl, wherein R 2 C 1-12 Alkyl groups are optionally substituted independently with one or more halogenated or -CN groups. In some embodiments, R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C3-5 The cycloalkyl group is optionally and independently substituted with one or more halogens or -CN.

[0165] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 2 It is H independently each time it appears.

[0166] In other embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 2 It is C independently each time it appears. 1-12 Alkyl, wherein R 2 C 1-12 Alkyl groups are optionally substituted independently with one or more halogenated groups or -CN. In some embodiments, R 2 C 1-6 Alkyl, wherein R 2 C 1-6 Alkyl groups are optionally substituted independently with one or more halogenated groups or -CN. In some embodiments, R 2 C 1-6 Alkyl, wherein R 2 C 1-6 Alkyl groups are optionally substituted independently with one or more halogens. In some embodiments, R 2 C 1-3 Alkyl, wherein R 2 C 1-3 Alkyl groups are optionally substituted independently with one or more halogenated or -CN groups. In some embodiments, R 2 C 1-3 Alkyl, wherein R 2 C 1-3 The alkyl group is optionally substituted independently with one or more halogens. In other embodiments, R 2 It is an unsubstituted isopropyl group. In other embodiments, R 2 It is an ethyl group, where R is an ethyl group. 2 The ethyl group is optionally and independently substituted with one or more halogens. In some embodiments, each of the one or more halogens is independently fluorinated. In some embodiments, R 2 It is -CH2CH2F. In other embodiments, R 2 It is -CH2CF3. In some embodiments, R 2 It is an unsubstituted ethyl group. In other embodiments, R 2 It is a methyl group, where R 2 The methyl group is optionally substituted with one or more halogenated groups or -CN. In some embodiments, R2 The methyl group is an unsubstituted methyl group.

[0167] In other embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 2 C 3-6 cycloalkyl, wherein R 2 C 3-6 The cycloalkyl group is optionally substituted with one or more halogenated groups or -CN. In other embodiments, R 2 C 3-5 cycloalkyl, wherein R 2 C 3-5 The cycloalkyl group is optionally substituted with one or more halogenated groups or -CN. In other embodiments, R 2 C 5-6 cycloalkyl, wherein R 2 C 5-6 The cycloalkyl group is optionally substituted with one or more halogenated groups or -CN. In some embodiments, R 2 It is cyclopropyl, wherein the cyclopropyl group is optionally substituted with one or more halogenated or -CN groups. In some embodiments, R 2 It is the unsubstituted cyclopropyl group.

[0168] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Each time it appears, it is independently and independently of each other as H, halogen, cyano, C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each is independently H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0169] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Each is independently represented by H.

[0170] In some embodiments, Q 1 C 3-15 cycloalkyl, wherein Q 1 C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In some embodiments, Q 1 C 3-10 cycloalkyl, wherein Q 1 C 3-10 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In other embodiments, Q 1 C 3-8 cycloalkyl, wherein Q 1 C 3-8 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In other embodiments, Q 1 C 3-6 cycloalkyl, wherein Q 1 C 3-6 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In a further embodiment, Q 1 C 3-5 cycloalkyl, wherein Q 1 C3-5 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In other embodiments, Q 1 It is cyclopropyl, where Q 1 The cyclopropyl group is optionally surrounded by one or more R q replace.

[0171] In some embodiments, Q 1 For the unreplaced C 3-15 Cycloalkyl. In other embodiments, Q 1 For the unreplaced C 3-10 Cycloalkyl. In a further embodiment, Q 1 For the unreplaced C 3-8 Cycloalkyl. In other embodiments, Q 1 For the unreplaced C 3-6 Cycloalkyl. In some embodiments, Q 1 For the unreplaced C 3-5 Cycloalkyl. In a further embodiment, Q 1 It is the unsubstituted cyclopropyl group.

[0172] In some embodiments, when Q 1 When it is cyclohexyl, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0173] In some embodiments, Q 1 It is an unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, Q 1 For one or more R q Replaced 5- to 6-membered heteroaryl groups. In some embodiments, each R q Independently halogenated, C 1-6 Alkoxy group, -NHC(O)-C 1-12 Alkyl, -CN, or -NO2. In some embodiments, each R qIndependently halogenated (e.g., -Cl or -F). In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic N atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic S atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic O atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl group is selected from the group consisting of: thiophene, furan, pyrrole, oxazole, thiazole, pyridine, and pyrimidine. In some embodiments, Q 1 It is a substituted or unsubstituted 5- to 6-membered heteroaryl group, and R 1 C 1-3 Alkyl (e.g., isopropyl). In some embodiments, Q 1 For substituted or unsubstituted 5- to 6-membered heteroaryl groups, R 1 C 1-3 Alkyl (e.g., isopropyl), and R 2 C 1-12 Alkyl (e.g., methyl).

[0174] In some embodiments, when Q 1 When R is a 5- to 6-membered heteroaryl group (e.g., substituted or unsubstituted), 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, when Q... 1 When R is pyridine, thiazole, pyrazole, imidazole, thiophene, or oxazole 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, when Q... 1 For one or more R q When replacing 5- to 6-membered heteroaryl groups, each R q Independently halogenated, C 1-6 Alkoxy group, -NHC(O)-C 1-12 Alkyl, -CN or -NO2, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0175] In which Q 1 In any variation of the aryl group detailed herein, in some embodiments the aryl group is a monocyclic phenyl moiety that is unsubstituted or substituted with one or more R groups. q replace.

[0176] In some embodiments, Q 1 For the unreplaced C 6-20 Aryl. In some embodiments, Q 1 Q is an unsubstituted phenyl group. In some embodiments, Q 1 For one or more R q Replacement C 6-20 Aryl. In some embodiments, each R q Independently halogenated (e.g., -Cl or -F). In some embodiments, Q 1 C is either replaced or not replaced. 6-20 Aryl (e.g., phenyl), and R1 C 1-3 Alkyl (e.g., isopropyl). In some embodiments, Q 1 C is either replaced or not replaced. 6-20 Aryl (e.g., phenyl), R 1 C 1-3 Alkyl (e.g., isopropyl), and R 2 C 1-12 Alkyl (e.g., methyl).

[0177] In some embodiments, when Q 1 C 6-20 Aryl, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 When cycloalkyl or 3- to 15-membered heterocyclic groups are involved, R... 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, when Q... 1 It is a biphenyl, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 When cycloalkyl or 3- to 15-membered heterocyclic groups are involved, R... 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0178] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 Halogenated, cyano, C 1-12 Alkyl, C 3-15Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each is independently H or C 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 For H.

[0179] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 Halogenated, C 1-12 Alkyl, C 3-15 Cycloalkyl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each is independently H or C 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where Rq C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 For H. In some embodiments, Q 1 C 3-15 cycloalkyl, wherein Q 1 C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 H. In other embodiments, Q 1 C 3-10 cycloalkyl, wherein Q 1 C 3-10 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, and Q 2 For H. In other embodiments, Q 1 C 3-8 cycloalkyl, wherein Q 1 C 3-8 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, and Q 2 H. In other embodiments, Q 1 C 3-6 cycloalkyl, wherein Q 1 C 3-6 cycloalkyl groups are optionally surrounded by one or more R q Replace, and Q 2 H. In a further embodiment, Q 1 C 3-5 cycloalkyl, wherein Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, and Q 2 H. In other embodiments, Q 1It is cyclopropyl, where Q 1 The cyclopropyl group is independently and optionally separated by one or more R q Replace, and Q 2 H. In other embodiments, Q 1 It is cyclopropyl, where Q 1 The cyclopropyl group is optionally separated by one or more R q Replace, and Q 2 For H. In some embodiments, Q 1 It is an unsubstituted cyclopropyl group, and Q 2 For H.

[0180] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is further optionally substituted with one or more halogenated, cyano, or OH groups. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 Aryl group is optionally bounded by one or more R s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C1-12 The alkyl group is further optionally substituted with one or more halogenated, cyano, or OH groups. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 Aryl group is optionally bounded by one or more R s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is further optionally substituted with one or more halogenated, cyano, or OH groups. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-16 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-12 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-10 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-8 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 The aryl group is not substituted. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form a C6 aryl group, in which Q... 1 and Q 2 The formed C6 aryl group is not substituted. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form a C6 aryl group, in which Q... 1 and Q 2 The formed C6 aryl group is reacted with one or more Rs Replace, where R s Halogenated or C 1-6 Alkyl group.

[0181] In any of the variations detailed in this article, where Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl, in some embodiments, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl fused to Q 1 and Q 2 The connected triazole moiety.

[0182] In some embodiments, R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0183] In some embodiments, R 1 It is C independently each time it appears. 1-12 Alkyl, wherein R 1 C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 1-6 Alkyl, wherein R 1 C 1-6 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 1-3 Alkyl, wherein R 1 C 1-3 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 Each time it appears, it is independently C that has not been replaced. 1-12 Alkyl group. In other embodiments, R 1 Each time it appears, it is independently C that has not been replaced. 1-6 Alkyl group. In some embodiments, R 1 Each occurrence is independently of the unsubstituted tert-butyl group. In a further embodiment, R 1 Each time it appears, it is independently C that has not been replaced. 1-3 Alkyl group. In other embodiments, R 1 Each time it appears, it is independently an unsubstituted isopropyl group.

[0184] In some embodiments, R 1 It is C independently each time it appears. 3-15 cycloalkyl, wherein R 1 C 3-15 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 3-10 cycloalkyl, wherein R 1 C 3-10 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 It is C independently each time it appears. 3-8 cycloalkyl, wherein R 1 C 3-8 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12Alkyl substitution. In other embodiments, R 1 It is C independently each time it appears. 3-6 cycloalkyl, wherein R 1 C 3-6 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is independently cyclohexyl each time it appears, where R 1 The cyclohexyl group is independently and optionally converted by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 Each occurrence is independently of the unsubstituted cyclohexyl group. In some embodiments, R 1 It is independently cyclohexyl each time it appears, where R 1 The cyclohexyl group is independently reacted by one or more C 1-12 Alkyl substitution. In some embodiments, R 1 It is independently cyclohexyl each time it appears, where R 1 The cyclohexyl group is independently substituted by one or more methyl groups.

[0185] In some embodiments, R 1 Each occurrence is independently a 3- to 15-membered heterocyclic group, where R 1 The 3- to 15-membered heterocyclic groups are independently and optionally construed by one or more C groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 Each occurrence is independently a 3- to 10-membered heterocyclic group, where R 1 The 3- to 10-membered heterocyclic groups are independently and optionally constituting one or more C groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 Each occurrence is independently a 3- to 8-membered heterocyclic group, where R 1 The 3- to 8-membered heterocyclic groups are independently and optionally construed by one or more C groups.1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In a further embodiment, R 1 Each occurrence is independently a 3- to 6-membered heterocyclic group, where R 1 The 3- to 6-membered heterocyclic groups are independently and optionally constituting one or more C groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is an independent 6-membered heterocyclic group each time it appears, where R 1 The 6-membered heterocyclic group is independently and optionally construed by one or more C... 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 Each occurrence is independently an unsubstituted 6-membered heterocyclic group. In other embodiments, R 1 It is an independent 6-membered heterocyclic group each time it appears, where R 1 The 6-membered heterocyclic group is independently and optionally construed by one or more C... 1-12 Alkyl substitution. In some embodiments, R 1 It is an independent 6-membered heterocyclic group each time it appears, where R 1 The 6-membered heterocyclic group is independently and optionally separated by one or more -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 It is an independent 6-membered heterocyclic group each time it appears, where R 1 The 6-membered heterocyclic group is independently and optionally surrounded by one or more -S(O)2-C 1-12 Alkyl substitution. In some embodiments, R 1 Each time it appears, it is independently an unsubstituted piperidinyl group. In other embodiments, R 1 It is independently piperidinyl in each occurrence, where R 1 The piperidinyl group is independently bounded by one or more C14 groups. 1-12 Alkyl, -C(O)-C 1-12 Alkyl or -S(O)2-C 1-12 Alkyl substitution. In other embodiments, R 1 Each time it appears, it is independently an unsubstituted tetrahydro-2H-pyran.

[0186] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 The attached chiral carbon atom has an R stereochemical configuration. In other embodiments, R 1 The attached chiral carbon atom has an S stereochemical configuration.

[0187] In some embodiments, this document provides a compound of formula (I), or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (I'):

[0188] (I').

[0189] Or its medicinal salt, in which

[0190] X 1 It is independently H or -C(O)-C each time it appears. 1-12 alkyl;

[0191] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0192] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0193] R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl,

[0194] Where R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and

[0195] Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-6cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0196] Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0197] Q 1 The C mentioned 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q The C mentioned 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0198] Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated, C 1-6 Alkoxy group, -NHC(O)-C 1-12 Alkyl, -CN, or -NO2;

[0199] Q 2 Each time it appears, it is independently H, halogenated, cyano, or C.1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0200] Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0201] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0202] Among them, Q 1 and Q 2 The C formed 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein Rs The C mentioned 1-12 The alkyl group is independently and optionally further substituted by one or more halogenated, cyano, or OH groups;

[0203] The condition is when Q 1 When R is cyclohexyl, biphenyl, or a 5- to 6-membered heteroaryl group, 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0204] In some embodiments, Q 1 C 3-15 cycloalkyl, wherein Q 1 C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, Q 2 Each occurrence is independently H, and R 1 It is C independently each time it appears. 1-12 Alkyl, wherein R 1 C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, Q 1 C 3-15cycloalkyl, Q 2 Each occurrence is independently H, and R 1 It is C independently each time it appears. 1-6 Alkyl group. In some embodiments, Q 1 It is cyclopropyl, Q 2 For H, and R 1 The form is tert-butyl, making compound (I) a compound of formula (IA):

[0205] (IA),

[0206] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0207] In some embodiments, this document provides a compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 C 1-12 Alkyl, wherein R 2 C 1-12 The alkyl group is optionally substituted independently with one or more halogenated or -CN groups. In some embodiments, R 2 C 1-6 Alkyl, wherein R 2 C 1-6 Alkyl groups are optionally substituted independently with one or more halogenated or -CN groups. In some embodiments, R 2 For the unreplaced C 1-6 Alkyl group. In some embodiments, R 2 It is a methyl group.

[0208] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 C 3-15 cycloalkyl, wherein Q 1 C 3-15 cycloalkyl groups are optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, Q2 For H, and R 2 C 1-12 Alkyl, wherein R 2 C 1-12 The alkyl group is optionally substituted with one or more halogenated groups or -CN. In other embodiments, Q 1 C 3-15 cycloalkyl, Q 2 For H, and R 2 C 1-6 Alkyl, wherein R 2 C 1-6 The alkyl group is optionally substituted with one or more halogens. In some embodiments, Q 1 It is cyclopropyl, Q 2 For H, and R 2 C 1-6 Alkyl, wherein R 2 C 1-6 The alkyl group is optionally substituted with one or more halogens. In some embodiments, the one or more halogens are fluorinated. In some embodiments, Q 1 It is cyclopropyl, Q 2 For H, and R 2 The presence of a methyl group makes compound (I) a compound of formula (IB):

[0209] (IB),

[0210] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0211] In some embodiments, this document provides a compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 C 1-6 Alkyl group. In other embodiments, R 1 C 3-6 cycloalkyl, wherein C 3-6cycloalkyl groups are optionally surrounded by one or more C 1-12 Alkyl substitution. In some embodiments, R 1 It consists of 3- to 6-membered heterocyclic groups, where R 1 The 3- to 6-membered heterocyclic groups are optionally surrounded by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0212] In some embodiments, this document provides a compound of formula (I) (such as a compound of formula (IA) or (IB)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H, C 1-12 Alkyl or -C(O)-C 1-12 Alkyl group. In other embodiments, X 1 -C(O)-C 1-12 Alkyl group. In some embodiments, X 1 It is -C(O)-CH3. In some embodiments, X 1 C 1-12 Alkyl group. In some embodiments, X 1 C 1-12 The alkyl group is not substituted. In some embodiments, this document provides a compound of formula (I) (such as a compound of formula (IA) or (IB)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H. In some embodiments, X 1 H is present, such that compound (I) is a compound of formula (IC):

[0213] (IC),

[0214] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing. In the examples, R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-6 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-6 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; and Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0215] In some embodiments, this document provides a compound of formula (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; and Q 1 and Q 2 Independently, and each time it appears, it is either H or C. 3-15 Cycloalkyl.

[0216] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, and R 1 The attached chiral carbon atom has an S stereochemical configuration, in which R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2For H or C 1-12 Alkyl; and Q 1 and Q 2 Independently, and each time it appears, it is either H or C. 3-15 Cycloalkyl.

[0217] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, and R 1 The attached chiral carbon atom has an S stereochemical configuration, in which R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; Q 1 It is cyclopropyl; and Q 2 For H.

[0218] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, and R 1 The attached chiral carbon atom has an S stereochemical configuration, in which R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Methyl; Q 1 It is cyclopropyl; and Q 2 For H.

[0219] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X1 For H; R 1 Choose from the group consisting of: tert-butyl, isopropyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, and R 1 The attached chiral carbon atom has an S stereochemical configuration, in which R 1 The cyclohexyl, pyranyl, and piperidinyl groups are each independently and optionally separated by one or more C16 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; and Q 1 and Q 2 Independently, and each time it appears, it is either H or C. 3-15 Cycloalkyl.

[0220] In some respects, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 It is independently H or -C(O)-C each time it appears. 1-12 Alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-5 cycloalkyl, C 6-20 Aryl, -C(O)-O(R) a) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and wherein Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q C 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 Alkyl, wherein Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R qReplace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0221] In some of the foregoing embodiments, R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted with one or more halogenated or -CN groups. In some of the foregoing embodiments, Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-5 cycloalkyl, C 6-20 Aryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a Rb and R c Independently, and each time it appears, it is either H or C. 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and wherein Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q C 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 Alkyl, wherein Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0222] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (ID):

[0223] (ID),

[0224] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein: X 1 It is independently H or -C(O)-C each time it appears. 1-12 Alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens; Q 1 For H, C 6-20 Aryl, 5- to 6-membered heteroaryl or C 3-5 cycloalkyl, wherein Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated; Q 2 It is independently H or C each time it appears. 3-5 cycloalkyl; or Q 1 and Q 2Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 Aryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s It is independently halogenated or C each time it appears. 1-6 Alkoxy; the condition is when Q 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0225] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (ID):

[0226] (ID),

[0227] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein: X 1 It is independently H or -C(O)-C each time it appears. 1-12 Alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens; Q 1 For H or C 3-5 cycloalkyl; and Q 2 It is independently H or C each time it appears. 3-5 Cycloalkyl.

[0228] In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 It is H independently each time it appears.

[0229] In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 For H; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups; R 2 Methyl; Q 1 C 3-5 cycloalkyl; and Q 2 For H. In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups; R 2 Methyl; Q 1 It is a 5- to 6-membered heteroaryl group; and Q 2 For H. In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 For H; R 1 It is isopropyl; and R 2 It is methyl; and Q 2 For H.

[0230] In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; Q 1 For H or C 3-15 cycloalkyl; and Q 2 For H or C 3-15 Cycloalkyl. In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 H or methyl; Q 1 It is H or cyclopropyl; and Q 2 For H.

[0231] In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; Q 1 C 6-20Aryl or 5- to 6-membered heteroaryl; and Q 2 For H or C 3-15 Cycloalkyl. In some embodiments, this document provides a compound of formula (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl; Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl.

[0232] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IE):

[0233] (IE),

[0234] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein: Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-5 cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0235] Q 1 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0236] Q 1 The C mentioned 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 acetylinyl or , where R q The C mentioned 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and

[0237] Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated;

[0238] Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Independently, and each time it appears, it is either H or C. 1-12 alkyl,

[0239] Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, C2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or , where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution,

[0240] Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl compounds,

[0241] Among them, Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally surrounded by one or more R groups. s Replace, where R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0242] In some embodiments, this document provides a compound of formula (IE), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 C 6-20 Aryl or 5- to 6-membered heteroaryl; and Q 2 For H or C 3-5 Cycloalkyl. In some embodiments, this document provides a compound of formula (IE), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 It is an unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, Q 1 For one or more R q Replaced 5- to 6-membered heteroaryl groups. In some embodiments, each Rq Independently halogenated (e.g., -Cl or -F). In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic N atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic S atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl group has one or more cyclic O atoms. In some embodiments, Q 1 The 5- to 6-membered heteroaryl groups are selected from the group consisting of: thiophene, furan, pyrrole, oxazole, thiazole, pyridine, and pyrimidine.

[0243] In some embodiments, this document provides a compound of formula (IE), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 For the unreplaced C 6-20 Aryl. In some embodiments, Q 1 Q is an unsubstituted phenyl group. In some embodiments, Q 1 For one or more R q Replacement C 6-20 Aryl (e.g., phenyl). In some embodiments, each R q Independently halogenated (e.g., -Cl or -F).

[0244] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IF):

[0245] (IF),

[0246] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0247] X 1 For H, C 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0248] R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0249] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0250] R 2 For H, C 1-12 Alkyl or C 3-5 cycloalkyl,

[0251] Where R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted with one or more halogens or -CN;

[0252] R s Each time it appears, it is independently OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 Alkyl group, -SO2NH2, C 1-6 Alkoxy or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is independently and optionally further substituted with one or more halogenated, cyano, or OH groups.

[0253] In some embodiments, this document provides a compound of formula (IF), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 For H or C 1-12 Alkyl; R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H, C 1-12Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted by one or more halogens or -CN; R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0254] In some embodiments, this document provides a compound of formula (IF), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 For H; R 1 It is isopropyl; and R 2 It is a methyl group.

[0255] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15 cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1 The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 Each cycloalkyl group is independently and optionally substituted with one or more halogens; Q 1 For H, C 3-5 cycloalkyl, C 6-20 Aryl or 5- to 6-membered heteroaryl, of which Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, and wherein Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R qIndependently halogenated; and Q 2 H is given, provided that Q is given. 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl or C 3-15 cycloalkyl; or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally bonded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0256] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15 cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1 The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Methyl; Q 1 C 3-5 cycloalkyl; and Q 2 For H.

[0257] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15 cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Methyl; Q 1 It consists of 5 to 6 heteroaryl groups, of which Q 1 The 5- to 6-membered heteroaryl group is optionally substituted by one or more halogenated groups; and Q 2 For H.

[0258] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 1 It is isopropyl; R 2 It is methyl; and Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally surrounded by one or more R s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0259] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 2 It is methyl; and Q 2 For H.

[0260] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 For H; R 1 It is isopropyl; R 2 Methyl; Q 1 For H, C 3-5 cycloalkyl, C 6-20 Aryl or 5- to 6-membered heteroaryl, of which Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, and wherein Q 1The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated; and Q 2 H is given, provided that Q is given. 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl or C 3-15 cycloalkyl; or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally bonded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0261] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15 cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1 The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 C 1-12 Alkyl or C 3-5 Each cycloalkyl group is independently and optionally substituted with one or more halogens; Q 1 For H, C 3-5 cycloalkyl, C 6-20 Aryl or 5- to 6-membered heteroaryl, of which Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C1-12 Alkyl, and wherein Q 1 The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated; and Q 2 H is given, provided that Q is given. 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl or C 3-15 cycloalkyl; or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally bonded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0262] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15 cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1 The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Methyl; Q 1 C 3-5 cycloalkyl; and Q 2 For H.

[0263] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 3-15cycloalkyl groups are independently and optionally C 1-12 Alkyl substitution, or R 1 The 3- to 15-membered heterocyclic groups are independently and optionally C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Methyl; Q 1 It consists of 5 to 6 heteroaryl groups, of which Q 1 The 5- to 6-membered heteroaryl group is optionally substituted by one or more halogenated groups; and Q 2 For H.

[0264] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 1 It is isopropyl; R 2 It is methyl; and Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally bonded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0265] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 2 It is methyl; and Q 2 For H.

[0266] In some embodiments, this document provides a compound of formula (I'), or a pharmaceutical salt thereof, wherein: X 1 For H; R 1 It is isopropyl; R 2 Methyl; Q 1 For H, C 3-5 cycloalkyl, C 6-20 Aryl or 5- to 6-membered heteroaryl, of which Q 1 C 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, and wherein Q 1The 5- to 6-membered heteroaryl groups are independently and optionally controlled by one or more R groups. q Replace, where each R q Independently halogenated; and Q 2 H is given, provided that Q is given. 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl or C 3-15 cycloalkyl; or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl or 5- to 20-membered heteroaryl compounds, of which Q 1 and Q 2 The formed 5- to 20-membered heteroaryl groups are optionally bonded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkyl group.

[0267] It should be understood that X provided in this article 1 R 1 R 2 Q 1 Q 2 R a R b R c R q and R s Any variation or embodiment can be related to X 1 R 1 R 2 Q 1 Q 2 R a R b R c R q and R s Each other variation or combination of embodiments is described individually and specifically, as each and every combination has been described separately.

[0268] In some embodiments, this document provides a compound of formula (I) (such as compounds of formula (IA), (IB), (IC), or (ID)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound has a molecular weight of up to about 500 Da. In some embodiments, the compound has a molecular weight of not more than 500 Da. In some embodiments, the compound has a molecular weight between about 100 Da and about 500 Da, between about 200 Da and about 500 Da, between about 300 Da and about 500 Da, or between about 400 Da and about 500 Da. In some embodiments, the compound has a molecular weight of up to about 450 Da. In some embodiments, the compound has a molecular weight of not more than 450 Da. In some embodiments, the compound has a molecular weight between about 300 Da and about 450 Da. In some embodiments, the compound has a molecular weight of up to about 400 Da. In some embodiments, the compound has a molecular weight of not more than 400 Da. In some embodiments, the compound has a molecular weight between about 100 Da and about 400 Da, between about 200 Da and about 400 Da, or between about 300 Da and about 400 Da. In some embodiments, the compound has a molecular weight between about 300 Da and about 400 Da. In some embodiments, references to the molecular weight of a compound herein refer to the molecular weight of the compound in its free base form. It should be understood that the examples provided in this paragraph are applicable in some embodiments to compounds of formula (I) (such as compounds of formula (IA), (IB), (IC), (ID), (IE), or (IF)), or their stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing.

[0269] In some embodiments, this document provides a compound of formula (I) (such as a compound of formula (IA), (IB), (IC), or (ID)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound has five or fewer hydrogen bond donors (HBDs). In some embodiments, the compound has four or fewer HBDs. In some embodiments, the compound has three or fewer HBDs. In some embodiments, the compound has two or fewer HBDs. In some embodiments, this document provides a compound of formula (I) (such as a compound of formula (IA), (IB), (IC), (ID), (IE), or (IF)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound has five or fewer (e.g., four, three, or two) hydrogen bond donors (HBDs).

[0270] In some embodiments, this document provides a compound of formula (I) (such as compounds of formula (IA), (IB), (IC), or (ID)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound has a molecular weight of up to about 500 Da and has three or fewer HBDs. In some embodiments, the compound has a molecular weight of up to about 400 Da and has two or fewer HBDs. In some embodiments, the compound has a molecular weight between about 300 Da and about 400 Da and has two or fewer HBDs. It should be understood that the examples provided in this paragraph are applicable in some embodiments to compounds of formula (I) (such as compounds of formula (IA), (IB), (IC), (ID), (IE), or (IF)), or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing.

[0271] In the embodiments, this document provides a compound of formula (I) (such as a compound of formula (IA), (IB), (IC), (ID), (IE) or (IF)), or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound is selected from the compounds in Table 1.

[0272] Table 1

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] In one embodiment, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0282] In one embodiment, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound is selected from the group consisting of:

[0283] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0284] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0285] 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0286] 1-(3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0287] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-methylcyclohexyl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0288] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0289] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(piperidin-4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0290] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-methylpiperidin-4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0291] 1-(2-(1-acetylpiperidin-4-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0292] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0293] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0294] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(2,2,2-trifluoroethyl)pyrrolidine-2-carboxamide;

[0295] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-5-(methylcarbamoyl)pyrrolidine-3-yl acetate;

[0296] N-Cyclopropyl-1-(2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0297] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-isopropylpyrrolidine-2-carboxamide;

[0298] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-N-(2-fluoroethyl)-4-hydroxypyrrolidine-2-carboxamide;

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

[0300] 1-(2-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0301] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(1-methylcyclopropyl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0302] 1-(2-(4-cyclobutyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0303] 1-[2-(4-cyclopentyltriazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-methyl-pyrrolidine-2-carboxamide;

[0304] 1-(2-cyclohexyl-2-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0305] 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0306] 4-Hydroxy-1-(2-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbutyryl)-N-methylpyrrolidine-2-carboxamide;

[0307] 1-((5,6-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0308] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0309] 4-Hydroxy-N-methyl-1-[3-methyl-2-[4-(1H-pyrrolo-2-yl)triazol-1-yl]butyryl]pyrrolidin-2-carboxamide;

[0310] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(oxazol-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0311] 4-Hydroxy-N-methyl-1-[3-methyl-2-(4-thiazolyl-2-yltriazol-1-yl)butyryl]pyrrolidine-2-carboxamide;

[0312] 4-Hydroxy-N-methyl-1-[3-methyl-2-(4-oxazol-5-yltriazol-1-yl)butyryl]pyrrolidine-2-carboxamide;

[0313] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(thiazo-5-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0314] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0315] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0316] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0317] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0318] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0319] 4-Hydroxy-N-methyl-1-(3-methyl-2-(4-(pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide; and

[0320] 1-(2-(4-(5-chlorothiophene-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0321] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0322] The compound names included in Table 1 and the list above are from ChemDraw. ® Generated by software version 18.2.0.48.

[0323] As described herein, VHL ligands can exist in solid or liquid form. In the solid state, ligands can exist in crystalline or amorphous form, or as mixtures thereof. Those skilled in the art will understand that pharmaceutical solvates can be formed for crystalline or amorphous compounds. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. Solvates can involve non-aqueous solvents, such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they can involve water as a solvent incorporated into the crystal lattice. Solvates in which water is incorporated into the crystal lattice are generally referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing a variable amount of water. Such solvates are included in the subject matter described herein.

[0324] Those skilled in the art will further understand that certain VHL ligands (including their various solvates) existing in crystalline form as described herein can exhibit polymorphism (i.e., the ability to appear in different crystal structures). These different crystalline forms are generally referred to as “polymorphs.” Such polymorphs are the subject of this disclosure. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of their crystalline solid state. Therefore, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand that different polymorphs can be generated, for example, by changing or adjusting the reaction conditions or reagents used to prepare the compound. For example, changes in temperature, pressure, or solvent can lead to polymorphs. Additionally, under certain conditions, one polymorph can spontaneously transform into another.

[0325] The VHL ligands or pharmaceutical salts thereof described herein may exist in stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms). Various stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the subject matter disclosed herein. Similarly, it should be understood that compounds or salts of formula (I) may exist in tautomeric forms other than those shown in the formula, and these forms are also included within the scope of the subject matter disclosed herein. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomer / diastereomer-enriched mixtures. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined above.

[0326] The subject matter disclosed herein also includes the isotopic labeling of the compounds described herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds described herein and their medicinal salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I.

[0327] Other isotopes containing the aforementioned isotopes and / or other atoms, such as the VHL ligands disclosed herein and their pharmaceutical salts, are within the scope of the subject matter disclosed herein. This document discloses isotopically labeled compounds, such as those doped with radioactive isotopes (e.g., 3 H, 14 Compounds in group C) can be used for drug and / or substrate tissue distribution assays. Tritium compounds are commonly used (i.e.,...). 3 H) and carbon-14 (i.e. 14 C) Isotopes, because they are easy to prepare and detect. 11 C and 18 F isotopes can be used in PET (positron emission tomography), while 125 I- isotopes can be used in SPECT (single-photon emission computed tomography), all of which can be used for brain imaging. Further, heavier isotopes such as deuterium (i.e.,...) can be used... 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. Isotope-labeled compounds of Formula I can generally be prepared by performing the procedures disclosed in the following schemes and / or examples (by replacing the non-isotope-labeled reagent with an readily available isotope-labeled reagent).

[0328] In some embodiments, the VHL ligands provided herein are integrated into a heterobifunctional molecule. In some embodiments, the heterobifunctional molecule is a chemical degradation inducer (CIDE) having: (i) a VHL ligand as provided herein, and (ii) a portion capable of binding to a target protein for targeted degradation, wherein (i) and (ii) are covalently linked. In some embodiments, (i) and (ii) are covalently linked via a linker portion (such as a polyethylene glycol (PEG) chain or an alkyl chain). In some embodiments, the CIDE is capable of selectively degrading the target protein by forming a ternary complex between the target protein, the heterobifunctional molecule described herein, and the ubiquitin ligase. In some embodiments, the ubiquitin ligase is a VHL E3 ubiquitin ligase. The target protein may be, for example, a structural protein, an enzyme, a receptor, or a cell surface protein, in an illustrative and non-limiting manner.

[0329] In some embodiments, the heterobifunctional molecule is a compound of formula (II):

[0330] [A]-[B]-[C] (II),

[0331] Where [A] is the portion of the VHL ligand provided in this paper, [B] is the linker portion, and [C] is the protein-binding portion.

[0332] III. Formulation

[0333] On the other hand, this specification provides therapeutic or pharmaceutical compositions comprising an effective amount of at least one compound as described herein, including, for example, at least one VHL ligand. Pharmaceutical compositions comprising: an effective amount of at least one VHL ligand of this disclosure, and optionally an effective amount of one or more of the compounds otherwise described herein, combined with an effective amount of a carrier, additive or excipient, and optionally additional bioactive agents.

[0334] In some embodiments, the composition comprises pharmaceutical salts, particularly acid or base addition salts of compounds as described herein. The acids used to prepare the pharmaceutical acid addition salts of the aforementioned base compounds include those that form non-toxic acid addition salts, i.e., salts containing pharmaceutical anions, such as hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, gluconates, sucroseates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates [i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ates], etc.

[0335] Pharmaceutical base addition salts can also be used to produce pharmaceutical salt forms of compounds or derivatives. The chemical bases that can be used as reagents to prepare pharmaceutical basic salts of the inherently acidic compounds of the present invention are those chemical bases that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to: those basic salts derived from such pharmaceutical 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-methylglucosamine-(glucosamine); and lower alkanolammonium and other basic salts of pharmaceutical organic amines; etc.

[0336] The compositions described herein may be administered in single or divided doses via oral, parenteral, or topical routes in some embodiments. Administration of the compounds can range from continuous (intravenous infusion) to oral administration several times daily (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), oral, sublingual, and suppository administration, via inhalation spray, rectal, vaginal, or via an implanted reservoir, and other routes of administration. Enteric-coated oral tablets may also be used to improve the bioavailability of compounds from oral administration. The most effective dosage form will depend on the pharmacokinetics of the selected specific agent and the severity of the patient's disease. The compounds according to this disclosure may also be used as sprays, aerosols, or inhalers for intranasal, intratracheal, or pulmonary administration. Therefore, this disclosure also relates to pharmaceutical compositions comprising an effective amount of the compound according to this disclosure, optionally in combination with a pharmaceutical carrier, additive, or excipient. The compounds according to this disclosure may be administered in an immediate-release, intermediate-release, or sustained-release or controlled-release form. Sustained-release or controlled-release formulations are preferably administered orally, but can also be administered as suppositories and transdermal or other localized forms. Intramuscular injection in liposome form can also be used to control or maintain the release of the compound at the injection site.

[0337] Therefore, in one aspect, pharmaceutical formulations of VHL ligands as described herein can be prepared for parenteral administration in a unit-dose injectable form, together with a pharmaceutical parenteral medium. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. VHL ligands of desired purity are optionally mixed with one or more pharmaceutical excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A.) in a lyophilized formulation or aqueous solution for reconstitution.

[0338] The compositions disclosed herein can be formulated using one or more pharmaceutical carriers in a conventional manner and can also be administered in a controlled-release formulation. The compounds disclosed herein can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. According to this aspect, a pharmaceutical composition as described herein is provided comprising a VHL ligand in combination with one or more pharmaceutical excipients.

[0339] Typical formulations are prepared by mixing the compounds of this disclosure with excipients such as carriers and / or diluents. Suitable carriers, diluents, and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or excipient used will depend on the manner and purpose in which the compound is applied. Other pharmaceutical carriers that may be used in these pharmaceutical compositions include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0340] Solvents are typically selected based on those generally recognized by those skilled in the art as safe for use in mammals (GRAS). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the receptor at the dosage and concentration used, including buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0341] The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives to provide an aesthetically pleasing presentation of the VHL ligand or to aid in the preparation of the pharmaceutical product. The formulation can be prepared using conventional dissolution and mixing procedures.

[0342] Formulations can be made by mixing the compound with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration used) at ambient temperature, appropriate pH, and desired purity. The pH of the formulation depends primarily on the specific application and concentration of the compound, but can be in the range of about 3 to about 8. Formulations in an acetate buffer at pH 5 are suitable examples.

[0343] Pharmaceutical compositions may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. In particular, formulations intended for in vivo administration must be sterile. Such sterilization is readily achieved through filtration using sterile filter membranes. The suspension can be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as 1,3-butanediol). Sterile injectable formulations may also be prepared as lyophilized powders. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are traditionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) can also be used in the preparation of injectables, as well as natural medicinal oils (such as olive oil or castor oil, especially their polyoxyethylene forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants (such as Ph. Helv or similar alcohols).

[0344] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes, thereby making the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0345] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0346] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal use. These can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0347] The pharmaceutical compositions described herein can also be applied topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestine can be effective as a rectal suppository (see above) or as a suitable enema. Topically acceptable transdermal patches may also be used.

[0348] For topical application, the pharmaceutical composition may be formulated as a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polyoxypropylene compounds, emulsified waxes, and water. In certain preferred aspects of this disclosure, the compound may be coated onto a stent (which will be surgically implanted into a patient) to inhibit or reduce the likelihood of stent occlusion in the patient.

[0349] Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutical carriers. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0350] For ophthalmic applications, 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 preservatives (such as benzylalkonium chloride). Alternatively, for ophthalmic applications, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

[0351] The pharmaceutical compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0352] VHL ligand compositions can typically be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0353] The pharmaceutical compositions comprising VHL ligands disclosed herein can be formulated, administered, and applied in accordance with good medical practice (i.e., dosage, concentration, schedule, duration, medium, and route of administration). Factors to be considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the condition, the site of delivery, the method of administration, the timing of administration, and other factors known to the practicing physician. The "therapeuticly effective amount" of the compound to be administered will be constrained by such considerations and will be the minimum amount required to prevent, improve, or treat the condition. Such amounts are preferably below those that would be toxic to the host or significantly increase the host's susceptibility to adverse side effects.

[0354] VHL ligands can be formulated into pharmaceutical dosage forms to provide easily controlled drug dosage and enable patients to adhere to prescriptions. Depending on the method of administration, pharmaceutical compositions (or formulations) for administration can be packaged in various ways. Typically, articles for dispensing include containers in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include intervention protection components to prevent accidental contact with the packaged contents. Additionally, the container is labeled with a description of its contents. Appropriate warnings may also be included on the label.

[0355] Formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile injectable liquid carrier, such as water, before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing the active ingredient at the daily dose or a unit daily sub-dose, or an appropriate fraction thereof, as described above herein.

[0356] It should 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, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0357] Patients or subjects requiring therapy with the compounds described in this disclosure may be treated by administering to the patient (subject) an effective amount of the compounds described in this disclosure, including their pharmaceutical salts, solvates or polymorphs, optionally in a pharmaceutical carrier or diluent, alone or in combination with other known erythropoiesis stimulants, as otherwise identified herein.

[0358] The active compound is included in a pharmaceutical carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient for the desired indication without causing serious toxicity. For the conditions described herein, the preferred dose of the active compound ranges from about 10 ng / kg to 300 mg / kg, preferably from 0.1 mg / kg to 100 mg / kg daily, and more generally from 0.5 mg to about 25 mg per kilogram of recipient / patient body weight daily. Depending on the above factors, a typical daily dose range can be from about 1 µg / kg to 100 mg / kg or more. In a suitable carrier, a typical local dose range will be from 0.01% wt / wt to 5% wt / wt.

[0359] The compound can be conveniently administered in any suitable unit dosage form, including but not limited to unit dosage forms containing less than 1 mg, 1 mg to 3000 mg, preferably 5 mg to 500 mg of active ingredient per unit dosage form. Oral doses of about 25 mg to 250 mg are generally convenient.

[0360] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 mM to 30 mM, preferably about 0.1 mM to 30 mM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline or aqueous medium, or as a pill containing the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0361] The concentration of the active compound in a pharmaceutical composition will depend on the absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be alleviated. It should also be understood that, for any given subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges listed herein are merely exemplary and not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered once or divided into many smaller doses for administration at different time intervals.

[0362] In one embodiment, the active compound is prepared together with a carrier (such as a controlled-release formulation, including implants and microencapsulated delivery systems) that protects the compound from rapid elimination from the body. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be readily apparent to those skilled in the art.

[0363] Liposome suspensions can also serve as pharmaceutical carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the entire contents of which are incorporated herein by reference). For example, liposome formulations can be prepared by dissolving suitable lipids (lipids) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, thereby leaving a thin film of dried lipids on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the sides of the container and to disperse lipid aggregates, thereby forming a liposome suspension.

[0364] The term "medicinal salt" is used throughout this specification to describe, where applicable, the salt form of one or more of the compounds described herein, which are present to increase the solubility of the compound in the gastric juices of a patient's gastrointestinal tract, thereby promoting the dissolution and bioavailability of the compound. Pharmaceutical salts include, where applicable, those salts derived from pharmaceutical inorganic or organic bases and acids. Suitable salts include those derived from alkali metals (such as potassium and sodium), alkaline earth metals (such as calcium, magnesium, and ammonium salts), and many other acids and bases well known in the pharmaceutical industry. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to this disclosure.

[0365] The term "medicinal derivative" is used throughout the specification to describe any pharmaceutical prodrug form (such as esters, amides, other prodrug groups) that, upon administration to a patient, directly or indirectly provides the compound of the invention or an active metabolite of the compound of the invention.

[0366] The subject matter of this invention further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier. The veterinary carrier is a material that can be used to administer the composition and can be a solid, liquid, or gaseous material that is inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered parenterally or via any other intended route.

[0367] IV. Indications and Treatments

[0368] The VHL ligands disclosed herein are intended for use in the treatment of a variety of diseases, conditions, or illnesses. Therefore, it should be understood that any of the compounds provided herein can be used to treat diseases or illnesses regulated by VHL, such as any of the diseases and illnesses listed herein. It should also be understood that any of the compounds provided herein can be used to prepare a medicament for the treatment of conditions regulated by VHL, such as any of the diseases and illnesses listed herein.

[0369] The compounds disclosed herein are intended for therapeutic use. They are also intended for the treatment of diseases or indications associated with VHL activity, such as those described in Zhang et al., J. Med. Chem. 219, 62, 5725-5749 (the full text of which is incorporated herein by reference and in particular with respect to the indications and diseases disclosed therein, including conditions associated with anemia, ischemia, and tumors). Therefore, it should be understood that any of the compounds provided herein can be used to treat conditions regulated by VHL. In some embodiments, the VHL ligands disclosed herein can be used to treat cancers associated with VHL regulation. In some embodiments, the VHL ligands disclosed herein can be used to treat solid tumors. In some embodiments, solid tumors are breast cancer (such as triple-negative breast cancer), lung cancer, multiple myeloma, or renal cell carcinoma (RCC).

[0370] In an alternative aspect, the present invention relates to a method for enhancing erythropoiesis in a patient or subject in need, the method comprising administering to the patient or subject an effective amount of at least one compound as described above, optionally in combination with another erythropoiesis-stimulating compound. The method according to the invention can be used to increase the number of red blood cells (erythrocytes) and / or hematocrit in a patient by administering an effective amount of at least one compound described herein. Another aspect of the invention relates to treating anemia, including chronic anemia or localized ischemia, in a patient or subject in need, the method comprising administering to the patient in need an effective amount of at least one compound according to the invention. The method according to the invention can be used to treat anemia (including chronic anemia, such as anemia associated with chronic kidney disease, dialysis, and chemotherapy) and localized ischemia (including localized ischemia, stroke, and cardiovascular ischemia), and to limit damage resulting from those disease states and / or conditions.

[0371] Another aspect of the invention relates to enhancing wound healing and reducing scar tissue formation during wound healing by administering one or more compounds according to the invention to a patient in need. Further methods include inducing local angiogenesis in a patient or subject in need by administering an effective amount of at least one compound of the invention (optionally in combination with another erythropoiesis-stimulating compound). The following methods represent another aspect of the invention: stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and / or hematocrit in the patient; treating anemia (including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy), local ischemia, stroke, and damage to cardiovascular tissues during cardiovascular ischemia; and enhancing the wound healing process and preventing / reducing scarring associated with or secondary to the healing process.

[0372] Other methods of the invention involve locally enhancing angiogenesis by inducing VEGF in a patient or subject using at least one compound according to the invention (optionally in combination with erythropoiesis-stimulating compounds also described herein). Further methods of the invention involve reducing and / or inhibiting occlusion in surgically implanted stents in a patient or subject.

[0373] The compounds described herein can be administered to patients to treat a variety of diseases, conditions, or illnesses. In some embodiments, administration of the compounds described herein provides stimulation of erythropoiesis in a patient or subject, including inducing EPO production in the patient or subject. In other embodiments, administration of the compounds described herein is provided to treat chronic anemia and ischemia (which limits localized anemia, brain injury during ischemia and / or stroke, and damage to cardiovascular tissues during cardiovascular ischemia) and to enhance wound healing processes. The following methods represent additional therapeutic aspects of the invention: stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and / or hematocrit in the patient; treating anemia (including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy), ischemia, stroke, and damage to cardiovascular tissues during cardiovascular ischemia; and enhancing wound healing processes and preventing / reducing scarring secondary to healing. Locally enhancing angiogenesis (including wound healing and reducing stent occlusion) by inducing VEGF remains another aspect of the invention.

[0374] This document also provides the use of the compounds described herein in the preparation of a medicament for the treatment of a variety of diseases, conditions, and illnesses. In one embodiment, this document provides the use of the compounds described herein in the preparation of a medicament for the treatment of anemia. In some embodiments, the anemia is chronic anemia, or anemia associated with chronic kidney disease, dialysis, or cancer chemotherapy, or any combination thereof. In other embodiments, this document provides the use of the compounds described herein in the preparation of a medicament for the treatment of damage to the cardiovascular system during ischemia, stroke, or any combination thereof. In some embodiments, this document provides the use of the compounds described herein in the preparation of a medicament for the enhancement of wound healing in a person with this need. In other embodiments, this document provides the use of the compounds described herein in the preparation of a medicament for the reduction of scarring secondary to wound healing in a person with this need. In some embodiments, this document provides the use of the compounds described herein in the preparation of a medicament for the enhancement of angiogenesis or arteriovenous formation, or both, in a person with this need. In some embodiments, the enhancement of angiogenesis or arteriovenous formation, or both, occurs locally in the person. In some embodiments, this document provides the use of compounds as described herein in the preparation of a medicament for use in reducing the likelihood of stent occlusion in persons with such need.

[0375] This document also provides compounds, as described elsewhere herein, 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, this document provides compounds, as described elsewhere herein, for use in the treatment of damage to the cardiovascular system during local ischemia, stroke, or local ischemia, or any combination thereof. In some embodiments, this document provides compounds, as described elsewhere herein, for use in enhancing wound healing in persons with this need. In other embodiments, this document provides compounds, as described elsewhere herein, for use in reducing scarring secondary to wound healing in persons with this need. In some embodiments, this document provides compounds, as described elsewhere herein, for use in enhancing angiogenesis or arteriovenous formation, or both, in persons with this need. In some embodiments, the enhancement of angiogenesis or arteriovenous formation, or both, occurs locally in the person. In some embodiments, this document provides compounds, as described elsewhere herein, for use in reducing the likelihood of stent occlusion in persons with this need.

[0376] The terms “co-administration” or “combination therapy” should mean the simultaneous administration of at least two compounds or compositions to a patient such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time point. Although the compounds described in this disclosure can be co-administered to a patient simultaneously, the term includes both simultaneous or different-time administration of two or more agents, provided that an effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred aspects of the invention, one or more of the above-described compounds of the invention are co-administered in combination with at least one additional bioactive agent having erythropoietic stimulating activity as further described herein, in order to enhance erythropoiesis, treat chronic anemia and ischemia (limiting localized anemia, ischemia, and / or brain injury during stroke and damage to cardiovascular tissues during cardiovascular ischemia), and enhance wound healing processes and stimulate angiogenesis and inhibit or prevent occlusion in surgically implanted stents. In a particularly preferred aspect of the invention, the co-administration of the compounds results in synergistic erythropoietic activity and / or therapy.

[0377] The term “another erythropoiesis stimulant” should refer to conventional peptides such as EPO (procrit or epogen) or darbapoietin α (the synthetic form of erythropoietin).

[0378] The compositions of the present invention can be formulated using one or more pharmaceutical carriers in a conventional manner and can also be administered as controlled-release formulations. Pharmaceutical carriers that can be used in these pharmaceutical compositions include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0379] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, locally, rectally, nasally, orally, vaginally, or via an implanted reservoir. As used herein, the term "parenterical" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0380] The sterile injectable form of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0381] Among the acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glycerol derivatives) can be used to prepare injectable formulations, such as olive oil or castor oil, especially their polyoxyethylated forms, as natural medicinal oils. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants (such as Ph. Helv or similar alcohols).

[0382] The pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0383] Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0384] The pharmaceutical compositions of the present invention can also be applied topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestine can be effective as a rectal suppository formulation (see above) or as a suitable enema formulation. Topically acceptable transdermal patches can also be used. For topical application, the pharmaceutical compositions can be formulated as suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for the topical application of the compounds of the present invention include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. In some preferred aspects of the invention, the compounds can be coated onto a stent (which will be surgically implanted into a patient) to inhibit or reduce the likelihood of stent occlusion in the patient.

[0385] Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutical carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. For ophthalmic 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 preservatives (such as benzylalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

[0386] The pharmaceutical compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0387] The amount of compound in the pharmaceutical composition of the present invention that can be combined with a carrier material to produce a single dosage form will vary depending on the host and disease being treated and the specific method of administration. Preferably, the composition should be formulated to contain an active ingredient (alone or in combination with at least one other compound or erythropoiesis stimulant (EPO, darbapoietin α) according to the present invention) in amounts between about 0.05 mg and about 750 mg or more, more preferably about 1 mg and about 600 mg, and even more preferably about 10 mg and about 500 mg, to particularly enhance erythropoiesis, treat chronic anemia and ischemia (limiting localized anemia, brain injury during stroke, and damage to cardiovascular tissues during cardiovascular ischemia), and enhance wound healing processes and stimulate angiogenesis and inhibit or prevent occlusion in surgically implanted stents.

[0388] It should 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, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0389] Patients or subjects requiring therapy with the compounds described herein may be treated by administering to the patient (subject) an effective amount of the compounds described herein, including their pharmaceutical salts, solvates, or polymorphs, optionally in a pharmaceutical carrier or diluent, alone or in combination with other known erythropoiesis stimulants, as otherwise identified herein. These compounds may be administered via any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or by aerosol. The active compound is included in a pharmaceutical carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient for the desired indication without causing serious toxicity to the treated patient. For all conditions mentioned herein, the preferred dose of the active compound is in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 mg / kg to 100 mg / kg daily, and more generally about 0.5 mg to 25 mg per kilogram of recipient / patient body weight daily. In a suitable carrier, typical local doses will range from 0.01% wt / wt to 5% wt / wt. The compound can be conveniently administered in any suitable unit dosage form, including but not limited to unit dosage forms containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 mg to 500 mg of active ingredient per unit dosage form. Oral doses of approximately 25 mg to 250 mg are generally convenient.

[0390] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 mM to 30 mM, preferably about 0.1 μM to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline or aqueous medium, or as a pill containing the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0391] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values ​​will also vary depending on the severity of the condition to be alleviated. It should also be understood that, for any given subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges listed herein are merely exemplary and not intended to limit the scope or practice of the claimed compositions.

[0392] The active ingredient can be administered once or divided into many smaller doses for administration at different time intervals. Oral compositions typically contain an inert diluent or an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound or its prodrug derivative can be combined with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binder and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; dispersants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit is in capsule form, it may also contain a liquid carrier, such as fatty oil, in addition to the materials of the types described above. In addition, the dosage unit form may contain various other materials that change the physical form of the dosage unit, such as sugar coating, shellac, or enteric solvent.

[0393] The active compound or its pharmaceutical salt can be applied as a component of elixirs, suspensions, syrups, rice paper wrappers, chewing gum, etc. In addition to the active compound, the syrup may also contain sucrose as a sweetener, as well as certain preservatives, dyes and pigments, and flavorings. The active compound or its pharmaceutical salt can also be mixed with other active substances that do not impair the desired effect, or with substances that complement the desired effect (such as erythropoietin stimulants, including EPO and darbapoietin α); and so on. In some preferred aspects of the invention, one or more compounds according to the invention are co-administered with another bioactive agent (such as an erythropoietin stimulant or a wound healing agent, including antibiotics, as otherwise described herein).

[0394] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for tonication, such as sodium chloride or dextrose. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. If administered intravenously, physiological saline or phosphate-buffered saline (PBS) is a preferred carrier. In one embodiment, the active compound is prepared together with a carrier (such as a controlled-release formulation, including implants and microencapsulated delivery systems) that protects the compound from rapid elimination from the body. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be readily apparent to those skilled in the art.

[0395] Liposome suspensions can also serve as pharmaceutical carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the entire contents of which are incorporated herein by reference). For example, liposome formulations can be prepared by dissolving suitable lipids (lipids) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, thereby leaving a thin film of dried lipids on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the sides of the container and to disperse lipid aggregates, thereby forming a liposome suspension.

[0396] V. Products

[0397] On the other hand, this document describes articles, for example, providing "kits" containing materials for treating the aforementioned diseases and conditions. The kit includes a container containing VHL ligands. The kit may further include a label or instruction manual on or associated with the container. The term "instruction manual" is used to refer to instructions typically included in the commercial packaging of a therapeutic product, containing information regarding indications, usage, dosage, administration, contraindications, and / or warnings related to the use of such therapeutic products.

[0398] Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. A “vial” is a container suitable for holding liquid or lyophilized formulations. In one embodiment, a vial is a disposable vial, such as a 20 cc disposable vial with a stopper. Containers can be formed from a variety of materials such as glass or plastic. Containers can hold VHL ligands or formulations thereof effective for treating conditions 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).

[0399] At least one active agent in the composition is a VHL ligand of this disclosure. The label or package insert indicates that the composition is intended to treat a selected condition, such as cancer. Additionally, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition such as hyperproliferative disorders, atherosclerosis, neurodegeneration, cardiomegaly, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or package insert indicates that the composition containing the VHL ligand is intended to treat a condition caused by abnormal cell growth. The label or package insert may also indicate that the composition is intended to treat other conditions. Alternatively or additionally, the article may further include a second container containing a pharmaceutical buffer, such as bactericidal water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. Other substances required from a commercial and user perspective may also be included, including other buffers, diluents, filters, needles, and syringes.

[0400] The kit may further include instructions for the administration of the VHL ligand and the second pharmaceutical formulation (if present). For example, if the kit includes a first composition containing a VHL ligand and a second pharmaceutical formulation, the kit may further include instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to patients in need of this.

[0401] In another embodiment, the kit is suitable for delivering VHL ligands in solid oral forms, such as tablets or capsules. Such kits preferably comprise a plurality of unit doses. Such kits may include cards with doses oriented in sequence according to their intended use. An example of such kits is blister packaging. Blister packaging is well known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals. If desired, memory aids may be provided, for example, in the form of numbers, letters, or other markings, or by calendar inserts indicating dates on which the dose can be administered in a specified treatment schedule.

[0402] 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 preparation, wherein the second pharmaceutical preparation comprises a second compound having anti-excessive proliferation activity. Alternatively or additionally, the kit may further include a third container containing a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. Other substances required from a commercial and user perspective may also be included, including additional buffers, diluents, filters, needles, and syringes.

[0403] In some other embodiments where the kit includes a VHL ligand and a second therapeutic agent, the kit may include containers (such as separate bottles or separate foil packs) for containing individual compositions; however, individual compositions may also be contained in a single, non-separate container. Typically, the kit includes instructions for administering the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when the prescribing physician wishes to titrate a combination of various components.

[0404] VI. Examples

[0405] The following synthetic reaction schemes detailed in the general schemes and examples are merely illustrative of some methods that can be used to synthesize the compounds disclosed herein (or their embodiments or aspects). Various modifications can be made to these synthetic reaction schemes with reference to the disclosure contained herein, and suggestions are made to those skilled in the art.

[0406] The starting materials and reagents used to prepare these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or prepared by methods known to those skilled in the art, according to the methods described in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, vols. 1–15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, vols. 1–5 and supplements; and Organic Reactions, Wiley & Sons: New York, 1991, vols. 1–40.

[0407] If necessary, starting materials and intermediates for the synthetic reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Conventional methods can be used to characterize these materials, including physical constants and spectral data.

[0408] Unless otherwise stated, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, and in a temperature range of about -78°C to about 150°C, more preferably in a temperature range of about 0°C to about 125°C.

[0409] Although certain exemplary embodiments are depicted and described herein, compounds (or embodiments or aspects thereof) disclosed herein may be prepared using suitable starting materials in accordance with the methods generally described herein and / or by means of methods available to those skilled in the art.

[0410] All reactions involving air-sensitive reagents were carried out under an inert atmosphere. Unless otherwise specified, reagents were purchased as is from the commercial supplier.

[0411] abbreviation

[0412] Use the following abbreviations in the examples:

[0413] ABPR - Automatic Back Pressure Regulator

[0414] Ac2O - Acetic anhydride

[0415] ACN - Acetonitrile

[0416] Boc - tert-butyloxycarbonyl

[0417] Cbz - Carboxybenzyl

[0418] CD3OD - Deuterated Methanol

[0419] CDCl3- Deuterated chloroform

[0420] CV - Cylinder Volume

[0421] Cy3PHBF4- Tricyclohexylphosphine tetrafluoroborate

[0422] DBU-1,8-diazabicyclo[5.4.0]undec-7-ene

[0423] DCM - Dichloromethane

[0424] DEA - Diethanolamine

[0425] DIPEA or DIEA-N,N-diisopropylethylamine

[0426] DME - Dimethoxyethane

[0427] DMF - Dimethylformamide

[0428] DMEM - Dulbecco's modified Eagle's medium

[0429] DMSO - Dimethyl sulfoxide

[0430] DMSO-d6-deuterated dimethyl sulfoxide

[0431] DTT - Dithiothreitol

[0432] EDCI - N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0433] EDTA - ethylenediaminetetraacetic acid

[0434] ESI - Electrospray Ionization

[0435] ESI-MS - Electrospray Ionization Mass Spectrometry

[0436] EtOAc - Ethyl acetate

[0437] EtOH - Ethanol

[0438] FA - Formic acid

[0439] Fmoc - fluorenylmethoxycarbonyl

[0440] HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0441] HEPES - 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0442] Hex - Hexane

[0443] HOAc - Acetic acid

[0444] HOBt or HOBT - Hydroxybenzotriazole

[0445] HPLC - Ultra-high performance liquid chromatography

[0446] hr - hours

[0447] KOH - Potassium hydroxide

[0448] LC / MS or LCMS - Liquid Chromatography-Mass Spectrometry

[0449] LG - Leaving Group

[0450] MeOH - methanol or methyl alcohol

[0451] MSD - Quality Selection Detector

[0452] MTBE - Methyl tert-butyl ether

[0453] NIS - N-iodosuccinimide

[0454] NMR - Nuclear Magnetic Resonance

[0455] PBS - Phosphate-Buffered Saline

[0456] Pd / C - Palladium supported on carbon

[0457] PEG - Polyethylene Glycol

[0458] PG - Protecting group

[0459] rt / RT - Room temperature

[0460] R T - Retention time

[0461] RP-HPLC - Reversed-phase high-performance liquid chromatography

[0462] SFC - Supercritical Fluid Chromatography

[0463] TAMRA - Carboxytetramethylrhodamine

[0464] TCEP - Tris(2-carboxyethyl)phosphine

[0465] TEA - Triethylamine

[0466] TFA - Trifluoroacetic acid

[0467] THF - Tetrahydrofuran

[0468] TMSI - Trimethylsilyl iodide

[0469] UV - Ultraviolet rays

[0470] LC / MS method

[0471] Method A: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, employing 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 an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 20% to 80% solvent B over 3.6 min, 80% to 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.

[0472] Method B: Experiments were performed on a SHIMADZU 2020 HPLC system combined with an ESI-based MSD mass spectrometer using a Shim-pack XR-ODS C18 50 x 3.0 mm column and a flow rate of 1.2 ml / min. The solvent system followed a gradient: starting with 95% aqueous solution of 0.05% TFA (solvent A) and 5% acetonitrile solution of 0.05% TFA (solvent B), gradually increasing to 100% solvent B over 1.1 min. The final solvent system was held constant for 0.6 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0473] Method C: Experiments were performed on a SHIMADZU 2020 HPLC system combined with an ESI MSD mass spectrometer using an Ascentis Express C18 50 x 2.1 mm column and a flow rate of 1.0 ml / min. The solvent system followed a gradient: starting with 95% aqueous solution of 0.05% TFA (solvent A) and 5% acetonitrile solution of 0.05% TFA (solvent B), increasing to 100% solvent B over 1.1 min. The final solvent system was held constant for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0474] Method D: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an 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 followed a gradient: starting with a 95% aqueous solution of 0.05% TFA (solvent A) and a 5% acetonitrile solution of 0.05% TFA (solvent B), gradually increasing to 95% solvent B over 2.0 min. The final solvent system was held constant for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0475] Method E: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, using a CORTECS C18 50 x 3.1 mm column and a flow rate of 1.0 ml / min. The solvent system followed a gradient: starting with 95% aqueous solution of 0.05% TFA (solvent A) and 5% acetonitrile solution of 0.05% TFA (solvent B), increasing rapidly over 1.1 min to 100% solvent B. The final solvent system was held constant for 0.5 min. The LC column temperature was 45 °C. UV absorbance was collected from 190 nm to 400 nm.

[0476] Method F: Experiments were performed on a Shimadzu 2020 HPLC system combined with a Shimadzu MSD mass spectrometer using an ESI source, employing a Poroshell HPH-C18 50 x 3.0 mm column and a flow rate of 1.2 mL / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 10% to 50% solvent B over 3.5 min, then 50% to 95% solvent B over 0.5 min, and held at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0477] Method G: Experiments were performed on a SHIMADZU 2020 HPLC system combined with an ESI-based MSD mass spectrometer using an XSELECT CSH C18 50 x 3.0 mm column and a flow rate of 1.5 ml / min. The solvent system followed a gradient: starting with 90% aqueous solution of 0.1% FA (solvent A) and 10% acetonitrile solution of 0.1% FA (solvent B), increasing over 1.1 min to 100% solvent B. The final solvent system was kept constant for 0.6 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0478] Method H: Experiments were performed on a SHIMADZU 2020 HPLC system combined with an ESI MSD mass spectrometer using an Accucore C18 50 x 2.1 mm column and a flow rate of 1.0 ml / min. The solvent system followed a gradient: starting with 90% aqueous solution of 0.1% FA (solvent A) and 10% acetonitrile solution of 0.1% FA (solvent B), increasing over 2 min to 95% solvent B. The final solvent system was held constant for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0479] Method I: Experiments were performed on a Shimadzu LCMS-2020 mass spectrometer coupled to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation was performed using a CAPCELL CORE C18, 50 x 2.1 mm column at a flow rate of 1 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 5% to 95% solvent B over 2.0 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.

[0480] Method J: Experiments were 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 Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 5% to 70% solvent B over 3.7 min, 70% to 95% solvent B 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.

[0481] Method K: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.2 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was methanol. The gradient was 30% to 95% solvent B over 10 min and held at 95% B for 2 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0482] Method L: Experiments were performed on a Shimadzu LCMS-2020 mass spectrometer 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 at a flow rate of 1.0 ml / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 10% to 95% solvent B over 1.1 min and held at 95% B for 0.5 min. The LC column temperature was 35 °C. UV absorbance was collected from 190 nm to 400 nm.

[0483] Method M: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation was performed using an MKRP18e, 25 x 2 mm column at a flow rate of 1.5 mL / min. Solvent A was 4 L of 1.5 mL TFA aqueous solution, and solvent B was 4 L of 0.75 mL TFA acetonitrile solution. The gradient included 5% to 95% solvent B over 0.7 min and held at 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0484] Method N: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation was performed using an MKRP18e, 25 x 2 mm column at a flow rate of 1.5 mL / min. Solvent A was 4 L of 1.5 mL TFA aqueous solution, and solvent B was 4 L of 0.75 mL TFA acetonitrile solution. The gradient consisted of 10% to 80% solvent B over 7 min and maintained at 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0485] Method O: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation was performed using an MKRP18e, 25 x 2 mm column at a flow rate of 1.5 mL / min. Solvent A was 4 L of 1.5 mL TFA aqueous solution, and solvent B was 4 L of 0.75 mL TFA acetonitrile solution. The gradient included 0% to 60% solvent B over 7 min and maintained at 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0486] Method P: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, employing 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 an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 5% to 95% solvent B over 2.0 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.

[0487] Method Q: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, employing 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 an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 5% to 60% solvent B over 3.2 min, 60% to 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 190 nm to 400 nm.

[0488] Method R: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, employing 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 an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 20% to 60% solvent B over 3.6 min, 60% to 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.

[0489] Method S: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.5 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient was as follows: 5% solvent B held for 0.8 min, 5% to 40% solvent B for 7.2 min, 40% to 95% solvent B for 2.0 min, and 95% B held for 2.0 min. The LC column temperature was 60 °C. UV absorbance was collected from 190 nm to 400 nm.

[0490] Method T: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.5 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient was 10% to 60% solvent B over 10 min, 60% to 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.

[0491] Method U: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.0 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient was 10% to 60% solvent B over 10 min, 60% to 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.

[0492] Method V: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.0 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient was 5% to 95% solvent B over 8 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.

[0493] Method W: Experiments were performed on a Shimadzu 2020 HPLC system combined with a Shimadzu MSD mass spectrometer using an ESI source, employing a Poroshell HPH-C18 50 x 3.0 mm column and a flow rate of 1.2 mL / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 10% to 95% solvent B over 2.0 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.

[0494] Method X: Experiments were performed on a Shimadzu 2020 HPLC system combined with a Shimadzu MSD mass spectrometer using an ESI source, employing a Poroshell HPH-C18 50 x 3.0 mm column and a flow rate of 1.2 mL / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 10% to 70% solvent B over 3.5 min, 70% to 95% solvent B over 0.5 min, and held at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0495] Method Y: Experiments were performed on a Shimadzu 2020 HPLC system combined with a Shimadzu MSD mass spectrometer using an ESI source, employing a Poroshell HPH-C18 50 x 3.0 mm column and a flow rate of 1.2 mL / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 30% to 70% solvent B over 4.0 min, 70% to 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.

[0496] Method Z: Experiments were performed on a Shimadzu 2020 HPLC system combined with a Shimadzu MSD mass spectrometer using an ESI source, employing a Poroshell HPH-C18 50 x 3.0 mm column and a flow rate of 1.2 mL / min. Solvent A was an aqueous solution of 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient was 30% to 95% solvent B over 4.0 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.

[0497] Method AA: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an Accucore C18 50 x 2.1 mm column and a flow rate of 1.0 ml / min. Solvent A was an aqueous solution of 0.1% FA, and solvent B was an acetonitrile solution of 0.1% FA. The gradient was 10% to 95% solvent B over 3.0 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.

[0498] Method BB: Experiments were performed on a SHIMADZU 2020 HPLC system combined with a SHIMADZU MSD mass spectrometer using an ESI source, using an Accucore C18 50 x 2.1 mm column and a flow rate of 1.0 ml / min. Solvent A was an aqueous solution of 0.1% FA, and solvent B was an acetonitrile solution of 0.1% FA. The gradient was 10% to 50% solvent B for 3.5 min, 50% to 95% solvent B for 0.5 min, and held at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0499] Method CC: Experiments were 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 Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient followed 5% to 50% solvent B over 3.5 min, 50% to 100% solvent B over 0.2 min, and held at 100% B for 1.0 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0500] Methods: Experiments were performed on a Shimadzu LCMS-2020 mass spectrometer coupled to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation was performed using a Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was an acetonitrile solution of 0.05% TFA. The gradient was 5% to 95% solvent B over 2.0 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.

[0501] Methods: Experiments were performed on a SHIMADZU 2020 HPLC system combined with an ESI MSD mass spectrometer using an Ascentis Express C18 50 x 2.1 mm column and a flow rate of 1.2 ml / min. Solvent A was an aqueous solution of 0.05% TFA, and solvent B was MeOH. The gradient was 30% to 85% solvent B over 10 min and held at 80% B for 3.2 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0502] Method FF: Experiments were performed on an MK RP18e 25-2 mm column in conjunction with a mass spectrometer using ESI as the ionization source. Solvent A was 1.5 mL / 4 L of aqueous TFA, and solvent B was 0.75 mL / 4 L of acetonitrile TFA. The gradient consisted of 5% to 95% solvent B over 0.7 min, and maintained at 95% for 0.4 min at a flow rate of 1.5 mL / min. The LC column temperature was 50 °C. UV absorbance was collected at 220 nm and 254 nm.

[0503] Method GG: In combination with an Xtimate C18 2.1 mass spectrometer using ESI as the ionization source. Experiments were performed on a 30 mm, 3 μm column. Solvent A was 1.5 mL / 4 L of aqueous TFA, and solvent B was 0.75 mL / 4 L of acetonitrile TFA. The gradient consisted of 10% to 80% solvent B over 6 min, and was maintained at 80% for 0.5 min at a flow rate of 0.8 mL / min. The LC column temperature was 50 °C. UV absorbance was collected at 220 nm and 254 nm.

[0504] SFC method

[0505] Method 1: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: ethanol (0.05% DEA); Gradient: from 5% to 40% B over 5 min and from 40% to 5% B over 0.5 min, holding at 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi.

[0506] Method 2: Column: Chiralcel OD-3 100×4.6 mm ID, 3µm; Mobile phase: A: CO2; B: ethanol (0.05% DEA); Gradient: from 5% to 40% B for 4.5 min, held at 40% for 2.5 min, then held at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0507] Method 3: Column: Chiralcel OJ-3 100×4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: methanol (0.05% DEA); Gradient: from 5% to 40% B over 4.5 min, held at 40% for 0.5 min, then held at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0508] Method 4: Column: ChiralCel OJ-H 150×4.6 mm ID, 5um; Mobile phase: A: CO2; B: ethanol (0.05% DEA); Gradient: from 5% to 40% B over 5.5 min, then 5% B over 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40℃.

[0509] Method 5: Column: Chiralcel OJ-H 150 4.6 mm ID, 5 μm; Mobile phase: A: CO2; B: ethanol (0.05% DEA); Gradient: Hold 5% for 0.5 min, then from 5% to 40% B for 3.5 min, hold 40% for 2.5 min, then hold 5% B for 1.5 min; Flow rate: 3 mL / min; Column temperature: 40 °C.

[0510] Method 6: Column: Chiralpak AD-3 150×4.6 mm ID, 3µm; Mobile phase: A: CO2; B: Isopropanol (0.05% DEA); Gradient: from 5% to 40% B for 5 min, held at 40% for 2.5 min, then held at 5% B for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi.

[0511] Method 7: Column: Chiralcel OJ-3 100×4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: ethanol (0.05% DEA); Gradient: from 5% to 40% B for 4.5 min, held at 40% for 2.5 min, then held at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0512] Recordings were performed at 400 MHz, 500 MHz, or 600 MHz using a Bruker Avance 400, 500, or 600 spectrometer. 1 H-NMR spectrum. 1 H-NMR data are reported in the following format: chemical shifts (multiplicity, coupling constant, and integral). Chemical shifts are reported in ppm, with residual solvent resonances used as internal standards (CDCl3: 7.26 ppm, DMSO-d6: 2.50 ppm, CD3OD: 3.31 ppm). Multiplicity is abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, dt = doublet of triplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dddd = doublet of doublet of doublet, tt = triplet of triplet.

[0513] The following general protocols are used for the preparation of the disclosed compounds, intermediates, and pharmaceutical salts thereof. The disclosed compounds and intermediates can be prepared using standard organic synthesis techniques and from commercially available starting materials and reagents. It should be understood that the synthetic processes used to prepare the disclosed compounds and intermediates will depend on the specific substituents present in the compound or intermediate and may require various standard protecting, deprotecting, and transforming steps in organic synthesis, but may not be described in the following general protocols. It should also be understood that any of the steps shown in any of the following general protocols can be used in any chemically feasible combination and sequence to obtain the desired intermediate or disclosed compound. It should be noted that in the following general protocols, the various parts are as defined elsewhere herein. In the following general protocols and examples, Indicates the solid support material—such as RinkAmide resin.

[0514] Option 1

[0515]

[0516] Option 2

[0517]

[0518] Option 3

[0519]

[0520] Option 4

[0521]

[0522] Option 5

[0523]

[0524] Option 6

[0525]

[0526] The following examples are provided by way of illustration and not limitation. Some of the compounds used in the following examples may exist as tautomers. Although the illustrations of the compounds provided below depict only a single tautomer, these illustrations should not be regarded in a limiting sense; rather, the corresponding tautomers are also intended to be included in the following examples as if each and every tautomer of the compound were depicted individually.

[0527] Example S1: Synthesis of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 1)

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

[0529]

[0530] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added to the vessel, and the resin was allowed to swell under nitrogen for 30 minutes. The resin was then drained under vacuum. 10 mL of a 20% solution of 4-methylpiperidine in N,N-dimethylformamide was drawn into the vessel, and the reaction was carried out under nitrogen for 15 minutes to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection step was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalent), ethyl cyano(hydroxyimino)acetate (3.0 equivalent), and N,N'-diisopropylcarbodiimide (3.0 equivalent) in 10 mL of N,N-dimethylformamide was added, and the mixture was subsequently aspirated 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 vacuum. The washing process was repeated 3 times. 10 mL of a 20% solution of 4-methylpiperidine in N,N-dimethylformamide was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalence), ethyl cyano(hydroxyimino)acetate (3.0 equivalence), and N,N'-diisopropylcarbodiimide (3.0 equivalence) in 10 mL of N,N-dimethylformamide was added, and the combined mixture was then drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. Copper(I) hexafluorophosphate (acetonitrile) (0.2 equivalence) was added directly to the peptide synthesis vessel to perform a "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into a reactor vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum.A pyrolysis solution was prepared by mixing 5% triisopropylsilane into 95% trifluoroacetic acid. The pyrolysis solution was aspirated into a reactor dish and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound.

[0531] The collected precipitate was purified by RP-HPLC (acetonitrile 30% to 60% / 0.225% FA aqueous solution) to give (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 1) as a white solid (15 mg, 44.7% yield). ESI-MS: m / z [M+H] + The calculated value is 336.2, and the actual measured value is also 336.2.

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d,J= 4.8 Hz, 1H), 7.45 (s, 1H), 6.89(s, 1H), 5.36 (d,J= 16.9 Hz, 1H), 4.37 - 4.22 (m, 2H), 3.72 (dd,J= 10.8, 4.0Hz, 1H), 3.55 (dt,J= 11.1, 1.8 Hz, 1H), 2.08 - 1.90 (m, 2H), 1.82 (dddd,J=17.2, 12.7, 8.1, 4.7 Hz, 1H), 1.01 - 0.91 (m, 9H), 0.91 - 0.84 (m, 2H), 0.80- 0.66 (m, 2H).

[0533] Example S2: Synthesis of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 2)

[0534] Perform the synthesis according to the following scheme:

[0535]

[0536] Preparation of intermediate 2b

[0537] KOH (85.5 g, 1.526 mol) was dissolved in 1 L of distilled water and subsequently treated with THF (1 L), followed by the addition of intermediate 2a (100 g, 0.763 mol) in an ice-cold bath. Boc₂O (250 g, 1.467 mol) was then added dropwise. The reaction mixture was stirred overnight at room temperature, and THF was subsequently removed using a rotary evaporator. The aqueous layer was washed with MTBE (2 × 700 mL). The residual aqueous solution was adjusted to pH 3 by adding 1 M KHSO₄. The acidic solution was extracted with ethyl acetate (3 x 700 mL). The combined organic extracts were washed with H₂O and brine and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure to give intermediate 2b (150 g, 0.649 mol, 85% yield) as a yellow slurry, which was used for the next step without purification.

[0538] 1 H NMR: (400 MHz, DMSO-d6) δ 12.44 (br s, 1H), 5.01 (br s, 1H), 4.28 -4.11 (m, 1H), 4.11 - 3.95 (m, 1H), 3.50 - 3.25 (m, 1H), 3.25 - 3.04 (m, 1H), 2.19 - 1.95 (m, 1H), 1.95 - 1.68 (m, 1H), 1.31 (d, 9H).

[0539] Preparation of intermediate 2c

[0540] At -40°C, 126 mL (0.905 mol) of triethylamine was added to a solution of 150 g (0.649 mol) of intermediate 2b in 2700 mL of anhydrous THF, followed by the addition of 70 mL (0.563 mol) of ethyl chloroformate in 300 mL of anhydrous THF at -30°C. The resulting mixture was stirred at the same temperature for 1 hour. Then, 170 mL of a 40% (v / v) aqueous solution of methylamine was added at -30°C, and the temperature of the reaction mixture was raised to room temperature. The reaction was then allowed to continue for 12 hours. At the end of this period, THF was removed by rotary evaporation, and the mixture was mixed with a small amount of aqueous sodium chloride solution and extracted three times with ethyl acetate. The combined extracts were washed with aqueous sodium chloride solution and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure to give 100 g (0.410 mol, 63.3%) of intermediate 2c as a colorless oil.

[0541] 1 H NMR: (400 MHz, DMSO-d6) δ 7.94 - 7.62 (m, 1H), 5.04 - 4.75 (m, 1H), 4.25 - 4.09 (m, 1H), 4.09 - 3.80 (m, 2H), 3.41 - 3.30 (m, 1H), 3.25 - 3.11(m, 1H), 2.53 (d, J = 8.3, 4.5 Hz, 3H), 2.00 - 1.92 (m, 1H), 1.82 - 1.65 (m,1H), 1.31 (d, J = 28.0 Hz, 9H).

[0542] Preparation of intermediate 2d

[0543] A solution of 10% HCl in dioxane (500 mL) was added dropwise to a solution of intermediate 2c (100 g, 0.410 mol) in MTBE (1 L). At the end of the addition, the mixture was stirred at room temperature for 8 hr. The reaction was then completed, and the formed precipitate was filtered, treated with diethyl ether, filtered again, and the residue was dried under vacuum to give title intermediate 2d (60 g, 0.335 mol, 82% yield) as a white powder.

[0544] 1 H NMR: (500 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.90 - 8.69 (m, 1H), 8.58 (br s, 1H), 5.60 (br s, 1H), 4.46 - 4.31 (m, 1H), 4.31 - 4.16 (m, 1H), 3.35 - 3.19 (m, 1H), 3.12 - 2.91 (m, 1H), 2.64 (d, J = 4.7, 1.3 Hz, 3H), 2.36- 2.13 (m, 1H), 1.91 - 1.63 (m, 1H).

[0545] Preparation of intermediate 2f

[0546] Trifluoromethanesulfonyl azide formulation: Sodium azide solution (125 g, 1.92 mol) was dissolved in distilled water (620 mL) containing DCM (1000 mL) and cooled in an ice bath. Trifluoromethanesulfonyl anhydride (120 mL, 0.71 mol) was slowly added over 30 min with stirring for 2 h. The organic phase was removed, and the aqueous fraction was extracted with DCM (2 × 200 mL). The organic fractions containing trifluoromethanesulfonyl azide were combined, washed once with saturated disodium carbonate, and used without further purification. Intermediate 2e (50 g, 0.38 mol) was combined with potassium carbonate (80 g, 0.58 mol), copper(II) sulfate pentahydrate (3 g, 0.012 mol), distilled water (630 mL), and methanol (1250 mL). A DCM solution (1000 mL) of trifluoromethanesulfonyl azide was added, and the mixture was stirred overnight at ambient temperature and pressure. Subsequently, the organic solvent was removed under reduced pressure, and the aqueous slurry was diluted with water (1000 mL). The solution was acidified to pH 6 with sodium bisulfate and extracted three times with EtOAc to remove sulfonamide byproducts. The aqueous phase was then acidified to pH 2 with concentrated HCl. The product was obtained from another round of EtOAc extraction (3 × 600 mL). These organic phases were combined, dried over sodium sulfate, and evaporated to dryness to give 30 g of intermediate 2f as a white solid in 51% yield, requiring no further purification.

[0547] 1 ¹H NMR: (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 3.83 (s, 1H), 0.93 (s, 9H). LCMS: (Method 5-95 AB, ESI, 2 min): R T = 1.159 min, [MH] - = 156.2.

[0548] Preparation of 2g of intermediate

[0549] Oxaloyl chloride (25 ml, 0.29 mol) was added to a solution of intermediate 2f (30 g, 0.19 mol) in dichloromethane (DCM) (250 ml), followed by 2 drops of DMF. The mixture was stirred at room temperature for 2 h, and then excess oxaloyl chloride and dichloromethane were removed under vacuum to provide 2 g (33 g, 99% yield) of crude intermediate.

[0550] 1¹H NMR: (400 MHz, chloroform-d) δ 4.01 (s, 1H), 1.07 (s, 9H).

[0551] Preparation of intermediate 2h

[0552] Triethylamine (120 mL, 0.862 mol) was slowly added to a solution of intermediate 2d (80 g, 0.449 mol) in THF (1200 mL) under stirring at -20 °C, followed by the addition of substance intermediate 2 g (60 g, 0.342 mol). The reaction mixture was further stirred at -20 °C for 2 h and then stirred overnight at room temperature. The mixture was evaporated to obtain a slurry solution, diluted with ethyl acetate (1000 mL) and washed with 1N HCl (500 mL), followed by washing with 10% sodium bicarbonate aqueous solution (500 mL) and brine (500 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under vacuum to give 55 g (56%) of pure product intermediate 2h (shown by NMR as a mixture of rotational isomers).

[0553] 1 H NMR: (500 MHz, DMSO-d6) δ 8.27 - 7.82 (m, 1H), 5.16 - 4.89 (m, 1H), 4.51 - 4.34 (m, 1H), 4.34 - 4.19 (m, 1H), 3.87 (s, 1H), 3.73 - 3.57 (m, 1H), 3.56 - 3.38 (m, 2H), 2.62 (d, J = 4.6 Hz, 3H), 2.27 - 1.97 (m, 1H), 1.97 -1.69 (m, 1H), 0.97 (d, J = 25.7 Hz, 9H).

[0554] LCMS: (Method 5-95 AB, ESI, 6 min): R T = 2.094 min, [M+H] + = 284.4

[0555] Preparation of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 2)

[0556] To a solution of intermediate 2h (0.5 g, 1.76 mmol) and cyclopropylacetylene (0.14 g, 2.12 mmol) in THF (5 mL), a solution of sodium ascorbate (0.34 g, 1.71 mmol) in distilled water (2 mL) and a solution of copper(II) sulfate pentahydrate (0.15 g, 0.6 mmol) in distilled water (3 mL) were added. The mixture was stirred overnight at 25 °C. Then, a 25% ammonia solution was added, and the mixture was purified using preparative HPLC. The chromatographic operating conditions are given below: Equipment (mobile phase, column): SYSTEM 0-50% 0.5-6.5 min water-acetonitrile; flow rate 30 mL / min (loaded pump 4 mL / min acetonitrile); target mass 349; column SunFireC18 100x19 mm 5 μm (R)

[0557] As a result, the target compound ((2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; compound 2) (104 mg, 0.298 mmol) was obtained in an overall yield of 16.8%.

[0558] ESI-MS: m / z [M+H] + The calculated value is 350.2, and the actual measured value is also 350.2.

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.88 (m, 2H), 5.39 (s, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.35 - 4.23 (m, 2H), 3.71 (dd, J = 10.9, 3.9 Hz, 1H),3.61 - 3.50 (m, 1H), 2.62 - 2.51 (m, 3H), 2.05 - 1.88 (m, 2H), 1.82 (ddd, J =13.1, 9.0, 4.4 Hz, 1H), 0.97 (s, 8H), 0.93 (s, 2H), 0.87 (ddd, J = 8.3, 4.0,2.2 Hz, 2H), 0.72 (tt, J = 4.7, 2.0 Hz, 2H).

[0560] Example S3: (2S,4R)-1-((S)-2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl Synthesis of 4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 3)

[0561] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0562]

[0563] 0.100 mmol of 4-formyl-3-methoxy-phenoxymethyl polystyrene resin was added to a plastic peptide synthesis vessel. 10 mL of 1,2-dichloroethane was added to the vessel, and the resin was allowed to swell under nitrogen for 30 min. The resin was then drained under vacuum. 1 mL of methylamine (DEA controlled substance, 2.0 M tetrahydrofuran solution) was added to the plastic reactor, and the mixture was allowed to react at room temperature for 2 hr. The reactor was opened, and sodium cyanoborohydride (10.0 equivalents) and acetic acid (2 equivalents) were added. The reactor was kept open on the manifold, and the contents were mixed by pipette and reacted overnight at room temperature. The resin was washed with 10 mL of methanol and 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (3.0 equivalents), 1-hydroxy-7-azabenzotriazole (3.0 equivalents), and N,N-diisopropylethylamine (6.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the resulting mixture was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated 3 times. A 10 mL solution of 20% 4-methylpiperidine in N,N-dimethylformamide was drawn into a reactor vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (S)-2-((((9Hfluorene-9-yl)methoxy)carbonyl)amino)-2-cyclohexylacetic acid (3.0 equivalents) and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the resulting mixture was drawn into a synthesis vessel and reacted under nitrogen for 2 hr. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A 10 mL solution of 20% 4-methylpiperidine in N,N-dimethylformamide was drawn into a reactor vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was then removed under vacuum, and the deprotection process was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. This washing process was repeated three times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane, and the mixture was drawn into a reactor vessel and reacted under nitrogen for 1 hour to convert the amine to the azide. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. This washing process was repeated three times. Copper(I) hexafluorophosphate (acetonitrile) (0.2 equivalents) was added directly to the peptide synthesis vessel to perform a "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into a reactor vessel and allowed to react overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane into 95% trifluoroacetic acid. The solution was drawn into a reactor vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the target compound.

[0564] The collected precipitate was purified by RP-HPLC (30% to 60% acetonitrile / 0.225% FA aqueous solution) to give (2S,4R)-1-((S)-2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 3) as a white solid (13.4 mg, 35.6% yield). ESI-MS: m / z [M+H] + The calculated value is 376.2, and the actual measured value is also 376.2.

[0565] 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 7.91 (q, J = 4.6Hz, 0H), 5.21 (d, J = 10.4 Hz, 0H), 4.37 - 4.17 (m, 1H), 3.91 (s, 16H), 3.76(dd, J = 10.7, 4.2 Hz, 0H), 3.59 (dt, J = 10.7, 1.7 Hz, 0H), 2.57 (d, J = 4.6Hz, 2H), 2.08 (s, 1H), 2.03 - 1.77 (m, 2H), 1.68 (d, J = 11.7 Hz, 1H), 1.63 -1.56 (m, 1H), 1.08 (ddt, J = 34.5, 12.1, 6.7 Hz, 2H), 0.96 - 0.80 (m, 2H), 0.78 - 0.66 (m, 1H).

[0566] Example S4: (2S,4R)-1-((S)-3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy Synthesis of β-N-methylpyrrolidine-2-carboxamide (compound 4)

[0567] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0568]

[0569] 0.100 mmol of 4-formyl-3-methoxy-phenoxymethyl polystyrene resin was added to a plastic peptide synthesis vessel. 10 mL of 1,2-dichloroethane was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then drained under vacuum. 1 mL of methylamine (DEA controlled substance, 2.0 M tetrahydrofuran solution) was added to the plastic reactor, and the reaction was carried out at room temperature for 2 hr. The reactor was opened, and sodium cyanoborohydride (10.0 equivalents) and acetic acid (2 equivalents) were added. The reactor was kept open at the manifold, mixed by a pipette, and reacted overnight at room temperature. The resin was washed sequentially with 10 mL of methanol, 10 mL of N,N-dimethylformamide, and 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalent), ethyl cyano(hydroxyimino)acetate (3.0 equivalent), and N,N'-diisopropylcarbodiimide (3.0 equivalent) in 10 mL of N,N-dimethylformamide was added, and the mixture was subsequently aspirated 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 vacuum. The washing process was repeated 3 times. 10 mL of a 20% solution of 4-methylpiperidine in N,N-dimethylformamide was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalence), ethyl cyano(hydroxyimino)acetate (3.0 equivalence), and N,N'-diisopropylcarbodiimide (3.0 equivalence) in 10 mL of N,N-dimethylformamide was added, and the mixture was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. Copper(I) hexafluorophosphate (acetonitrile) (0.2 equivalence) was added directly to the peptide synthesis vessel to perform a "click" reaction on the resin. A mixture of ethynyltrimethylsilane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into a reactor vessel and reacted overnight under nitrogen.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane into 95% trifluoroacetic acid. The solution was aspirated into a reactor vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound.

[0570] The collected precipitate was purified by RP-HPLC (30% to 60% acetonitrile / 0.225% FA aqueous solution) to give (2S,4R)-1-((S)-3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 4) as a white solid (14.1 mg, 45.4% yield). ESI-MS: m / z [M+H] + The calculated value is 310.2, and the actual measured value is also 310.2.

[0571] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d,J= 1.1 Hz, 1H), 7.94 (q,J= 4.6 Hz,1H), 7.73 (d,J= 1.1 Hz, 1H), 5.53 (s, 1H), 4.34 - 4.26 (m, 3H), 2.59 (d,J=4.6 Hz, 3H), 2.10 - 1.89 (m, 2H), 1.82 (dtd,J= 12.9, 8.7, 4.4 Hz, 2H), 0.98 (s, 9H).

[0572] Example S5: (2S,4R)-1-[2-(4-cyclopropyltriazol-1-yl)-2-(1-methylcyclohexyl)acetyl]-4-hydroxy Synthesis of 2-methyl-N-methyl-pyrrolidine-2-carboxamide (compound 5)

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

[0574]

[0575] 0.100 mmol of 4-formyl-3-methoxy-phenoxymethyl polystyrene resin was added to a plastic peptide synthesis vessel. 10 mL of 1,2-dichloroethane was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then drained under vacuum. 1 mL of methylamine (DEA-controlled substance, 2.0 M tetrahydrofuran solution) was added to the plastic reactor, and the mixture was allowed to react at room temperature for 2 hr. The reactor was opened, and sodium cyanoborohydride (10.0 equivalents) and acetic acid (2 equivalents) were added. The reactor was kept open on the manifold, mixed by a pipette, and reacted overnight at room temperature. The resin was washed with 10 mL of methanol, 10 mL of N,N-dimethylformamide, and then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxyhexafluorophosphate (3.0 equivalents), 1-hydroxy-7-azabenzotriazole (3.0 equivalents), and N,N-diisopropylethylamine (6.0 equivalents) in 10 mL of N,N-dimethylformamide was aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated 3 times. A 10 mL solution of 20% 4-methylpiperidine in N,N-dimethylformamide was drawn into a reactor vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated 3 times. A mixture of 3.0 equivalences of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-(1-methylcyclohexyl)acetic acid and 3.0 equivalences of N,N'-diisopropylcarbodiimide was added to 10 mL of N,N-dimethylformamide, and the mixture was drawn into a synthesis vessel and reacted under nitrogen for 2 hr. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. The washing process was repeated 3 times. A 10 mL solution of 20% 4-methylpiperidine in N,N-dimethylformamide was drawn into a reactor vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was then removed under vacuum, and the deprotection process was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. This washing process was repeated three times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane. The mixture was drawn into a reactor vessel and reacted under nitrogen for 1 hour to convert the amine to the azide. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. This washing process was repeated three times. Copper(I) hexafluorophosphate (acetonitrile) (0.2 equivalents) was added directly to the peptide synthesis vessel to perform a "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into a reactor vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane into 95% trifluoroacetic acid. The solution was drawn into a reactor vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The collected precipitate was purified by RP-HPLC (30% to 60% acetonitrile / 0.05% TFA aqueous solution) to give (2S,4R)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-methylcyclohexyl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 5) as a white solid (2.0 mg, 2.0% yield). ESI-MS: m / z [M+H]. + The calculated value is 390.2, and the actual measured value is also 390.2. 1H NMR (400 MHz, MeOD) δ 7.88 (d,J=33.3 Hz, 1H), 5.42 (d,J= 21.9 Hz, 1H), 4.49 - 4.37 (m, 2H), 3.92 - 3.45 (m,2H), 2.86 - 2.62 (m, 3H), 2.16 (dddd,J= 15.4, 7.6, 3.7, 1.7 Hz, 1H), 2.08 -1.90 (m, 2H), 1.64 - 1.17 (m, 10H), 1.14 - 1.04 (m, 3H), 1.02 - 0.89 (m, 2H),0.86 - 0.70 (m, 2H).

[0576] Example S6: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(tetrahydro-2H-pyridine) Synthesis of (4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 6)

[0577] Perform the synthesis according to the following scheme:

[0578]

[0579] Preparation of intermediate 6b

[0580] Preparation of TfN3.

[0581] Add NaN3 (105 g, 1615 mmol, 20 equivalents) to a mixture of DCM (700 mL) and distilled water (434 mL) and cool to 0°C to 5°C. Slowly add Tf2O (54.6 mL, 91.56 g, 324 mmol, 4 equivalents) while maintaining the temperature below 5°C. Then stir the mixture at 5°C to 10°C for 2 hours and separate the layers. Wash the organic layer with a saturated NaHCO3 solution (3 × 500 mL). The obtained TfN3 is immediately used as the DCM solution for the next step (Caution! Do not concentrate the TfN3 solution, as it will spontaneously explode!).

[0582] Intermediate 6a (14 g, 80.8 mmol, 1 equivalent) was dissolved in MeOH (200 mL). CuSO4 solution (20.16 mL, 0.8 mmol, 1 mol%, 0.04 M distilled aqueous solution) was added to the resulting solution, followed by TEA (16.8 mL, 12.2 g, 120.7 mmol, 1.5 equivalent). Freshly prepared TfN3 solution (4 equivalents) was added dropwise at room temperature, and the reactants were left to stand while stirring for up to 18 hours. The mixture was then concentrated under vacuum and diluted with MTBE (500 mL), washed with ammonia solution (2 × 500 mL), washed with 1M NaHSO4 aqueous solution (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude intermediate 6b (26 g) as a yellow oil, which was used for the next step without further purification.

[0583] 1 ¹H NMR (500 MHz, DMSO-d⁶) δ 4.20 (d, J = 5.7 Hz, 1H), 3.82 (dd, 2H), 3.72 (s, 3H), 3.33 - 3.21 (m, 2H), 2.05 - 1.96 (m, 1H), 1.48 - 1.29 (m, 4H). LCMS does not provide information.

[0584] Preparation of intermediate 6c

[0585] Crude intermediate 6b (26 g) was dissolved in a mixture of THF (866 mL) and distilled water (216 mL). The resulting solution was cooled to 0-5 °C. Cyclopropylacetylene (22.1 mL, 17.26 g, 261.1 mmol), sodium ascorbate (26 g, 131.2 mmol), and CuSO4 pentahydrate (9.5 g, 38 mmol) were then added, and the reaction mixture was stirred at room temperature for 18 hours, leaving the reaction mixture in place. After this period, the mixture was concentrated under vacuum and diluted with MTBE (700 mL), washed with ammonia solution (2 × 500 mL), washed with brine (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate 6c (6.2 g, 23.4 mmol, 29% yield after two steps) as a yellow oil, which was used for the next step without further purification.

[0586] 1H NMR (600 MHz, DMSO-d6) δ 7.95 (s, 1H), 5.24 (d,J= 9.1 Hz, 1H), 3.82 (dd,J= 11.2, 3.3 Hz, 1H), 3.76 (dd,J= 11.0, 2.6 Hz, 1H), 3.67 (s, 3H), 3.27(td,J= 11.9, 2.0 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.46 - 2.40 (m, 1H), 1.98 -1.88 (m, 1H), 1.56 (dd, 1H), 1.28 - 1.20 (m, 2H), 0.97 (dd,J= 12.9 Hz, 1H), 0.90 - 0.84 (m, 2H), 0.73 - 0.68 (m, 2H).

[0587] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.835 min, [M+H] + = 266.2.

[0588] Preparation of intermediate 6d

[0589] Intermediate 6c (6.2 g, 23.4 mmol, 1 equivalent) was dissolved in THF (150 mL) and water (30 mL), and then LiOH was added. H2O (1.47 g, 35 mmol, 1.49 equivalents) was added, and the resulting solution was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, the residue was diluted with water (300 mL) and washed with MTBE (300 mL), the aqueous layer was acidified to pH 2 with NaHSO4 1M solution, extracted with EtOAc (2 × 300 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain intermediate 6d (5.52 g, 22 mmol, 94% yield) as a pale yellow solid.

[0590] 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 7.90 (s, 1H), 5.06 (d,J=8.8 Hz, 1H), 3.78 (dd,J= 26.3, 11.3 Hz, 2H), 3.32 - 3.13 (m, 2H), 2.42 - 2.31(m, 1H), 1.96 - 1.85 (m, 1H), 1.61 (dd,J= 13.5 Hz, 1H), 1.30 - 1.13 (m, 2H), 0.99 (dd,J= 12.7 Hz, 1H), 0.90 - 0.81 (m, 2H), 0.74 - 0.63 (m, 2H).

[0591] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.943 min, [M+H] + = 252.2.

[0592] Preparation of compound 6

[0593] Intermediate 6d (3.8 g, 15.1 mmol, 1 equivalent) was dissolved in anhydrous DMF (50 mL), followed by the addition of (2S,4R)-4-hydroxy-N-methylpyrrolidine-2-carboxamide hydrochloride (3 g, 16.6 mmol, 1.1 equivalent), HATU (6.3 g, 16.6 mmol, 1.1 equivalent), and DIPEA (6.59 mL, 4.9 g, 37.8 mmol, 2.5 equivalent), and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under vacuum and diluted with water (100 mL), washed with EtOAc (2 × 200 mL), and the aqueous layer was concentrated under reduced pressure.

[0594] The obtained crude residue (9.9 g) was purified by rapid chromatography (1 - Column: 330 g to 330.0 g (5 bar). Eluent: MTBE / MeOH gradient from 0 CV 100 / 0% to 19.13 CV 0 / 100%; elution steps: 1 - 0 CV 100 / 0%, 2 - 1 CV 100 / 0%, 3 - 3.52 CV 77 / 23%, 4 - 4.92 CV 77 / 23%, flow rate: 100.0 mL / min; 5 - 8.27 CV 77 / 23%, 6 - 13.10 CV 33 / 67%, 7 - 15.53 CV 33 / 67%, 8 - 15.53 CV 0 / 100%, 9 - 19.13 CV 0 / 100%, Flow rate: 150.0 mL / min. Detection: Channel 1: UV400: SIG1 → 205 nm; Channel 2: UV400: SIG2 → 235 nm. Temperature: Ambient temperature. Column: 80 g - 80.0 g (5 bar). Eluent: MeCN / MeOH gradient from 0 CV 100 / 0% to 19.84 CV 0 / 100%; Elution steps: 1 - 0 CV 100 / 0%, 2 - 1.25 CV 100 / 0%, 3 - 1.89 CV 94 / 6%, 4 - 2.50 CV 90 / 10%, 5 - 7.38 CV 90 / 10%, 6 - 7.38 CV 0 / 100 %, Flow rate: 100.0 mL / min; 7 - 7.42 CV 0 / 100%, 8 - 19.84 CV 0 / 100%, Flow rate: 200.0 mL / min. Detection: Channel 1: UV400: SIG1 → 205 nm; Channel 2: UV400: SIG2 → 235 nm. Temperature: Ambient temperature) to obtain crude product (2 g) containing approximately 50% (by HNMR and LC-MS) of the desired diastereomer. The mixture was purified by preparative HPLC (equipment (mobile phase, column): SYSTEM. 15-15% water-acetonitrile 2-9 min; flow rate 30 mL / min (load pump 4 mL / min acetonitrile); target mass 378; column sunfire 150. A mixture of 538.5 mg was obtained by 50 mm 5 μm (R) containing approximately 80% (by ¹H NMR and LC-MS) of the desired diastereomer. 100 mg of this crude product was sent for chiral separation (system: Chiralpak AD-HI (250 μL)). 20.5 mkm), mobile phase: CO2-MeOH, 70-30. Flow rate: 40 ml / min, replenishment = 15 ml / min, 40℃, wavelength: 215 nm. Retention time (isomer 1 (S)) = 2.42. Retention time (isomer 2 (R)) = 4.54, to give compound 6 as a yellow oil (49.86 mg, 0.132 mmol, 0.9% yield).

[0595] 1 H NMR (500 MHz, chloroform-d) δ 7.68 (s, 1H), 6.37 (d,J= 4.4 Hz, 1H), 5.24(d,J= 10.4 Hz, 1H), 4.59 - 4.55 (m, 1H), 4.43 (dd,J= 7.9 Hz, 1H), 4.01 (dd,J=11.5, 3.3 Hz, 1H), 3.91 (dd,J= 9.7 Hz, 2H), 3.81 (dd,J= 10.9, 4.0 Hz, 1H), 3.40 (t,J= 11.3 Hz, 1H), 3.30 (t,J= 11.8 Hz, 1H), 2.83 (d,J= 4.7 Hz, 3H),2.45 - 2.40 (m, 1H), 2.32 - 2.25 (m, 2H), 2.14 - 2.09 (m, 1H), 1.98 - 1.90(m, 1H), 1.87 (dd,J= 12.9 Hz, 1H), 1.43 - 1.32 (m, 2H), 0.99 - 0.96 (m, 2H), 0.87 - 0.83 (m, 2H).

[0596] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.628 min, [M+H] + = 378.2.

[0597] Example S7: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(piperidin-4-yl)ethyl Synthesis of acyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 7)

[0598] The synthesis was carried out according to the following scheme:

[0599]

[0600] Preparation of intermediate 7b

[0601] DBU (81 mL, 82.46 g, 541.8 mmol, 1.35 equivalents) was added dropwise at -20 °C to a solution of N-Cbz-2-phosphonoglycine trimethyl ester (164 g, 495 mmol, 1.23 equivalents) in anhydrous THF (700 mL) under an inert argon atmosphere. The mixture was stirred at -20 °C for 1 hour, and at the same temperature, a solution of intermediate 7a (80 g, 401.4 mmol, 1 equivalent) in anhydrous THF (300 mL) was added dropwise. The resulting mixture was then heated to room temperature and stirred for 18 hours. When the solvent was removed under reduced pressure, the residue was dissolved in EtOAc (1000 mL), and the organic phase was washed with water (1000 mL), washed with 1 M NaHSO4 solution (2 x 1000 mL), and subsequently dried over anhydrous sodium sulfate. The crude product obtained after solvent evaporation was purified by crystallization from MTBE and subsequently ground with hexane to give intermediate 7b (90.1 g, 222.7 mmol, 55.5% yield) as a pale yellow solid.

[0602] 1 ¹H NMR (600 MHz, chloroform-d) δ 7.39 - 7.28 (m, 5H), 6.04 (s, 1H), 5.12 (s, 2H), 3.74 (s, 3H), 3.52 - 3.43 (m, 4H), 2.91 - 2.80 (m, 2H), 2.42 - 2.35 (m, 2H), 1.45 (s, 9H).

[0603] LCMS (Method 5-95 AB, ESI, 2 min): R T = 1.148 min, [M+H-(t-BuCO2)] + = 305.2.

[0604] Preparation of intermediate 7c

[0605] Intermediate 7b (90.1 g, 222.7 mmol, 1 equivalent) was dissolved in anhydrous THF (900 mL), followed by the addition of activated carbon-supported Pd (15 g, 5% w / w, 7 mmol, 3.1 mol%), and the reaction mixture was hydrogenated at 1 atm for 18 hours. The catalyst was then removed by filtration, and the filtrate was concentrated under vacuum. The obtained crude residue (60 g) was purified by silica gel chromatography (column: 800 g - 800.0 g (5 bar). Eluent: MTBE / MeOH gradient from 0 CV 100 / 0% to 16 CV 0 / 100%; elution steps: 1 - 0 CV 100 / 0%, 2 - 2.15 CV 95 / 5%, 3 - 3.47 CV 95 / 5%, 4 - 3.63 CV 89 / 11%, 5 - 3.64 CV 89 / 11%, 6 - 5.48 CV 74 / 26%, 7 - 7.29 CV 74 / 26%, 8 - 16 CV 0 / 100. Flow rate: 150.0 mL / min. Detection: Channel 1: UV400: SIG1→205). nm; Channel 2: UV400: SIG2→235 nm. Temperature: ambient temperature) to obtain intermediate 7c as a pale yellow oil (37.2 g, 136.6 mmol, 61.3% yield).

[0606] 1 ¹H NMR (400 MHz, chloroform-d) δ 4.20 - 4.04 (m, 2H), 3.71 (s, 3H), 3.31 (d, J = 5.7 Hz, 1H), 2.72 - 2.55 (m, 2H), 1.81 - 1.71 (m, 1H), 1.66 - 1.57 (m, 1H), 1.56 - 1.48 (m, 1H), 1.42 (s, 10H), 1.39 - 1.21 (m, 3H).

[0607] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.921 min, [M+H-(t-Bu)] + = 217.2.

[0608] Preparation of intermediate 7d

[0609] Preparation of TfN3. NaN3 (56.15 g, 863.8 mmol, 7.5 equivalents) was added to a mixture of DCM (739 mL) and distilled water (471 mL) and cooled to 0°C to 5°C. Tf2O (58.2 mL, 97.6 g, 346 mmol, 3 equivalents) was slowly added dropwise, maintaining the temperature below 5°C. The resulting mixture was stirred at 5°C to 10°C for 2 hours, and then the layers were separated. The organic layer was washed with a saturated NaHCO3 solution (3 × 500 mL). The obtained TfN3 was immediately used as the DCM solution for the next step (Caution! Do not concentrate the TfN3 solution, as it will spontaneously explode!).

[0610] Intermediate 7c (31.4 g, 115.3 mmol, 1 equivalent) was dissolved in MeOH (300 mL). CuSO4 solution (28.75 mL, 1.15 mmol, 1 mol%, 0.04 M distilled aqueous solution) was added to the resulting solution, followed by TEA (24 mL, 17.4 g, 172.4 mmol, 1.5 equivalent). Freshly prepared TfN3 solution (3 equivalents) was added dropwise at room temperature, and the reaction mixture was then stirred for 18 hours. The resulting mixture was concentrated under vacuum and diluted with MTBE (700 mL), washed with ammonia solution (2 × 500 mL), washed with 1M NaHSO4 aqueous solution (2 × 500 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give crude intermediate 7d (32 g, 107.27 mmol, 93% yield) as a yellow oil, which was used for the next step without further purification.

[0611] 1 H NMR (400 MHz, DMSO-d6) δ 4.23 (d,J= 5.6 Hz, 1H), 3.97 - 3.84 (m,2H), 3.70 (s, 3H), 2.79 - 2.54 (m, 2H), 1.98 - 1.86 (m, 1H), 1.47 (dd,J=23.8, 13.4 Hz, 2H), 1.34 (s, 9H), 1.21 - 1.07 (m, 2H).

[0612] LCMS (Method 5-95 AB, ESI, 2 min): R T = 1.327 min, [M+H-(t-Bu)] + = 243.2.

[0613] Preparation of intermediate 7e

[0614] Intermediate 7d (32 g, 107.27 mmol, 1 equivalent) was dissolved in a mixture of THF (800 mL) and distilled water (200 mL), and the resulting solution was cooled to 0°C to 5°C. Cyclopropylacetylene (18 mL, 14 g, 212.7 mmol, 2 equivalents), sodium ascorbate (21.2 g, 107.27 mmol, 1 equivalent), and CuSO4 pentahydrate (2.7 g, 10.8 mmol, 0.1 equivalents) were then added, and the reaction mixture was stirred at room temperature for 18 hours, leaving the reaction mixture in the mixture. The resulting mixture was concentrated under vacuum and diluted with MTBE (700 mL), washed with ammonia solution (2 × 500 mL) and brine (2 × 500 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude intermediate 7e (39 g, 107 mmol, 99% yield) as a yellow oil, which was used for the next step without further purification.

[0615] 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 5.31 (d,J= 8.8 Hz, 1H), 3.92(dd,J= 30.8, 11.0 Hz, 2H), 3.70 (s, 3H), 2.79 - 2.60 (m, 1H), 2.46 - 2.33 (m,1H), 1.99 - 1.90 (m, 1H), 1.69 - 1.62 (m, 1H), 1.36 (s, 10H), 1.09 - 1.00 (m,2H), 0.94 - 0.86 (m, 2H), 0.78 - 0.68 (m, 2H).

[0616] LCMS (Method 5-95 AB, ESI, 2 min): R T = 1.342 min, [M+H] + = 365.2, [M+H-(t-Bu)] + = 309.2.

[0617] Preparation of intermediate 7f

[0618] Intermediate 7e (39 g, 107 mmol, 1 equivalent) was dissolved in THF (350 mL) and water (70 mL), and then LiOH was added. H2O (6.7 g, 159.5 mmol, 1.49 equivalents) was added, and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure, the residue was diluted with water (300 mL) and washed with MTBE (300 mL), the aqueous layer was acidified to pH 2 with NaHSO4 1M solution, extracted with EtOAc (2 × 300 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under vacuum to give intermediate 7f (33 g, 94.2 mmol, 88% yield) as a pale yellow solid.

[0619] 1 H NMR (500 MHz, DMSO-d6) δ 13.55 (s, 1H), 7.89 (s, 1H), 5.12 (d,J=8.5 Hz, 1H), 3.90 (dd,J= 29.8, 13.2 Hz, 2H), 2.75 - 2.57 (m, 2H), 2.40 - 2.29(m, 1H), 1.96 - 1.88 (m, 1H), 1.73 - 1.67 (m, 1H), 1.35 (s, 9H), 1.17 - 0.96(m, 3H), 0.92 - 0.82 (m, 2H), 0.77 - 0.65 (m, 2H).

[0620] LCMS (Method 5-95 AB, ESI, 2 min): R T = 1.186 min, [M+H] + = 351.2, [M+H-(t-Bu)] + = 295.0.

[0621] Preparation of 7g of intermediate

[0622] Intermediate 7f (16 g, 45.7 mmol, 1 equivalent) was dissolved in anhydrous DMF (200 mL), followed by the sequential addition of (2S,4R)-4-hydroxy-N-methylpyrrolidine-2-carboxamide hydrochloride (9.1 g, 50.4 mmol, 1.1 equivalent), HATU (19.2 g, 50.5 mmol, 1.1 equivalent), and DIPEA (20 mL, 14.8 g, 114.9 mmol, 2.5 equivalent), with the reaction mixture retained while stirring at room temperature for 18 hours. After this period, the mixture was concentrated under vacuum and diluted with EtOAc (1000 mL), washed with saturated aqueous solution of NaHCO3 (1000 mL), 1M aqueous solution of NaHSO4 (2 × 1000 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

[0623] The obtained crude residue (32.2 g) was purified by silica gel chromatography (column: 330 g - 330.0 g (5 bar). Eluent: hexane / IPA + MeOH (2:1) gradient from 0 CV 100 / 0% to 23.47 CV 0 / 100%; elution steps: 1 - 0 CV 100 / 0%, 2 - 1.33 CV 99 / 1%, 3 - 1.34 CV 84 / 16%, 4 - 4.20 CV 84 / 16%, 5 - 4.21 CV 80 / 20%, 6 - 4.22 CV 77 / 23%, 7 - 11.62 CV 50 / 50%, 8 - 14.34 CV 50 / 50%, 9 - 14.34). CV 0 / 100%, 10 - 23.47 CV 0 / 100%. Flow rate: 150.0 mL / min. Detection: Channel 1: UV400: SIG1 → 205 nm; Channel 2: UV400: SIG2 → 215 nm; Channel 3: UV400: SIG3 → 235 nm. Temperature: Ambient temperature) to obtain a crude product (3 g) containing approximately 70% (by HNMR) of the desired diastereomer. 2 g of this crude product was sent for chiral separation (system: ColumnOD-H (250)). 20, 5mkm), mobile phase: hexane-IPA-MeOH, 90-5-5. Flow rate: 22 mL / min. 20℃. Wavelength: 205 nm, 225 nm. Retention time (desired isomer) = 12.6. Retention time (side chain isomer) = 15.7. ) to obtain 7 g (1.32 g, 2.77 mmol, 6% yield) of an intermediate as a light beige solid.

[0624] 1 H NMR (400 MHz, chloroform-d) δ 7.64 (s, 1H), 6.52 (d,J= 3.3 Hz, 1H), 5.18 (d,J= 10.5 Hz, 1H), 4.55 - 4.50 (m, 1H), 4.38 (dd,J= 7.8 Hz, 1H), 4.21 - 4.11(m, 1H), 4.10 - 4.01 (m, 1H), 3.89 - 3.71 (m, 2H), 2.81 (d,J= 4.8 Hz, 3H), 2.74 - 2.67 (m, 1H), 2.61 - 2.53 (m, 1H), 2.31 (dd,J= 19.4, 8.2 Hz, 1H), 2.24- 2.16 (m, 1H), 2.14 - 2.03 (m, 1H), 1.97 - 1.86 (m, 2H), 1.41 (s, 9H), 1.26- 1.20 (m, 1H), 1.16 - 1.10 (m, 1H), 1.05 - 0.90 (m, 3H), 0.90 - 0.76 (m, 3H).

[0625] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.952 min, [M+H] + = 477.4, [M+H-(t-Bu)] + = 421.2.

[0626] Preparation of compound 7

[0627] 7 g of intermediate (1.32 g, 2.77 mmol, 1 equivalent) was dissolved in MeOH (20 mL), and HCl (4.95 mL, 8.71 mmol, 3 equivalents, 1.76 M Et₂O solution) was added. The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was evaporated under vacuum at 40 °C to obtain compound 7 as a white solid (1.11 g, 2.69 mmol, 97% yield).

[0628] 1 H NMR (500 MHz, chloroform-d) δ 8.39 (s, 1H), 5.73 (d,J= 9.6 Hz, 1H), 4.47- 4.42 (m, 1H), 4.42 - 4.33 (m, 1H), 3.83 (dd,J= 11.1, 3.7 Hz, 1H), 3.77 (dd,J= 10.8 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.37 - 3.30 (m, 1H), 3.01 - 2.88 (m,2H), 2.68 (d,J= 4.0 Hz, 3H), 2.65 - 2.60 (m, 1H), 2.25 - 2.12 (m, 2H), 2.10 -2.01 (m, 1H), 1.99 - 1.89 (m, 1H), 1.62 (p,J= 12.8 Hz, 2H), 1.45 - 1.39 (m,1H), 1.15 - 1.10 (m, 2H), 0.95 - 0.86 (m, 2H).

[0629] LCMS (Method 5-95 AB, ESI, 2 min): R T = 0.637 min, [M+H] + = 377.4.

[0630] Example S8: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-methylpiperidine- Synthesis of 4-(4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 8)

[0631] The synthesis was carried out according to the following scheme:

[0632]

[0633] Compound 7 (0.2 g, 0.48 mmol, 1 equivalent) was dissolved in MeOH (4 mL), followed by the addition of paraformaldehyde (0.108 g, 3.6 mmol, 7.5 equivalent), TEA (0.334 mL, 0.242 g, 2.4 mmol, 5 equivalent), HOAc (0.274 mL, 0.288 g, 4.8 mmol, 10 equivalent), and NaBH3CN (0.150 g, 2.4 mmol, 5 equivalent). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was carefully quenched with TFA (2 mL), stirred for 1 hour, and then sent for preparative HPLC purification (equipment (mobile phase, column): SYSTEM 0-25% 0.5-6.5 min water-acetonitrile; flow rate 30 ml / min (loaded pump 4 ml / min H2O+TFA); target mass 391; column SunFireC18 100x19 mm 5 μm (R)) to obtain compound 8 as a yellow oil (0.1283 g, 0.25 mmol, 53% yield).

[0634] 1 H NMR (400 MHz, methanol-d4) δ 7.82 (s, 1H), 5.41 (d,J= 9.8 Hz, 1H), 4.48- 4.43 (m, 1H), 4.40 (dd,J= 8.3 Hz, 1H), 3.86 (dd,J= 10.9, 4.0 Hz, 1H), 3.66(dd,J= 10.9 Hz, 1H), 3.54 (dd,J= 12.8 Hz, 1H), 3.45 (dd,J= 12.3 Hz, 1H), 3.03- 2.87 (m, 2H), 2.83 (s, 3H), 2.73 (s, 3H), 2.59 - 2.47 (m, 1H), 2.27 - 2.12(m, 2H), 2.02 - 1.88 (m, 3H), 1.58 (pd,J= 13.3, 4.1 Hz, 2H), 1.33 (dd,J= 15.1Hz, 1H), 1.00 - 0.90 (m, 2H), 0.78 - 0.72 (m, 2H).

[0635] LCMS (Method 5-95 AB, ESI): R T = 0.756 min, [M+H] + = 391.2.

[0636] Example S9: (2S,4R)-1-((S)-2-(1-acetylpiperidin-4-yl)-2-(4-cyclopropyl-1H-1,2,3-trimethylolpropionic acid) Synthesis of (1-azolyl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 9)

[0637] The synthesis was carried out according to the following scheme:

[0638]

[0639] Compound 7 (0.31 g, 0.75 mmol, 1 equivalent) was dissolved in DMF (3 mL), followed by the addition of pyridine (0.182 mL, 0.178 g, 2.25 mmol, 3 equivalents) and Ac2O (0.091 mL, 0.098 g, 0.96 mmol, 1.3 equivalents), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then purified by preparative HPLC (equipment (mobile phase, column): SYSTEM 15-15% 0.5-6 min water-acetonitrile; flow rate 30 mL / min (loaded pump 4 mL / min H2O); target mass 419; column SunFireC18 100x19 mm 5 μm (R)) to obtain compound 9 (0.0778 g, 0.19 mmol, 25% yield) as a white solid.

[0640] 1 H NMR (400 MHz, chloroform-d) δ 7.67 (s, 1H), 6.70 (s, 1H), 5.25 - 5.14(m, 1H), 4.67 - 4.47 (m, 2H), 4.38 (dd,J= 8.0 Hz, 1H), 3.87 (dd,J= 11.7 Hz,1H), 3.81 - 3.68 (m, 2H), 3.68 - 3.35 (m, 2H), 2.99 (dt,J= 45.5, 12.8 Hz,1H), 2.81 (s, 3H), 2.58 - 2.32 (m, 2H), 2.17 - 2.08 (m, 2H), 2.03 (d,J= 11.1Hz, 3H), 1.99 - 1.85 (m, 2H), 1.29 - 1.04 (m, 3H), 0.99 - 0.90 (m, 2H), 0.84- 0.75 (m, 2H).

[0641] LCMS (Method 5-95 AB, ESI, 6 min): R T = 1.268 min, [M+H] + = 419.0.

[0642] Example S10: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-(1-(methylsulfonyl) Synthesis of (4-yl)piperidine-4-yl)acetyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 10)

[0643] The synthesis was carried out according to the following scheme:

[0644]

[0645] Compound 7 (0.3 g, 0.73 mmol, 1 equivalent) was dissolved in DMF (5 mL), followed by the addition of DIPEA (0.393 mL, 0.291 g, 2.26 mmol, 3.1 equivalent) and MsCl (0.062 mL, 0.092 g, 0.8 mmol, 1.1 equivalent), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then purified by preparative HPLC (equipment (mobile phase, column): SYSTEM 0-25% 0.5-6.5 min water-acetonitrile; flow rate 30 mL / min (loaded pump 4 mL / min H2O); target mass 377; 455; column SunFireC18 100x19 mm 5 μm (R)) to obtain compound 10 (0.0778 g, 0.19 mmol, 25% yield) as a yellow solid.

[0646] 1 H NMR (500 MHz, methanol-d4) δ 7.83 (s, 1H), 5.40 (d,J= 10.5 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.40 (dd,J= 8.5 Hz, 1H), 3.92 (dd,J= 11.0, 4.0 Hz, 1H), 3.77 (dd,J= 9.2 Hz, 2H), 3.68 (dd,J= 12.1 Hz, 1H), 2.82 (s, 3H), 2.75 (s,3H), 2.72 (d,J= 11.6 Hz, 1H), 2.67 (td,J= 12.1, 2.5 Hz, 1H), 2.44 - 2.31 (m,1H), 2.21 - 2.13 (m, 1H), 2.11 (dd,J= 13.0 Hz, 1H), 2.05 - 1.93 (m, 2H), 1.47(qd,J= 12.9, 4.3 Hz, 1H), 1.37 (qd,J= 12.4, 3.9 Hz, 1H), 1.15 (dd,J= 13.4 Hz,1H), 0.99 - 0.93 (m, 2H), 0.80 - 0.74 (m, 2H).

[0647] LCMS (Method 5-95 AB, ESI): R T = 2.202 min, [M+H] + = 455.4.

[0648] Example S11: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)- 4-Hydroxy-N-methylpyrrolidine-2-carboxamide (compound 11) and (2S,4R)-1-((R)-2-(4-cyclopropyl-1H-1,2,3- Synthesis of Triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (Compound 12)

[0649]

[0650] Preparation of intermediate 11b

[0651]

[0652] 1H-imidazolium-1-sulfonyl azide (1.79 g, 8.54 mmol) was added to a mixture of (S)-2-amino-3-methylbutyric acid (1.00 g, 8.54 mmol), potassium carbonate (2.97 g, 21.3 mmol), and copper sulfate (136.6 mg, 0.85 mmol) in methanol (20 mL) at 25 °C. The reaction was stirred for 16 h and diluted with water (60 mL). Methanol was removed under reduced pressure, and the aqueous residue was washed with ethyl acetate (100 mL). The aqueous solution was then adjusted to pH 5 by adding potassium bisulfate and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried and concentrated under vacuum to give crude (S)-2-azido-3-methylbutyric acid (1.20 g, 98.2% yield) as a yellow oil.

[0653] Preparation of intermediate 11c

[0654]

[0655] A mixture of (S)-2-azido-3-methylbutyric acid (1.00 g, 6.99 mmol), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (1.01 g, 6.99 mmol), N,N-diisopropylethylamine (5.77 mL, 34.9 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (2.66 g, 6.99 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 3 h and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried, and concentrated to give crude (2S,4R) as a blue oil. 4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (1.00 g, 53% yield).

[0656] Preparation of intermediate 11d

[0657]

[0658] To a solution of sodium L-ascorbate (2.93 g, 14.8 mmol) in water (20 mL) and tert-butanol (20 mL), ethynylcyclopropane (0.31 mL, 3.7 mmol), copper sulfate pentahydrate (1.51 g, 4.81 mmol), and methyl (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylate (1.00 g, 3.70 mmol) were added. The reaction was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, petroleum ether solution of 0-4% ethyl acetate) to give methyl (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylate as a yellow solid (1.10 g, 88.4% yield).

[0659] Preparation of intermediate 11e

[0660]

[0661] Lithium hydroxide monohydrate (37.42 mg, 0.89 mmol) was added to a solution of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylate (300 mg, 0.89 mmol) in water (5 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was separated between ethyl acetate (20 mL) and water (15 mL). The aqueous layer was then adjusted to pH 4 by adding hydrochloric acid (2 M) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried and concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 69.6% yield) as a pale yellow oil.

[0662] Preparation of intermediate 11f

[0663]

[0664] A mixture of (2S, 4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (100 mg, 0.31 mmol), N,N-diisopropylethylamine (0.22 mL, 1.24 mmol), methylamine hydrochloride (20.8 mg, 0.31 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxyhexafluorophosphate) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 10-40 / 0.075% TFA aqueous solution) to give (2S, 4R) as a white solid. 4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (50.0 mg, 48.1% yield).

[0665] Preparation of Compound 11 and Compound 12

[0666]

[0667] The above diastereomeric mixture was further separated by a chiral SFC to obtain the first eluting isomer A and the second eluting isomer B:

[0668] Isomer A: (peak 1, retention time = 3.089 min) (28.1 mg, 54.6% yield), is a white solid. 1 HNMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 6.61 (br d,J= 4.4 Hz, 1H), 5.17 (d,J=10.0 Hz, 1H), 4.54 (br s, 1H), 4.44 (t,J= 7.6 Hz, 1H), 3.94 (br d,J= 10.4 Hz,2H), 3.79 - 3.76 (m, 1H), 2.82 (d,J= 4.8 Hz, 3H), 2.71 (d,J= 4.8 Hz, 1H),2.48 - 2.46 (m, 1H), 2.31 - 2.30 (m, 1H), 2.01 - 2.10 (m, 1H), 1.89 - 1.96 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.91 - 0.98 (m, 2H), 0.75 - 0.84 (m, 5H). LCMS (Method 5-95 AB, ESI): R T = 0.796 min, [M+H] + = 336.1.

[0669] Isomer B: (peak 2, retention time = 3.461 min) (16.7 mg, 33% yield), is a white solid. 1HNMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 6.60 (br s, 1H), 5.15 (d,J= 9.2 Hz, 1H), 4.62 - 4.77 (m, 1H), 4.45 - 4.59 (m, 1H), 3.60 - 3.76 (m, 1H), 3.55 - 3.52(m, 1H), 2.91 (d,J= 4.8 Hz, 1H), 2.74 (d,J= 4.8 Hz, 3H), 2.46 - 2.57 (m, 1H),2.31 - 2.41 (m, 1H), 2.11 - 2.25 (m, 1H), 1.89 - 2.04 (m, 1H), 1.05 (d, J = 6.4 Hz, 2H), 0.91 - 1.03 (m, 3H), 0.79 - 0.87 (m, 2H), 0.72 - 0.75 (m, 1H), 0.75 (d, J = 6.8 Hz, 1H), 0.68 (d, J = 6.8 Hz, 1H). LCMS (Method 5-95 AB, ESI): R T = 0.616min, [M+H] + = 336.1.

[0670] Example S12: (3R,5S)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl Synthesis of 5-(methylcarbamoyl)pyrrolidine-3-yl acetate (compound 13)

[0671] Perform the synthesis according to the following scheme:

[0672]

[0673] Acetyl chloride (12.35 µL, 0.172 mmol) was added to a solution of compound 2 (50 mg, 0.143 mmol), 4-dimethylaminopyridine (1.74 mg, 0.0143 mmol), and N,N-diisopropylethylamine (29 µL, 0.172 mmol) in dichloromethane (5 mL) cooled to 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h and then overnight at room temperature. The reaction was monitored by LCMS analysis. After complete conversion of the starting material (1), the reaction mixture was quenched with 1 mL of saturated aqueous NH4Cl solution and purified by preparative HPLC.

[0674] Sample information: 20-35% water-acetonitrile, 2-7 min; flow rate 30 ml / min; (load pump 4 ml / min acetonitrile); target mass 392; column SunFireC18 100x19 mm 5 μm (L). Results: The target compound (compound 13) (21 mg, 0.053 mmol) was obtained in an overall yield of 37.6%.

[0675] ESI-MS: m / z [M+H] + The calculated value is 392.2, and the actual measured value is also 392.2.

[0676] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 6.9 Hz, 2H), 5.41 (s, 1H), 5.29 - 5.16 (m, 1H), 4.30 (t, J = 8.3 Hz, 1H), 3.90 (dd, J = 12.0, 4.2 Hz,1H), 3.80 - 3.67 (m, 1H), 2.63 - 2.51 (m, 3H), 2.19 (ddt, J = 13.8, 8.0, 1.9Hz, 1H), 2.12 - 1.91 (m, 2H), 1.92 (s, 2H), 1.00 - 0.82 (m, 12H), 0.78 - 0.66(m, 2H)

[0677] Example S13: (2S,4R)-N-cyclopropyl-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3- Synthesis of dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 14)

[0678]

[0679] Preparation of intermediate 14b

[0680]

[0681] 1H-imidazolium-1-sulfonyl azide (12.8 g, 61.0 mmol) was added to a mixture of (S)-2-amino-3,3-dimethylbutyric acid (8.0 g, 61.0 mmol), potassium carbonate (21.2 g, 152 mmol), and copper(II) sulfate (976 mg, 6.10 mmol) in methanol (100 mL) at 25 °C. The reaction was stirred for 16 h and diluted with water (60 mL). Methanol was removed under reduced pressure, and the aqueous residue was washed with ethyl acetate (100 mL). The separated aqueous phase was adjusted to pH = 3 by adding potassium bisulfate and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried and concentrated to dryness to give crude (S)-2-azido-3,3-dimethylbutyric acid (8.00 g, 83.5% yield) as a yellow oil.

[0682] Preparation of intermediate 14c

[0683]

[0684] A solution of (S)-2-azido-3,3-dimethylbutyric acid (7.00 g, 44.5 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxyhexafluorophosphate (16.9 g, 44.5 mmol), and N,N-diisopropylethylamine (36.8 mL, 223 mmol) in N,N-dimethylformamide (10 mL) was stirred at 20 °C for 5 min, followed by the addition of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (6.47 g, 44.5 mmol). The reaction mixture was stirred at 25 °C for 8 h, separated between water (50 mL) and ethyl acetate (50 mL). The separated organic layer was rinsed with brine (50 mL). Wash, dry and concentrate to give crude (2S,4R)-1-((S)-2-azido-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylate as a blue oil (12.0 g, 94.8% yield).

[0685] Preparation of intermediate 14d

[0686]

[0687] To a solution of sodium L-ascorbate (25.1 g, 127 mmol) in water (100 mL) and tert-butanol (100 mL), ethynylcyclopropane (3.58 mL, 42.21 mmol), copper(II) sulfate (14.5 g, 46.4 mmol), and methyl (2S,4R)-1-((S)-2-azido-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylate (12.0 g, 42.2 mmol) were added. The reaction was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-4% methanol in dichloromethane solution) to give methyl (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil (6.00 g, 40.6% yield).

[0688] Preparation of intermediate 14e

[0689]

[0690] Lithium hydroxide monohydrate (2.05 g, 85.6 mmol) was added to a solution of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylate (6.00 g, 17.1 mmol) in water (10 mL) and tetrahydrofuran (50 mL). The reaction was stirred at 25 °C for 16 h and separated between ethyl acetate (50 mL) and water (15 mL). The aqueous layer was then adjusted to pH 4 by adding hydrochloric acid (2 M) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried and concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (3.00 g, 52.1% yield) as a pale yellow solid.

[0691] Synthesis of (2S,4R)-N-cyclopropyl-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 14)

[0692]

[0693] A mixture of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (70.0 mg, 0.21 mmol), cyclopropylamine (0.02 mL, 0.25 mmol), N,N-diisopropylethylamine (0.09 mL, 0.52 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (95.0 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20 °C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 22-52 / 0.2% FA). (The aqueous solution was used to obtain compound 14, (2S, 4R)-N-cyclopropyl-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide as a white solid (29.1 mg, 35% yield). 1 H NMR (400 MHz, MeOH-d4) δ 8.09 - 8.04 (m, 1H), 5.48 (s, 1H), 4.50 - 4.34(m, 2H), 3.89 - 3.85 (m, 1H), 3.78 - 3.69 (m, 1H), 2.71 - 2.56 (m, 1H), 2.19- 2.11 (m, 1H), 2.05 - 1.95 (m, 2H), 1.14 - 1.02 (m, 9H), 1.02 - 0.95 (m,2H), 0.86 - 0.68 (m, 4H), 0.67 - 0.44 (m, 2H). LCMS (Method 5-95 AB, ESI): R T =0.873 min, [M+H] + = 376.2.

[0694] Example S14: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl Synthesis of 4-hydroxy-N-(2,2,2-trifluoroethyl)pyrrolidine-2-carboxamide (compound 15)

[0695]

[0696] At 0 °C, 2,2,2-trifluoroethyl-1-amine (35.4 mg, 0.36 mmol), N,N-diisopropylethylamine (0.09 mL, 0.52 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (135.6 mg, 0.36 mmol) were added to a mixture of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate) in N,N-dimethylformamide (5 mL). The reaction was stirred at 25 °C for 16 h and concentrated under vacuum to remove the solvent. The residue was purified by preparative HPLC (water (0.225% FA) - CAN 32% ~ 62%) to give compound 15, (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(2,2,2-trifluoroethyl)pyrrolidine-2-carboxamide (55 mg, 54.8% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.74 (d,J= 6.4 Hz, 1H), 7.97 (s, 1H), 5.40 (s, 1H), 5.19 (d,J= 3.6 Hz, 1H), 4.39 (t,J= 8.4 Hz, 1H), 4.33 (s, 1H), 4.05 - 3.96 (m, 1H), 3.86 - 3.80 (m, 1H), 3.73 (dd,J= 3.6, 10.8 Hz, 1H), 3.60 (d,J= 10.8 Hz, 1H), 2.07 - 2.02 (m, 1H), 1.98 - 1.92 (m, 1H), 1.84 - 1.77 (m, 1H), 0.95 - 0.83 (m, 11H), 0.77 - 0.69 (m, 2H). LCMS (Method 5-95 AB, ESI): R T = 0.754 min, [M+H] + =418.1.

[0697] Example S15 (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanediol Synthesis of acyl)-4-hydroxy-N-isopropylpyrrolidine-2-carboxamide (compound 16)

[0698]

[0699] A mixture of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (70.0 mg, 0.21 mmol), propan-2-amine (0.02 mL, 0.25 mmol), N,N-diisopropylethylamine (0.09 mL, 0.52 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxyhexafluorophosphate (95.0 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20 °C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55 / 0.2% FA). (The aqueous solution was used to obtain compound 16,(2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-isopropylpyrrolidine-2-carboxamide as a white solid (23.4 mg, 29.5% yield). 1 H NMR (400 MHz, MeOH-d4) δ 8.06 - 8.02 (m, 1H), 5.47 (s, 1H), 4.47 -4.39 (m, 2H), 4.00 - 3.85 (m, 2H), 3.74 - 3.70 (m, 1H), 2.19 - 2.14 (m, 1H), 2.08 - 1.93 (m, 2H), 1.25 (d,J= 8.8 Hz, 3H), 1.14 (d,J= 8.8 Hz, 3H), 1.07 -1.03 (m, 9H), 1.01 - 0.96 (m, 2H), 0.81 - 0.75 (m, 2H). LCMS (Method 5-95 AB, ESI): R T = 0.912 min, [M+H] + = 378.5.

[0700] Example S16: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl Synthesis of (N-(2-fluoroethyl)-4-hydroxypyrrolidine-2-carboxamide (compound 17)

[0701]

[0702] A mixture of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (70.0 mg, 0.21 mmol), 2-fluoroethylamine hydrochloride (0.04 mL, 0.25 mmol), N,N-diisopropylethylamine (0.09 mL, 0.52 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (95.0 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20 °C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55 / 0.225% FA). (The aqueous solution was used to obtain compound 17, (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-N-(2-fluoroethyl)-4-hydroxypyrrolidine-2-carboxamide as a white solid (26.6 mg, 33.2% yield). 1 H NMR (400 MHz, MeOH-d4) δ 7.97 (s, 1H), 5.46 (s, 1H), 4.55 - 4.41 (m, 4H), 3.90 - 3.86 (m, 1H), 3.73 (br d,J= 11.2 Hz, 1H), 3.62 -3.40 (m, 2H), 2.23 - 2.17 (m, 1H), 2.09 - 1.93 (m, 2H), 1.06 - 1.03 (m, 9H), 1.00 - 0.96 (m, 2H), 0.81 - 0.74 (m, 2H). LCMS (Method 5-95 AB, ESI): R T = 0.831min, [M+H] + = 382.3.

[0703] Example S17: (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl Synthesis of (N-ethyl-4-hydroxypyrrolidine-2-carboxamide (compound 18))

[0704]

[0705] A mixture of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (70.0 mg, 0.21 mmol), ethylamine hydrochloride (0.03 mL, 0.25 mmol), N,N-diisopropylethylamine (0.09 mL, 0.52 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (95.0 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20 °C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55% / 0.225% FA). (The aqueous solution was used to obtain compound 18, (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-N-ethyl-4-hydroxypyrrolidine-2-carboxamide as a white solid (19.9 mg, 26.0% yield). 1 ¹H NMR (400 MHz, MeOH-d⁴) δ 7.98 - 7.97 (m, 1H), 5.46 (s, 1H), 4.74 - 4.40 (m, 2H), 3.90 - 3.56 (m, 2H), 3.26 - 3.07 (m, 2H), 2.40 - 2.17 (m, 1H), 2.06 - 1.93 (m, 2H), 1.17 - 1.11 (m, 3H), 1.07 - 1.03 (m, 9H), 0.99 - 0.96 (m, 2H), 0.79 - 0.76 (m, 2H). LCMS (Method 5-95 AB, ESI): R T = 0.847 min, [M+H] + =364.2.

[0706] Example S18: (2S, 4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutane Synthesis of acyl)-4-hydroxy-N-(1-(trifluoromethyl)cyclopropyl)pyrrolidine-2-carboxamide (compound 19)

[0707]

[0708] To a solution of (2S, 4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (50.0 mg, 0.15 mmol), 1-(trifluoromethyl)cyclopropylamine hydrochloride (28.8 mg, 0.18 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.4500 mmol) in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (67.8 mg, 0.18 mmol) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was separated between water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and concentrated to dryness. The residue was purified by reversed-phase chromatography (water (0.2% FA) - ACN 31% ~ 61%) to give compound 19, (2S, 4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(trifluoromethyl)cyclopropyl)pyrrolidine-2-carboxamide (21.0 mg, 30.3% yield) as a white solid. 1 H NMR (400 MHz, MeOH -d4) (ppm) δ = 7.96 (s, 1H), 5.45 (s,1H), 4.49 - 4.37 (m, 2H), 3.88 - 3.85 (m, 1H), 3.75 - 3.72 (m, 1H), 2.18 -2.01 (m, 1H), 1.98 - 1.94 (m, 2H), 1.26 - 1.06 (m, 3H), 1.05 (s, 9H), 1.00 -0.95 (m, 3H), 0.78 - 0.77 (m, 2H). LCMS (5-95AB, ESI): RT = 0.765 min, [M + H]+= 444.1.

[0709] Example S19: (2S, 4R)-1-((S)-2-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutane Synthesis of acyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (compound 20)

[0710]

[0711] Preparation of intermediate 20b

[0712]

[0713] A solution of isobutyl chloroformate (5.61 mL, 43.2 mmol) in tetrahydrofuran (15 mL) was added to a solution of (2S, 4R)-1-(tert-butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.0 g, 43.2 mmol) and triethylamine (6.03 mL, 43.2 mmol) in tetrahydrofuran (120 mL). The resulting mixture was stirred at -40 °C for 1 h. Methylamine (11.2 mL, 100 mmol) (40% aqueous solution) was added to the reaction mixture, and the reaction mixture was heated to 25 °C and stirred for another 1 h.

[0714] The reaction mixture was separated between water (200 mL) and ethyl acetate (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 100-200 mesh, petroleum ether solution of 0-50% ethyl acetate) to give racemic (2S, 4R)-4-hydroxy-2-(methylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (7.6 g, 71.9% yield) as a colorless oil.

[0715] Preparation of intermediate 20c

[0716]

[0717] Racemic (2S,4R)-4-hydroxy-2-(methylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 12.3 mmol) was added to a solution of hydrochloric acid (15.4 mL, 6.14 mmol) in methanol (10.0 mL) (4 M methanol solution). The reaction mixture was stirred at 25 °...

Claims

1. A compound of formula (I): (I)， Or its stereoisomers or tautomers, or pharmaceutical salts, wherein: X 1 For H or -C(O)-C 1-12 alkyl; R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, Where R 1 The C mentioned 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H, C 1-12 Alkyl or C 3-5 cycloalkyl, Where R 2 The C mentioned 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted with one or more halogens; Q 1 For H, C 3-6 cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, Q 1 The C mentioned 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, and Q 1 The 5- to 6-membered heteroaryl group is independently and optionally constituting one or more R q Replace, where each R q Independently halogenated; Q 2 It is independently H each time it appears. Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, Among them, Q 1 and Q 2 The C formed 6-20 Aryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s It is either halogen or C each time it appears. 1-6 Alkoxy; The condition is when Q 1 When R is cyclohexyl or a 5- to 6-membered heteroaryl group, 1 C 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 The C mentioned 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

2. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 2 It is C independently each time it appears. 1-6 Alkyl, wherein R 2 The C mentioned 1-6 The alkyl group may optionally be substituted with one or more halogens.

3. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 2 It is independently ethyl in each occurrence, where R 2 The ethyl group is optionally substituted with one or more halogens.

4. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 2 Each time it appears, it is independently a methyl group, where R 2 The methyl group may optionally be substituted with one or more halogens.

5. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 2 Each time it appears, it is independently an unsubstituted methyl group.

6. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein: Q 1 For H, C 3-6 cycloalkyl, C 6-20 Aryl, 5- to 6-membered heteroaryl, and Q 1 The C mentioned 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where each R q Independently for C 1-12 Alkyl, and Q 1 The 5- to 6-membered heteroaryl group is independently and optionally constituting one or more R q Replace, where each R q Independently halogenated; Q 2 It is H independently each time it appears.

7. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 C 3-5 cycloalkyl, wherein Q 1 The C mentioned 3-5 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 alkyl.

8. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 For the unreplaced C 3-5 Cycloalkyl.

9. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 It is the unsubstituted cyclopropyl group.

10. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 C 6-20 Aryl or 5- to 6-membered heteroaryl.

11. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 It is a 5- to 6-membered heteroaryl group, which is either unsubstituted or substituted by one or more halogens.

12. The compound according to claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 The 5- to 6-membered heteroaryl group comprises one or more cyclic atoms, wherein at least one of the cyclic atoms is N.

13. The compound according to claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 The 5- to 6-membered heteroaryl group comprises one or more cyclic atoms, wherein at least one of the cyclic atoms is S.

14. The compound according to claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 The 5- to 6-membered heteroaryl group comprises one or more cyclic atoms, wherein at least one of the cyclic atoms is O.

15. The compound according to claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 The 5- to 6-membered heteroaryl groups are selected from the group consisting of: thiophene, furan, pyrrole, oxazole, thiazole, pyridine, and pyrimidine.

16. The compound according to claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 The C mentioned 6-20 The aryl group is an unsubstituted phenyl group.

17. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 2 It is H independently each time it appears.

18. The compound according to claim 1, wherein Q is... 1 and Q 2 The C formed 6-20 The aryl group was not replaced.

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

20. The compound according to claim 19, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 It is independently tert-butyl each time it appears.

21. The compound according to claim 19, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 It is an isopropyl group each time it appears.

22. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 It is C independently each time it appears. 3-15 cycloalkyl, wherein R 1 The C mentioned 3-15 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

23. The compound according to claim 22, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 It is independently cyclohexyl each time it appears, where R 1 The cyclohexyl group is independently and optionally converted by one or more C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

24. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 Each occurrence is independently a 3- to 15-membered heterocyclic group, where R 1 The 3- to 15-membered heterocyclic groups are independently and optionally construed by one or more C... 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

25. The compound according to claim 24, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein R 1 It is an independent 6-membered heterocyclic group each time it appears, where R 1 The 6-membered heterocyclic group is independently and optionally construed by one or more C... 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

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

27. The compound according to claim 1, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (I'). (I')， Or its medicinal salt.

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

29. The compound of claim 28, or a pharmaceutical salt thereof, wherein the compound of formula (IA) is selected from the group consisting of: , , , , , , and Or its medicinal salt.

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

31. The compound of claim 30, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , and Or its medicinal salt.

32. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (IC): (IC), in: R 1 C 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 The C mentioned 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 For H or C 1-12 alkyl; Q 1 For H or C 3-6 cycloalkyl; and Q 2 It is H independently each time it appears.

33. The compound of claim 32, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , and Or its medicinal salt.

34. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (ID): (ID), in: X 1 It is independently H or -C(O)-C each time it appears. 1-12 alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 The C mentioned 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; R 2 Each occurrence is independently H or C. 1-12 Alkyl or C 3-5 cycloalkyl, wherein R 2 The C mentioned 1-12 Alkyl or C 3-5 The cycloalkyl group is independently and optionally substituted with one or more halogens; Q 1 For H, C 6-20 Aryl, 5- to 6-membered heteroaryl or C 3-5 cycloalkyl, wherein Q 1 The 5- to 6-membered heteroaryl group is independently and optionally constituting one or more R q Replace, where each R q Independently halogenated; Q 2 It is H independently each time it appears; Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The C formed 6-20 Aryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s It is independently halogenated or C-type each time it appears. 1-6 Alkoxy; The condition is when Q 1 C 6-20 When aryl or 5- to 6-membered heteroaryl, R 1 C 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 The C mentioned 1-3 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally bounded by one or more C14 groups. 1-12 Alkyl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

35. The compound according to claim 34, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 For H, C 3-5 cycloalkyl, C 6-20 Aryl or 5- to 6-membered heteroaryl; Q 2 For H; or Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl.

36. The compound according to claim 34, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein X 1 For H; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups; R 2 Methyl; Q 1 C 6-20 Aryl; and Q 2 For H.

37. The compound according to claim 34, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein X 1 For H; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups; R 2 Methyl; Q 1 C 3-5 cycloalkyl; and Q 2 For H.

38. The compound according to claim 34, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein X 1 For H; R 1 It is C independently each time it appears. 1-12 Alkyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups; R 2 Methyl; Q 1 It is a 5- to 6-membered heteroaryl group; and Q 2 For H.

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

40. The compound according to claim 39, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein Q 1 C 6-20 Aryl or 5- to 6-membered heteroaryl; and Q 2 For H.

41. The compound of claim 39, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , and Or its medicinal salt.

42. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (IF): (IF), Or its stereoisomers or tautomers, or pharmaceutical salts, wherein n is 0, 1, 2, 3, or 4; and R s Halogen or C 1-6 Alkyl group.

43. The compound according to claim 42, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein X 1 For H; R 1 It is isopropyl; and R 2 It is a methyl group.

44. The compound according to claim 42, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein n is 0, 1, or 2; and R s Independently halogenated or C 1-6 Alkyl group.

45. The compound of claim 42, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: , and Or its medicinal salt.

46. ​​The compound according to claim 1, or a pharmaceutical salt thereof, wherein R 1 The attached chiral carbon atom is in the S stereochemical configuration.

47. The compound of claim 1, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: , , , , , ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or its medicinal salt.

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

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, and one or more pharmaceutical excipients.

50. The pharmaceutical composition of claim 49, further comprising additional bioactive agents.

51. Use of a composition comprising an effective amount of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or a composition according to claim 49 or claim 50, in the preparation of a medicament for treating VHL in regulatory cells.

52. Use of a composition comprising an effective amount of any one of the compounds according to claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or a composition according to claim 49 or claim 50, in the preparation of a medicament for treating VHL in inhibited cells.

53. The use of the compound, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, or the composition according to claim 49 or claim 50 in the preparation of a medicament for use in the treatment of anemia.

54. The use of the compound, stereoisomer or tautomer thereof, or pharmaceutical salt thereof, or the composition thereof according to any one of claims 1 to 48, in the preparation of a medicament for use in the treatment of chronic anemia, or anemia associated with chronic kidney disease, dialysis or cancer chemotherapy, or any combination thereof.

55. Use of the compound of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or a composition of claim 49 or claim 50 in the preparation of a medicament for use in the treatment of damage to the cardiovascular system during local ischemia, stroke, or any combination thereof.

56. Use of the compound of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, or a composition of claim 49 or claim 50 in the preparation of a medicament for use in enhancing wound healing in persons in need of such medicament.

57. Use of the compound of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, or a composition of claim 49 or claim 50 in the preparation of a medicament for use in reducing secondary scarring of wound healing in persons in need of such use.

58. Use of the compound of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, or a composition of claim 49 or claim 50 in the preparation of a medicament for use in enhancing angiogenesis or arterialization, or both, in a person who requires such enhancement.

59. The use of a compound, stereoisomer or tautomer thereof, or pharmaceutical salt, or composition according to claim 49 or claim 50 in the preparation of a medicament for use in reducing the likelihood of stent occlusion in persons with such need.

60. Use of the compound of any one of claims 1 to 48, or a stereoisomer or tautomer thereof, or a pharmaceutical salt, or a composition of claim 49 or claim 50 in the preparation of a medicament for use in the treatment of a disease or condition regulated by VHL.

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