Bifunctional degradation agents and uses thereof

Abstract

Provided herein are compounds and compositions that bind to p62 and a target of interest and promote degradation of the target of interest. In some embodiments, the compounds set forth herein are compounds of Formula I: A-B-C (I) or a pharmaceutically acceptable salt thereof wherein A is a factor that binds or associates with p62; b is a joint part; and C is a target binding moiety.

Description

Background Technology

[0001] p62 is a multifunctional protein that participates in the lysosomal degradation of ubiquitinated proteins via autophagy. (Liu WJ et al.) Cell Mol Biol Lett 13 December 2016; 21:29. The ubiquitin-proteasome system (UPS) and autophagy are “two major pathways of protein degradation in eukaryotic cells.” Shin WH et al., BMB Rep. January 2020; 53(1):56-63. These systems are essential for cell survival under normal conditions and under stress. Liu WJ et al., Cell Mol Biol Lett December 13, 2016; 21:29. Summary of the Invention

[0002] p62 is an autophagy substrate, and it has been shown that this substrate delivers ubiquitinated proteins to lysosomes for degradation. (Liu WJ et al.) Cell Mol Biol Lett December 13, 2016; 21:29. The therapeutic potential of using cellular degradation systems to guide the removal of specific targets has been well recognized and extensively studied for over a decade. See, for example, Bondeson and Crews. Annu Rev Pharmacol Toxicol 57:107-123 (September 6, 2017), and the references cited therein. p62 promotes autophagy by interacting with ubiquitin or polyubiquitin chains on certain cargoes and then delivering said cargoes to lysosomes for degradation. Liu WJ et al. in Cell Mol Biol Lett An overview of the relationship between p62 and autophagy was presented in the article dated December 13, 2016 at 21:29.

[0003] This application provides, in particular, novel compounds that utilize p62 to activate autophagy of cargoes or targets of interest and their uses. Without being bound by theory, it should be understood that the compounds described herein bind simultaneously to both p62 and the target of interest, thereby enabling p62 to deliver the cargoes of interest to the lysosome and thus initiating the degradation process of the target of interest.

[0004] In some embodiments, this disclosure provides compounds of formula I: ABC I Or its pharmaceutically acceptable salt, wherein A is the part that combines with or associates with p62; B is the connector part; and C represents the target binding portion.

[0005] In some embodiments, the compound of formula I is a compound of formula II-1 or formula II-2:

[0006] Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0007] In some embodiments, the compound of formula I is a compound of formula III-1 or formula III-2:

[0008] Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R cIndependently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0009] In some embodiments, this disclosure provides a pharmaceutical composition comprising the compounds set forth herein as well as a pharmaceutically acceptable carrier, filler, or diluent.

[0010] In some embodiments, this disclosure provides a method for treating a disease, condition, or ailment of a subject, the method comprising administering to the subject a compound described herein.

[0011] In some embodiments, this disclosure provides a method for inducing target degradation in a biological sample, the method comprising contacting the biological sample with a compound described herein.

[0012] In some embodiments, this disclosure provides compounds that bind to p62. In some embodiments, the compound that binds to p62 is a compound of formula X: X Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

[0013] In some embodiments, the compound that binds to p62 is a compound of formula XI: XI Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a . Attached Figure Description

[0014] Figure 1 The bar graph illustrates the degradation levels of the NSCLC-related EML4-ALK fusion by the active agent and the inactive control.

[0015] Figure 2 The bar graph illustrates the dose-dependent, compound-mediated cellular colocalization of endogenous p62 and endogenous ALK at 1 hour, 6 hours, and 24 hours. Co-treatment with early (PIK-III) or late (BafA1) autophagy inhibitors maintained p62 and ALK colocalization up to 24 hours. Detailed Implementation

[0016] This disclosure provides compounds and compositions that can be used to bind to p62, and in some embodiments, such compounds and compositions can be used to induce the degradation of a specific target by binding to p62 and the target of interest. In some embodiments, such compounds include those compounds of the various forms set forth herein or pharmaceutically acceptable salts thereof, wherein each variable is as defined and set forth herein.

[0017] Compounds and definitions The compounds disclosed herein include those outlined above, and are further explained by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the periodic table (CAS edition, Handbook of Chemistry and Physics, 75th edition). Furthermore, the general principles of organic chemistry are expounded in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, MB, and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0018] Unless otherwise stated, the structures illustrated herein are intended to include all stereoisomers (e.g., enantiomers or diastereomers) of the structure, as well as all geometric or conformational isomers of the structure. For example, the R and S configurations of each stereocenter are considered as part of this disclosure. Therefore, single stereochemical isomers of the provided compounds, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of this disclosure. For example, in some cases, Tables 1 and 2 show one or more stereoisomers of the compound, and unless otherwise indicated, represent each individual stereoisomer and / or mixtures. Unless otherwise stated, all tautomers of the provided compounds are within the scope of this disclosure.

[0019] Unless otherwise indicated, the structures illustrated herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of this invention (including those using deuterium or tritium instead of hydrogen, or using...) 13 C or 14 Compounds that are enriched with carbon (in place of carbon) are within the scope of this disclosure.

[0020] Approximately or about:As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to the reference value. Generally, those skilled in the art will understand the degree of difference covered by "approximately" or "about" in that context. For example, in some embodiments, the term "approximately" or "about" may cover a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less (i.e., ±) of the mentioned value.

[0021] Application: As used herein, the term "administering" generally refers to administering a composition to a subject to deliver a composition, or an agent included in a composition, to a target site or site of treatment. Those skilled in the art will recognize a variety of routes of administration that may be used to administer the composition to a subject (e.g., a human) where appropriate. For example, in some embodiments, administration may be via the eye, mouth, parenteral, or external application. In certain embodiments, administration may be via the bronchus (e.g., bronchial instillation), buccal, dermal (which may include, for example, one or more of the following: topical application to the dermis, intradermal, intradermal, transdermal, etc.), enteric, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, in a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, external, tracheal (e.g., intratracheal instillation), vaginal, or vitreous humor, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some specific embodiments, administration may be intravenous. In some specific embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administering a fixed number of doses. In some embodiments, administration may involve intermittent dosing (e.g., multiple doses at regular intervals) and / or periodic dosing (e.g., individual doses at equal time intervals). In some embodiments, administration may involve continuous dosing (e.g., infusion) for at least a selected time period. In some embodiments, administration may include a priming and booster regimen. A priming and booster regimen may include administering a first dose of a pharmaceutical composition (e.g., an immunogenic composition, such as a vaccine), followed by a second or subsequent dose of the pharmaceutical composition (e.g., an immunogenic composition, such as a vaccine) after a certain time interval. In the case of an immunogenic composition, a priming and booster regimen may increase the patient's immune response.

[0022] Lipids:The term "aliphatic" refers to a fully saturated or unsubstituted straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, or a fully saturated or containing one or more unsaturated units but not aromatic monocyclic or bicyclic hydrocarbon (also referred to herein as a "cyclic aliphatic group") having a single or more connection point to the rest of the molecule. Unless otherwise specified, the aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C14-C14). 1-6 In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms (e.g., C15, C25, C35, C45, C55, C65, C7 ... 1-5 In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms (e.g., C14, C24, C34, C44, C54, C64, C74, C84, C94, C94, C95, C96 ... 1-4 In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C14-C15). 1-3 In other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms (e.g., C14-C24). 1-2 Suitable aliphatic groups include (but are not limited to) substituted or unsubstituted straight-chain or branched alkyl, alkenyl, or alkynyl groups and their hybrids. Preferred aliphatic groups are C1. 1-6 alkyl.

[0023] alkyl: The term "alkyl" when used alone or as part of a larger part refers to having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C12, C23, C33, C43, C53, C63, C73, C83, C9 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2 The alkyl group may be optionally substituted with a straight-chain or branched saturated hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0024] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, "alkylene" is a divalent straight-chain or branched alkyl group. In some embodiments, the "alkylene chain" is polymethylene, i.e., -(CH2). n- where n is a positive integer, such as 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The optionally substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are optionally replaced by substituents. Suitable substituents include those set forth below with respect to the substituted aliphatic group, and also those set forth in this specification. It should be understood that two substituents of an alkylene group may together form a cyclic system. In some embodiments, two substituents may together form a 3- to 7-membered ring. Substituents may be on the same or different atoms. The suffix "-ene" or "-alkenyl," when attached to certain groups herein, is intended to refer to the bifunctional portion of said group. For example, "-ene" or "-alkenyl," when attached to "cyclopropyl," becomes "cyclopropene" or "cyclopropenyl" and is intended to refer to a bifunctional cyclopropyl group, such as... .

[0025] Alkenyl: The term "alkenyl," when used alone or as part of a larger part, refers to having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The optionally substituted straight-chain, branched, or cyclic hydrocarbon group of the alkenyl group. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0026] alkynyl group: The term "alkynyl" when used alone or as part of a larger body refers to having at least one triple bond and having (unless otherwise specified) 2–12, 2–10, 2–8, 2–6, 2–4, or 2–3 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The optional substituted straight-chain or branched hydrocarbon group of ). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0027] AntagonistAs those skilled in the art will understand, the term "antagonist" generally refers to an agent whose presence or level is associated with a reduction in the level or activity of a target compared to results observed in the absence of the agent (or at different levels). In some embodiments, an antagonist is an agent whose presence or level is associated with a target level or activity equivalent to or below a specific reference level or activity (e.g., a level or activity observed under appropriate reference conditions, such as in the presence of a known antagonist (e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist by directly affecting the target (e.g., directly interacting with the target); in some embodiments, an antagonist may be an indirect antagonist by indirectly exerting an effect (e.g., by acting on a target regulator, such as interacting with a target regulator, or interacting with some other component or entity).

[0028] Aryl: The term "aryl" refers to an aryl group having a total of 6 to 14 ring members (e.g., C6-C). 14 The system comprises monocyclic and bicyclic systems, wherein at least one ring in the system is aromatic and each ring contains 3 to 7 ring members. In some embodiments, the "aryl" contains a total of 6 to 12 ring members (e.g., C6-C12). 12 The term "aryl" is used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including (but not limited to) phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. Unless otherwise specified, "aryl" is a hydrocarbon. In some embodiments, the "aryl" ring system is an aromatic ring (e.g., phenyl) fused with a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include fused rings, including... , and .

[0029] Double ringThe term "bicyclic" or "bicyclic system" refers to any bicyclic system, i.e., a saturated or unsaturated carbon ring or heterocyclic ring having one or more shared atoms between the two rings of the system. Therefore, the term includes any permitted ring fusion, such as ortho-fusion or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring the presence of one or more heteroatoms in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridging bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbon ring or heterocyclic ring, saturated or partially unsaturated. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or atoms or valence bonds connecting two bridgeheads, wherein a “bridgehead” is any skeletal atom in a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridging bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group is optionally substituted. Exemplary bicycles include: An exemplary bridging dual ring includes: .

[0030] Biological samples:As used herein, the term "biological sample" generally refers to a sample obtained or derived from a biological source of interest (e.g., tissue or organism or cell culture) as described herein. In some embodiments, the source of interest includes an organism, such as an animal or human. In some embodiments, the biological sample is or contains biological tissue or fluid. In some embodiments, the biological sample may be or contain bone marrow; blood; blood cells; ascites; tissue or fine-needle biopsy samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washing or lavage solutions, such as catheter lavage or bronchoalveolar lavage fluid; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions and / or excretions; and / or cells derived therefrom. In some embodiments, the biological sample is or contains cells obtained from an individual. In some embodiments, the obtained cells are or include cells from the individual from which the sample was obtained. In some embodiments, the sample is a “primary sample” obtained directly from the source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be clear from the context, the term “sample” refers to a preparation obtained by processing (e.g., by removing one or more components and / or by adding one or more agents to) a primary sample. For example, using semi-permeable membrane filtration. Such a “processed sample” may contain, for example, nucleic acids or proteins extracted from the sample, or nucleic acids or proteins obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, separation and / or purification of certain components.

[0031] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or medium applied together with the composition. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, including petroleum, animal, vegetable, or synthetically derived oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid components.

[0032] Composition: Those skilled in the art will understand that the term "composition" can be used to refer to a discrete physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition may be in any form, such as a gas, gel, liquid, solid, etc.

[0033] Cyclic aliphaticAs used herein, the term "cycloaliphatic" refers to a monocyclic C-type carbon atom that is fully saturated or contains one or more unsaturated units but is not aromatic. 3-8 Hydrocarbons or bicyclic C 6-12 Hydrocarbons are molecules that have one or more connection points with the rest of the molecule.

[0034] cycloalkyl As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic system having about 3 to about 10 ring carbon atoms that are optionally substituted. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0035] Dosage form or Unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) administered to a subject. Typically, each of these units contains a predetermined amount of the active agent. In some embodiments, this amount is an amount (or a portion thereof) of a unit dose suitable for administration according to a dosing regimen, said amount being determined to be associated with a desired or beneficial outcome when administered to the relevant population (i.e., according to a therapeutic dosing regimen).

[0036] Dosing regimen or Treatment plan: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a set of unit doses (usually more than one), which are typically administered individually to a subject at time intervals. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each time-spaced from the other doses. In some embodiments, the individual doses are spaced from each other by the same length of time interval; in some embodiments, the dosing regimen comprises multiple doses and at least two different time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen have the same unit dose amount. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount identical to the first dose amount. In some embodiments, when administered across a relevant population (i.e., a therapeutic dosing regimen), the dosing regimen is associated with a desired or beneficial outcome.

[0037] Effective doseThe term "effective amount" refers to an amount of compound sufficient to achieve a beneficial or desired outcome (e.g., therapeutic, ameliorative, inhibitory, or preventative results). Effective amounts may be administered once or multiple times, applied, or dosed, and are not intended to be limited to a particular formulation or route of administration.

[0038] excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc.

[0039] halogen: The term "halogen" or "halogen group" refers to F, Cl, Br, or I.

[0040] Mixed fats As used herein, the term "heteroaliphatic" or "heteroaliphatic group" refers to a hydrocarbon moiety having 1 to 5 heteroatoms in addition to carbon atoms, which may be straight-chain (i.e., unbranched), branched, or cyclic ("heterocyclic") and may be fully saturated or contain one or more unsaturated units, but is not aromatic. The term "heteroatom" means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. The term "nitrogen" also includes substituted nitrogen. Unless otherwise specified, a heteroaliphatic group contains 1 to 10 carbon atoms, wherein 1 to 3 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaliphatic group contains 1 to 4 carbon atoms, wherein 1 to 2 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In other embodiments, the heteroaliphatic group contains 1 to 3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced by a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include (but are not limited to) straight-chain or branched heteroalkyl, heteroalkenyl, and heteroynyl groups. For example, 1 to 10 atom heteroaliphatic groups include the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, etc.

[0041] heteroaryl:The terms “heteroaryl” and “heteroaryl-”, when used alone or as part of a larger part (e.g., “heteroarylalkyl” or “heteroarylalkoxy”), refer to a monocyclic or bicyclic group having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups include (but are not limited to) thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, thiazolyl, pyridinyl, pyrazinyl, indazinyl, purine, naphridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, thiophenolopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or linking point is located on the heteroaryl ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4- H- Quinazinyl, carbazolyl, acridinel, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene," any of which includes optionally substituted rings. Examples of monocyclic and bicyclic heteroaryl rings include: Heteroatoms: As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen.

[0042] Heterocyclic rings:As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic group,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, 6- to 10-membered bicyclic, or 10- to 16-membered polycyclic heterocyclic portion that is saturated or partially unsaturated and has one or more (e.g., one to four) heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrrolidinyl groups). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure, and any ring atom may optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include (but are not limited to) azirrobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxyl, dioxacyclopentyl, diazaphenyl, oxazolyl, thioazolyl, morpholinyl, and thiomorpholinyl. The heterocyclic group may be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indololinyl, isoidololinyl, benzodioxanepentenyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocycles can also be spirocyclic systems (e.g., 7- to 11-membered spirocyclic fused heterocycles having one or more heteroatoms as defined above (e.g., one, two, three, or four heteroatoms) in addition to a carbon atom). Bicyclic heterocycles can also be bridging ring systems (e.g., 7- to 11-membered bridging heterocycles having one, two, or three bridging atoms).

[0043] regulator As used herein, the term "modulator" refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can increase or decrease the activity of a class of molecules compared to the activity in the absence of a modulator. For example, a modulator can be an agonist or antagonist of a specific target, as those terms are defined herein. For example, in some embodiments, the modulator is an agonist. In some embodiments, the modulator is an antagonist.

[0044] Oral:As used herein, the phrase "oral administration" has the meaning as understood in the art, referring to the oral administration of a compound or composition.

[0045] extraintestinal: As used herein, the phrase “parenteral administration and administered parenterally” has the meaning as understood in the art, referring to administration methods that are usually administered by injection, other than enteral and topical administration, and including (but not limited to) intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intravertebral, and intrasternal injections and infusions.

[0046] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but not to include aromatic (e.g., aryl or heteroaryl) moiety as defined herein.

[0047] patient or Subjects: As used herein, the terms "patient" or "subject" refer to any organism to which the provided composition is applied or may be applied for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject has or is susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received a therapy for the diagnosis and / or treatment of a disease, condition, or disorder.

[0048] Pharmaceutical composition:As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment or dosing regimen, the active agent showing a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for administration by: oral administration, such as enemas (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), pellets, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; topical administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0049] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and that are commensurate with a reasonable benefit / risk ratio.

[0050] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salt" refers to a salt suitable for use in a pharmaceutical context, meaning a salt that, within reasonable medical judgment, is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. in... J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in , 66: 1-19 (1977). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0051] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (edited). Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al. Journal of Pharmaceutical Sciences 1977, 66 (1), 1-19; P. Gould, International Journal of Pharmaceutics 1986, 33 , 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on its website). This publicly available information is incorporated into this article by reference.

[0052] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen salts. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which are formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0053] polypeptide As used herein, the term "peptide" generally has its meaning as understood in the art, namely, a polymer of at least three amino acids linked together, for example, by peptide bonds. Those skilled in the art will understand that the term "peptide" is intended to be broad enough to encompass not only peptides having the complete sequences listed herein, but also peptides representing functional fragments of such complete peptides (i.e., fragments retaining at least one active component). Furthermore, those skilled in the art will understand that protein sequences generally allow for some substitutions that do not impair activity. Therefore, any peptide that retains activity and shares at least about 30%-40% overall sequence identity with another peptide of the same class (typically greater than about 50%, 60%, 70%, or 80%) and further typically includes at least one region with significantly higher identity (typically greater than 90% or even 95%, 96%, 97%, 98%, or 99%) in one or more highly conserved regions, typically encompassing at least 3-4 amino acids and often up to 20 or more, is covered within the relevant term "peptide" as used herein. Peptides may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, the protein may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.

[0054] Prevention or prevention): As used herein, the term "prevention" when used in connection with the occurrence of a disease, condition, and / or disorder means reducing the risk of developing said disease, condition, and / or disorder and / or delaying the onset of one or more features or symptoms of said disease, condition, or disorder. Prevention is considered complete when the onset of a disease, condition, or disorder has been delayed for a predetermined period of time.

[0055] Replaced or Optional replacement: As described herein, the compounds of the present invention may contain a "optionally substituted" portion. Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by suitable substituents. "Substituted" applies to one or more hydrogens that are explicit or implicit in the structure (e.g., It means at least ;and It means at least , or Unless otherwise indicated, a "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The substituent combinations contemplated by the present invention are preferably those that form stable or chemically viable compounds. As used herein, the term "stable" means that for one or more purposes provided herein, the compound does not undergo substantial change when subjected to conditions that allow it to be generated, detected, and in some embodiments, to be recovered, purified, and used. A group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. A group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0056] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2)0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0- 4SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring) or 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or although defined above, two independently occurring R° together with their intermediate atom form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0057] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° atoms and their intermediate atoms) are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2CH(OR ● )2、-O(halogenated R) ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0- 2SH、-(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0058] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6An aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the ortho-substituted carbon atom attached to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 It is an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0059] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic group, unsubstituted -OPh, or unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring R groups.† Together with its intermediate atom, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0061] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] Small molecules: As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule smaller than about 5 kilodaltons (kD). In some embodiments, the small molecule is smaller than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is smaller 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 smaller 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 not a polymer.

[0063] In some embodiments, the small molecule does not include a polymeric portion. In some embodiments, the small molecule is not and / or does not contain proteins or polypeptides (e.g., not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not contain polynucleotides (e.g., not an oligonucleotide). In some embodiments, the small molecule is not and / or does not contain polysaccharides; for example, in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, the small molecule is not a lipid.

[0064] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., containing at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0065] Those skilled in the art who read this disclosure will understand that some of the small molecule compounds described herein may be provided and / or used in any of a variety of forms, such as crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0066] Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, according to this disclosure, such small molecules can be used as individual enantiomers, diastereomers, or geometric isomers, or as mixtures of stereoisomers; in some embodiments, according to this disclosure, such small molecules can be used as racemic mixtures.

[0067] Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, according to this disclosure, such small molecules can be used as individual tautomers or in a form that alternates between tautomeric forms.

[0068] Those skilled in the art will understand that some small molecule compounds have structures that allow isotopic substitution (e.g. 2 H or 3 H replaces H; 11 C 13 C or 14 C replaces 12 C; 13 N or 15 N replaces 14 N; 17 O or 18 O replaced 16 O; 36 Cl replaced 35 Cl or 37 Cl; 18 F replaces 19 F; 131 I replace 127 I; etc.). In some embodiments, according to this disclosure, such small molecules may be used in one or more isotopically modified forms or mixtures thereof.

[0069] In some embodiments, references to a particular small molecule compound may refer to a specific form of the compound. In some embodiments, the particular small molecule compound may be provided and / or used in salt form (e.g., as an acid addition salt or a base addition salt, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0070] In some embodiments, if the small molecule compound is a compound that is present or found in nature, then according to this disclosure, the compound may be provided and / or used in a form different from that which is present or found in nature. Those skilled in the art will understand that in some embodiments, if a formulation of a particular small molecule compound contains an absolute or relative amount of the compound or a particular form thereof that differs from the absolute or relative amount of the compound or form present in a reference formulation of interest (e.g., a primary sample from a source of interest, such as a biological or environmental source) (for another component of the formulation, including, for example, another form of the compound), then the formulation is different from the compound present in the reference formulation or source. Therefore, in some embodiments, for example, a formulation of a single stereoisomer of a small molecule compound may be considered as a different form of the compound rather than a racemic mixture of the compound; a specific salt of a small molecule compound may be considered as a form different from another salt form of the compound; a formulation of a compound containing only one form of a conformational isomer ((Z) or (E)) containing a double bond may be considered as a different form of the compound from a formulation containing another conformational isomer ((E) or (Z)) containing the double bond; a formulation in which one or more isotopes are different from the isotopes present in a reference formulation may be considered as a different form; and so on.

[0071] Those skilled in the art will understand that, as used herein, in small molecule structures... The specified key refers to a single bond (e.g., a saturated bond) in some embodiments and a double bond (e.g., an unsaturated bond) in others. For example, the following structure: Intended to cover and both.

[0072] Those skilled in the art will further understand that, in small molecule structures, as used herein, the symbols... and They are interchangeable, and each refers to the junction between two atoms. Alternatively, the symbol... This refers to the point where the rings are connected in a spiral-ring manner.

[0073] treat:As used herein, the term "treat" (or "treatment") means any method used to partially or completely alleviate, improve, reduce, suppress, prevent, delay the onset, reduce the severity, and / or decrease the incidence of one or more symptoms or features of a disease, condition, and / or disorder. Treatment may be administered to a subject who does not exhibit signs of a disease, condition, and / or disorder. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, condition, and / or disorder, for example, for the purpose of reducing the risk of developing symptoms associated with said disease, condition, and / or disorder.

[0074] Compounds for binding p62 In some aspects, this disclosure provides compounds for binding to p62. In some embodiments, the compounds are bifunctional, wherein the compounds comprise a p62-binding moiety that binds to or associates with p62 and a target-binding moiety that binds to or associates with a target and thereby promotes autophagic degradation of the target. As used herein, the target or p62 is "associated" in part via various chemical interactions known to those skilled in the art. For example, the target or p62 can be associated in part via hydrogen bonding, van der Waals forces, London dispersion forces, ionic bonding, etc. In some embodiments, p62 binding is determined according to the methods set forth herein (e.g., Example C1). In some embodiments, the compounds for binding p62 and the target of interest are compounds of formula I: ABC I Or its pharmaceutically acceptable salt, wherein A is the part that combines with or associates with p62; B is the connector part; and C represents the target binding portion.

[0075] In some embodiments, A is a polypeptide or peptide mimic moiety that binds to or associates with p62. In some embodiments, A is a moiety comprising two or three conjugated amino acids (e.g., canonical or uncanonical amino acids) linked by peptide bonds (an amide that links two consecutive amino acids from the C1 of one amino acid to the N2 of another). In some embodiments, A is a peptide mimic moiety. As used herein, a peptide mimic moiety is a small protein-like chain that mimics a peptide. In some embodiments, a peptide mimic is a moiety comprising a modified peptide, a structural mimic of a peptide, a peptide fold, a mechanical mimic, or other structural analogue.

[0076] In some implementations, A is the following part: Furthermore, the compound of formula I is a compound of formula II-1 or formula II-2:

[0077] Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a-C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0078] In some embodiments, the compounds described herein are compounds of formula II-1: II-1 Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R cIndependently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0079] In some embodiments, the compounds described herein are compounds of formula II-2: II-2 Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0080] In some implementations, A is the following part: Furthermore, the compound of formula I is a compound of formula III-1 or formula III-2:

[0081] Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0082] In some embodiments, the compounds described herein are compounds of formula III-1:

[0083] Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0084] In some embodiments, the compounds described herein are compounds of formula III-2:

[0085] Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0086] Unless otherwise specified, the descriptions of values ​​and variables herein are intended to apply to all provided formulas (e.g., any one of formulas II-1, II-2, III-1, III-2, etc.).

[0087] As outlined herein, ring A is a optionally substituted 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, ring A is a triazole, imidazole, oxazole, thiazole, pyrrole, pyrazole, pyridine, pyrimidine, pyrazine, or triazine.

[0088] In some implementation schemes, ring A is selected from: in Indicates with G 3 The connection point, and Indicates with G 2 The connection point.

[0089] As outlined in this article, G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b Replacement. In some implementations, G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 aryl or guanidine, wherein G 1 Optionally by one or more R b Replacement. In some implementations, G 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, or a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally separated by one or more R b replace.

[0090] In some implementations, G 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and optionally surrounded by one or more R b Replacement. In some implementations, G 1 It is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally separated by one or more R b Replacement. In some implementations, G 1 It is an unsubstituted 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, G 1 It is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R... bReplacement. In some implementations, G 1 It is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, which is substituted with one or more of a halogen, -NH2, or optionally substituted C1-C6 aliphatic groups. In some embodiments, G 1 It is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, which is coated with halogen, -NH2, or -C(NH)NR°2 or -(CH2). 0-4 One or more of the C1-C6 aliphatic groups are substituted in C(O)NR°2. In some embodiments, G 1 It is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, which is substituted with one or more of -NH2 or -CH3. In some embodiments, G 1 For one or more R b The substituted imidazole, pyridyl, pyrrole, pyrazolyl, pyrimidinyl, or thiazolyl groups. In some embodiments, G 1 The group is an imidazole, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, or thiazolyl group substituted with one or more of a halogen, -NH2, or C1-C6 aliphatic group. In some embodiments, G 1 The pyridinyl group is optionally substituted with an imidazole group or substituted with one or more of a halogen, -NH2, or C1-C6 aliphatic group. In some embodiments, G 1 It is an unsubstituted imidazole or pyridinyl group. In some embodiments, G 1 It is an imidazole or pyridinyl group substituted with one or more of -NH2 or -CH3.

[0091] In some implementations, G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, optionally separated by one or more R b Replacement. In some implementations, G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, optionally separated by one or more -N(R) atoms. a )2 or halogen substitution. In some implementations, G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, which is substituted with one or more of a halogen, -NH2, or optionally substituted C1-C6 aliphatic groups. In some embodiments, G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more of a halogen, -NH2, or -CH3. In some embodiments, G 1 To be optionally used by one or more R bSubstituted with benzimidazolyl, indazole, indolyl, or pyrrolopyridyl. In some embodiments, G 1 To be optionally used by one or more R b Substituted benzimidazolyl or indoleyl. In some embodiments, G 1 It is a benzimidazolyl, indazole, indole, or pyrrolopyridyl group substituted with one or more of a halogen, -NH2, or C1-C6 aliphatic group. In some embodiments, G 1 It is a benzimidazolyl or indole group substituted with one or more of a halogen, -NH2, or C1-C6 aliphatic group. In some embodiments, G 1 It is a benzimidazole, indazole, indole, or pyrrolopyridyl group substituted with one or more of -NH2 or CH3. In some embodiments, G 1 It is either a benzimidazolyl group that is optionally substituted or an indole group that is substituted with one or more of -NH2 or -CH3.

[0092] In some implementations, G 1 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally separated by one or more R atoms. b Replacement. In some implementations, G 1 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with one or more of a halogen, -NH2, or C1-C6 aliphatic group. In some embodiments, G 1 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, and optionally substituted with -NH2 or -CH3.

[0093] In some implementations, G 1 To be optionally used by one or more R b Replacement C6-C 12 Aryl. In some implementations, G 1 C6-C that is optionally substituted with one or more of halogen, -N(R°)2, R°, -NO2 or -C(NH)N(R°2) 12 Aryl. In some implementations, G 1 C6-C, optionally substituted with halogen or -NH2 12 Aryl.

[0094] In some implementations, G 1 It is guanidine.

[0095] In some implementations, G 1 It is -C(O)NH2.

[0096] In some implementations, G 1 Selected from: In some implementations, G 1 Selected from: in Indicates the connection point with part B, and Indicates the relationship with part of G 2 The connection point.

[0097] In some implementations, G 1 Selected from: , , and ,in Indicates the connection point with part B, and Indicates the relationship with part of G 2 The connection point.

[0098] As outlined in this article, G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a ()- or C1-C6 aliphatic group- a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, wherein G 2 Optionally by one or more R b replace.

[0099] In some implementations, G 2 To be optionally used by one or more R b Replaced C1-C6 aliphatic groups. In some embodiments, G 2 To be optionally used by one or more R b Substituted C1-C6 alkyl groups. In some embodiments, G 2 For optional use by -N(R) a 2-substituted C1-C6 alkyl groups. In some embodiments, G 2 For -N(R) a 2-substituted C1-C6 alkyl groups. In some embodiments, G 2 It is a methylene, ethylene, propylene, or n-butylene substituted with -NH2.

[0100] In some implementations, G 2 To be optionally used by one or more R b Replacement -N(R) a)-C1-C6 aliphatic groups. In some implementations, G 2 To be optionally used by one or more R b The substituted -NH-C1-C6 aliphatic group. In some embodiments, G 2 To be optionally used by one or more R b Substituted -NH-C1-C6 alkyl group. In some embodiments, G 2 It is an -NH-C1-C6 alkylene group optionally substituted with a C1-C6 aliphatic group.

[0101] In some implementations, G 2 To be optionally used by one or more R b Substituted C1-C6 aliphatic group -N(R) a In some implementations, G 2 To be optionally used by one or more R b The C1-C6 aliphatic group -NH- is substituted. In some embodiments, G 2 To be optionally used by one or more R b Substituted C1-C6 alkylene-NH-. In some embodiments, G 2 It is a C1-C6 alkylene-NH- optionally substituted with a C1-C6 aliphatic group.

[0102] In some implementations, G 2 To be optionally used by one or more R b The -O-C1-C6 aliphatic group is replaced. In some embodiments, G 2 To be optionally used by one or more R b Substituted -O-C1-C6 alkylene groups.

[0103] In some implementations, G 2 To be optionally used by one or more R b The substituted -C(O)-C1-C6 aliphatic group. In some embodiments, G 2 To be optionally used by one or more R b Substituted -C(O)-C1-C6 alkylene groups.

[0104] In some implementations, G 2 To be optionally used by one or more R b Replacement C6-C 12 Aryl-C0-C6 aliphatic group. In some embodiments, G 2 To be optionally used by one or more R b Replacement C6-C 12 Aryl. In some implementations, G 2 To be optionally used by one or more R bSubstituted phenyl groups. In some embodiments, G... 2 To be optionally used by one or more R b Replacement C6-C 12 Aryl-C1-C6 aliphatic group. In some embodiments, G 2 To be optionally used by one or more R b Substituted phenyl-C1-C6 aliphatic group.

[0105] In some implementations, G 2 To be optionally used by one or more R b Substituted (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S) -C1-C6 aliphatic groups. In some embodiments, G 2 To be optionally controlled by one or more -N(R) a )2-substituted (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S) -C1-C6 aliphatic groups. In some embodiments, G 2 To be optionally controlled by one or more N(R) a )2-substituted piperidine-C1-C6 aliphatic group. In some embodiments, G 2 It is a piperidine-C1-C6 aliphatic group that is optionally substituted with one or more NH2 groups.

[0106] In some implementations, G 2 To be optionally used by one or more R b Replaces 2- to 10-membered heteroaliphatic groups. In some implementations, G 2 To be optionally used by one or more R b Substituted -C1-C3 aliphatic group -NH-C1-C3 aliphatic group.

[0107] In some implementations, G 2 Selected from: in This represents -C(O)-N(R) in formula II-1 or II-2. a - or the connection point with A in Equation III-1 or Equation III-2, and Indicates with G 1 The connection point.

[0108] As explained in this article, G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c Substitution. In some embodiments (e.g., some embodiments of compounds of formula II-1 or III-1), G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-、C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c Substitution. In some embodiments (e.g., some embodiments of compounds of formula II-2 or III-2), G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C1-C6 aliphatic groups, C3-C 12 Cyclic aliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C6 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, wherein G 3 Optionally by one or more R c replace.

[0109] In some implementations, G 3 To be optionally used by one or more R c Replaced C1-C7 aliphatic groups. In some embodiments, G 3 To be optionally used by one or more R c Substituted C1-C7 alkyl groups. In some embodiments, G 3 It can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, or heptyl. In some embodiments, G 3 To be optionally used by one or more R c Substituted C1-C7 alkylene groups. In some embodiments, G 3 It can be methylene, ethylene, propylene, butylene, pentylene, hexylene, or heptylene. In some embodiments, G 3 C1-C7 aliphatic groups optionally substituted with one or more of the following: optionally substituted C3-C6 cyclic aliphatic groups, -OR a or -C(O)-OR aIn some implementations, G 3 The C1-C7 aliphatic groups are optionally substituted with C3-C6 cyclic aliphatic groups. In some embodiments, G 3 C1-C7 aliphatic groups are optionally substituted with C1-C6 aliphatic groups. In some embodiments, G 3 The C1-C7 aliphatic group is optionally replaced by a C1-C6 aliphatic group, wherein the C1-C6 aliphatic group is optionally replaced by -(CH2). 0-4 OR° or -(CH2) 0-4 SR° replacement. In some implementations, G 3 For optional use -OR a Replaced C1-C6 aliphatic groups.

[0110] In some implementations, G 3 To be optionally used by one or more R c Substituted C1-C6 aliphatic group -C(O)-N(R) a )-C0-C6 aliphatic group. In some implementations, G 3 To be optionally used by one or more R c Substituted C1-C6 aliphatic group -C(O)-N(R) a In some implementations, G 3 To be optionally used by one or more R c Substituted C1-C6 aliphatic group -C(O)-N(R) a )-C1-C6 aliphatic groups. In some implementations, G 3 To be optionally controlled by one or more -OR a Substituted C1-C6 aliphatic group -C(O)-N(R) a )-C1-C6 aliphatic group.

[0111] In some embodiments of formula II-1 or III-1, G 3 for: , or in Indicates the connection point with part B, and This represents -C(O)-N(R) in Equation II-1 a The connection point of ring A in equation III-1.

[0112] In some embodiments of formula II-2 or III-2, G 3 for: , or .

[0113] In some implementations, G 3 To be optionally used by one or more R c Replacement C3-C 12 Cyclic aliphatic group. In some implementations, G 3 To be optionally used by one or more R c Replaced C3-C6 cyclic aliphatic groups. In some embodiments, G 3 To be optionally used by one or more R c Substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0114] In some implementations, G 3 A 4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. c Replacement. In some implementations, G 3 A 4- to 6-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. c Replacement. In some implementations, G 3 A 6- to 9-membered bicyclic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. c Replacement. In some implementations, G 3 It is pyrrolidine, piperazine, tetrahydropyran, or piperidine, each optionally being reacted with one or more R c Replacement. In some implementations, G 3 It is a 4- to 6-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with C1-C6 aliphatic groups. In some embodiments, G 3 It is a 4- to 6-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with C1-C6 aliphatic groups, said C1-C6 aliphatic groups optionally being -(CH2). 0-4 C(O)NR°2 or -(CH2) 0-4 C(O)R° substitution, where R° is C 1-6 An aliphatic group or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally surrounded by -(CH2). 0-2 R ● replace.

[0115] In some implementations, G 3 It is a C1-C6 aliphatic group -C(O)- containing 1 to 3 heteroatoms selected from N, O and S, consisting of a 4- to 9-membered heterocycle, optionally separated by one or more R c Replacement. In some implementations, G3 It is a C1-C6 aliphatic group -C(O)-containing a 4- to 6-membered monocyclic heterocycle with 1 to 3 heteroatoms selected from N, O and S, optionally separated by one or more R c Replacement. In some implementations, G 3 It is a C1-C6 aliphatic-C(O)- 6- to 9-membered bicyclic heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally separated by one or more R c replace.

[0116] In some embodiments of formula II-1 or III-1, G 3 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , and ,in This indicates the connection point with part B.

[0117] In some embodiments of formula II-1 or III-1, G 3 Selected from: , , , , , , , , , , , , , , and .

[0118] In some embodiments of formula II-2 or III-2, G 3 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0119] In some embodiments of formula II-2 or III-2, G 3 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0120] As explained in this article, each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups. In some embodiments, R a For H. In some implementations, R a The C1-C6 aliphatic groups are optionally substituted.

[0121] As explained in this article, each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens. In some embodiments, R b -N(R) a 2. In some implementation schemes, R b The C1-C6 aliphatic groups are optionally substituted. In some embodiments, R b It is a halogen.

[0122] As explained in this article, each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a In some implementations, R c The C1-C6 aliphatic groups are optionally substituted. In some embodiments, R c The C3-C6 cyclic aliphatic group is optionally substituted. In some embodiments, R c C6-C is optionally replaced 12 Aryl. In some implementations, R c The substituted 4- to 12-membered heteroaryl groups are optionally substituted. In some embodiments, R c The 4- to 6-membered heterocyclic rings are optionally substituted. In some embodiments, R c For -OR a In some implementations, R c It is a -C(O)-C1-C6 aliphatic group. In some embodiments, R c -C(O)-OR a .

[0123] As described herein, B is the connector portion. In some embodiments, B is the connector portion, which is a covalently bonded connection at one end to G.1 (in Equations II-2 and III-2) or G 3 (In Equations II-1 and III-1) and covalently bonded at the other end to the divalent portion of C. In some embodiments, B is C that is optionally substituted. 2-30 Aliphatic groups, wherein one or more carbons are optionally and independently marked with -Cy-, -NR Z -、-N(R Z )C(O)-、-C(O)N(R Z )-、-N(R Z )C(O)O-、-OC(O)N(R Z )-、-N(R Z )C(O)N(R Z )-、-C(O)N(R Z SO2(R) Z )-、-SO2(R Z )N(R Z The following are substitutions: -C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-; wherein each -Cy- is independently a substituted 3-12-membered divalent C3-C6 cyclic aliphatic group, a 5- to 12-membered heterocyclic ring having 1-3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, and S; and each R Z Independently H or selected from C1-C 20 Aliphatic group or C3-C 12 The cyclic aliphatic group is optionally substituted with a group.

[0124] In some implementations, B is C2-C, which is optionally replaced. 10 Aliphatic groups, optionally substituted 2- to 10-membered heteroaliphatic groups, -C2-C 10 Aliphatic group -Cy- or -C2-C 10 Aliphatic group -C(O)-. In some embodiments, B is optionally substituted C2-C. 10 An aliphatic group or optionally substituted 2- to 10-membered heteroaliphatic group. In some embodiments, B is optionally substituted C2-C. 10 Aliphatic group. In some embodiments, B is an optionally substituted 2- to 10-membered heteroaliphatic group.

[0125] In some implementations, B is a connector, which is optionally replaced by C. 2-30 Aliphatic group. In some embodiments, B is a connector, which is optionally substituted C. 2-30Aliphatic group, wherein one or more carbons are replaced by -O-. In some embodiments, B is a connector, which is optionally substituted C. 2-30 Aliphatic group, wherein one or more carbons are replaced by -C(O)-. In some embodiments, B is a connector, which is optionally substituted C. 2-30 An aliphatic group, wherein one or more carbons are independently replaced by -Cy-, wherein -Cy- is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, B is a connector, which is an optionally substituted C 2-30 An aliphatic group in which one or more carbons are independently replaced by -Cy-, wherein -Cy- is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom.

[0126] In some implementations, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently replaced by -O- and / or -C(O)-. In some embodiments, B is a connector, which is optionally substituted C. 2-30 Aliphatic groups, wherein one or more carbons are independently surrounded by -O- and / or -N(R) Z )C(O)- replaces, where R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently surrounded by -O- and / or -C(O)N(R) Z )- replaces, where R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently surrounded by -N(R) Z )C(O)- and / or -C(O)- are replaced, and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently bounded by -C(O)N(R) Z )- and / or -C(O)- are used instead, and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently replaced by -Cy- and / or -C(O)-, wherein -Cy- is a C6 cycloalkyl group and / or a 6-membered divalent heterocyclic ring having 2 nitrogen atoms.

[0127] In some implementations, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently converted by -O-, -N(R) ZThe substitution is made by C(O)- and / or -Cy-, where -Cy- is a substituted 3-12-membered divalent heteroaryl ring having 1-4 nitrogen heteroatoms, and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently bounded by -O-, -C(O)N(R) Z )- and / or -Cy- are substituted, where -Cy- is a substituted 3-12-membered divalent heteroaryl ring having 1-4 nitrogen heteroatoms, and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently surrounded by -N(R) Z )C(O)-, -O- and / or -C(O)- are replaced, and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently bounded by -C(O)N(R) Z -, -O- and / or -C(O)- are replaced, and R Z For H.

[0128] In some implementations, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently converted by -O-, -N(R) Z -C(O)-, -C(O)- and / or -Cy- are substituted, wherein -Cy- is a C6 cycloalkyl group and R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 2-30 Aliphatic groups, wherein one or more carbons are independently bounded by -O-, -C(O)N(R) Z -, -C(O)- and / or -Cy- are substituted, wherein -Cy- is a C6 cycloalkyl group and R Z For H.

[0129] In some implementations, B is a connector, which is optionally replaced by C. 1-10 Aliphatic group. In some embodiments, B is a connector, which is optionally substituted C. 1-10 An aliphatic group, in which one carbon atom is replaced by -C(O)-. In some embodiments, B is a connector, which is optionally replaced by a C atom. 1-10 Aliphatic group, wherein one or more carbons are replaced by -C(O)-. In some embodiments, B is a connector, which is optionally substituted C. 1-6 Aliphatic group, wherein two carbons are replaced by -C(O)-. In some embodiments, B is a linker, which is optionally substituted C1-. 10Aliphatic groups, wherein one or more carbons are independently surrounded by -N(R) Z )C(O)- replaces, where R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C1- 10 Aliphatic groups, wherein one or more carbons are independently bounded by -C(O)N(R) Z )- replaces, where R Z H is used. In some embodiments, B is a connector, which is optionally replaced by C. 1-10 An aliphatic group, wherein one carbon atom is replaced by -Cy-, where -Cy- is a 6-membered divalent heterocyclic ring having one nitrogen atom. In some embodiments, B is a linker, which is optionally substituted C. 1-10 An aliphatic group in which one carbon atom is replaced by -Cy-, where -Cy- is a 6-membered divalent heterocyclic ring with two nitrogen atoms.

[0130] In some implementations, B is a connector, which is optionally replaced by C. 1-10 Aliphatic group, wherein two carbons are replaced by -O-. In some embodiments, B is a connector, which is optionally substituted C1-. 10 An aliphatic group, wherein one or more carbons are independently replaced by -C(O)- and / or -Cy-, wherein -Cy- is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, B is a connector, which is an optionally substituted C 1-10 An aliphatic group, wherein two carbons are independently replaced by -C(O)- and -Cy-, wherein -Cy- is an optionally substituted 3-12-membered divalent heteroaryl ring having 1-4 nitrogen heteroatoms. In some embodiments, B is a linker, which is an optionally substituted C 1-10 An aliphatic group, wherein two carbons are independently replaced by -C(O)- and -Cy-, wherein -Cy- is an optionally substituted 6-membered divalent heteroaryl ring having one nitrogen atom. In some embodiments, B is a linker, which is an optionally substituted C1- 10 Aliphatic groups, wherein one or more carbons are independently replaced by -C(O)- and / or -Cy-, wherein -Cy- is an optionally substituted C7 cycloalkyl group.

[0131] In some implementations, part A is derived from the compounds in Table A: Table A In some implementations, B is a connector portion selected from Table B: Table B , , , , , , , , , , , , , , , , , , , and , where t is an integer between 1 and 20.

[0132] In some implementations, B is a connector portion selected from the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , where t is an integer between 1 and 20.

[0133] As defined above, C represents the target-binding moiety. In some embodiments, C represents the target-binding moiety that binds to a kinase, kinase fusion, protein of interest, and / or fusion protein. In some embodiments, C represents the target-binding moiety that binds to ALK, BRD4, EML4, Myddosome (IRAK4), Myddosome (MALT1), FGFR, RET, HTT, Tau, NLRP3 inflammasome, EGFR / RTK, androgen receptor, ACC2, KMO, IAPP, TSPO, STING, cGAS, or USP30. In some embodiments, C represents the target-binding moiety that binds to ALK, Myddosome (IRAK4), MALT1, BRD4, FGFR, or RET.

[0134] In some implementations, C represents the target-binding portion that binds to ALK. In some implementations, C represents the target-binding portion of ALK and is derived from compounds described in the following literature: WO2017053657; WO2010143664; J Med Chem. 2015, 10;58(23):9296-9308; J. Med. Chem. 2019, 62,10927-10954; ACS Omega, Vol. 7, 2022, 32442-32456; KR1691536; WO2012106540; WO2006021881; US7964592; Clinical Cancer Research (2015), 21(11), 2436-2439; Journal of Oncology Pharmacy Practice (2017), 23(8). 602-614; WO2009143389; Drugs (2021), 81(2), 267-275; New England Journal of Medicine (2020), 383(21), 2018-2029; WO2013132376; WO2017004342; Cancer Discovery (2018), 8(10), 1227-1236; WO2020069106; Mol Cancer Ther. 2021 Sep;20(9):1499-1507; EMBO MolecularMedicine 14: e14296 (2022); Acta Pharmaceutica Sinica B11(2), 2021, 355-372; J Med Chem 2016, 14; 59(7):3392-408; or Cancer Lett. 2016, 28; 372(2):179-86.

[0135] In some embodiments, C is a target-binding moiety that binds to ALK and is derived from compounds selected from: In some implementations, C is the target-binding portion that binds to ALK, and is selected from: In some embodiments, C is a target-binding moiety that binds to BRD4. In some embodiments, C is a binding moiety that binds to BRD4 and is derived from the compound described in Nature. 2010 Dec 23;468(7327):1067-73. In some embodiments, C is a target-binding moiety that binds to BRD4 and is derived from the compound: In some implementations, C is the target-binding portion that binds to BRD4, and is: In some embodiments, C is a target-binding moiety bound to Myddosome (IRAK4). In some embodiments, C is a target-binding moiety bound to Myddosome (IRAK4) and is derived from compounds described in the following literature: WO2011043371; WO2019133531; WO2015068856; US20180111917; WO2019160915; WO2018098367; Bioorg Med Chem Lett 2006;16(11):2842-5; ACS Med Chem Lett., 2019, 10 Page 1081; WO2015103453; Cell ChemBio, 2020. 27 Pages 11-10; WO2018060174; ACSMedChem Lett., 2021. 12 , page 82; WO2019099926; Bioorganic&Medicinal Chemistry Letters (2014), 24(9), 2066-2072; Bioorganic&Medicinal Chemistry Letters (2008), 18(11), 3211-3214; WO2021018118; or WO2022147465.

[0136] In some implementations, C is the target-binding portion that binds to Myddosome (IRAK4) and originates from: In some implementations, C is the target-binding portion that binds to Myddosome (IRAK4) and is selected from: In some embodiments, C is a target-binding moiety bound to Myddosome (MALT1). In some embodiments, C is a target-binding moiety bound to Myddosome (MALT1) and is derived from compounds described in the following literature: J Med Chem., Dec 10, 2020; 63(23):14594-14608; J Med Chem. Dec 10, 2020; 63(23):14576-14593; Cancer Cell. Dec 11, 2012; 22(6):812-24; WO2020111087; or WO2018020474. In some embodiments, C is a target-binding moiety bound to Myddosome (MALT1) and is derived from: In some implementations, C is the target-binding portion that binds to Myddosome (MALT1), which is selected from: In some embodiments, C is a target-binding moiety that binds to the FGFR. In some embodiments, C is a target-binding moiety that binds to the FGFR and is derived from compounds described in the following literature: WO2008075068; WO2006000420; Cancer Discovery, 2018, 8(3):354-369; Mol Cancer Ther. 2017, 16(6) 1010-1020; Oncotarget, 2016 7: 24252-24268; WO2013108809; or US20160136168. In some embodiments, C is a target-binding moiety that binds to the FGFR and is derived from: , , or .

[0137] In some implementations, C is the target-binding portion that binds to the FGFR, and is selected from: , , , and .

[0138] In some embodiments, C is a target-binding moiety bound to RET. In some embodiments, C is a target-binding moiety bound to RET and is derived from compounds described in the following literature: ACS Med. Chem. Lett. 2021, 12, 12; Mol. Cancer Ther. 2021, 20 (12_Supplement): P233 (PDB: 7DUA); WO2018071447; Int. J. Mol. Sci. 2021, 22(4), 1887; or WO2017079140. In some embodiments, C is a target-binding moiety bound to RET and is derived from: In some implementations, C is the target-binding portion that binds to RET, and is selected from: , , , and .

[0139] In some embodiments, C is a target-binding moiety bound to HTT. In some embodiments, C is a target-binding moiety bound to HTT and is derived from compounds described in the following literature: ACS Med Chem Lett 2020, 63, 8608-8633; WO2020176424; WO2021127265; or ACIE 2017, 56, 11530-11533. In some embodiments, C is a target-binding moiety bound to HTT and is derived from: In some implementations, C is the target-binding portion that binds to HTT, and is selected from: In some embodiments, C is a target-binding moiety bound to Tau. In some embodiments, C is a target-binding moiety bound to Tau and is derived from compounds described in the following literature: eLife 2019;8:e45457; WO2021011913; JMC 2016, 59, 4778-4789; EJ Nucl Med Mol Imag 2019, 46, 2178-2189; or JMC 2019, 62, 2974-2987. In some embodiments, C is a target-binding moiety bound to Tau and is derived from: .

[0140] In some implementations, C is a target-binding portion that binds to Tau, and is selected from: In some embodiments, C is a target-binding moiety that binds to the NLRP3 inflammasome. In some embodiments, C is a target-binding moiety that binds to the NLRP3 inflammasome and is derived from the compounds described in WO2019092170. In some embodiments, C is a target-binding moiety that binds to the NLRP3 inflammasome and is selected from: , , and .

[0141] In some embodiments, C is a target-binding moiety that binds to EGFR / RTK. In some embodiments, C is a target-binding moiety that binds to EGFR / RTK and is derived from compounds described in Cell Chem Bio 2018, 25, 67-77. In some embodiments, C is a target-binding moiety that binds to EGFR / RTK and is selected from: and .

[0142] In some embodiments, C is a target-binding moiety that binds to an androgen receptor. In some embodiments, C is a target-binding moiety that binds to an androgen receptor and is derived from compounds described in ACS Med Chem Lett 2020, 11, 1539-1547 or WO2018071606. In some embodiments, C is a target-binding moiety that binds to an androgen receptor and is selected from: and .

[0143] In some embodiments, C is a target-binding moiety bound to ACC2. In some embodiments, C is a target-binding moiety bound to ACC2 and is derived from compounds described in WO201307169 or BOMCL 2011, 21, 6314-6318. In some embodiments, C is a target-binding moiety bound to ACC2 and is derived from: or .

[0144] In some implementations, C is the target binding portion that binds to ACC2, and is selected from: and .

[0145] In some embodiments, C is a target-binding moiety bound to KMO. In some embodiments, C is a target-binding moiety bound to KMO and is selected from compounds described in JMC 2017, 60, 3383-3404. In some embodiments, C is a target-binding moiety bound to KMO and is derived from the following compounds: In some implementations, C is the target-binding portion that binds to KMO, and is: In some embodiments, C is a target-binding moiety bound to IAPP. In some embodiments, C is a target-binding moiety derived from compounds described in Diabetologica 2018, 61, 2215-2224. In some embodiments, C is a target-binding moiety bound to IAPP and is derived from the following compounds: In some implementations, C represents the target-binding portion that binds to the IAPP, and is: In some embodiments, C is a target-binding moiety bound to TSPO. In some embodiments, C is a target-binding moiety bound to TSPO and is derived from compounds described in the following literature: JMC 2017, 60, 7897-7909; Life Sci 1983, 32, 1849-1856; J. Pharmacol. Exp. Ther. 1992, 262, 971-978; or JMC 2015, 58, 7449-7464. In some embodiments, C is derived from the following target-binding moieties: , or .

[0146] In some implementations, C is the target-binding portion that binds to TSPO, and is selected from: , , , and .

[0147] In some embodiments, C is a target-binding moiety bound to STING. In some embodiments, C is a target-binding moiety bound to STING and is derived from compounds described in ACS Med Chem Lett 2019, 10, 92-97, WO2020132582, or Science 2020, 369, 6506, eaba6098. In some embodiments, C is a target-binding moiety bound to STING and is derived from: , , , , or .

[0148] In some implementations, C is the target-binding portion that binds to STING, and is selected from: , , , , and .

[0149] In some embodiments, C is a target-binding moiety bound to cGAS. In some embodiments, C is a target-binding moiety bound to cGAS and is derived from compounds described in Nat Commun 10, 2261, 2019 or JOC 2020, 85, 1579. In some embodiments, C is a target-binding moiety bound to cGAS and is derived from: , or .

[0150] In some implementations, C is the target-binding portion that binds to cGAS, and is selected from: , , , and .

[0151] In some embodiments, C is a target-binding moiety bound to USP30. In some embodiments, C is a target-binding moiety bound to USP30 and is derived from the compound described in WO2020212350. In some embodiments, C is a target-binding moiety bound to USP30 and is derived from: or .

[0152] In some implementations, C is the target-binding portion that binds to the USP30, and is selected from: and .

[0153] In some embodiments, C is a target-binding moiety bound to p62. In some embodiments, C is a target-binding moiety bound to p62 and is derived from compounds described in WO2020022783 or Nat Commun. 24 July 2017;8(1):102. In some embodiments, C is a target-binding moiety bound to p62 and is selected from: and .

[0154] In some implementations, C is the target-binding portion that binds to p62, and is selected from: , and .

[0155] In some implementations, C is a C1-C substituted with halogen. 20Aliphatic group. In some embodiments, C is C1-C. 20 Aliphatic group -Cl.

[0156] In some implementations, the compounds described herein are compounds of formula IVa: IVa Or its pharmaceutically acceptable salts, wherein B, C, R a R b and G 3 As described in the categories and subcategories of this article.

[0157] In some implementations, the compounds described herein are compounds of formula IVb: IVb Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0158] In some embodiments, the compounds described herein are compounds of formula IVc-1. IVc-1 Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0159] In some embodiments, the compound described herein is a compound of formula IVc-2. IVc-2 Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0160] In some embodiments, the compounds described herein are compounds of formula IVd-1. IVd-1 Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0161] In some embodiments, the compound described herein is a compound of formula IVd-2. IVd-2 Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0162] In some embodiments, the compounds described herein are compounds of formula IVe-1. IVe-1 Or its pharmaceutically acceptable salts, wherein B, C, R a R b and G 3 As described in the categories and subcategories of this article.

[0163] In some embodiments, the compound described herein is a compound of formula IVe-2. IVe-2 Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0164] In some embodiments, the compounds described herein are compounds of formula IVf. IVf Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0165] In some embodiments, the compounds described herein are compounds of formula IVg. IVg Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subcategories of this article.

[0166] In some embodiments, the compounds described herein are compounds of formula IVh. IVh Or its pharmaceutically acceptable salts, wherein B, C, R a and G 3 As described in the categories and subclasses of this article, and W 1 W 2 W 3 and W 4Each of them is independently selected from N, CH and CR. b And R b This is explained in the categories and subcategories of this article.

[0167] In some embodiments, the compounds described herein are compounds of formula IVi. IVi Or its pharmaceutically acceptable salts, wherein B, C, R a R b and G 3 As described in the categories and subcategories of this article.

[0168] In some embodiments, the compounds described herein are compounds of formula IVj. IVj Or a pharmaceutically acceptable salt thereof, wherein R a G 3 As described in the categories and subclasses of this article, and W 5 W 6 W 7 and W 8 Each of them is independently selected from N and CR. d , where each R d Independently selected from H, -N(R) a 2. Optionally substituted C1-C6 aliphatic groups, halogens, or part of BC, wherein W 1 W 2 W 3 or W 4 One of them is CR d And R d For part of BC.

[0169] In some embodiments, compounds of formulas I-IVj are selected from Table 1, or pharmaceutically acceptable salts thereof: Table 1 In some embodiments, the compound of formula I is selected from:

[0170] In some embodiments, the compound that binds to p62 is compound X: X Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

[0171] In some embodiments, the compound that binds to p62 is a compound of formula XI: XI Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to four heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to three heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R)a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

[0172] In some implementations of equation X or equation XI, the variable rings A and G 1 G 2 G 3 R a R b and R c Any of them as defined in the categories and subclasses of Formula I in this paper.

[0173] In some embodiments, the compound of formula X or formula XI is selected from Table 2, or a pharmaceutically acceptable salt thereof: Table 2 In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to the compounds provided herein should be construed as including references to their salts.

[0174] Uses, preparation and application Pharmaceutically acceptable compositions According to another embodiment, this disclosure provides a composition comprising a compound set forth herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or mediator. In some embodiments, the composition set forth herein is formulated for administration to a patient in need of the composition. In some embodiments, the composition set forth herein is formulated for oral administration to a patient.

[0175] According to the methods of this disclosure, the compounds and compositions are administered in any amount and via any route of administration effective for treating or alleviating the severity of the condition described herein. The exact amount required will vary from subject to subject, depending on the subject's species, age and general condition, severity of infection, specific agent, mode of administration, etc. The compounds described herein are preferably formulated in unit dosage forms for ease of administration and uniform dosage.

[0176] The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, externally, rectally, nasally, buccally, vaginally, intraperitoneally, intracerebrospinally, or via an implantable cartridge. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0177] The compositions described herein can be in sterile injectable form as aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are often used as solvents or suspension media.

[0178] For this purpose, any mild, non-volatile oil, including synthetic mono- or diglycerides of glycerol, may be used. Like pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially in their polyoxyethylated form), fatty acids (such as oleic acid and its glycerol derivatives) may be used to prepare injectable formulations. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0179] Injectable formulations may be sterilized, for example, by filtration via a bacterial trapping filter or by incorporation of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0180] To prolong the effects of the disclosed compounds, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Therefore, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of the parenteral administration of the compound can be achieved by dissolving or suspending the compound in an oily medium. Injectable storage forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid). The rate of compound release can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Storage injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0181] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food. The pharmaceutically acceptable 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 also typically added. For oral administration in capsule form, diluents available include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if necessary.

[0182] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) slowing agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and / or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0183] In soft and hard filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol, similar types of solid compositions can also be used as fillers. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain light-blocking agents and may also have a composition that optionally releases the active ingredient only or preferentially in a portion of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. In soft and hard filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol, similar types of solid compositions can also be used as fillers.

[0184] The active compound may also be in the form of microencapsulation having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules with coatings and shells (e.g., enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation) can be prepared. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is common practice, such dosage forms may also contain substances other than inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. It may optionally contain a light-blocking agent and may also have a composition that optionally releases the active ingredient in a delayed manner only or preferentially in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0185] Liquid dosage forms for oral administration include (but are not limited to) pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0186] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in suppository form for rectal administration. These compositions can be prepared by mixing the agent with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0187] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax), which is solid at ambient temperature but liquid at body temperature, and thus melts in the rectal or vaginal cavity and releases the active compound.

[0188] The pharmaceutically acceptable compositions described herein can also be applied topically, particularly when the therapeutic target includes areas or organs that can be easily reached by topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily available.

[0189] External application to the lower intestine can be achieved using rectal suppositories (see above) or appropriate enema formulations. Transdermal patches may also be used.

[0190] For topical application, the provided pharmaceutically acceptable compositions may be formulated in suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for the compounds described herein for topical application include (but are not limited to) mineral oils, liquid paraffins, white paraffins, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oils, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecanool, benzyl alcohol, and water.

[0191] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative (e.g., benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment (e.g., paraffin oil).

[0192] The pharmaceutically acceptable compositions described herein can also be administered via nasal aerosol or inhalation. These compositions are prepared according to techniques well-known in the field of pharmaceutical formulation and can be prepared as solutions in saline containing benzyl alcohol or other suitable preservatives, absorption enhancers (to improve bioavailability), fluorocarbons, and / or other conventional solubilizers or dispersants.

[0193] Dosage forms for external or transdermal application of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Where desired, the active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of this disclosure. Additionally, this disclosure contemplates the use of transdermal patches, which offer the added advantage of controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0194] Diseases, symptoms and illnesses This disclosure covers the insight that the compounds and compositions provided herein can be used to direct autophagy to a target. This disclosure also covers the insight that directing autophagy to a specific target can be used to treat specific diseases, conditions, and disorders. In some implementations, the disease, condition, or disorder is selected from the following: NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer's disease, diabetes (e.g., type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-related periodic syndrome, Parkinson's disease, and Lewy body dementia. Lewy bodies), multiple system atrophy, axonal dystrophy, primary age-related tau proteinopathy (PART) dementia, chronic traumatic encephalopathy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Guam-type Parkinson's dementia complex), ganglioglioma and gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenate-associated neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy's disease. Diseases including rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Aicardia-Goutieres syndrome, ataxia, familial frostbite lupus, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD-TDP), and amyotrophic lateral sclerosis.

[0195] In some implementations, a specific target binding moiety (e.g., part C' in Formula I above) may be selected to modulate the selected target (and thereby induce its degradation) to treat a selected disease, condition, or ailment. Those skilled in the art can use known binding moieties to identify specific binding moieties based on the desired disease, condition, or ailment to be treated.

[0196] In some implementations, the target is lipid droplets, and the disease, condition, or ailment to be treated is selected from NASH and NAFLD.

[0197] In some implementations, the target is COP9, and the disease, condition, or ailment is cancer.

[0198] In some implementations, the target is MYC, and the disease, condition, or ailment is Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, lung cancer, or stomach cancer.

[0199] In some implementations, the target is myddosome, and the disease, condition, or disorder is active B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, or Waldenström macroglobulinemia.

[0200] In some implementations, the target is an inflammasome, and the disease, condition, or disorder is gout, atherosclerosis, Alzheimer's disease, type II diabetes, experimental autoimmune encephalitis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-associated periodic syndrome (CAPS), colon cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, and gastrointestinal cancer.

[0201] In some implementations, the target is KRAS, and the disease, condition, or disorder is colorectal cancer, lung cancer, leukemia, pancreatic cancer, In some implementations, the target is α-synuclein, and the disease, condition, or disorder is Parkinson's disease, Lewy body dementia, multiple system atrophy, or axonal dystrophy.

[0202] In some implementations, the target is tau, and the disease, condition, or disorder is Alzheimer's disease, primary age-related tau proteinopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia associated with chromosome 17 with Parkinson's disease (FTDP-17), Listik-Bodigo disease (Guam-type Parkinson's dementia complex), ganglioglioma, gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, or lipofuscin deposition disease.

[0203] In some implementations, the target is estrogen receptor-α, and the disease, condition, or ailment is breast cancer.

[0204] In some implementations, the target is the androgen receptor, and the disease, condition, or disorder is prostate cancer or spinal and bulbar muscular atrophy (SBMA) / Kennedy disease.

[0205] In some implementations, the target is KSR1, and the disease, condition, or ailment is cancer.

[0206] In some implementations, the target is islet amyloid peptide (IAPP), and the disease, condition, or disorder is type II diabetes.

[0207] In some implementations, the target is IRAK4, and the disease, condition, or disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or psoriasis.

[0208] In some implementations, the target is PINK1, and the disease, condition, or disorder is Parkinson's disease, Huntington's disease, or spinocerebellar ataxia.

[0209] In some implementations, the target is TDP43, and the disease, condition, or disorder is familial amyotrophic lateral sclerosis or frontotemporal dementia (FTLD-TDP).

[0210] Exemplary Implementation This disclosure provides the following non-restrictive numbered implementation schemes.

[0211] Implementation Scheme 1. A compound of Formula I: ABC I Or its pharmaceutically acceptable salt, wherein A is the part that combines with or associates with p62; B is the connector part; and C represents the target binding portion.

[0212] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein A is a polypeptide or peptide mimic moiety that binds to or associates with p62.

[0213] Implementation Scheme 3. The compound as described in Implementation Scheme 1 or 2, wherein A is a dipeptide or peptide mimic moiety that binds to or associates with p62.

[0214] Implementation Scheme 4. The compound as described in Implementation Scheme 1, wherein the compound is a compound of Formula II-1 or Formula II-2: Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0215] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of Formula III-1 or Formula III-2:

[0216] Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

[0217] Implementation Scheme 6. The compound as described in Implementation Scheme 4 or 5, wherein G 1 It is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted.

[0218] Implementation Scheme 7. The compound as described in Implementation Scheme 4 or 5, wherein G 1 It is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, optionally surrounded by -N(R a )2 or one or more of the halogens are substituted.

[0219] Implementation Scheme 8. The compound as described in Implementation Scheme 4 or 5, wherein G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, optionally separated by one or more -N(R) atoms. a )2 or halogen substitution.

[0220] Implementation Scheme 9. The compound of any one of Implementation Schemes 4-8, wherein the compound is a compound of Formula II-1 or Formula III-1.

[0221] Implementation Scheme 10. The compound as described in Implementation Scheme 9, wherein G 1 Selected from: Implementation Scheme 11. The compound of any one of Implementation Schemes 4-8, wherein the compound is a compound of Formula II-2 or Formula III-2.

[0222] Implementation Scheme 12. The compound as described in Implementation Scheme 11, wherein G 1 Selected from: in Indicates the connection point with part B, and Indicates the relationship with part of G 2 The connection point.

[0223] Implementation Scheme 13. The compound as described in any one of Implementation Schemes 4-12, wherein G 2 It is a C1-C6 aliphatic group or a C1-C6 aliphatic group - a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, wherein G 2 Optionally by one or more R b replace.

[0224] Implementation Scheme 14. The compound as described in Implementation Scheme 13, wherein G 2 To be optionally used by one or more R b Replaced C1-C6 aliphatic groups.

[0225] Implementation Scheme 15. The compound as described in Implementation Scheme 14, wherein G 2 To be optionally controlled by one or more -N(R) a )2-substituted C1-C6 aliphatic groups.

[0226] Implementation Scheme 16. The compound as described in Implementation Scheme 15, wherein G 2 It is a C1-C6 aliphatic group that has been replaced by -NH2.

[0227] Implementation Scheme 17. The compound as described in Implementation Scheme 16, wherein G 2 It is a C1-C6 aliphatic group substituted with -NH2, wherein the carbon atom bonded to -NH2 is in the form of... S Enantiomeric configuration.

[0228] Implementation Scheme 18. The compound as described in Implementation Scheme 13, wherein G 2 It is a C1-C6 aliphatic group - a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, wherein G 2 Optionally by one or more R b replace.

[0229] Implementation Scheme 19. The compound as described in Implementation Scheme 18, wherein G 2 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0230] Implementation Scheme 20. The compound as described in any one of Implementation Schemes 4-12, wherein G 2 Selected from: ,in This represents -C(O)-N(R) in formula II-1 or II-2. a - or the connection point with A in Equation III-1 or Equation III-2, and Indicates with G 1 The connection point.

[0231] Implementation Scheme 21. The compound as described in any one of Implementation Schemes 4-20, wherein G 3 C1-C7 aliphatic group -C(O)N(R) a - or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, wherein G 3 Optionally by one or more R c replace.

[0232] Implementation Scheme 22. The compound as described in Implementation Scheme 21, wherein G 3 C1-C7 aliphatic group -C(O)N(R) a ), which is optionally substituted with halogens or optionally with substituted C1-C6 aliphatic groups.

[0233] Implementation Scheme 23. The compound as described in Implementation Scheme 22, wherein G 3 C1-C7 alkyl-C(O)N(R) a ), which is optionally substituted with halogens or optionally with substituted C1-C6 aliphatic groups.

[0234] Implementation Scheme 24. The compound as described in Implementation Schemes 9, 10 or 13-20, wherein G 3 Selected from: ,in This indicates the connection point with part B.

[0235] Implementation Scheme 25. The compound as described in any one of Implementation Schemes 11-20, wherein G 3 Selected from: Implementation Scheme 26. The compound as described in Implementation Scheme 24, wherein G 3 Selected from: , , , , , , , , , , , , , , , and ,in This indicates the connection point with part B.

[0236] Implementation Scheme 27. The compound as described in Implementation Scheme 25, wherein G 3 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0237] Implementation Scheme 28. The compound of any one of Implementation Schemes 5-27, wherein ring A is: , , , , , , or .

[0238] Implementation Scheme 29. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVa: IVa Or its pharmaceutically acceptable salt.

[0239] Implementation Scheme 30. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVb. IVb Or its pharmaceutically acceptable salt.

[0240] Implementation Scheme 31. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVc-1: IVc-1 Or its pharmaceutically acceptable salt.

[0241] Implementation Scheme 32. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVd-1: IVd-1 Or its pharmaceutically acceptable salt.

[0242] Implementation Scheme 33. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVe-1: IVe-1 Or its pharmaceutically acceptable salt.

[0243] Implementation Scheme 34. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVf: IVf Or its pharmaceutically acceptable salt.

[0244] Implementation Scheme 35. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVg: IVg Or its pharmaceutically acceptable salt.

[0245] Implementation Scheme 36. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVh. IVh Or its pharmaceutically acceptable salt, wherein W 1 W 2 W3 and W 4 Each of them is independently selected from N, CH and CR. b .

[0246] Implementation Scheme 37. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVi. IVi Or its pharmaceutically acceptable salt.

[0247] Implementation Scheme 38. The compound as described in Implementation Scheme 4, wherein the compound is a compound of formula IVj. IVj Or its pharmaceutically acceptable salt, wherein W 5 W 6 W 7 and W 8 Each of them is independently selected from N and CR. d , where each R d Independently selected from H, -N(R) a 2. Optionally substituted C1-C6 aliphatic groups, halogens, or part of BC, wherein W 1 W 2 W 3 or W 4 One of them is CR d And R d For part of BC.

[0248] Implementation Scheme 39. The compound of any one of Implementation Schemes 1-38, wherein the linker is optionally substituted C 2-30 Aliphatic groups, wherein one or more carbons are optionally and independently marked with -Cy-, -NR Z -、-N(R Z )C(O)-、-C(O)N(R Z )-、-N(R Z )C(O)O-、-OC(O)N(R Z )-、-N(R Z )C(O)N(R Z-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2- are replaced, wherein each -Cy- is independently a 3-12-membered divalent heterocyclic ring having 1-3 heteroatoms selected from N, O and S, a 3-8-membered divalent heteroaryl ring having 1-4 heteroatoms selected from N, O and S, a C3-C6 cycloalkyl ring, or a C6-C6 cycloalkyl ring. 12 Aryl, and each R Z Independently H or selected from C1-C 20 Aliphatic group or C3-C 12 The cyclic aliphatic group is optionally substituted with a group.

[0249] Implementation Scheme 40. The compound as described in any one of Implementation Schemes 1-39, wherein B is a connector portion selected from Table B.

[0250] Implementation Scheme 41. The compound of any one of Implementation Schemes 1-40, wherein C is a target-binding moiety that binds to ALK, BRD4, p62, Myddosome (IRAK4), Myddosome (MALT1), FGFR, RET, HTT, EML4, Tau, NLRP3 inflammasome, EGFR / RTK, androgen receptor, ACC2, KMO, IAPP, TSPO, STING, cGAS, or USP30.

[0251] Implementation Scheme 42. The compound as described in Implementation Scheme 1, wherein the compound is selected from Table 1.

[0252] Implementation Scheme 43. A pharmaceutical composition comprising any one of the compounds described in Implementation Schemes 1-42 and a pharmaceutically acceptable carrier, filler, or diluent.

[0253] Implementation Scheme 44. A method for treating a disease, symptom, or ailment of a subject, said method comprising administering a compound of any one of Implementation Schemes 1-42 or a pharmaceutical composition of Implementation Scheme 43.

[0254] Implementation Scheme 45. The method as described in Implementation Scheme 44, wherein the disease, condition, or disorder is selected from NASH, NAFLD, cancers (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, gout, atherosclerosis, Alzheimer's disease, diabetes (e.g., type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-related periodic syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tau protein lesions (PART) dementia, chronic Traumatic encephalopathy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with Parkinson's disease associated with chromosome 17 (FTDP-17), Listik-Bodigo disease (Guam-type Parkinson's dementia complex), ganglioglioma and gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ekaterie-Gutierrez syndrome, ataxia, familial frostbite lupus, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD-TDP), and ALS.

[0255] Implementation Scheme 46. A method for inducing target degradation in a biological sample, the method comprising contacting the biological sample with a compound of any one of Implementation Schemes 1-42 or a pharmaceutical composition of Implementation Scheme 43.

[0256] Implementation Scheme 47. The compound of any one of Implementation Schemes 1-42 or the pharmaceutical composition of Implementation Scheme 43, for use in medicine.

[0257] Implementation Scheme 48. Use of the compound as described in any one of Implementation Schemes 1-42 or the pharmaceutical composition as described in Implementation Scheme 43 for the treatment of a disease, symptom, or ailment.

[0258] Implementation Scheme 49. The use as described in Implementation Scheme 48, wherein the disease, condition, or disorder is NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, gout, atherosclerosis, Alzheimer's disease, diabetes (e.g., type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-related periodic syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tau protein lesions (PART) dementia, chronic Traumatic encephalopathy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with Parkinson's disease associated with chromosome 17 (FTDP-17), Listik-Bodigo disease (Guam-type Parkinson's dementia complex), ganglioglioma and gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ekaterie-Gutierrez syndrome, ataxia, familial frostbite lupus, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD-TDP), and amyotrophic lateral sclerosis. Implementation Scheme 50. A compound of formula X: X Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

[0259] Implementation Scheme 51. A compound of formula XI: XI Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a)-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

[0260] Implementation Scheme 52. The compound as described in Implementation Scheme 50 or 51, wherein the compound is selected from Table 2.

[0261] Example As illustrated in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method illustrates the synthesis of certain compounds of this disclosure, the following general method and other methods known to those skilled in the art are applicable to all compounds and their respective subclasses and species as described herein.

[0262] Abbreviation Table

[0263] Analytical instruments and purification NMR instrument details: Varian 400 MHz, Probe-1: Auto XID, Probe-2: ATB.

[0264] LCMS Instrument Details: Shimadzu LCMS-2010EV system, coupled with SPD-M20A PDA and ELS detector. Softa Model 400.

[0265] LCMS Method 1 - Acidic Conditions Column: X-Select C18 CSH (3.0*50) mm 2.5 μm; Manufactured by: Waters Mobile phase A: Water containing 0.05% formic acid:acetonitrile (95:5); pH = 3.5 Mobile phase B: Acetonitrile containing 0.05% formic acid Column oven temperature: 50°C Flow rate: 1.2 ml / min PDA: 210 nm Maxplot Gradient procedure: MS parameters Mode: Dual (+ / -) Detector voltage: 1.5 kV Scan range: 80-2000 amu Scan speed: 2000 LCMS Method 2 - Alkaline Conditions Column: X-Select C18 CSH (3.0*50) mm 2.5 μm; Manufactured by: Waters Mobile phase A: 5 mM ammonium bicarbonate; pH = 8.8 Mobile phase B: Acetonitrile Column oven temperature: 50°C Flow rate: 1.2 ml / min PDA: 210 nm Maxplot Gradient procedure: MS parameters Mode: Dual (+ / -) Detector voltage: 1.5 kV Scan range: 80-2000 amu Scan speed: 2000 HPLC Method 1 - Acidic Conditions Column: X-Select CSH C18 (4.6*150) mm; 5 μm; Manufactured by: Waters Flow rate: 1.0 mL / min PDA: 210 nm maxplot Gradient procedure: HPLC Method 2 - Alkaline Conditions Column: Xbridge C18 (4.6*150) mm, 5 μm; Manufactured by: Waters Flow rate: 1.2 mL / min PDA: 210 nm maxplot Gradient procedure: INT-1. (Z)-N 2 ,N w ,N w' Synthesis of -tris(tert-butoxycarbonyl)-L-arginine Step 1. (Z)-N 2 N w N w' Synthesis of -tris(tert-butoxycarbonyl)-L-arginine (INT-1) (2S)-2-amino-5-iminocarbamoylvaleric acid (8.70 g, 49.9 mmol) was added to a solution of t-BuOH (150 mL) and H₂O (150 mL) in a 500 mL round-bottom flask. The mixture was cooled to 0 °C in an ice bath, and NaOH (6.96 g, 174 mmol) was added. The solution was stirred at 0 °C for 5 min. Then, Boc₂O (43.30 g, 199.0 mmol) was added to the mixture in several portions. The reaction mixture was stirred at room temperature for two days. t-BuOH (150 mL) was evaporated under reduced pressure, and the residue was acidified with citric acid to pH 3. The above solution was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and evaporated under vacuum to give (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}valeric acid (INT-1). Yield: 7.73 g, 33%; Appearance: white solid; 1 H NMR (300 MHz, DMSO- d 6) δ 12.09 (s,1H), 9.41- 8.85 (m, 2H), 7.06 ( J = 8.0 Hz, 1H), 3.94 - 3.73 (m, 3H), 1.61 -1.53 ​​(m, 2H), 1.49 (s, 9H), 1.41 (s, 9H), 1.39 - 1.26 (m, 11H). HPLC purity: 85.0%; C 21 H 38 LCMS calculated value of N4O8: 474.27; observed value: 475.3 [M+H] + .

[0266] INT-2. Synthesis of (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}valeric acid Step 1 Synthesis of methyl (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pent-4-acetylic acid TEA (802 mg, 7.95 mmol), Pd / (PPh3)Cl2 (111 mg, 0.16 mmol), CuI (30.2 mg, 0.16 mmol), and (2S)-2-{[(tert-butoxy)carbonyl]amino}pentan-4-acetylic acid methyl ester (540 mg, 2.38 mmol) were added to a solution of 3-iodopyridin-2-amine (350 mg, 1.59 mmol) in DMF (2 mL). The mixture was stirred at 80 °C for 1 h under N2. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by rapid silica gel chromatography (EA-PE = 0%-50%) to obtain methyl (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pent-4-acetylic acid (430 mg, 1.34 mmol, 100% purity, 84.8% yield), which was a yellow oil.

[0267] Step 2 Synthesis of methyl (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate Pd / C (426 mg, 4.02 mmol) was added to a solution of (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentan-4-acetylic acid methyl ester (430 mg, 1.34 mmol) in MeOH (5 mL) under N2. The suspension was degassed six times with H2. The mixture was stirred under H2 at room temperature for 16 h. After filtration through a diatomaceous earth mat, the organic layer was concentrated to dryness under reduced pressure to give (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanate methyl ester (433 mg, 1.33 mmol, 100% purity, 100% yield) as a yellow oil.

[0268] Step 3 Synthesis of (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}valeric acid (INT-2) LiOH (63.3 mg, 2.64 mmol) was added to a solution of methyl (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate (430 mg, 1.32 mmol) in H₂O (2 mL) and THF (2 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give (2S)-5-(2-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate (INT-2) as a yellow solid (408 mg, 1.31 mmol, 100% purity, 100% yield).

[0269] Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazol-1-yl)valeric acid Step 1 . ( S Synthesis of benzyl 2-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate Sodium borohydride (2.36 g, 62.6 mmol, 2.0 equivalent) was added to a stirred solution of 1-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylic acid 2-benzyl ester (10.0 g, 31.3 mmol, 1.0 equivalent) in tetrahydrofuran (120.0 mL) and water (20.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then heated to room temperature and stirred at room temperature for 1 h. LC-MS showed that the reaction was complete and a product was formed. The reaction mixture was concentrated under vacuum, and the residue was suspended in EA and washed with water. The aqueous layer was extracted with EA, and the combined organic extracts were washed with water and brine, dried, and concentrated under vacuum to give a crude product. The crude product was purified by rapid chromatography using 0-50% EA in PE to give a colorless oil (2... S )-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoic acid benzyl ester (3.96 g, 100% purity, 38% yield).

[0270] Step 2 . ( S )-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1 H Synthesis of 1-imidazol-1-yl)benzyl valerate To (2) S A solution of 2-[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoic acid benzyl ester (3.96 g, 12.2 mmol, 1.0 equivalent) in tetrahydrofuran (40.0 mL) was supplemented with 2-nitro-1 H-Imidazole (2.75 g, 24.4 mmol, 2.0 equivalent), triphenylphosphine (6.39 g, 24.4 mmol, 2.0 equivalent), and diisopropyl azodicarbonate (4.93 g, 24.4 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was complete and the product was produced. The reaction mixture was concentrated to give ( S )-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1 H 1,1-imidazol-1-yl)benzyl valerate (13.2 g, crude product). The crude product was used directly in the next step without further purification.

[0271] Step 3 . ( S )-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1 H Synthesis of 1-imidazol-1-yl)valeric acid To (2) S )-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1 H Benzyl valerate (13.2 g, 31.5 mmol, crude) was dissolved in methanol (120.0 mL) with lithium hydroxide (1.50 g, 63.0 mmol, 2.0 equivalent) and water (40.0 mL). The reaction mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was complete, and the solvent was removed by evaporation under vacuum. The residue was dissolved in water and EA, and the resulting mixture was extracted three times with EA to remove byproducts from the previous reaction. The aqueous layer was acidified to pH = 1 with 1 N HCl (aqueous solution) and extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give (2 S )-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1 H 1-Imidazol-1-yl)valeric acid (INT-3). Yield: 3.34 g, 84%; Appearance: white solid; 1 H NMR (400 MHz, DMSO-) d 6) δ 12.61 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.39 (s, 1H),7.18 (d, J = 0.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.44 - 4.35 (m, 2H), 3.90- 3.84 (m, 1H), 1.95 - 1.75 (m, 2H), 1.72 - 1.64 (m, 1H), 1.56 - 1.44 (m, 1H), 1.35 (s, 9H); HPLC purity: 100%; C 13 H 20 LCMS calculated value of N4O6: 328.14; observed value: 219.1 [M+H] + .

[0272] INT-4 and INT-9. (2S)-5-(2-amino-1H-1,3-benzodiazol-1-yl)-2-{[(tert-butoxy)carbonyl] Synthesis of aminovaleric acid.

[0273] Step 1 Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}benzyl glutaric acid 1-ester 2,5-dioxopyrrolidine-1-yl ester At 0 °C, (4S)-5-(benzyloxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentanoic acid (10.0 g, 29.6 mmol) and NHS (3.73 g, 32.5 mmol) were placed in 150 mL of DCM in a 500 mL three-necked round-bottom container, and DCC (7.27 g, 35.5 mmol) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with DCM (300 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude (2S)-2-{[(tert-butoxy)carbonyl]amino}glutaric acid 1-benzyl ester 2,5-dioxopyrrolidine-1-yl ester (11.5 g, 26.5 mmol, 92% purity, 83% yield) as a white solid, which was used directly in the next step.

[0274] Step 2 Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoic acid benzyl ester (2S)-2-{[(tert-butoxy)carbonyl]amino}benzyl glutarate 1-ester 2,5-dioxopyrrolidine-1-yl ester (12.0 g, 27.6 mmol) was placed in THF (120 mL) at 0 °C under a nitrogen atmosphere, followed by the dropwise addition of NaBH4 (2.09 g, 55.2 mmol) in THF / H2O (5:1, 60 mL). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1.0 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless oil (2... S Benzyl 2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoate (7.40 g, 22.8 mmol, 96% purity, 90% yield).

[0275] Step 3 Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazol-1-yl)pentanoic acid benzyl ester (INT-4) DIAD (1.87 g, 9.27 mmol) was added dropwise to a stirred solution of 2-nitro-1H-1,3-benzodiazole (1.00 g, 6.18 mmol), (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxyvalerate benzyl ester (2.0 g, 6.18 mmol), and PPh3 (2.58 g, 9.88 mmol) in THF (30 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (NH3·H2O buffer) to give benzyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazol-1-yl)valerate (INT-4) as a yellow solid (2.10 g, 4.48 mmol, 95.6% purity, 72.5% yield). 17 H 22 LCMS calculated value of N4O6: 378.385; observed value: 323.1 [(M- t -Bu+H) + ].

[0276] Step 4 Synthesis of (2S)-5-(2-amino-1H-1,3-benzodiazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}valeric acid (INT-9) (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazol-1-yl)pentanoic acid benzyl ester (2.00 g, 4.26 mmol) was added to a 100 mL round-bottom flask containing MeOH (30 mL) at room temperature under a nitrogen atmosphere, along with Pd / C (455 mg, 4.26 mmol, 10%). The reaction mixture was then degassed and purged three times with hydrogen. The resulting reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give (2S)-5-(2-amino-1H-1,3-benzodiazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (INT-9). Yield: 1.0 g, 65%; ¹H NMR (300 MHz, DMSO-d6) δ 7.35 (s, 1H), 7.14 (t, J = 7.7 Hz, 2H), 6.91 - 6.74 (m, 2H), 6.63 (s, 2H), 4.79 - 4.66 (m, 1H), 3.96 - 3.90 (m, 2H), 1.67 - 1.55 (m, 2H), 1.38 (s, 9H), 1.26 - 1.08 (m, 2H). HPLC purity: 85.2%; C 17 H 24 LCMS calculated value of N4O4: 348.18; observed value: 349.1 [M+H] + .

[0277] INT-5 and INT-6. 9-Ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-6,11-dihydro-5H-benzene Synthesis of [b]carbazole-3-carboxynitrile (INT-6).

[0278] Step 1. Synthesis of tert-butyl piperazine-1-carboxylate (INT-5) Pd₂(dba)₃ (2.07 g, 2.27 mmol), S-Phos (930 mg, 2.27 mmol), and NaHMDS (1 M, 90 mL, 90.8 mmol) were added to a solution of 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (10.0 g, 22.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.63 g, 24.9 mmol) in THF (200 mL) at room temperature. The resulting mixture was stirred at 70 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The reaction was quenched by adding water (100.0 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with petroleum ether / ethyl acetate (0% to 30% ethyl acetate) to give tert-butyl 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazine-1-carboxylate (11.0 g, 22.0 mmol, 90% purity, 95% yield) as a yellow solid.

[0279] Step 2. Synthesis of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile (INT-6) A solution of 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazine-1-carboxylic acid tert-butyl ester (100 mg, 200 μmol) in DCM (1 mL) and TFA (1 mL) was prepared at room temperature and then stirred for 3.0 h. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (NH3·H2O buffer) to give 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazine-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (29.7 mg, 74.7 μmol) (INT-6) as a white solid. Yield: 29.7 mg, 37.2%; Appearance: white solid; 1HNMR (300 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 8.08 - 7.97 (m, 2H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.33 (s, 1H), 2.90 (s, 8H), 2.72 (d, J = 7.5 Hz, 2H), 1.76 (bs, 6H), 1.27 (t, J = 7.0, 6.5 Hz, 3H). HPLC purity: 99.3%; C 25 H 26 LCMS calculated value of N4O: 398.21; observed value: 399.3 [M+H] + .

[0280] INT-7. (R)-8-(4-(4-(3-aminopyrrolidone-1-yl)butyryl)piperazin-1-yl)-9-ethyl-6,6-di Synthesis of methyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile.

[0281] Step 1 . 4-[(3 R Synthesis of methyl 3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyrate 4-Bromobutyrate (193 mg, 1.07 mmol), K₂CO₃ (147 mg, 1.07 mmol), and NaI (160 mg, 1.07 mmol) were added to a solution of 4-bromobutyrate (193 mg, 1.07 mmol) in DMF (5 mL), and the reaction mixture was stirred at 80 °C for 3 h. The reactants were added to water (60 mL) and extracted with EA (60 mL x 3). The organic layer was washed with water (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (PE / EA = 1 / 1) to give the product 4-[(3 R 3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]methyl butyrate (250 mg, 872 μmol, 90% purity, 82% yield) Step 2 . 4-[(3 R Synthesis of 3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyric acid To 4-[(3) RMethyl 3-[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyrate (300 mg, 1.04 mmol) was added to a solution of THF (3 mL) / MeOH (1 mL) / H2O (1 mL), and lithium hydroxide (218 mg, 5.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give a yellow oily substance of 4-[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyrate. R) -3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyric acid (283 mg, 1.04 mmol, 90% purity, 100% yield).

[0282] Step 3 9-Ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5 H 6 H ,11 H Synthesis of benzo[b]carbazole-3-carboxynitrile To 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H 440 mg, 882 μmol of benzo[b]carbazole-8-yl}piperazine-1-carboxylic acid tert-butyl ester was added to a solution of TFA (71.4 μL, 882 μmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a yellow oily substance of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazine-1-yl)-5 H 6 H ,11 H -Benzo[b]carbazole-3-carboxynitrile (330 mg, 828 μmol, 93% purity, 94% yield).

[0283] Step 4 . N-[(3 R Synthesis of tert-butyl carbamate (4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]pyrrolidine-3-yl]carbamate To 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5 H 6 H ,11 H 4-[(3-carbazole-3-carboxynitrile (350 mg, 878 μmol) was added to a solution of benzo[b]carbazole-3-carboxynitrile (350 mg, 878 μmol) in DMF (10 mL). RThe reaction mixture was prepared by stirring at room temperature for 4 h with 285 mg, 1.05 mmol, DIPEA (723 μL, 4.39 mmol), and HATU (497 mg, 1.31 mmol) of 3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyric acid (285 mg, 1.05 mmol), DIPEA (723 μL, 4.39 mmol), and HATU (497 mg, 1.31 mmol). Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (300 mL x 3). The organic layer was washed with water (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (DCM / MeOH = 10 / 1) to give the product N-[(3-... R )-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H Benz[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]pyrrolidine-3-yl]tert-butyl carbamate (450 mg, 689 μmol, 100% purity, 79% yield).

[0284] Step 5 . 8-(4-{4-[(3 R )-3-aminopyrrolidone-1-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5 H 6 H ,11 H Synthesis of benzo[b]carbazole-3-carboxynitrile To N-[(3) R )-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H 400 mg, 612 μmol of benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]pyrrolidine-3-yl]tert-butyl carbamate was added to a solution in DCM (5 mL), and TFA (1.5 mL, 612 μmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a yellow oily substance of 8-(4-{4-[(3 R )-3-aminopyrrolidone-1-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5 H 6 H ,11 H -Benzo[b]carbazole-3-carboxynitrile INT-7 (300 mg, 542 μmol, 94% purity, 89% yield). C 33H 40 LCMS calculated value of N6O2: 552.32; observed value: 553.2 [M+H] + .

[0285] INT-8. 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazol-1-yl)pentyl Synthesis of amide-1-pyrrolidine-1-yl)butyric acid.

[0286] Step 1 Synthesis of ethyl (R)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)butyrate At room temperature, ethyl 4-bromobutyrate (1.25 g, 6.43 mmol) and K₂CO₃ (2.20 g, 16.0 mmol) were added to a solution of N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl ester (1 g, 5.36 mmol) in DMF (10 mL). The reaction mixture was stirred at 80 °C for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-10%) to give ethyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyrate (1.26 g, 4.19 mmol, 100% purity, 78% yield) as a pale yellow oil.

[0287] Step 2 Synthesis of ethyl (R)-4-(3-aminopyrrolidone-1-yl)butyrate TFA (1 ml, 4.19 mmol) was added to a solution of ethyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butyrate (160 mg, 532 μmol) in DCM (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give ethyl 4-[(3R)-3-aminopyrrolidine-1-yl]butyrate (106 mg, 529 μmol, 100% purity, 100% yield) as a pale yellow oil.

[0288] Step 3 Synthesis of ethyl 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazol-1-yl)pentamido)pyrrolidine-1-yl)butyrate At room temperature, (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)valeric acid (190 mg, 581 μmol), DIPEA (343 mg, 2.64 mmol), and DEPBT (237 mg, 793 μmol) were added to a solution of ethyl 4-[(3R)-3-aminopyrrolidone-1-yl]butyrate (106 mg, 529 μmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-10%) to obtain ethyl 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)pentamido]pyrrolidine-1-yl]butyrate (170 mg, 332 μmol, 100% purity, 62% yield), which was a light yellow oil.

[0289] Step 4. Synthesis of 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazol-1-yl)pentamido)pyrrolidine-1-yl)butyric acid LiOH (39.8 mg, 1.66 mmol) was added to a solution of ethyl 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)pentamido]pyrrolidine-1-yl]butyrate (170 mg, 332 μmol) in THF (5 mL) and H2O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 5–6 with 1 N HCl (aqueous solution), and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-30%) to yield a pale yellow oil, 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)pentamido]pyrrolidine-1-yl]butyric acid (INT-8) (120 mg, 248 μmol, 100% purity, 75% yield). 21 H 34 LCMS calculated value of N6O7: 482.25; observed value: 483.1 [M+H]+ .

[0290] INT-10. 8-(4-{4-[(4R)-4-amino-3,3-dimethylpyrrolidin-1-yl]butyryl}piperazin-1-yl)- Synthesis of 9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile Step 1 . 4-[(4 R Synthesis of methyl butyrate 4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyrate Towards N -[(3 R A solution of tert-butyl 4,4-dimethylpyrrolidone-3-yl]carbamate (250 mg, 1.16 mmol) and methyl 4-bromobutyrate (376 mg, 2.08 mmol) in MeCN (5 mL) was mixed with DIPEA (599 mg, 4.64 mmol) and stirred at 80 °C for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by rapid silica gel chromatography (DCM / MeOH = 20 / 1) to give a yellow oily product 4-[(4-] R Methyl butyrate (300 mg, 954 μmol) of 4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidone-1-yl]butyrate.

[0291] Step 2 . 4-[(4 R Synthesis of 4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyric acid To 4-[(4) R Methyl 4-[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyrate (300 mg, 954 μmol) was added to a solution of THF (5 mL) and water (2.5 mL), and LiOH (45.6 mg, 1.9 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product 4-[(4-[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyrate. R )-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyric acid (279 mg, 927 μmol) was used directly in subsequent steps.

[0292] Step 3 . N -[(3 R )-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11H -benzo[ b Synthesis of tert-butyl carbamate (carbazole-8-ylpiperazin-1-yl)-4-oxobutyl]-4,4-dimethylpyrrolidine-3-yl]carbamate To 4-[(4) R A solution of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5-[[(tert-butoxy)carbonyl]amino]-3,3-dimethylpyrrolid-1-yl]butyric acid (200 mg, 665 μmol), DIPEA (429 mg, 3.32 mmol), and HATU (379 mg, 997 μmol) in DMF (5 mL) was added. H 6 H ,11 H -benzo[ b Carbazole-3-carboxynitrile (265 mg, 665 μmol) was reacted and stirred at room temperature for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by preparative HPLC (ACN / water / 0.1% FA) to give a product as a yellow solid. N -[(3 R )-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b [Carbazole-8-yl]piperazin-1-yl]-4-oxobutyl]-4,4-dimethylpyrrolidone-3-yl]tert-butyl carbamate (263 mg, 386 μmol).

[0293] Step 4. 8-(4-{4-[(4 R )-4-amino-3,3-dimethylpyrrolidone-1-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5 H 6 H ,11 H -benzo[ b Synthesis of Carbazole-3-carboxynitrile Towards N -[(3 R )-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b[Carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]-4,4-dimethylpyrrolidone-3-yl]tert-butyl carbamate (70 mg, 102 μmol) was added to a solution of TFA (1.5 mL) in DCM (3 mL), and the mixture was stirred at room temperature for 40 min. After the mixture was concentrated, it was concentrated under reduced pressure to obtain a crude residue, which was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to obtain the product 8-(4-{4-[(4 R )-4-amino-3,3-dimethylpyrrolidone-1-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5 H 6 H ,11 H -benzo[ b Carbazole-3-carboxynitrile (INT-10). Yield: 15 mg, 25%; Appearance: white solid; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 8.4Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.0, 1.2 Hz, 1H), 7.39 (s,1H), 3.65 (s, 4H), 3.01 - 2.79 (m, 6H), 2.75 (q, J = 7.6 Hz, 2H), 2.46 - 2.07(m, 7H), 1.75 (s, 6H), 1.70 - 1.55 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H), 1.08 -0.69 (m, 6H); HPLC purity: 92.64%; C 35 H 44 LCMS calculated value of N6O2: 580.78; observed value: 581.1 [M+H] + .

[0294] INT-11. (R)-8-(4-(4-(7-amino-5-azaspiro[2.4]hept-5-yl)butyryl)piperazin-1-yl)-9- Synthesis of ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile.

[0295] Step 1 Synthesis of methyl 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]hept-5-yl]butyrate 4-Bromobutyrate methyl ester (300 mg, 1.65 mmol), DIEA (637 mg, 4.94 mmol) and N A solution of tert-butyl 4-[(7R)-5-azaspiro[2.4]hept-7-yl]carbamate (354 mg, 1.65 mmol) in MeCN (5 mL) was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under vacuum to give methyl 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2.4]hept-5-yl]butyrate (301 mg, 965 μmol, 86.0% purity, 59.0% yield) as a yellow oil, which was used directly in the next step.

[0296] Step 2 Synthesis of 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]hept-5-yl]butyric acid A solution of methyl 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]hept-5-yl]butyrate (350 mg, 1.12 mmol) and NaOH (134 mg, 3.36 mmol) in MeOH / H2O (1:1, 10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to give crude 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]hept-5-yl]butyric acid (256 mg, 860 μmol, 86.0% purity, 77.0% yield) as a yellow oil, which was used directly in the next step.

[0297] Step 3 Synthesis of N-[(7R)-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]-5-azaspiro[2.4]hept-7-yl]tert-butyl carbamate A mixture of 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]hept-5-yl]butyric acid (300 mg, 1.00 mmol), DIEA (398 mg, 1.00 mmol), and 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (398 mg, 1.00 mmol) in DMF (5 mL) was stirred at room temperature for 10 min. HATU (455 mg, 1.20 mmol) was then added, and the reaction mixture was stirred at room temperature for 1.0 h. The mixture was concentrated in vacuum, and the residue was purified by preparative HPLC (NH3·H2O buffer) to give N-[(7R)-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazo-8-yl}piperazin-1-yl)-4-oxobutyl]-5-azaspiro[2.4]hept-7-yl]carbamate tert-butyl ester (346 mg, 509 μmol, 87.0% purity, 51.0% yield) as a yellow solid.

[0298] Step 4 Synthesis of 8-(4-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxylonitrile (INT-11).

[0299] A solution of N-[(7R)-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]-5-azaspiro[2.4]hept-7-yl] tert-butyl carbamate (180 mg, 265 μmol) in TFA / DCM (1:1, 5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give 8-(4-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]butyryl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile INT-11 (127 mg, 220 μmol, 85% purity, 83% yield), which was used directly in the next step.

[0300] INT-12. (2S)-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H, 6H,11H-Benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]pyridin-3-yl}-2-{[(tert-butoxy)carbonyl] Synthesis of aminovaleric acid Step 1 . (2 S Synthesis of methyl 5-(2-amino-5-bromopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pent-4-acetylic acid At room temperature to (2 S Methyl 2-{[(tert-butoxy)carbonyl]amino}pent-4-acetylic acid (250 mg, 1.10 mmol), 5-bromo-3-iodopyridin-2-amine (273 mg, 916 μmol), Pd(PPh3)2Cl2 (128 mg, 183 μmol), and CuI (17.4 mg, 91.6 μmol) were added to a solution of DMF (5 mL) with TEA (463 mg, 4.58 mmol). The reaction mixture was stirred at 80 °C for 4 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-5%) to give a yellow solid (2 S Methyl 5-(2-amino-5-bromopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pent-4-acetylic acid (258 mg, 647 μmol, 100% purity, 71% yield).

[0301] Step 2 (3) E )-4-{6-amino-5-[(4 S Synthesis of 4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopent-1-yn-1-yl]pyridin-3-yl}but-3-enoic acid At room temperature to (2 S Methyl 5-(2-amino-5-bromopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pent-4-ynyl ester (290 mg, 728 μmol), but-3-enoic acid (155 mg, 1.81 mmol), (acetyloxy)palladium acetate (24.4 mg, 109 μmol), P( o TEA (367 mg, 3.63 mmol) was added to a solution of 3-tol)3 (66.3 mg, 218 μmol) in CH3CN (5 mL). The reaction mixture was stirred at 120 °C for 0.5 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography (MeOH / DCM = 0-10%) to give a brown solid (3-tol) E)-4-{6-amino-5-[(4 S )-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopent-1-yn-1-yl]pyridin-3-yl}but-3-enoic acid (185 mg, 458 μmol, 92% purity, 63% yield).

[0302] Step 3 4-{6-amino-5-[(4 S Synthesis of 4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridin-3-yl}butyric acid At room temperature to (3 E )-4-{6-amino-5-[(4 S Pd / C (97.3 mg, 91.6 μmol) was added to a solution of 4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopent-1-yn-1-yl]pyridin-3-yl}but-3-enoic acid (185 mg, 458 μmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under H2 for 16 h. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure to give 4-{6-amino-5-[(4-butoxy)carbonyl]amino}-5-methoxy-5-oxopent-1-yn-1-yl]pyridin-3-yl}but-3-enoic acid as a pale yellow solid. S )-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridin-3-yl}butyric acid (155 mg, 378 μmol, 85% purity, 83% yield).

[0303] Step 4 . (2 S )-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b Synthesis of methyl valerate [carbazole-8-yl]piperazin-1-yl]-4-oxobutyl]pyridin-3-yl]-2-[(tert-butoxy)carbonyl]amino]valerate At room temperature, 4-{6-amino-5-[(4 S )-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridin-3-yl}butyric acid (155 mg, 378 μmol) and 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5 H 6 H ,11 H -benzo[ bCarbazole-3-carboxynitrile (150 mg, 378 μmol) was added to a solution of DCM (5 mL) with DIPEA (242 mg, 1.88 mmol) and HATU (172 mg, 453 μmol). The reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-10%) to give a yellow solid (2... S )-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b Methyl carbazo-8-yl}piperazin-1-yl)-4-oxobutyl]pyridin-3-yl}-2-{[(tert-butoxy)carbonyl]amino}valerate (103 mg, 130 μmol, 91% purity, 35% yield).

[0304] Step 5 . (2 S )-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b Synthesis of [carbazole-8-yl]piperazin-1-yl]-4-oxobutyl]pyridin-3-yl]-2-{[(tert-butoxy)carbonyl]amino}valeric acid At room temperature to (2 S )-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b Methyl valerate (103 mg, 130 μmol) of [carbazole-8-yl]piperazin-1-yl]-4-oxobutyl]pyridin-3-yl]-2-{[(tert-butoxy)carbonyl]amino}valerate (103 mg, 130 μmol) was added to a solution of THF (5 mL) and H2O (2 mL) with LiOH·H2O (27.2 mg, 650 μmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give (2)Li salt form. S)-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5- H 6 H ,11 H -benzo[ b [Carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]pyridin-3-yl}-2-{[(tert-butoxy)carbonyl]amino}valeric acid (100 mg, 128 μmol, 91% purity, 100% yield), was used in the next step without further purification.

[0305] INT-13. (S)-5-(2-amino-4-(5-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11- Dihydro-5H-benzo[b]carbazole-8-yl)piperazin-1-yl)-5-oxopentyl)-1H-imidazol-1-yl)-2-((tert-butoxycarbonyl) Synthesis of α-aminovaleric acid.

[0306] Step 1. Synthesis of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazol-1-yl)valerate. A mixture of (2S)-5-bromo-2-{[(tert-butoxy)carbonyl]amino}valerate tert-butyl ester (5.00 g, 14.1 mmol), K₂CO₃ (5.83 g, 42.3 mmol), 2-nitro-1H-imidazole (1.75 g, 15.5 mmol), and DMF (50 mL) at room temperature was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature and quenched by adding water (100.0 mL). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated brine (3 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)valerate tert-butyl ester (4.50 g, 11.7 mmol, 90% purity, 82% yield), which was a yellow solid.

[0307] Step 2. Synthesis of tert-butyl (2S)-5-(4-bromo-2-nitro-1H-imidazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate. A mixture of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)valerate tert-butyl ester (4.00 g, 10.4 mmol), NBS (2.77 g, 15.6 mmol), and DMF (50 mL) at room temperature was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature and quenched by adding water (100.0 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated brine (3 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain (2S)-5-(4-bromo-2-nitro-1H-imidazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}tert-butyl valerate (3.00 g, 6.47 mmol, 90% purity, 65% yield), which was a yellow solid.

[0308] Step 3. Synthesis of methyl pent-4-enoate (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoate TEA (2.17 g, 21.5 mmol) and Pd2(dba)3 (788 mg, 862 μmol) and P(O-Tol)3 (1.31 g, 4.31 mmol) were added to a solution of (2S)-5-(4-bromo-2-nitro-1H-imidazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate (2.00 g, 4.31 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, H2O / MeCN containing 0.1% NH4OH in a 10% to 50% gradient over 10 min; detector, UV 254 nm) to give methyl (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoate (1.00 g, 2.01 mmol, 90% purity, 47% yield).

[0309] Step 4. Synthesis of (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoic acid LiOH (205 mg, 5.00 mmol) was added to a stirred solution of (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoic acid (500 mg, 1.00 mmol) in MeOH (5 mL) and H2O (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give crude (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoic acid (300 mg, 621 μmol, 90% purity, 62% yield) as a yellow solid.

[0310] Step 5. Synthesis of (2S)-5-(4-bromo-2-nitro-1H-imidazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}valerate K₂CO₃ (426 mg, 3.09 mmol) was added to a solution of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (450 mg, 1.13 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred for 15 min at room temperature. (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazol-4-yl}pent-4-enoic acid (500 mg, 1.03 mmol) and HATU (585 mg, 1.54 mmol) were added to the above mixture at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The reaction was quenched by adding water (200 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 x 100 mL). The resulting solid was dried under infrared light. This yielded (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{4-[(1E)-5-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-5-oxopent-1-en-1-yl]-2-nitro-1H-imidazol-1-yl}tert-butyl valerate (400 mg, 463 μmol, 90% purity, 50% yield) as a yellow solid.

[0311] Step 6. Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{4-[(1E)-5-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-5-oxopent-1-en-1-yl]-2-nitro-1H-imidazol-1-yl}valeric acid.

[0312] At room temperature, tert-butyl valerate (400 mg, 463 μmol) of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{4-[(1E)-5-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-5-oxopent-1-en-1-yl]-2-nitro-1H-imidazol-1-yl}valerate (400 mg, 463 μmol) was added to a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{4-[(1E)-5-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-5-oxopent-1-en-1-yl]-2-nitro-1H-imidazol-1-yl}valerate (400 mg, 463 μmol) in MeOH (10 mL) and H₂O (5 mL). The resulting mixture was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, water containing MeCN, in a 30% to 55% gradient over 10 min; detector, UV 220 nm. This yielded (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{4-[(1E)-5-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-5-oxopent-1-en-1-yl]-2-nitro-1H-imidazol-1-yl}valeric acid (INT-13). Yield: 300 mg, 90%; Appearance: yellow solid; 1 H NMR (300 MHz, DMSO-d6)δ8.22 (d, J = 3.2 Hz, 1H), 8.05 (s, 1H), 7.96 - 7.91 (m, 2H), 7.68 (s, 1H),7.47 - 7.30 (m, 2H), 6.46 - 6.28 (m, 1H), 5.99 - 5.97 (m, 1H), 4.29 - 4.28(m, 1H), 3.69 - 3.67 (m, 4H), 2.92 - 2.86 (m, 6H), 2.82 - 2.69 (m, 4H), 2.57(d, J = 6.4 Hz, 2H), 1.79 - 1.60 (m, 10H), 1.36 (s, 9H), 1.29 (t, J = 5.4 Hz, 3H). HPLC purity: 90%; C43 H 50 LCMS calculated value of N8O8: 806.38; observed value: 807.5 [M+H] + .

[0313] INT-14. N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]amino Synthesis of tert-butyl formate.

[0314] Step 1 Synthesis of N-[(3R)-1-ethylpyrrolidone-3-yl]tert-butyl carbamate At room temperature N 1-[(3R)-1-ethylpyrrolidine-3-yl]tert-butyl carbamate (4.00 g, 21.4 mmol) and bromoethane (2.78 g, 25.6 mmol) were added to a stirred solution in MeCN (50 mL) with K₂CO₃ (8.84 g, 64.1 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. This yielded N-[(3R)-1-ethylpyrrolidine-3-yl]tert-butyl carbamate (2.40 g, 11.1 mmol, 85% purity, 53% yield) as a yellow solid.

[0315] Step 2 Synthesis of (R)-1-ethylpyrrolidine-3-amine hydrochloride A solution of N-[(3R)-1-ethylpyrrolidine-3-yl]carbamate tert-butyl ester (2.40 g, 11.1 mmol) in HCl / dioxane (4 M, 20 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give a brown solid (R)-1-ethylpyrrolidine-3-amine HCl salt (1.60 g, 10.6 mmol, 80% purity, crude product), which was used directly in the next step.

[0316] Step 3 Synthesis of N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidone-3-yl]carbamoyl}butyl]tert-butyl carbamate A mixture of (2S)-5-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butoxy)carbonyl]amino}valeric acid (2.00 g, 5.45 mmol), (3R)-1-ethylpyrrolidine-3-amine hydrochloride (985 mg, 6.54 mmol), and NMI (1.55 g, 19.0 mmol) in MeCN (20 mL) was stirred at 0 °C for 10 min. TCFH (1.83 g, 6.54 mmol) was then added, and the reaction mixture was stirred at room temperature for 3.0 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10% to 40% ethyl acetate) elution to give N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl] tert-butyl carbamate (1.80 g, 3.89 mmol, 95% purity, 71% yield) as a white solid.

[0317] Step 4. Synthesis of N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidone-3-yl]carbamoyl}butyl] tert-butyl carbamate (INT-14) N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl] tert-butyl carbamate (1.8 g, 3.89 mmol) was added to a 50 mL round-bottom flask containing MeOH (20 mL) at room temperature under a nitrogen atmosphere, along with Pd / C (372 mg, 3.50 mmol, 10%). The reaction mixture was then degassed and purged three times with hydrogen. The resulting reaction mixture was stirred for 3 hours under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated under vacuum to give N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl] tert-butyl carbamate (INT-14) as a white solid. Yield: 1.20 g, 94%; 1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J = 7.40 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.19 - 4.03(m, 1H), 3.93 - 3.81 (m, 1H), 2.95 - 2.83 (m, 1H), 2.67 - 2.53 (m, 4H), 2.45- 2.24 (m, 4H), 2.15 - 1.98 (m, 1H), 1.66 - 1.42 (m, 4H), 1.38 (s, 9H), 1.01(t, J = 7.2 Hz, 3H). HPLC purity: 90%; C 16 H 32 LCMS calculated value of N4O3: 328.25; observed value: 329.1 [M+H] + .

[0318] INT-15. 8-[4-(4-aminobutyryl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H, Synthesis of 6H,11H-benzo[b]carbazole-3-carboxynitrile.

[0319] Step 1 Synthesis of N-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]carbamate tert-butyl A mixture of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (500 mg, 1.25 mmol), 4-{[(tert-butoxy)carbonyl]amino}butyric acid (254 mg, 1.25 mmol), and DIEA (483 mg, 3.75 mmol) in DMF (10 mL) was stirred at room temperature for 10 min. HATU (570 mg, 1.50 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (NH3·H2O buffer) to give N-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazo-8-yl}piperazin-1-yl)-4-oxobutyl]carbamate (690 mg, 1.18 mmol, 98.0% purity, 95.0% yield) as a white solid.

[0320] Step 2. Synthesis of 8-[4-(4-aminobutyryl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile (INT-15) A solution of N-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]carbamate (700 mg, 1.19 mmol) in TFA / DCM (1:1, 10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give 8-[4-(4-aminobutyryl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carboxynitrile TFA salt (INT-15). Yield: 600 mg, crude product; 1 H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.33 (d, J =8.1 Hz, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.62 (d, J =1.4 Hz, 1H), 7.39 (s,1H), 3.81 - 3.55 (m, 4H), 3.05 - 2.92 (m, 4H), 2.92 - 2.80 (m, 2H), 2.80 -2.70 (m, 2H), 1.82 (t, J = 7.5 Hz, 2H), 1.76 (s, 6H), 1.36 - 1.16 (m, 5H). HPLC purity: 92.4%; C 29 H 33 LCMS calculated value of N5O2: 483.26; observed value: 484.3 [M+H] + .

[0321] INT-16. (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)- Synthesis of pyridazona-1(4,3)-pyrazola-5(1,2)-benzerocyclopentaenoic acid (INT-16): Step 1 Synthesis of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine DIAD (228 g, 1.13 mol, 1.50 equivalent) was added dropwise to a stirred solution of (1S)-1-(5-fluoro-2-iodophenyl)ethanol (200 g, 751 mmol, 1.00 equivalent) and 2-aminopyridin-3-ol (91.1 g, 827 mmol, 1.10 equivalent) and PPh3 (295 g, 1.13 mol, 1.50 equivalent) in THF (4.00 L) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched with H2O (100 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0 to 50% ethyl acetate) elution to obtain 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine (220 g, 57%), which was a yellow oil.

[0322] Step 2 Synthesis of methyl 2-[(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate In a pressure vessel, Pd(dppf)Cl2 (44.9 g, 61.4 mmol, 0.1 equivalent) was added to a solution of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine (220 g, 614 mmol, 1.00 equivalent) and TEA (186 g, 1.84 mol, 3.0 equivalent) in MeOH (8.00 L). The mixture was purged three times with carbon monoxide and then pressurized to 20.0 Psi at 100 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0 to 50% ethyl acetate) elution to obtain methyl 2-[(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (220 g, 86%), which was a green oil.

[0323] Step 3 Synthesis of methyl 2-[(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate NBS (88.3 g, 496 mmol, 1.20 equivalent) was added dropwise to a stirred solution of methyl 2-[(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (120 g, 413 mmol, 1.00 equivalent) in MeCN (1.00 L) under N2 atmosphere at 0 °C. The resulting mixture was stirred at 0 °C–10 °C for 2 hours under N2 atmosphere. The mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (1.00 L). The mixture was alkalized to pH 8–9 using saturated NaHCO3 solution. The mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0 to 30% ethyl acetate) elution to obtain methyl 2-[(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (60.0 g, 33%) as a yellow solid.

[0324] Step 4 Synthesis of methyl (R)-2-(1-((2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-3-yl)oxy)ethyl)-4-fluorobenzoate Pd(dppf)Cl2 (13.2 g, 16.3 mmol, 0.100 equivalent) was added to a solution of methyl 2-[(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (60.0 g, 163 mmol, 1.00 equivalent) and KOAc (39.9 g, 406 mmol, 2.50 equivalent), and bis(pinacol)diboron (49.5 g, 195 mmol, 1.20 equivalent) in dioxane (600 mL). The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and used directly in the next step.

[0325] Step 5 Synthesis of methyl 2-[(1R)-1-([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazol-4-yl)pyridin-3-yl]oxyethyl]-4-fluorobenzoate N-[(5-cyano-4-iodo-1H-pyrazol-3-yl)methyl]-N-methylcarbamate tert-butyl ester (47.9 g, 132 mmol, 1.10 equivalents), H2O (200 mL), K2CO3 (49.8 g, 360 mmol, 3.00 equivalents), and Pd(DTBPF)Cl2 (15.7 g, 24.0 mmol, 0.20 equivalents) were added to the mixture from the previous step at room temperature. After stirring at 100 °C for 16 hours under a nitrogen atmosphere, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and H2O (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0 to 80% ethyl acetate) elution to obtain methyl 2-[(1R)-1-([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazol-4-yl)pyridin-3-yl]oxyethyl]-4-fluorobenzoate (25.0 g, 31%) as a yellow solid.

[0326] Step 6 Synthesis of methyl 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazol-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoate Methyl 2-[(1R)-1-([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazol-4-yl)pyridin-3-yl]oxyethyl]-4-fluorobenzoate (25.0 g, 47.7 mmol, 1.00 equivalent) in HCl (gas) was added to a stirred solution in 1,4-dioxane (4 M, 250 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under vacuum. The crude product, methyl 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazol-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoate HCl salt (18.0 g, 71%), was used directly in the next step without further purification.

[0327] Step 7. Synthesis of 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazol-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoic acid At room temperature, methyl 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (18.0 g, 42.4 mmol, 1.00 equivalent) was added in portions to a stirred solution of 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoate (13.0 g, 1.00 equivalent) in MeOH (100 mL) and H₂O (50 mL). The resulting mixture was stirred at 40 °C for 3 hours. The mixture was then cooled to room temperature. The mixture was concentrated under vacuum to give a crude product, 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoic acid (13.0 g, 1.00 equivalent), as a pale yellow solid. 56%), which is used directly in the next step.

[0328] Step 8 Synthesis of (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaza-1(4,3)-pyrazola-5(1,2)benzerocyclopentafen-15-carboxynitrile PH-CSM-INT-10 / CSM-2362073 (INT-16) PyBOP (24.7 g, 47.5 mmol, 1.50 equivalent) was added in portions to a stirred solution of 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazol-4-ylpyridin-3-yl)oxy]ethyl]-4-fluorobenzoic acid (13.0 g, 31.7 mmol, 1.00 equivalent) and K₂CO₃ (8.76 g, 63.3 mmol, 2.00 equivalent) in DMF (200 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, H₂O containing MeCN (0.01% TFA), in a 30% to 55% gradient over 15 min; detector, UV 254. nm. (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaza-1(4,3)-pyrazola-5(1,2)-benzerocyclopentaenoic acid-15-carboxynitrile (PH-CSM-INT-10 / CSM-2362073(INT-16)) was obtained. Yield: 6.0 g, 45%. Appearance: white solid; 1H NMR (400 MHz, DMSO-d6, ppm) δ 14.70 (s, 1H), 8.1 (bs, 2H), 7.64 (s, 1H), 7.60 - 7.53 (m, 2H), 7.25 (td, J = 8.5, 2.7 Hz, 1H), 7.08 (s, 1H), 5.77 (m, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.36 (d, J = 5.1 Hz, 1H), 3.02 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H). HPLC purity: 85.0%; LCMS calculated value of C20H17FN6O2: 392.14; observed value: 393.2 [M+H]+.

[0329] Step 9. Synthesis of N-[(5-cyano-4-iodo-1H-pyrazol-3-yl)methyl]-N-methylcarbamate tert-butyl ester INT-17 NIS (42.9 g, 190 mmol, 1.00 equivalent) was added in portions to a stirred solution of N-[(5-cyano-1H-pyrazole-3-yl)methyl]-N-methylcarbamate tert-butyl ester (45.0 g, 190 mmol, 1.00 equivalent) in MeCN (400 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography by elution with ethyl acetate / petroleum ether (0 to 50% ethyl acetate) to give N-[(5-cyano-4-iodo-1H-pyrazole-3-yl)methyl]-N-methylcarbamate tert-butyl ester INT-17 (40.0 g, 52%) as a yellow solid.

[0330] INT-18. (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11-(piperidin-4-ylmethyl)-11H-3- Synthesis of oxa-7-aza-2(3,5)-pyridaza-1(4,3)-pyrazola-5(1,2)-benzerocyclopentafen-15-carboxynitrile.

[0331] Step 1. Synthesis of tert-butyl (R)-4-((26-amino-15-cyano-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaza-1(4,3)-pyrazola-5(1,2-benzerocyclopentaeno-11-yl)methyl)piperidine-1-carboxylic acid ester DIAD (230 mg, 1.14 mmol) was added to a stirred solution of (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaz-1(4,3)-pyrazola-5(1,2)-benzerocyclopentaenoic acid 15-carboxynitrile (300 mg, 764 μmol), 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (197 mg, 916 μmol), and PPh3 (298 mg, 1.14 mmol) in THF (10 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 3 hours. The reaction was quenched with H2O (1 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain (R)-4-((26-amino-15-cyano-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaza-1(4,3)-pyrazola-5(1,2)-benzocyclopentafan-11-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 339 μmol, 80% purity, 44% yield). 1¹H NMR (300 MHz, DMSO-d⁶) δ 7.66 - 7.56 (m, 3H), 7.50 - 7.44 (m, 1H), 6.82 (d, J = 1.9 Hz, 1H), 5.62 (q, J = 6.8 Hz, 1H), 4.26 - 4.22 (m, 2H), 3.99 - 3.89 (m, 2H), 3.00 (s, 3H), 2.81 - 2.61 (m, 3H), 2.18 - 2.03 (m, 2H), 1.69 (d, J = 6.1 Hz, 3H), 1.61 - 1.46 (m, 4H), 1.40 (s, 9H). HPLC purity: 80%; C 31 H 36 LCMS calculated value of FN7O4: 589.28; observed value: 590.3 [M+H] + .

[0332] INT-19. Synthesis of 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid Step 1 Synthesis of ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxyprop-2-enoate Ethyl 3-cyclopropyl-3-oxopropionic acid (5.00 g, 32.0 mmol) and (diethoxymethoxy)ethane (9.48 g, 64.0 mmol) were placed in Ac2O (60 mL) at room temperature. The resulting mixture was stirred overnight at 130 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum to give ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxyprop-2-enoate (5.77 g, 27.2 mmol, 82.4% purity, 84.5% yield) as a yellow oil, which was used directly in the next step.

[0333] Step 2 Synthesis of ethyl 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylate A solution of ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxyprop-2-enoate (4.00 g, 18.8 mmol) and 3-chloro-1H-pyrazole-5-amine (2.20 g, 18.8 mmol) in EtOH (80 mL) was stirred overnight at 80 °C. The mixture was cooled to room temperature, filtered, and the filter cake was washed with Et2O (3 x 30 mL). The mixture was concentrated under vacuum to give ethyl 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.62 g, 9.89 mmol, 97.4% purity, 52.5% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.94 (s,1H), 4.37 (q, J = 7.1 Hz, 2H), 2.98 - 2.84 (m, 1H), 1.73 - 164 (m, 2H), 1.36(t, J = 7.1 Hz, 3H), 1.25 - 1.14 (m, 2H).

[0334] Step 3 Synthesis of 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (INT-19) To a solution of ethyl 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2.00 g, 7.52 mmol) in EtOH (20 mL) and H₂O (20 mL), NaOH (889 mg, 22.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was adjusted to pH 3 with 2 M HCl, and the precipitated solid was collected by filtration and washed with water (3 x 20 mL). The resulting solid was dried under infrared light. This yielded 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (INT-19). Yield: 1.8 g, 83%; HPLC purity: 98.6%; C 10 LCMS calculated value of H8ClN3O2: 237.03; observed value: 238.1 [M+H] + .

[0335] INT-20. 1-(2-{4-[(3R)-3-aminopyrrolidine-1-yl]butoxy}-5-chloropyridin-3-yl)-3-{2- Synthesis of chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}urea.

[0336] Step 1 Synthesis of 4-[(5-chloro-3-nitropyridin-2-yl)oxy]but-1-ol A solution of N-(17-hydroxy-3,6,9,12,15-pentaheptadecane-1-yl)carbamate tert-butyl ester (2.16 g, 5.67 mmol) and butane-1,4-diol (2.33 g, 25.9 mmol) in DMF (10.0 mL) was added at 0 °C. t -BuOK (2.90 g, 25.9 mmol). The mixture was stirred at 0 °C for 2 hours. The mixture was then heated to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC (NH3·H2O buffer) to give 4-[(5-chloro-3-nitropyridin-2-yl)oxy]but-1-ol (2.56 g, 10.4 mmol, 86% purity, 40% yield) as a brown oil.

[0337] Step 2 Synthesis of 4-[(5-chloro-3-nitropyridin-2-yl)oxy]butyraldehyde A solution of 4-[(5-chloro-3-nitropyridin-2-yl)oxy]butan-1-ol (2.00 g, 8.10 mmol) and IBX (2.94 g, 10.5 mmol) in MeCN (30 mL) was stirred at 80 °C for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with MeCN (3 x 30 mL), and the filtrate was concentrated under reduced pressure to give crude 4-[(5-chloro-3-nitropyridin-2-yl)oxy]butanal (1.46 g, 6.00 mmol, 86% purity, 74% yield) as a yellow oil, which was used directly in the next step.

[0338] Step 3 Synthesis of N-[(3R)-1-{4-[(5-chloro-3-nitropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]tert-butyl carbamate To a solution of 4-[(5-chloro-3-nitropyridin-2-yl)oxy]butyraldehyde (1.80 g, 7.35 mmol) and N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl ester (1.36 g, 7.35 mmol) in MeOH (30 mL), NaBH3CN (1.49 g, 22.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give N-[(3R)-1-{4-[(5-chloro-3-nitropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl ester (1.20 g, 2.89 mmol, 92% purity, 40% yield) as a brown solid.

[0339] Step 4 Synthesis of N-[(3R)-1-{4-[(3-amino-5-chloropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]tert-butyl carbamate Under a nitrogen atmosphere at room temperature, N-[(3R)-1-{4-[(5-chloro-3-nitropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl ester (1.00 g, 2.41 mmol) was placed in MeOH (20 mL) in a 250 mL round-bottom flask, and Raney nickel (282 mg, 4.82 mmol) was added. The reaction mixture was then degassed and purged three times with hydrogen. The resulting reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give N-[(3R)-1-{4-[(3-amino-5-chloropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl ester (725 mg, 1.88 mmol, 85% purity, 78% yield) as a grayish-white solid.

[0340] Step 5 Synthesis of N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}carbamoyl)amino]pyridin-2-yl}oxy)butyl]pyrrolidine-3-yl]tert-butyl carbamate 2-Chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-carboxylic acid (306 mg, 1.29 mmol), DPPA (530 mg, 1.93 mmol), and TEA (390 mg, 3.87 mmol) were placed in 10 mL of dioxane in a 40 mL four-necked round-bottom container and stirred at room temperature for 30 min. Then, N-[(3R)-1-{4-[(3-amino-5-chloropyridin-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl ester (500 mg, 1.29 mmol) was added, and the reaction mixture was stirred at 100 °C for 4.0 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using petroleum ether:ethyl acetate = 1:1 elution to obtain N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}carbamoyl)amino]pyridin-2-yl}oxy)butyl]pyrrolidine-3-yl]carbamate tert-butyl ester (113 mg, 183 μmol, 76% purity, 14% yield) as a brown solid.

[0341] Step 6 Synthesis of 1-(2-{4-[(3R)-3-aminopyrrolidone-1-yl]butoxy}-5-chloropyridin-3-yl)-3-{2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}urea (INT-20) A solution of N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}carbamoyl)amino]pyridin-2-yl}oxy)butyl]pyrrolidine-3-yl]carbamate tert-butyl ester (140 mg, 225 μmol) in TFA / DCM (1:1, 5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give 1-(2-{4-[(3R)-3-aminopyrrolidine-1-yl]butoxy}-5-chloropyridin-3-yl)-3-{2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl}urea INT-20 (103 mg, 199 μmol, 88% purity, 94% yield) as a TFA salt, which was a brown oil.

[0342] INT-21 and INT-22. (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl Synthesis of methyl 4-[(tert-butoxy)carbonyl]amino]butyl]amino]-3-nitrophenyl)prop-2-enoate (INT-22) Step 1 Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]tert-butyl carbamate A mixture of (2S)-5-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butoxy)carbonyl]amino}valeric acid (2.1 g, 5.73 mmol), 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one hydrochloride (1.03 g, 6.30 mmol), and DIEA (2.20 g, 17.1 mmol) in DMF (30.0 mL) was stirred at room temperature for 10 min. HATU (2.61 g, 6.87 mmol) was then added, and the reaction mixture was stirred at room temperature for 1.0 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether:ethyl acetate (50% to 80% ethyl acetate) to give N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]carbamate tert-butyl ester (2.00 g, 4.19 mmol, 95% purity, 73% yield) as a white solid.

[0343] Step 2 Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-aminobutyl]tert-butyl carbamate (INT-21) Pd / C (445 mg, 4.19 mmol, 10%) was added to a solution of N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]carbamate (2.0 g, 4.19 mmol) in MeOH (20 mL) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature under a hydrogen atmosphere for 3 hours using a hydrogen gasbag, filtered through a diatomaceous earth pad, and concentrated under reduced pressure to give N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-aminobutyl]carbamate (1.40 g, 4.08 mmol, 90% purity, 95% yield) as a colorless oil.

[0344] Step 3 Synthesis of methyl propionate (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoate At room temperature, place N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-aminobutyl]carbamate tert-butyl ester (900 mg, 2.62 mmol), (2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate methyl ester (884 mg, 3.93 mmol), DIEA (1.01 g, 7.86 mmol), and 1,4-dioxane (10.0 mL) into a 100 mL three-necked round-bottom container. Stir the resulting mixture overnight at 110 °C under a nitrogen atmosphere (1 atm). Allow the mixture to cool to room temperature. The resulting mixture was concentrated in vacuum, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile phase containing 0.05% ammonia, in a 60% to 80% gradient over 20 min; detector, UV 254 nm. The result was a yellow solid (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolid-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoate methyl ester (1.00 g, 1.82 mmol, 90% purity, 69% yield).

[0345] Step 4 Synthesis of methyl 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)propionate Pd / C (115 mg, 1.09 mmol, 10%) was added to a solution of methyl (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidin-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoate (600 mg, 1.09 mmol) in MeOH (12.0 mL) under a nitrogen atmosphere. The mixture was hydrogenated in a hydrogen atmosphere at room temperature for 2 hours using a hydrogen gasbag, filtered through a diatomaceous earth pad and concentrated under reduced pressure to give methyl 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)propionate (450 mg, 865 μmol, 85% purity, 79% yield) as a yellow oil.

[0346] Step 5Synthesis of methyl propionate 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazol-5-yl} Place methyl 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)propionate (400 mg, 769 μmol), cyanogen bromide (488 mg, 4.61 mmol), and EtOH (8.0 mL) into a 50 mL round-bottom container. Stir the resulting mixture at room temperature for 2 hours. The resulting mixture was concentrated in vacuum, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile phase containing 0.05% ammonia, in a 40% to 70% gradient over 20 min; detector, UV 254 nm. The result was methyl 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazol-5-yl}propionate (250 mg, 459 μmol, 80% purity, 59% yield) as a white solid.

[0347] Step 6 Synthesis of methyl propionate (INT-22) of (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoate.

[0348] LiOH (18.4 mg, 1.76 mmol) was added to a solution of methyl 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazol-5-yl}propionate (240 mg, 440 μmol) in THF:H2O (2:1, 4.8 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2–3 with 1 M HCl. The precipitate was collected by filtration and washed with water (50 mL). This produces 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazol-5-yl}propionic acid (INT-22). Yield: 210 mg, 90.1%; Appearance: white solid; 1H NMR (300 MHz, DMSO-d6) δ 8.76 - 8.52 (m, 1H), 7.39 -7.13 (m, 1H), 7.02 - 6.91 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.20 (s, 2H), 4.27 - 4.07 (m, 1H), 3.52 - 3.08 (m, 9H), 2.86 - 2.70 (m, 2H), 2.17 (t, J =7.7 Hz, 2H), 2.01 - 1.84 (m, 2H), 1.66 - 1.54 (m, 5H), 1.35 (s, 9H). HPLC purity: 92.4%; C 26 H 38 LCMS calculated value of N6O6: 530.29; observed value: 531.2 [M+H] + .

[0349] INT-23 and INT-24. (16R)-19-amino-4-(6-bromohexyl)-13-fluoro-8,16-dimethyl-9-oxo- 17-Oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 ]22-1(22),2,5,10(15),11,13, 18,20-octaeno-3-carboxynitrile (INT-23) and (16R)-19-amino-5-(6-bromohexyl)-13-fluoro-8,16-dimethyl-9-oxo 17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 ]22-1(22),2(6),3,10(15), Synthesis of 11,13,18,20-octaene-3-carboxynitrile (INT-24): Step 1. (16R)-19-amino-4-(6-bromohexyl)-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 Synthesis of 22-1(22),2,5,10(15),11,13,18,20-octaene-3-carboxylon Place (16R)-19-amino-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] into a 40 mL vial. 2 , 6 .0 10 ,15 [22),2,5,10(15),11,13,18,20-octaeno-3-carboxylonitrile (200 mg, 509 μmol), 1,6-dibromohexane (246 mg, 1.01 mmol), K₂CO₃ (280 mg, 2.03 mmol), and MeCN (4.0 mL). The resulting reaction mixture was heated to 60 °C for 3.0 h. The mixture was then cooled to room temperature.] The resulting mixture was concentrated under vacuum, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile phase containing 0.05% ammonia, in a 70% to 100% gradient over 20 min; detector, UV 254 nm. The result was a white solid (16R)-19-amino-4-(6-bromohexyl)-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0]. 2 , 6 .0 10 , 15 [Twenty-two-1(22), 2,5,10(15),11,13,18,20-octaene-3-carboxynitrile INT-23 (150 mg, 270 μmol, 90% purity, 53% yield) and (16R)-19-amino-5-(6-bromohexyl)-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] as a white solid. 2 , 6 .0 10 , 15 ]Twenty-two-1(22),2(6),3,10(15),11,13,18,20-octaene-3-carboxynitrile INT-24 (70.0 mg, 126 μmol, 89% purity, 25% yield).

[0350] INT-25. 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-methyl Synthesis of methyl ester (INT-25) Step 1. Synthesis of methyl 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of methyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.20 g, 10.4 mmol), 2-[(1R)-1-aminoethyl]-4-fluorophenol hydrochloride (2.00 g, 10.4 mmol), and DIEA (4.02 g, 31.2 mmol) in MeCN (20 mL) was stirred at room temperature for 3 hours at 80 °C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to give methyl 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate (2.30 g, 6.96 mmol, 85.0% purity, 53.2% yield) as a yellow solid.

[0351] Step 2.5 Synthesis of methyl pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of methyl 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidin-3-carboxylate (2.30 g, 6.96 mmol), N-[(2R)-2-hydroxypropyl]tert-butyl carbamate (1.82 g, 10.4 mmol), and PPh3 (2.72 g, 10.4 mmol) in THF (20 mL) and DCM (20 mL) was incubated at 0 °C. DTBAD (2.39 g, 10.4 mmol) was then added to the mixture under a nitrogen atmosphere at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with H2O (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain methyl 5-{[(1R)-1-(2-{[(2S)-1-{[(tert-butoxy)carbonyl]amino}propyl-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.60 g, 3.28 mmol, 90.0% purity, 50.5% yield).

[0352] Step 3.5 Synthesis of methyl pyrazolo[1,5-a]pyrimidine-3-carboxylate (INT-25) A mixture of methyl 5-{[(1R)-1-(2-{[(2S)-1-{[(tert-butoxy)carbonyl]amino}propyl-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.60 g, 3.28 mmol) in HCl / dioxane (20 mL, 4 M) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give a yellow solid of methyl 5-{[(1R)-1-(2-{[(2S)-1-aminopropyl-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate HCl salt (1.40 g, 3.61 mmol, crude product), which was used directly in the next step.

[0353] INT-26. 2-[(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5, 8,20-Tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 ]22-1(22),2,5,10(15),11,13,18,20-octaene-4- Synthesis of hydroxyacetic acid.

[0354] Step 1.2 - [(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 Synthesis of tert-butyl acetate (22), 2, 5, 10 (15), 11, 13, 18, 20-octaen-4-yl) (16R)-19-amino-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15A mixture of 22-1(22),2,5,10(15),11,13,18,20-octaeno-3-carboxynitrile (400 mg, 1.01 mmol), K2CO3 (418 mg, 3.03 mmol), tert-butyl 2-bromoacetate (294 mg, 1.51 mmol), and DMF (4 mL) was prepared at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, water containing MeCN, gradient from 30% to 70% over 20 min; detector, UV 254 nm. This produced a yellow solid of 2-[(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 [22,2,5,10(15),11,13,18,20-octaen-4-yl]tert-butyl acetate (200 mg, 394 μmol, 85% purity, 39% yield) and (R)-2-(26-amino-13-cyano-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridaz-1(4,5)-pyrazola-5(1,2)-benzerocyclooctaban-11-yl)tert-butyl acetate (90 mg, 184 μmol, 85% purity, 18% yield) as a yellow solid.

[0355] Step 2.2 - [(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15 Synthesis of 22-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetic acid (INT-26) 2-[(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] 2 , 6 .0 10 , 15A solution of tert-butyl acetate (200 mg, 394 μmol) in TFA:DCM (1:1, 2 mL) was stirred at room temperature for 12.0 h. The resulting mixture was concentrated under vacuum to give a yellow oily substance as a TFA salt of 2-[(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0]. 2 , 6 .0 10 , 15 [22,2,5,10(15),11,13,18,20-octaen-4-yl]acetic acid (170 mg, 377 μmol, crude product), which is used directly in the next step.

[0356] INT-27. Synthesis of (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoic acid become.

[0357] Step 1. Synthesis of methyl (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoate At room temperature, N-[(7R)-5-azaspiro[2.4]hept-7-yl]carbamate tert-butyl ester (500 mg, 2.35 mmol), methyl 6-bromohexanoate (491 mg, 2.35 mmol), and K₂CO₃ (972 mg, 7.05 mmol) were added to a stirred solution in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 2 hours. The mixture was then cooled to room temperature. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, H2O / MeCN containing 0.1% NH4OH in a 10% to 60% gradient over 12 min; detector, UV 254 nm) to give methyl (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoate as a yellow solid (780 mg, 2.29 mmol, 91.2% purity, 97.5% yield).

[0358] Step 2. Synthesis of (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoic acid (INT-27) NaOH (274 mg, 6.86 mmol) was added to a solution of (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoate (780 mg, 2.29 mmol) in THF: H2O (2:1, 16 mL) at room temperature. The resulting mixture was stirred at room temperature for 1.0 h. The mixture was acidified to pH 2-3 with 1 M HCl. The precipitated solid was collected by filtration and washed with water (50 mL). This yielded (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]hept-5-yl)hexanoic acid (INT-27). Yield: 720 mg, crude product; Appearance: white solid; HPLC purity: 88.1%; C 17 H 30 LCMS calculated value of N₂O₄: 326.22; observed value: 327.1 [M+H] + .

[0359] INT-28. 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyric acid synthesis.

[0360] Step 1. Synthesis of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidone-1-yl]butyrate N-[(3R)-4,4-dimethylpyrrolidone-3-yl]carbamate tert-butyl hydrochloride (200 mg, 797 μmol), methyl 4-bromobutyrate (25 mg, 1.19 mmol), K₂CO₃ (329 mg, 2.39 mmol), and MeCN (4 mL) were placed in a 50 mL round-bottom container. The resulting mixture was stirred at 80 °C for 5.0 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidone-1-yl]butyrate (210 mg, 667 μmol, 70% purity, 84% yield) as a yellow oil.

[0361] Step 2. 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidone-1-yl]butyric acid Synthesis of (INT-28) A mixture of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyrate (110 mg, 349 μmol) and LiOH·H2O (43.6 mg, 1.04 mmol) in THF / H2O (2:1, 3 mL) was stirred at room temperature for 3.0 h. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (NH3·H2O buffer) to give 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolid-1-yl]butyric acid (100 mg, 332 μmol, 75% purity, 85% yield) as a white solid.

[0362] Example A1. (S)-N-((R)-1-acetylpyrrolidone-3-yl)-2-amino-5-guanidinopentanamide (A-1) synthesis: Step 1. Synthesis of (R)-(1-acetylpyrrolidone-3-yl)carbamate tert-butyl ester AcCl (2.50 g, 32.1 mmol) was added to a stirred solution of N-[(3R)-pyrrolidine-3-yl]carbamate (5.00 g, 26.8 mmol) and pyridine (6.34 g, 80.3 mmol) in DCM (50 mL) at 0 °C. After addition, the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with petroleum ether:ethyl acetate = 1:2 to give N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate (4.59 g, 20.1 mmol, 90% purity, 75% yield) as a white solid.

[0363] Step 2. Synthesis of (R)-1-(3-aminopyrrolidone-1-yl)ethyl-1-one A solution of N-[(3R)-1-acetylpyrrolidone-3-yl]carbamate tert-butyl ester (5.10 g, 22.3 mmol) in TFA (50 mL) was stirred at room temperature for 2.0 h. The resulting mixture was concentrated under vacuum to give crude 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one (2.97 g, 23.1 mmol, crude product) as a TFA salt, which was a brown oil.

[0364] Step 3. Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}butyl]carbamate tert-butyl HATU (399 mg, 1.05 mmol) was added to a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}valeric acid (500 mg, 1.05 mmol), 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one (134 mg, 1.05 mmol), and DIEA (134 mg, 1.05 mmol) in DCM (10 mL) at -40 °C. After 2.0 hours, the reaction mixture was heated to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}butyl]carbamate tert-butyl ester (424 mg, 725 μmol, 90% purity, 69% yield), which was a light yellow solid.

[0365] Step 4. Synthesis of (S)-N-((R)-1-acetylpyrrolidone-3-yl)-2-amino-5-guanidinopentanamide (A-1): A solution of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}butyl]carbamate (450 mg, 769 μmol) in dioxane (5 mL) was added dropwise with HCl / dioxane (2 M in dioxane, 3.8 mL, 7.68 mmol) and stirred at room temperature for 3.0 h. The resulting mixture was concentrated under vacuum to give (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-iminocarbamoylpentanamide HCl salt (A-1). Yield: 99.9 mg, 45.8%; Appearance: brown semi-solid; 1 H NMR (300 MHz, DMSO- d6) δ 4.34 - 4.17 (m, 1H), 3.70 - 3.22 (m, 4H), 3.20 - 3.12 (m, 2H), 2.20 - 1.96 (m, 1H), 1.97 - 1.91 (m, 3H), 1.80 - 1.71 (m, 4H), 1.57 - 1.43 (m, 2H). HPLC purity: 97.0%; C 12 H 24 LCMS calculated value of N6O2: 284.20; observed value: 285.20 [M+H] + .

[0366] The following examples were prepared using standard chemical operations and procedures similar to those used in the preparations of the previous examples. Analytical data are given in the table below.

[0367] Example A2. Scheme 3. (S)-2-amino-5-guanidino-N-((S)-1-(methylamino)-1-oxo-3-(tetrahydro- Synthesis of 2H-pyran-4-yl)prop-2-yl)pentanamide (A-23): Step 1. Synthesis of tert-butyl (S)-(1-(methylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propyl-2-yl)carbamate A solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(oxecyclohexane-4-yl)propionic acid (200 mg, 0.731 mmol), MeNH2·HCl (98.5 mg, 1.46 mmol), HATU (333 mg, 0.877 mmol), and DIEA (376 mg, 2.92 mmol) in DMF (3 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether / ethyl acetate (1:1) to give N-[(1S)-1-(methylcarbamoyl)-2-(oxecyclohexane-4-yl)ethyl]tert-butyl carbamate (200 mg, 0.698 mmol, 80% purity, 95% yield) as a white solid.

[0368] Step 2. Synthesis of (S)-2-amino-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propionamide hydrochloride A solution of N-[(1S)-1-(methylcarbamoyl)-2-(oxecyclohexane-4-yl)ethyl]carbamate tert-butyl ester (100 mg, 0.349 mmol) in HCl / dioxane (4 M, 1.2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain a crude product, (2S)-2-amino-N-methyl-3-(oxecyclohexane-4-yl)acrylamide HCl salt (80.0 mg, 359 μmol, 80% purity, 98% yield), which was used directly in the next step without further purification.

[0369] Step 3. Synthesis of N-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1S)-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl}butyl]amino})methylene]tert-butyl carbamate A solution of (2S)-2-amino-N-methyl-3-(oxacyclohexane-4-yl)propionamide hydrochloride (70 mg, 0.314 mmol), (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}valeric acid (INT-1) (123 mg, 0.261 mmol), HATU (119 mg, 0.314 mmol), and DIEA (167 mg, 1.30 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain N-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1S)-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl}butyl]amino})methylene]carbamate tert-butyl ester (60.0 mg, 0.933 mmol, 92% purity, 29% yield) as a white solid.

[0370] Step 4. Synthesis of (S)-2-amino-5-guanidino-N-((S)-1-(methylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propyl-2-yl)pentanamide (A-23) A solution of N-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1S)-1-(methylcarbamoyl)-2-(oxecyclohexane-4-yl)ethyl]carbamoyl}butyl]amino})methylene]carbamate tert-butyl ester (50 mg, 0.777 mmol) in HCl / dioxane (4 M, 0.5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (0.02% HCl aqueous phase) to give (2S)-2-amino-5-iminocarbamoyl-N-[(1S)-1-(methylcarbamoyl)-2-(oxecyclohexane-4-yl)ethyl]pentanamide HCl salt (A-23). ​​Yield: 15.0 mg, 56%; Appearance: white solid. 1 H NMR (300 MHz, DMSO- d 6)δ8.72 (d, J = 7.8 Hz, 1H), 8.41 - 8.25 (m, 3H), 8.11 - 8.02 (m, 1H), 7.87 - 7.78(m, 1H), 4.37 - 4.24 (m, 1H), 3.90 - 3.80 (m, 3H), 3.32 - 3.20 (m, 2H), 3.19- 3.09 (m, 2H), 2.59 (d, J = 4.5 Hz, 3H), 1.83 - 1.70 (m, 2H), 1.65 - 1.46 (m, 7H), 1.21 - 1.05 (m, 2H). HPLC purity: 98%; C 15 H 30 LCMS calculated value of N6O3: 342.24; observed value: 343.3 [M+H] + .

[0371] Example A3. (2S,3S)-2-((S)-2-amino-3-(6-aminopyridin-3-yl)propionamido)-N,3-dimethyl Synthesis of pyralidamide (A-24): Step 1 Synthesis of methyl (S)-3-(6-aminopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propionate BrCH2CH2Br (259 mg, 1.38 mmol) was added to a stirred suspension of Zn (1.79 g, 27.6 mmol) in anhydrous DMF (30 mL), and the mixture was stirred at 50 °C for 30 min. The reaction mixture was then cooled to room temperature. TMS-Cl (29.9 mg, 276 μmol) was added to the mixture, and the mixture was stirred vigorously for another 30 min. Methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-iodopropionate (1.70 g, 5.19 mmol) in DMF was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then allowed to stand for another 30 min, and the supernatant was transferred via syringe to a mixture of 5-bromopyridine-2-amine (600 mg, 3.46 mmol), Pd2(dba)3 (79.2 mg, 86.5 μmol), and S-phos (71.0 mg, 173 μmol). The reaction mixture was stirred at 50 °C for 16 h. After being poured into water, the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to give methyl (2S)-3-(6-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propionate (650 mg, 2.20 mmol) as a white solid.

[0372] Step 2 Synthesis of (S)-3-(6-aminopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propionic acid LiOH (258 mg, 10.8 mmol) was added to a solution of methyl (2S)-3-(6-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propionate (640 mg, 2.16 mmol) in THF (5 mL) and H2O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 5-6 with 1 N HCl (aqueous solution) and concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase combi flash (Biotage, 130 g Agela C18, MeCN / H2O (0.5% FA)) to give (2S)-3-(6-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propionate (300 mg, 1.06 mmol) as a white solid.

[0373] Step 3Synthesis of tert-butyl ((S)-3-(6-aminopyridin-3-yl)-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-1-oxopropyl-2-yl)carbamate DEPBT (261 mg, 876 μmol) was added to a solution of (2S)-3-(6-aminopyridin-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propionic acid (270 mg, 959 μmol), (2S,3S)-2-amino-N,3-dimethylpentanamide (115 mg, 797 μmol), and DIPEA (514 mg, 3.98 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase combi flash (Biotage, 10 g Agela C18, MeCN / H2O (0.1% NH4HCO3)) to give N-[(1S)-2-(6-aminopyridin-3-yl)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}ethyl]tert-butyl carbamate (40.0 mg, 98.1 μmol) as a white solid.

[0374] Step 4 Synthesis of (2S,3S)-2-((S)-2-amino-3-(6-aminopyridin-3-yl)propionamido)-N,3-dimethylpentanamide A solution of N-[(1S)-2-(6-aminopyridin-3-yl)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}ethyl]tert-butyl carbamate (120 mg, 294 μmol) in 4 M HCl (1,4-dioxane solution) (5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was further purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give (2S,3S)-2-[(2S)-2-amino-3-(6-aminopyridin-3-yl)propamido]-N,3-dimethylpentanamide (A-24). Yield: 12.2 mg, 13%; Appearance: white solid; 1 H NMR (400 MHz, DMSO) δ 7.96 - 7.79 (m, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.4, 2.4 Hz, 1H), 6.34 (d, J= 8.4 Hz, 1H), 5.66 (s, 2H), 4.09 (t, J = 8.0 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.57 (d, J = 4.8 Hz, 3H), 2.47 - 2.31 (m, 2H), 1.77 (s, 2H), 1.66 - 1.57 (m, 1H), 1.43 - 1.28 (m, 1H), 1.04 - 0.89 (m, 1H), 0.85 - 0.70 (m, 6H); HPLC purity: 93%; C 15 H 25 LCMS calculated value of N5O2: 307.20; observed value: 308.4 [M+H] + .

[0375] Example A4. (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-(2-aminopyridine-3-yl) Synthesis of α-pentanamide (A-25): Step 1. Synthesis of N-[(3R)-1-acetylpyrrolidine-3-yl]tert-butyl carbamate TEA (324 mg, 3.21 mmol) and acetyl chloride (125 mg, 1.60 mmol) were added to a solution of N-[(3R)-1-acetylpyrrolidone-3-yl]carbamate (200 mg, 1.07 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by rapid silica gel chromatography (MeOH-DCM = 0%–5%) to give N-[(3R)-1-acetylpyrrolidone-3-yl]carbamate (200 mg, 0.88 mmol, 100% purity, 81.9% yield) as a colorless oil.

[0376] Step 2 Synthesis of 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one TFA (1 mL) was added to a solution of N-[(3R)-1-acetylpyrrolidone-3-yl]carbamate tert-butyl ester (200 mg, 0.88 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one (112 mg, 0.88 mmol, 100% purity, 100% yield) as a colorless oil.

[0377] Step 3Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-(2-aminopyridin-3-yl)butyl] tert-butyl carbamate Add DIPEA (152 mg, 1.17 mmol), (2S)-5-(2-aminopyrrolidone-1-yl)-2-{[(tert-butoxy)carbonyl]amino}valeric acid (INT-2) (120 mg, 0.39 mmol), and DEPBT (139 mg, 0.47 mmol) to a solution of 1-[(3R)-3-aminopyrrolidone-1-yl]ethyl-1-one (50 mg, 0.39 mmol) in DMF (5 mL). Stir the mixture at room temperature for 16 h. Pour the reaction mixture into water (20 mL) and extract with EA (20 mL x 3). Wash the combined organic layers with anhydrous sodium sulfate and filter. The filtrate was concentrated and purified by silica gel chromatography (MeOH-DCM = 0%-20%) to obtain N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-(2-aminopyridin-3-yl)butyl]carbamate (60.0 mg, 0.14 mmol, 100% purity, 36.8% yield) as a yellow solid.

[0378] Step 4 Synthesis of (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-(2-aminopyridin-3-yl)pentanamide (A-25).

[0379] TFA (1 mL) was added to a solution of N-[(1S)-1-{[(3R)-1-acetylpyrrolidone-3-yl]carbamoyl}-4-(2-aminopyridin-3-yl)butyl]carbamate (40 mg, 0.10 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to give a crude compound. The mixture was diluted with MeOH and adjusted to pH 9 with NH4OH. The mixture was further purified by preparative HPLC (1 / 1000 NH4HCO3, acid method) to give (2S)-N-[(3R)-1-acetylpyrrolidone-3-yl]-2-amino-5-(2-aminopyridin-3-yl)pentanamide (A-25). Yield: 15.4 mg, 50.6%; Appearance: white solid; Yield: 16.0 mg, 50.6%; Appearance: white solid; 1 H NMR (400MHz, DMSO- d 6) δ 8.17 - 7.97 (m, 1H), 7.77 (dd, J= 4.8, 1.6 Hz, 1H), 7.17 (d, J =7.2 Hz, 1H), 6.46 (dd, J = 7.2, 5.0 Hz, 1H), 5.65 (d, 2H), 4.30 -4.15 (m, 1H), 3.96 -3.61 (m, 1H), 3.49-3.42 (m, 2H), 3.24 - 3.11 (m, 2H), 2.37 (t, J = 6.8Hz, 2H), 2.11 -1.94 (m, 1H), 1.91 (d, J = 8.4 Hz, 3H), 1.85-1.69 (m, 1H), 1.63 -1.36 (m, 4H); HPLC purity: 96.52%; C 16 H 25 LCMS calculated value of N5O2: 319.41; observed value: 320.2 [M+H] + .

[0380] The following examples were prepared using standard chemical operations and procedures similar to those used in the preparations of the previous examples. Analytical data are given in the table below.

[0381] Example A5. (2S,3S)-2-((S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide (2S,3S)-N,3-dimethylpentanamide (A-27) and (2S,3S)-2-((R)-2-amino-3-(1H-pyrrolo[2,3-b]pyridine-3- Synthesis of (N,3-dimethylpentanamide)-N,3-dimethylpentanamide (A-28): Step 1 3-Bromo-1-(4-methylbenzenesulfonyl)-1 H Synthesis of pyrrolo[2,3-b]pyridine To 3-bromo-1 H -pyrrolo[2,3- b Pyridine (1.00 g, 5.07 mmol) was dissolved in dichloromethane (5 mL) and then mixed with p-toluenesulfonyl chloride (966 mg, 5.07 mmol), 4-dimethylaminopyridine (619 mg, 5.07 mmol), and triethylamine (513 mg, 5.07 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by rapid silica gel chromatography (SiO2, petroleum ether / EtOAc = 10 / 3) to give 3-bromo-1-(4-methylbenzenesulfonyl)-1- as a white solid. H -pyrrolo[2,3-b Pyridine (900 mg, 2.56 mmol, 100% purity, 56% yield).

[0382] Step 2 . (2 S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b Synthesis of methyl pyridin-3-yl]propionate 1,2-Dibromoethane (255 mg, 1.36 mmol) was added to a stirred suspension of zinc powder (1.77 g, 27.2 mmol) in DMF (5 mL), and the mixture was stirred at 50 °C for 30 min. The reaction mixture was then cooled to room temperature. Trichlorosilane (29 mg, 272 μmol) was added to the mixture, and the mixture was stirred vigorously again for 30 min. The mixture was then added to a stirred suspension of zinc powder (1.77 g, 27.2 mmol) in DMF (5 mL). R Methyl 2-[(tert-butoxy)carbonyl]amino}-3-iodopropionate (1.11 g, 3.40 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was then allowed to stand for another 30 min, and the supernatant was transferred via syringe to 3-bromo-1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b The reaction mixture was prepared in pyridine (600 mg, 1.70 mmol), tris(dibenzylacetone)palladium (92.4 mg, 101 μmol), and X-Phos (96.7 mg, 203 μmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by rapid silica gel chromatography (SiO2, petroleum ether / EtOAc = 10 / 7) to give a white solid (2... S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b Methyl pyridin-3-yl]propionate (450 mg, 950 μmol, 87% purity, 56% yield).

[0383] Step 3 . (2 S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3-b Synthesis of pyridin-3-yl]propionic acid To (2) S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b A solution of methyl pyridin-3-yl]propionate (450 mg, 950 μmol) in tetrahydrofuran (3 mL) was mixed with lithium hydroxide (22.7 mg, 950 μmol) and water (1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a white solid (2... S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b ]pyridin-3-yl]propionic acid (436 mg, 948 μmol, 100% purity, 100% yield).

[0384] Step 4. N -[(1S)-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1 H Synthesis of -pyrrolo[2,3-b]pyridin-3-yl]ethyl]tert-butyl carbamate To (2) S )-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b ]pyridin-3-yl]propionic acid (450 mg, 979 μmol) at N , N Add DEPBT (583 mg, 1.95 mmol) to the solution of dimethylformamide (10 mL). N , N -Diisopropylethylamine (126 mg, 979 μmol) and (2 S ,3 S )-2-amino- N3-Dimethylpentanamide (210 mg, 1.46 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by rapid silica gel chromatography (SiO2, petroleum ether / EtOAc = 5 / 4) to give a yellow solid. N -[(1 S )-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b 3-pyridinyl]ethyl]carbamate tert-butyl ester (380 mg, 648 μmol, 89% purity, 66% yield).

[0385] Step 5 . N -[(1 S )-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1 H -pyrrolo[2,3- b Synthesis of tert-butyl pyridin-3-yl]ethyl]carbamate Towards N -[(1 S )-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1 H -pyrrolo[2,3- b Potassium carbonate (530 mg, 3.84 mmol) was added to a solution of 450 mg (768 μmol) of pyridin-3-yl]ethyl]carbamate in methanol (5 mL). The resulting mixture was stirred at 65 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give a white solid. N -[(1 S )-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1 H -pyrrolo[2,3- b3-pyridin-3-yl]ethyl]carbamate tert-butyl ester (330 mg, 764 μmol, 100% purity, 99% yield).

[0386] Step 6 . (2 S ,3 S )-2-[(2 S )-2-amino-3-{1 H -pyrrolo[2,3- b ]pyridin-3-yl}propionamidyl]- N 3-Dimethylpentanamide (16.5 mg, 49.7 μmol) and (2 S ,3 S )-2-[(2 R )-2-amino-3-{1 H -pyrrolo[2,3- b ]pyridin-3-yl}propionamidyl]- N Synthesis of 3-dimethylpentanamide Towards N -[(1 S )-1-{[(1 S ,2 S )-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1 H -pyrrolo[2,3- b HCl-dioxane (729 mg, 20.0 mmol) was added to a solution of 100 mg, 231 μmol of pyridin-3-yl[ethyl]carbamate tert-butyl ester. The resulting mixture was stirred at room temperature for 1 h. The pH was adjusted to 7-8 with NH4OH and filtered. The reaction solution was concentrated and purified by preparative HPLC (ACN / H2O / 0.5% NH4HCO3) to obtain a crude product, which was then subjected to SFC (mobile phase: CO2 / EtOH [1% NH3 (7 M in MeOH)] = 60 / 40. Flow rate: 3 ml / min. Back pressure: 2000 psi. Column: Daicel AD-3 (4.6*100 mm 3 μm)) to obtain (2 S ,3 S )-2-[(2 S )-2-amino-3-{1 H -pyrrolo[2,3- b ]pyridin-3-yl}propionamidyl]- N 3-Dimethylpentanamide (A-27). Yield: 16.5 mg, 21%; Appearance: white solid; 1 H NMR (400 MHz, DMSO- d6 ) δ 11.34 (s, 1H), 8.16 (dd, J = 4.8, 1.2 Hz, 1H),7.99 - 7.85 (m, 3H), 7.26 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 7.6, 4.8 Hz, 1H), 4.08 (t, J = 8.4 Hz, 1H), 3.54 (dd, J = 7.6, 5.6 Hz, 1H), 3.03 (dd, J = 14.4, 5.2Hz, 1H), 2.73 (dd, J = 14.4, 8.0 Hz, 1H), 2.55 (d, J = 4.8 Hz, 3H), 1.95 - 1.64 (m, 2H), 1.64 - 1.55 (m, 1H), 1.33 - 1.22 (m, 1H), 0.99 - 0.84 (m, 1H), 0.78 - 0.68 (m, 6H); HPLC purity: 100%; C 17 H 25 LCMS calculated value of N5O2: 331.20; observed value: 332.4 [M+H] + . and (2 S ,3 S )-2-[(2 R )-2-amino-3-{1 H -pyrrolo[2,3- b ]pyridin-3-yl}propionamidyl]- N 3-Dimethylpentanamide (A-28). Yield: 39.8 mg, 52%; Appearance: white solid; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.36(s, 1H), 8.16 (dd, J = 4.8, 1.2 Hz, 1H), 8.00 - 7.84 (m, 3H), 7.28 (d, J = 2.8Hz, 1H), 7.00 (dd, J = 7.6, 4.8 Hz, 1H), 4.07 (t, J = 8.0 Hz, 1H), 3.49 (dd, J=7.6, 4.4 Hz, 1H), 3.04 (dd, J = 14.4, 4.4 Hz, 1H), 2.83 (dd, J = 14.4, 7.6 Hz, 1H), 2.56 (d, J = 4.8 Hz, 3H), 1.94 - 1.69 (m, 2H), 1.63 - 1.50 (m, 1H), 1.31 -1.21 (m, 1H), 0.97 - 0.80 (m, 1H), 0.74 (t, J = 7.2 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H); HPLC purity: 99.54%; C 17 H 25 LCMS calculated value of N5O2: 331.20; observed value: 332.4 [M+H] + .

[0387] The following examples were prepared using standard chemical operations and procedures similar to those used in the preparations of the previous examples. Analytical data are given in the table below.

[0388] Example A6. (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-((R)-1,4,4-trimethylpyrrole) Synthesis of alkyl-3-yl)pentanamide (A-39): Step 1 Synthesis of (R)-(1,4,4-trimethylpyrrolidone-3-yl)carbamate tert-butyl ester Paraformaldehyde (419 mg, 4.66 mmol) and NaBH4 (175 mg, 2.79 mmol) were added to a solution of N-[(3R)-4,4-dimethylpyrrolidone-3-yl]carbamate (200 mg, 933 μmol) in MeOH (5 mL) at room temperature. The reaction mixture was stirred at 40 °C for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamate (150 mg, 656 μmol, 100% purity, 70% yield) as a colorless oil.

[0389] Step 2 . ( R Synthesis of 1,4,4-trimethylpyrrolidine-3-amine TFA (1 ml, 6.56 mmol) was added to a solution of N-[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamate (150 mg, 656 μmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give (3R)-1,4,4-trimethylpyrrolidone-3-amine (84.0 mg, 655 μmol, 100% purity, 100% yield) as a pale yellow oil.

[0390] Step 3 Synthesis of tert-butyl ((S)-5-(2-nitro-1H-imidazol-1-yl)-1-oxo-1-(((R)-1,4,4-trimethylpyrrolidone-3-yl)amino)pentan-2-yl)carbamate At room temperature, a solution of (3R)-1,4,4-trimethylpyrrolidine-3-amine (50 mg, 389 μmol) in DMF (5 mL) was added with (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazol-1-yl)valeric acid (INT-3) (127 mg, 389 μmol), DEPBT (139 mg, 466 μmol), and DIPEA (50.5 mg, 389 μmol). The reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid silica gel chromatography (MeOH / DCM = 0-10%) to obtain N-[(1S)-4-(2-nitro-1H-imidazol-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamoyl}butyl]carbamate (70.0 mg, 159 μmol, 100% purity, 41% yield), which was a light yellow oil.

[0391] Step 4. ((S)-5-(2-amino-1H-imidazol-1-yl)-1-oxo-1-(((R)-1,4,4-trimethylpyrrolidone-3-yl)amino)pent-2-yl)tert-butyl carbamate (A-39) Pd / C (36.2 mg, 342 μmol) was added to a solution of N-[(1S)-4-(2-nitro-1H-imidazol-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamoyl}butyl]carbamate (100 mg, 228 μmol) in MeOH (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under reduced pressure to give N-[(1S)-4-(2-amino-1H-imidazol-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamoyl}butyl]carbamate (93.0 mg, 227 μmol, 100% purity, 99% yield) as a pale yellow oil.

[0392] Step 5 Synthesis of (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-((R)-1,4,4-trimethylpyrrolidone-3-yl)pentanamide TFA (1 ml, 227 μmol) was added to a solution of N-[(1S)-4-(2-amino-1H-imidazol-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidone-3-yl]carbamoyl}butyl]carbamate (93 mg, 227 μmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was then concentrated. The residue was dissolved in MeOH and the pH was adjusted to 9 with NH3 / MeOH, and then purified by preparative HPLC (0.1% NH4OH method) to give (2S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-[(3R)-1,4,4-trimethylpyrrolidone-3-yl]pentanamide (A-39). Yield: 23.0 mg, 32%; Appearance: white solid; 1H NMR (400 MHz, DMSO) δ 7.78 -7.65 (m, 1H), 6.51 (d, J = 1.2 Hz, 1H), 6.33 (d, 1H), 5.31 (d, J = 32.0 Hz, 2H), 3.92 (dd, J = 15.6, 7.2 Hz, 1H), 3.63 (t, J = 7.2 Hz, 2H), 3.16 (dd, J = 7.6, 5.0Hz, 1H), 2.84 - 2.75 (m, 1H), 2.31 (d, J = 8.8 Hz, 1H), 2.27 - 2.14 (m, 5H), 1.70 - 1.43 (m, 3H), 1.36 - 1.23 (m, 1H), 1.04 (s, 3H), 0.82 (d, J = 9.2 Hz, 3H); HPLC purity: 100%; C 15 H 28 LCMS calculated value of N6O: 308.43; observed value: 309.3 [M+H]+.

[0393] Example A7. (S)-N-((R)-1-acetylpyrrolidone-3-yl)-2-amino-5-(2-amino-1H-imidazol-1- Synthesis of α-pentanamide (A-40) Step 1 . ( R Synthesis of tert-butyl 1-(1-acetylpyrrolidine-3-yl)carbamate At 0℃ towards ( RA solution of tert-butyl pyrrolidone-3-ylcarbamate (2 g, 10.7 mmol) in DCM (50 mL) was mixed with acetyl chloride (1.67 g, 21.4 mmol) and triethylamine (2.16 g, 21.4 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-4%) to give a white solid ( R 1-(1-acetylpyrrolidone-3-yl)carbamate tert-butyl ester (2.4 g, 10.6 mmol, 100% purity, 99% yield).

[0394] Step 2 . ( R Synthesis of 1-(3-aminopyrrolidone-1-yl)ethyl-1-one hydrochloride Will( R A solution of tert-butyl 1-(1-acetylpyrrolidone-3-yl)carbamate (2.4 g, 10.5 mmol) in 50 mL of MeOH containing 4 M HCl was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to give a white solid. R 1-(3-aminopyrrolidone-1-yl)ethyl-1-one hydrochloride (1.72 g, 10.4 mmol, 100% purity, 100% yield). The crude product was used directly in the next step without further purification.

[0395] Step 3 . ( S )-5-((( R Synthesis of methyl 1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate At room temperature to ( S )-2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxovaleric acid (2.58 g, 9.90 mmol) was added to a solution of DMF (30 mL). R 1-(3-aminopyrrolidone-1-yl)ethyl-1-one hydrochloride (1.63 g, 9.90 mmol), EDCI (2.64 g, 13.8 mmol), HOBT (1.86 g, 13.8 mmol), and DIPEA (6.39 g, 49.5 mmol). The mixture was stirred at room temperature for 10 h. The mixture was quenched with water and extracted with EA. The organic layer was collected, washed with water, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-4%) to give a colorless oil. S )-5-((( RMethyl 1-acetylpyrrolidone-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (1.50 g, 4.03 mmol, 100% purity, 41% yield).

[0396] Step 4 . ( S )-5-((( R Synthesis of 1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid At room temperature to ( S )-5-((( R Methyl 1-(-1-acetylpyrrolidone-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (1.50 g, 4.03 mmol) was added to a solution of methyl 1-(-1-acetylpyrrolidone-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (1.50 g, 4.03 mmol) in THF (30 mL) and LiOH (106 mg, 4.43 mmol) and H₂O (10 mL) were added. The mixture was stirred at room temperature for 10 h. The mixture was quenched with 1 M HCl and extracted with EA. The organic layer was concentrated under vacuum to give a white solid ( S )-5-((( R 1-Acetylpyrrolidone-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (1.30 g, 3.63 mmol, 100% purity, 90% yield). The crude product was used directly in the next step without further purification.

[0397] Step 5 . (( S )-1-((( R Synthesis of tert-butyl carbamate (-1-acetylpyrrolidine-3-yl)amino)-5-hydroxy-1-oxopent-2-yl)carbamate At 0℃ towards ( S )-5-((( R 1-Acetylpyrrolidone-3-yl)amino)-4-((tert-butoxycarbonyl)-amino)-5-oxovaleric acid (500 mg, 1.39 mmol) was added to a stirred solution in DCM (10 mL) with BH3 (4 mL, 1 M in THF). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with MeOH and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-4%) to give a colorless oil. S )-1-((( R 1-Acetylpyrrolidone-3-yl)amino)-5-hydroxy-1-oxopent-2-yl)carbamate tert-butyl ester (125 mg, 363 μmol, 100% purity, 26% yield).

[0398] Step 6 . (( S )-1-((( R Synthesis of tert-butyl carbamate (-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazol-1-yl)-1-oxopentan-2-yl)carbamate At room temperature (( S )-1-((( R A solution of 1-acetylpyrrolidone-3-yl)amino)-5-hydroxy-1-oxopent-2-yl)carbamate tert-butyl ester (125 mg, 363 μmol) in THF (8 mL) was added to PPh3 (190 mg, 726 μmol), 2-nitro-1H-imidazolium (82 mg, 726 μmol), and DIAD (146 mg, 726 μmol). The mixture was stirred at room temperature for 12 h. The mixture was quenched with water and extracted with EA. The organic layer was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (MeOH / DCM = 0-4%) to give a colorless oil. S )-1-((( R 1-Acetylpyrrolidone-3-yl)amino)-5-(2-nitro-1H-imidazol-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl ester (85 mg, 193 μmol, 100% purity, 53% yield).

[0399] Step 7 . (( S )-1-((( R Synthesis of tert-butyl carbamate (-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-imidazol-1-yl)-1-oxopentan-2-yl)carbamate At room temperature to (( S )-1-((( R 1-Acetylpyrrolidone-3-yl)amino)-5-(2-nitro-1H-imidazol-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl ester (85 mg, 193 μmol) was added to a solution of MeOH (30 mL) with 10% Pd / C (30 mg). The mixture was stirred at room temperature under H2 atmosphere for 16 h. The mixture was filtered and concentrated under vacuum to give a colorless oil. S )-1-((( R1-Acetylpyrrolidone-3-yl)amino)-5-(2-amino-1H-imidazol-1-yl)-1-oxopentan-2-yl)tert-butyl carbamate (79 mg, 192 μmol, 100% purity, 100% yield). The crude product was used directly in the next step without further purification.

[0400] Step 8 . ( S )- N -(( R Synthesis of 1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-imidazol-1-yl)pentanamide Will(( S )-1-((( R A solution of tert-butyl carbamate (79 mg, 193 μmol) in (20 mL, 4 M in dioxane) was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was purified by preparative HPLC (ACN / water / 0.1% NH4OH) to obtain ( S )- N -(( R 1-Acetylpyrrolidone-3-yl)-2-amino-5-(2-amino-1H-imidazol-1-yl)pentanamide (A-40). Yield: 33.1 mg, 52%; Appearance: colorless oil. 1 H NMR (400 MHz, DMSO- d 6) δ 8.05 (dd, J 1 = 7.2, J 2 = 6.8 Hz, 1H), 6.52 (d, J = 1.2 Hz, 1H), 6.34 (d, J = 1.2 Hz, 1H), 5.27 (s, 2H), 4.27 - 4.16 (m, 1H), 3.65 - 3.62 (m, 2H), 3.50 - 3.42 (m, 2H), 3.22 - 3.08(m, 3H), 2.01 - 1.90 (m, 1H), 1.93 (d, J = 9.2 Hz, 3H), 1.86 - 1.70 (m, 1H), 1.67 - 1.41 (m, 3H), 1.30 - 1.26 (m, 1H); HPLC purity: 94.3%; C 14 H 24LCMS calculated value of N6O2: 308.39; observed value: 309.4 [M+H] + .

[0401] The following examples were prepared using standard chemical operations and procedures similar to those used in the preparations of the previous examples. Analytical data are given in the table below.

[0402] Example A8. (2S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-[(1S)-1-(methylcarbamoyl) Synthesis of [A-52](2-(oxacyclohexane-4-yl)ethyl]pentanamide (A-52): Step 1 . N -[(1 S Synthesis of tert-butyl carbamate [1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamate At room temperature to (2 S HATU (180 mg, 474 μmol) was added to a solution of 2-{[(tert-butoxy)carbonyl]amino}-3-(oxacyclohexane-4-yl)propionic acid (100 mg, 365 μmol), methylamine hydrochloride (29.5 mg, 438 μmol), and DIPEA (140 mg, 1.09 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The organic layer was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (DCM / MeOH = 20 / 1) to obtain a pale yellow oil. N -[(1 S 1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]tert-butyl carbamate (92.0 mg, 321 μmol, 100% purity, 88% yield).

[0403] Step 2 . (2 S )-2-amino- N Synthesis of methyl-3-(oxacyclohexane-4-yl)propionamide Will N -[(1 SA solution of tert-butyl [-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamate (92 mg, 321 μmol) in dioxane (4 M) (5 mL) containing HCl was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a pale yellow oil (2... S )-2-amino- N 3-Methyl-3-(oxecyclohexane-4-yl)propionamide (59.2 mg, 317 μmol, 100% purity, 99% yield).

[0404] Step 3 . N -[(1 S )-1-{[(1 S Synthesis of tert-butyl carbamate: 1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl]-4-(2-nitro-1H-imidazol-1-yl)butyl]carbamate At room temperature to (2 S )-2-amino- N 3-Methyl-3-(oxecyclohexane-4-yl)propionamide (59 mg, 316 μmol), (2 S )-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1 H A solution of 1-imidazol-1-yl)valeric acid (INT-3) (124 mg, 379 μmol) and DEPBT (113 mg, 379 μmol) in DMF (5 mL) was supplemented with DIPEA (122 mg, 948 μmol). The reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The organic layer was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (DCM / MeOH = 20 / 1) to obtain a colorless oil. N -[(1 S )-1-{[(1 S )-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl}-4-(2-nitro-1 H [-Imidazol-1-yl)butyl] tert-butyl carbamate (105 mg, 211 μmol, 100% purity, 67% yield).

[0405] Step 4.N -[(1 S )-4-(2-amino-1 H -imidazol-1-yl)-1-{[(1 SSynthesis of tert-butyl carbamate (1-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl]butyl]carbamate At room temperature N -[(1 S )-1-{[(1 S )-1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl}-4-(2-nitro-1 H Pd / C (10 mg) was added to a solution of tert-butyl [-imidazolium-1-yl]butyl]carbamate (105 mg, 211 μmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under H2 for 1 h. The reaction mixture was filtered and concentrated to give a pale yellow solid. N -[(1 S )-4-(2-amino-1 H -imidazol-1-yl)-1-{[(1 S 1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl]carbamoyl]butyl]carbamate tert-butyl ester (98.0 mg, 210 μmol, 100% purity, 100% yield).

[0406] Step 5 . (2 S )-2-amino-5-(2-amino-1 H -imidazol-1-yl)- N -[(1 S Synthesis of 1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethylpentanamide At room temperature N -[(1 S )-4-(2-amino-1 H -imidazol-1-yl)-1-{[(1 S 98 mg, 210 μmol of tert-butyl carbamate (TFA) was added to a solution of 1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethyl[carbamoyl]butyl]carbamate in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 7-8 with MeOH containing NH3 and concentrated to obtain a residue. The residue was further purified by preparative HPLC (ACN / water / 0.1% FA) to obtain (2 S )-2-amino-5-(2-amino-1H-imidazol-1-yl)- N -[(1 S1-(methylcarbamoyl)-2-(oxacyclohexane-4-yl)ethylpentanamide (A-52). Yield: 7.8 mg, 9.2%; Appearance: white solid; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 - 7.78 (m, 2H), 6.52 (d, J = 1.2 Hz, 1H), 6.34 (d, J = 1.2 Hz, 1H), 5.23 (s, 2H), 4.36 - 4.23 (m, 1H), 3.79 (dd, J = 11.2, 2.4 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 3.18 (tt, J = 11.6, 10.8 Hz, 3H), 2.56 (d, J = 4.6 Hz, 3H), 1.68 - 1.31 (m, 9H), 1.21 - 1.03 (m, 2H); HPLC purity: 82.6%; C 17 H 30 LCMS calculated value of N6O3: 366.24; observed value: 367.4 [M+H] + .

[0407] Example A9. (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-2-methyl-N-((2S,3S)-3-methyl Synthesis of 1-(methylamino)-1-oxopentan-2-yl)pentanamide (A-53).

[0408] Step 1 . ((2 S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)carbamic acid (9 H Synthesis of fluorene-9-yl)methyl ester To (2) S ,3 S )-2-({[(9 H A solution of fluorene-9-yl)methoxy]carbonyl}amino)-3-methylpentanoic acid (300 mg, 848 μmol) in DMF (3 mL) was mixed with DEPBT (301 mg, 1.01 mmol), DIEA (735 μL, 4.23 mmol), and methylamine hydrochloride (68.1 mg, 1.01 mmol). The mixture was stirred at room temperature for 3 h. Water was then added to the mixture, and the precipitate was collected by filtration to give a pale yellow solid ((2)S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)carbamic acid (9 H 9-fluorene-9-yl)methyl ester (228 mg, 622 μmol, 100% purity, 73.5% yield) Step 2 . (2 S ,3 S )-2-amino- N Synthesis of 3-dimethylpentanamide ((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)carbamic acid (9 H A mixture of fluorene-9-yl)methyl ester (228 mg, 622 μmol) and dimethylamine (3 mL, 622 μmol) in THF / MeOH (3 mL) was stirred overnight at room temperature. The mixture was then concentrated. The residue was dissolved in water (10 mL) and washed with EtOAc (2 x 10 mL). The aqueous phase was concentrated to give a colorless oil (2... S ,3 S )-2-amino- N 3-Dimethylpentanamide (88.8 mg, 615 μmol, 100% purity, 99% yield).

[0409] Step 3 . ( S )-2-((((9 H Synthesis of tert-butyl fluorene-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoate Add 2,2,2-trichloroacetylimine tert-butyl ester (2.46 g, 11.3 mmol) to a solution of (2S)-2-({[(9H-fluorene-9-yl)methoxy]carbonyl}amino)-2-methylpentane-4-enoic acid (1 g, 2.84 mmol) in DCM (40 mL). Stir the mixture at 35 °C for 3 days. The mixture was then concentrated and the residue was purified by silica gel column chromatography (PE: EtOAc = 30: 1) to give a colorless oil. S )-2-((((9 H 2-Fluorene-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoic acid tert-butyl ester (980 mg, 2.40 mmol, 100% purity, 85% yield).

[0410] Step 4. ( S )-2-((((9 HSynthesis of tert-butyl fluorene-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoate At 0℃ towards ( S )-2-((((9 H 9-BBN (3.72 mL, 1.86 mmol) was added to a solution of tert-butyl 2-methylpentan-4-enoate (190 mg, 466 μmol) in THF (10 mL). The mixture was stirred overnight at room temperature. The mixture was then cooled to 0 °C and quenched with water. A solution of NaOAc (633 mg, 4.66 mmol) in H2O (2 mL) and H2O2 (2 mL, 25.7 mmol) was then added dropwise. The mixture was stirred at room temperature for 1 h. The mixture was then diluted with EtOAc (35 mL) and washed with brine (3 x 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (PE / EtOAc = 2 / 1) to give a colorless oil. S )-2-((((9 H 5-fluorene-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoate tert-butyl ester (173 mg, 406 μmol, 100% purity, 87% yield).

[0411] Step 5 . ( S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H Synthesis of tert-butyl imidazole-1-yl)valerate At 0℃, towards ( S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoic acid tert-butyl ester (173 mg, 406 μmol), 2-nitro-1 H -Imidazole (55.0 mg, 487 μmol) and PPh3 (170 mg, 649 μmol) were added to a solution of THF (2 mL) with DIAD (127 μL, 649 μmol). The mixture was stirred overnight at room temperature. The mixture was then concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give a white solid ( S )-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H1-Imidazol-1-yl)tert-butyl valerate (170 mg, 326 μmol, 100% purity, 80.5% yield).

[0412] Step 6 . ( S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H Synthesis of 1-imidazol-1-yl)valeric acid Towards( S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H 170 mg (326 μmol) of tert-butyl valerate (-imidazolium-1-yl)valerate was added to a solution of TFA (0.5 mL, 6.72 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 h. The mixture was then concentrated to give a white solid. S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H 1-Imidazol-1-yl)valeric acid (150 mg, 322 μmol, 100% purity, 99% yield) was used directly in the next step without purification.

[0413] Step 7 . (( S )-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1 H -imidazol-1-yl)-1-oxopentan-2-yl)carbamic acid (9 H Synthesis of fluorene-9-yl)methyl ester Towards( S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1 H 1-Imidazol-1-yl)valerate (90 mg, 193 μmol) was added to a solution of DMF (3 mL) with DEPBT (69.0 mg, 231 μmol), DIEA (100 μL, 579 μmol), and (2) S ,3 S )-2-amino- N3-Dimethylpentanamide (139 mg, 965 μmol). The mixture was stirred overnight at room temperature. The mixture was then diluted with EtOAc (30 mL) and washed with brine (3 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (DCM / MeOH = 20 / 1) to give a grayish-white solid. S )-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1 H -imidazol-1-yl)-1-oxopentan-2-yl)carbamic acid (9 H 9-fluorene-9-yl)methyl ester (37.0 mg, 62.6 μmol, 100% purity, 32% yield).

[0414] Step 8 . (( S )-5-(2-amino-1 H -imidazol-1-yl)-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)amino)-1-oxopent-2-yl)carbamic acid (9 H Synthesis of fluorene-9-yl)methyl ester Towards(( S )-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1 H -imidazol-1-yl)-1-oxopentan-2-yl)carbamic acid (9 H Pd / C (6.63 mg, 62.6 μmol) was added to a solution of fluorene-9-yl)methyl ester (37 mg, 62.6 μmol) in MeOH (3 mL). The mixture was stirred at room temperature under H2 (1 atm) for 1 h. The mixture was then filtered. The filtrate was concentrated to give a light brown solid. S )-5-(2-amino-1 H -imidazol-1-yl)-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)amino)-1-oxopent-2-yl)carbamic acid (9 H 9-fluorene-9-yl)methyl ester (32.0 mg, 57.0 μmol, 100% purity, 91% yield).

[0415] Step 9 . ( S )-2-amino-5-(2-amino-1 H -imidazol-1-yl)-2-methyl- N -((2 S ,3 S Synthesis of 3-methyl-1-(methylamino)-1-oxopentan-2-yl)pentanamide (A-53) Will(( S )-5-(2-amino-1 H -imidazol-1-yl)-2-methyl-1-(((2) S ,3 S )-3-methyl-1-(methylamino)-1-oxopent-2-yl)amino)-1-oxopent-2-yl)carbamic acid (9 H A solution of fluorene-9-yl)methyl ester (32 mg, 57.0 μmol) in dimethylamine (3 mL, 57.0 μmol) was stirred at room temperature for 1 h. The mixture was then concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH: NH3 = 30: 1: 0.1) to obtain a crude product, which was further purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-2-methyl-N-((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)pentanamide (A-53). Yield: 12.0 mg, 62.5%; Appearance: Brown oily substance; 1H NMR (400 MHz, DMSO-d6) δ 8.06–7.94 (m, 2H), 6.49 (d, J = 1.4 Hz, 1H), 6.33 (d, J = 1.4 Hz, 1H), 5.20 (s, 2H), 4.10–4.06 (m, 1H), 3.59 (t, J = 7.0 Hz, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.10–1.90 (m, 2H), 1.74–1.55 (m, 3H), 1.52–1.32 (m, 3H), 1.12 (s, 3H), 1.07–0.94 (m, 1H), 0.85 -0.72 (m, 6H); HPLC purity: 100%; C 16 H 30 LCMS calculated value of N6O2: 338.24; observed value: 339.2 [M+H]+.

[0416] Example A10. (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-((R)-1-(4-(4-methylpiperazine) Synthesis of (1-azine-4-oxobutyl)pyrrolidine-3-yl)pentanamide (A-54) Step 1 . (( S )-1-((( R )-1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1 H Synthesis of tert-butyl (-imidazol-1-yl)-1-oxopentan-2-yl)carbamate 4-(( R )-3-(( S )-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1 H -imidazol-1-yl)pentamido)pyrrolidine-1-yl)butyric acid (60 mg, 124 μmol), 1-methylpiperazine (25 mg, 248 μmol), 1-[(dimethylamino)(dimethylimino)methyl]-3-oxo-2 H ,3 H -3λ5-[1,2,3]triazolo[5,4-b]pyridin-3-ylonium-2-oxide; hexafluoro-λ5-phosphoramide (94 mg, 248 μmol) and N , N A solution of diisopropylethylamine (48 mg, 372 μmol) in DMF (3 mL) was stirred at room temperature for 3 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic layer was washed with water (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid chromatography (MeOH / DCM = 0-6%) to give a colorless oil. S )-1-((( R )-1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1 H 1-Imidazol-1-yl)-1-oxopentan-2-yl)tert-butyl carbamate (66 mg, 116 μmol, 94% purity, 94% yield).

[0417] Step 2 . (( S )-5-(2-amino-1 H -imidazol-1-yl)-1-((( R Synthesis of tert-butyl carbamate (4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-1-oxopent-2-yl)carbamate At room temperature to ((S )-1-((( R )-1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1 H 46 mg, 81 μmol) of tert-butyl carbamate (-imidazol-1-yl)-1-oxopentan-2-yl)carbamate was added to a solution of 10% Pd / C (14 mg) in MeOH (3 mL). The reaction mixture was stirred under H2 for 2 h. The reaction mixture was filtered and concentrated to give a yellow solid. S )-5-(2-amino-1 H -imidazol-1-yl)-1-((( R 1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-1-oxopent-2-yl)carbamate tert-butyl ester (58 mg, 108 μmol, 90% purity, 96% yield) was used directly in the next step without further purification.

[0418] Step 3 . ( S )-2-amino-5-(2-amino-1 H -imidazol-1-yl)- N -(( R Synthesis of 1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)pentanamide At room temperature to (( S )-5-(2-amino-1 H -imidazol-1-yl)-1-((( R TFA (1 mL) was added to a solution of tert-butyl carbamate (58 mg, 108 μmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to give the crude product. The residue was purified by preparative HPLC (ACN / water / 0.1% NH3·H2O) to give ( S )-2-amino-5-(2-amino-1 H -imidazol-1-yl)- N -(( R 1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)pentanamide (A-54). Yield: 33.4 mg, 71%; Appearance: white solid; 1 H NMR (400 MHz, DMSO- d6) δ7.60 (s, 1H), 6.49 (d, J = 1.6 Hz, 1H), 6.34 (d, J = 1.6 Hz, 1H), 4.88 (s, 2H), 4.24 - 4.09 (m, 1H), 3.64 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 5.2 Hz, 4H), 3.14 -3.09 (m, 1H), 2.66 - 2.59 (m, 2H), 2.41 - 2.24 (m, 10H), 2.18 (s, 3H), 2.11 -2.02 (m, 1H), 1.69 - 1.53 (m, 6H), 1.41 - 1.29 (m, 1H); HPLC purity: 100.0%; C 28 H 30 LCMS calculated value of N4O2S: 434.59; observed value: 435.3 [M+H] + .

[0419] Example A11. (S)-N-((R)-1-acetylpyrrolidone-3-yl)-2-amino-5-(2-amino-1H-benzo) Synthesis of [d]imidazol-1-yl)pentanamide (A-55): Step 1 . ( R Synthesis of tert-butyl 1-(1-acetylpyrrolidine-3-yl)carbamate At 0℃ N -[(3 R [-pyrrolidone-3-yl]tert-butyl carbamate (300 mg, 1.61 mmol) was added to a solution of acetyl chloride (252 mg, 3.22 mmol) and TEA (325 mg, 3.22 mmol) in DCM (3 mL). The resulting mixture was stirred at 0 °C for 3 h. The mixture was quenched with water, and the aqueous layer was extracted with DCM (50 mL x 3). The organic layer was concentrated. The residue was purified by rapid chromatography (MeOH / DCM = 0-6%) to give a white solid ( R 1-(1-acetylpyrrolidone-3-yl)carbamate tert-butyl ester (265 mg, 1.16 mmol, 100% purity, 72% yield).

[0420] Step 2 Synthesis of (R)-1-(3-aminopyrrolidone-1-yl)ethyl-1-one Towards( RTFA (2 mL) was added to a solution of 175 mg (766 μmol)-(1-acetylpyrrolidone-3-yl)carbamate (4 mL) in DCM. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude ( ) product as a yellow oil. R 1-(3-aminopyrrolidone-1-yl)ethyl-1-one (98 g, 432 μmol, 100% purity, 56% yield).

[0421] Step 3 . (( S )-1-((( R Synthesis of tert-butyl carbamate (-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-benzo[d]imidazol-1-yl)-1-oxopentan-2-yl)carbamate Towards( R Add 1-(3-aminopyrrolidone-1-yl)ethyl-1-one (50 mg, 390 μmol) to a solution of DMF (2 mL) (2 S )-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazol-1-yl)valeric acid (147 mg, 390 μmol), DEPBT (175 mg, 585 μmol), and DIPEA (252 mg, 1.95 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EA (60 mL x 3). The organic layer was concentrated. The residue was purified by rapid chromatography (MeOH / DCM = 0-6%) to give a green oily substance. S )-1-((( R 1-Acetylpyrrolidone-3-yl)amino)-5-(2-nitro-1H-benzo[d]imidazol-1-yl)-1-oxopentan-2-yl)tert-butyl carbamate (100 mg, 204 μmol, 100% purity, 53% yield).

[0422] Step 4 . (( S )-1-((( R Synthesis of tert-butyl carbamate (-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-benzo[d]imidazol-1-yl)-1-oxopentan-2-yl)carbamate Towards( S )-1-((( R100 mg (204 μmol) of tert-butyl carbamate (100 mg, 204 μmol) was added to a solution of 1-(2-nitro-1H-benzo[d]imidazol-1-yl)-1-oxopentan-2-yl)carbamate in MeOH (3 mL) with 10% Pd / C (33 mg). The reaction mixture was stirred under H2 for 2 h. The reaction mixture was filtered and concentrated to give crude ((...) as a green oil. S )-1-((( R 1-Acetylpyrrolidone-3-yl)amino)-5-(2-amino-1H-benzo[d]imidazol-1-yl)-1-oxopent-2-yl)carbamate tert-butyl ester (94 mg, 204 μmol) was used directly in the next step without further purification.

[0423] Step 5. (S) )- N -(( R Synthesis of 1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-benzo[d]imidazol-1-yl)pentanamide Towards( S )-1-((( R 94 mg, 204 μmol of tert-butyl carbamate (TFA) was added to a solution of tert-butyl carbamate (94 mg, 204 μmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (ACN / water / 0.1% FA) to obtain ( S )- N -(( R 1-Acetylpyrrolidone-3-yl)-2-amino-5-(2-amino-1H-benzo[d]imidazol-1-yl)pentanamide (A-55). Yield: 22.9 mg, 31%; Appearance: colorless oil; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (dd, J = 13.2, 6.4 Hz, 1H), 8.32 (s, 2H), 7.16 (t, J =7.6 Hz, 2H), 6.95 (dt, J = 20.8, 7.2 Hz, 4H), 4.22 (dd, J = 30.8, 4.4 Hz, 1H), 4.02 (s, 2H), 3.51 (ddt, J= 17.2, 11.0, 5.6 Hz, 3H), 3.31 (dd, J = 11.2, 5.2 Hz,1H), 3.20 (ddd, J = 12.4, 7.6, 3.6 Hz, 1H), 2.01 (ddd, J = 25.6, 13.2, 7.6 Hz, 1H), 1.90 (s, 3H), 1.76 - 1.63 (m, 5H); HPLC purity: 98.2%; C 18 H 26 LCMS calculated value of N6O2: 358.45; observed value: 359.2 [M+H] + .

[0424] The following examples were prepared using standard chemical operations and procedures similar to those used in the preparations of the previous examples. Analytical data are given in the table below.

[0425] Example A12. (S)-2-amino-5-(2-amino-1H-imidazol-1-yl)-N-((S)-1-(5-(methoxymethyl) Synthesis of 2-( ... Step 1 Synthesis of (S)-(1-hydrazino-3,3-dimethyl-1-oxobut-2-yl)tert-butyl carbamate To (2) S Carbonyl diimidazole (1.54 g, 9.50 mmol) was added to a solution of 2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutyric acid (2 g, 8.64 mmol) in THF (20 mL), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 1.5 h, hydrazine hydrate (1.26 mL, 25.9 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (100 mL) and washed with water (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired intermediate as a colorless gel (2.00 g, 8.15 mmol, 94.7% yield, 90% purity).

[0426] Step 2 . ( S Synthesis of tert-butyl carbamate (1-(2-(2-methoxyacetyl)hydrazino)-3,3-dimethyl-1-oxobut-2-yl)carbamate Under a nitrogen atmosphere at 0°C, N-[(1] was added to a single-necked round-bottom flask containing N-[(1]]. S[1-(hydrazine carbonyl)-2,2-dimethylpropyl]tert-butyl carbamate (1.5 g, 6.11 mmol) was added to a solution of sodium bicarbonate (589 mg, 7.02 mmol) and methoxyacetyl chloride (695 mg, 6.41 mmol) in THF (10 mL), and the reaction mixture was slowly heated to room temperature for 30 min. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by rapid chromatography using 45% ethyl acetate in petroleum ether. The resulting 2.5 g crude compound was purified to give the title compound (2.00 g, 6.30 mmol, 103% yield, 96% purity) as a colorless gel.

[0427] Step 3 Synthesis of tert-butyl (S)-(1-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl)carbamate tert-butyl groups were added to a stirred solution of triphenylphosphine (2.96 g, 11.3 mmol) and iodine (2.86 g, 11.3 mmol) in DCM (5 ml) at room temperature. N -[(1 S A solution of tert-butyl carbamate (S)-1-[N (1.8 g, 5.67 mmol) and triethylamine (2.40 g, 23.8 mmol) in DCM (5 mL) was prepared. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with saturated sodium thiosulfate solution (2 x 50 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography and the product was separated by elution with 20% ethyl acetate in petroleum ether to give the title compound (1.18 g, 3.94 mmol, yield: 69.8%, purity: 95%) as a light brown gel.

[0428] Step 4 Synthesis of (S)-1-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl-1-amine Trifluoroacetic acid (4.49 g, 39.4 mmol) was added to a solution of N-[(1S)-1-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl]tert-butyl carbamate (1.18 g...

Claims

1. A compound of formula I: ABC I Or its pharmaceutically acceptable salt, wherein A represents the portion that binds to or associates with p62; B is the connector part; and C represents the target binding portion.

2. The compound of claim 1, wherein A is a polypeptide or peptide mimic moiety that binds to or associates with p62.

3. The compound of claim 1 or 2, wherein A is a dipeptide or peptide mimic moiety that binds to or associates with p62.

4. The compound of claim 1, wherein the compound is a compound of formula II-1 or II-2: Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic, -N(R a )-C1-C6 aliphatic, C1-C6 aliphatic-N(R a )-, -O-C1-C6 aliphatic, -C(O)-C1-C6 aliphatic, C6-C 12 aryl-C0-C6 aliphatic, 2 to 10 membered heteroaliphatic, or 4 to 6 membered heterocyclo- C1-C6 aliphatic comprising 1 to 3 heteroatoms selected from N, O and S, wherein G 2 is optionally substituted with one or more R b ; G 3 C1-C7aliphatic, C1-C7aliphatic-C(O)N(R a )-C0-C6aliphatic, C3-C 12 cycloaliphatic, 4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7aliphatic-C(O)-4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 is optionally substituted with one or more R c substituents; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; each R is independently selected from -N(R b a C1-C6 aliphatic, and halogen;​ Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

5. The compound of claim 1, wherein the compound is a compound of formula III-1 or formula III-2: Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic, -N(R a )-C1-C6 aliphatic, C1-C6 aliphatic-N(R a )-, -O-C1-C6 aliphatic, -C(O)-C1-C6 aliphatic, C6-C 12 aryl-C0-C6 aliphatic, 2 to 10 membered heteroaliphatic, or 4 to 6 membered heterocyclo-C1-C6 aliphatic comprising 1 to 3 heteroatoms selected from N, O and S, wherein G 2 is optionally substituted with one or more R b ; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a ; B is the connector part; and C represents the target binding portion.

6. The compound of claim 4 or 5, wherein G 1 It is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted.

7. The compound of claim 4 or 5, wherein G 1 It is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, optionally surrounded by -N(R a )2 or one or more of the halogens are substituted.

8. The compound of claim 4 or 5, wherein G 1 It is a 7- to 12-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, optionally separated by one or more -N(R) atoms. a )2 or halogen substitution.

9. The compound according to any one of claims 4-8, wherein the compound is a compound of formula II-1 or formula III-1.

10. The compound of claim 9, wherein G 1 Selected from: 。 11. The compound according to any one of claims 4-8, wherein the compound is a compound of formula II-2 or formula III-2.

12. The compound of claim 11, wherein G 1 Selected from: in Indicates the connection point with part B, and Indicates the relationship with part of G 2 The connection point.

13. The compound according to any one of claims 4-12, wherein G 2 It is a C1-C6 aliphatic group or a C1-C6 aliphatic group - a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, wherein G 2 Optionally by one or more R b replace.

14. The compound of claim 13, wherein G 2 To be optionally used by one or more R b Replaced C1-C6 aliphatic groups.

15. The compound of claim 14, wherein G 2 To be optionally controlled by one or more -N(R) a )2-substituted C1-C6 aliphatic groups.

16. The compound of claim 15, wherein G 2 It is a C1-C6 aliphatic group that has been replaced by -NH2.

17. The compound of claim 16, wherein G 2 It is a C1-C6 aliphatic group substituted with -NH2, wherein the carbon atom bonded to -NH2 is in the form of... S Enantiomeric configuration.

18. The compound of claim 13, wherein G 2 It is a C1-C6 aliphatic group - a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, wherein G 2 Optionally by one or more R b replace.

19. The compound of claim 18, wherein G 2 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

20. The compound according to any one of claims 4-12, wherein G 2 Selected from: in This represents -C(O)-N(R) in formula II-1 or II-2. a - or the connection point with A in Equation III-1 or Equation III-2, and Indicates with G 1 The connection point.

21. The compound according to any one of claims 4-20, wherein G 3 C1-C7 aliphatic group -C(O)N(R) a - or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, wherein G 3 Optionally by one or more R c replace.

22. The compound of claim 21, wherein G 3 C1-C7 aliphatic group -C(O)N(R) a ), which is optionally substituted with halogens or optionally with substituted C1-C6 aliphatic groups.

23. The compound of claim 22, wherein G 3 C1-C7 alkyl-C(O)N(R) a ), which is optionally substituted with halogens or optionally with substituted C1-C6 aliphatic groups.

24. The compound according to claims 9, 10 or 13-20, wherein G 3 Selected from: ， in This indicates the connection point with part B.

25. The compound according to any one of claims 11-20, wherein G 3 Selected from: 。 26. The compound of claim 24, wherein G 3 Selected from: ， in This indicates the connection point with part B.

27. The compound of claim 25, wherein G 3 Selected from: 。 28. The compound according to any one of claims 5-27, wherein ring A is: 。 29. The compound of claim s4, wherein the compound is a compound of formula IVa: IVa Or its pharmaceutically acceptable salt.

30. The compound of claim 4, wherein the compound is a compound of formula IVb. IVb Or its pharmaceutically acceptable salt.

31. The compound of claim 4, wherein the compound is a compound of formula IVc-1: IVc-1 Or its pharmaceutically acceptable salt.

32. The compound of claim 4, wherein the compound is a compound of formula IVd-1: IVd-1 Or its pharmaceutically acceptable salt.

33. The compound of claim 4, wherein the compound is a compound of formula IVe-1: IVe-1 Or its pharmaceutically acceptable salt.

34. The compound of claim 4, wherein the compound is a compound of formula IVf: IVf Or its pharmaceutically acceptable salt.

35. The compound of claim 4, wherein the compound is a compound of formula IVg: IVg Or its pharmaceutically acceptable salt.

36. The compound of claim 4, wherein the compound is a compound of formula IVh. IVh Or its pharmaceutically acceptable salt, wherein W 1 W 2 W 3 and W 4 Each of them is independently selected from N, CH and CR. b .

37. The compound of claim 4, wherein the compound is a compound of formula IVi. IVi Or its pharmaceutically acceptable salt.

38. The compound of claim 4, wherein the compound is a compound of formula IVj. IVj Or its pharmaceutically acceptable salt, wherein W 5 W 6 W 7 and W 8 Each of them is independently selected from N and CR. d , where each R d Independently selected from H, -N(R) a 2. Optionally substituted C1-C6 aliphatic groups, halogens, or part of BC, wherein W 1 W 2 W 3 or W 4 One of them is CR d And R d For part of BC.

39. The compound according to any one of claims 1-38, wherein the connector is an optionally substituted C 2-50 Aliphatic groups, wherein one or more carbons are optionally and independently marked with -Cy-, -NR Z -、-N(R Z )C(O)-、-C(O)N(R Z )-、-N(R Z )C(O)O-、-OC(O)N(R Z )-、-N(R Z )C(O)N(R Z -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2- are replaced, wherein each -Cy- is independently a 3-12-membered divalent heterocyclic ring having 1-3 heteroatoms selected from N, O, and S, a 3-8-membered divalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, a C3-C6 cycloalkyl ring, or a C6-C6 cycloalkyl ring. 12 Aryl, and each R Z Independently H or selected from C1-C 20 Aliphatic group or C3-C 12 The cyclic aliphatic group is optionally substituted with a group.

40. The compound according to any one of claims 1-39, wherein B is a connector portion selected from Table B.

41. The compound of any one of claims 1-40, wherein C is a target-binding moiety that binds to ALK, BRD4, p62, Myddosome (IRAK4), Myddosome (MALT1), FGFR, RET, HTT, EML4, Tau, NLRP3 inflammasome, EGFR / RTK, androgen receptor, ACC2, KMO, IAPP, TSPO, STING, cGAS, or USP30.

42. The compound of claim 1, wherein the compound is selected from Table 1.

43. A pharmaceutical composition comprising any one of claims 1-42 and a pharmaceutically acceptable carrier, filler, or diluent.

44. A method of treating a subject's disease, symptom, or ailment, the method comprising administering a compound according to any one of claims 1-42 or a pharmaceutical composition according to claim 43.

45. The method of claim 44, wherein the disease, condition, or disorder is selected from NASH, NAFLD, cancers (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, gastric cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, gout, atherosclerosis, Alzheimer's disease, diabetes (e.g., type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-related periodic syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tau protein disorder (PART) dementia. Chronic traumatic encephalopathy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with Parkinson's disease associated with chromosome 17 (FTDP-17), Listik-Bodigo disease (Guam-type Parkinson's dementia complex), ganglioglioma and gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ekaterie-Gutierrez syndrome, ataxia, familial frostbite lupus, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD-TDP), and ALS.

46. ​​A method for inducing target degradation in a biological sample, the method comprising contacting the biological sample with a compound of any one of claims 1-42 or a pharmaceutical composition of claim 43.

47. The compound of any one of claims 1-42 or the pharmaceutical composition of claim 43, for use in medicine.

48. Use of the compound as claimed in any one of claims 1-42 or the pharmaceutical composition as claimed in claim 43 for the treatment of a disease, symptom, or ailment.

49. The use as described in claim 48, wherein the disease, condition, or disorder is NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, gastric cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, IgM-secreting lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, gout, atherosclerosis, Alzheimer's disease, diabetes (e.g., type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryptothermal protein-related periodic syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tau proteinopathy (PART) dementia, Chronic traumatic encephalopathy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with Parkinson's disease associated with chromosome 17 (FTDP-17), Listik-Bodigo disease (Guam-type Parkinson's dementia complex), ganglioglioma and gangliocytoma, meningioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ekaterie-Gutierrez syndrome, ataxia, familial frostbite lupus, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD-TDP), and ALS.

50. A compound of formula X: X Or its pharmaceutically acceptable salt, wherein: G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

51. A compound of formula XI: XI Or its pharmaceutically acceptable salt, wherein: Ring A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted. G 1 Five- to twelve-membered heteroaryl groups containing one to six heteroatoms selected from N, O, and S; four- to six-membered heterocycles containing one to four heteroatoms selected from N, O, and S; C6-C 12 Aryl, guanidine, -C(O)NH2 or -C(NH)NH2, wherein G 1 Optionally by one or more R b replace; G 2 C1-C6 aliphatic group, -N(R) a )-C1-C6 aliphatic group, C1-C6 aliphatic group-N(R a -, -O-C1-C6 aliphatic group, -C(O)-C1-C6 aliphatic group, C6-C 12 Aryl-C0-C6 aliphatic group, 2- to 10-membered heteroaliphatic group, or (4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic group, wherein G 2 Optionally by one or more R b replace; G 3 C1-C7 aliphatic group, C1-C7 aliphatic group -C(O)N(R) a )-C0-C6 aliphatic groups, C3-C 12 Cycloaliphatic groups, 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic groups -C(O)- 4- to 9-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S, or S(O)2, wherein G 3 Optionally by one or more R c replace; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; Each R b Independently selected from -N(R) a 2. Optionally substituted C1-C6 aliphatic groups and halogens; Each R c Independently selected from optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C6 cyclic aliphatic groups, optionally substituted C6-C 12 aryl, optionally substituted 4- to 12-membered heteroaryl, optionally substituted 4- to 6-membered heterocycles, -OR a -C(O)-C1-C6 aliphatic groups and -C(O)-OR a .

52. The compound of claim 50 or 51, wherein the compound is selected from Table 2.

Images