Dual-function decomposition agents and their use

Abstract

Compounds and compositions that bind to p62 and a target of interest and promote the degradation of the target of interest are provided herein. In some embodiments, the compounds described herein are of formula I: A compound of TIFF2026518352000608.tif18165 or a pharmaceutically acceptable salt thereof, in the formula, A is a drug that binds to or associates with p62, B is the linker part, C is the target binding site.

Description

[Background technology]

[0001] p62 is a multifunctional protein involved in the lysosomal degradation of ubiquitinated proteins via the autophagy pathway. Liu WJ, et al., Cell Mol Biol Lett. 2016 Dec 13;21:29. The ubiquitin-proteasome system (UPS) and autophagy are "two major protein degradation pathways in eukaryotic cells." Shin WH, et al., BMB Rep. 2020 Jan;53(1):56-63. These systems are essential for cell survival both under normal conditions and under stress. Liu WJ, et al., Cell Mol Biol Lett. 2016 Dec 13;21:29. [Prior art documents] [Non-patent literature]

[0002] [Non-Patent Document 1] Liu WJ,et al.,Cell Mol Biol Lett.2016 Dec 13;21:29 [Non-Patent Document 2] Shin WH,et al.,BMB Rep.2020 Jan;53(1):56-63 [Overview of the Initiative] [Means for solving the problem]

[0003] p62 is an autophagy substrate that has been shown to deliver ubiquitinated proteins to lysosomes for degradation. (Liu WJ, et al., Cell Mol Biol Lett. 2016 Dec 13;21:29). The therapeutic potential of inducing the removal of specific targets using intracellular degradation systems is well understood and has been extensively investigated for over a decade. See, for example, Bondeson & Crews Annu Rev Pharmacol Toxicol 57:107-123 (Sept. 6, 2017) and the references cited therein. p62 contributes to the autophagy process by interacting with ubiquitin or polyubiquitin chains on certain cargoes and subsequently delivering those cargoes to lysosomes for degradation. An overview of the relationship between p62 and the autophagy process is provided in Liu WJ, et al., Cell Mol Biol Lett. 2016 Dec 13;21:29. This application provides, in particular, novel compounds and their uses that utilize p62 to activate autophagy of a cargo or target of interest. While not bound by theory, the compounds described herein are understood to bind to both p62 and the target of interest, thereby causing p62 to deliver the cargo of interest to the lysosome, thereby initiating the degradation process of the target of interest.

[0004] In some embodiments, the present disclosure relates to formula I: [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in the formula, A is the part that joins or associates with p62, B is the linker part, C is the target binding site.

[0005] In some embodiments, the compound of formula I is formula II-1 or II-2: [ka] is a compound or a pharmaceutically acceptable salt thereof, wherein G 1 is a 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, C6-C 12 aryl, guanidine, -C(O)NH2, or -C(NH)NH2, wherein G 1 is optionally substituted with one or more R b ; G 2 is 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 (a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic, wherein G 2 is optionally substituted with one or more R b ; G 3 is C1-C7 aliphatic, C1-C7 aliphatic-C(O)N(R a )-C0-C6 aliphatic, C3-C 12 cycloaliphatic, a 4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, C1-C7 aliphatic-C(O)-a 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 ; Each R a is independently selected from H and optionally substituted C1-C6 aliphatic, Each R b is independently selected from -N(R a )2, optionally substituted C1-C6 aliphatic, and halogen, Each R c is optionally substituted C1-C6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0006] In some embodiments, the compound of formula I is formula III-1 or III-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0007] In some embodiments, the present disclosure provides pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers, fillers, or diluents.

[0008] In some embodiments, the present disclosure provides a method for treating a disease, disorder, or condition of interest, which comprises administering a compound described herein to the subject.

[0009] In some embodiments, the present disclosure provides a method for inducing the degradation of a target in a biological sample, the method comprising contacting the biological sample with a compound described herein.

[0010] In some embodiments, the present disclosure provides compounds that bind to p62. In some embodiments, the compounds that bind to p62 are of formula X: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a)2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a It is selected independently of others.

[0011] In some embodiments, the compound that binds to p62 is of formula XI: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a It is selected independently of others. [Brief explanation of the drawing]

[0012] [Figure 1] The bar graph shows the degradation levels of NSCLC-related EML4-ALK fusions by the drug and an inactive control.

[0013] [Figure 2] The bar graphs show the dose-dependent intracellular colocalization of endogenous p62 and endogenous ALK mediated by the compound at 1 hour, 6 hours, and 24 hours. Co-treatment with early (PIK-III) or late (BafA1) autophagy inhibitors maintains p62 and ALK colocalization up to 24 hours. [Modes for carrying out the invention]

[0014] The present disclosure provides compounds and compositions useful for binding to p62, and in some embodiments, such compounds and compositions are useful for inducing the degradation of specific targets by binding p62 and a target of interest. In some embodiments, such compounds include those of the formulas described herein or pharmaceutically acceptable salts thereof, where each variable part is as defined and described herein.

[0015] Compounds and Definitions Compounds of the present disclosure generally include those described above, and are further exemplified by the classes, subclasses, and chemical species disclosed herein. As used herein, the following definitions apply unless otherwise specified. For purposes of the present disclosure, chemical elements are identified according to the Periodic Table of the Elements (CAS style) in the Handbook of Chemistry and Physics, 75 th th Edition. In addition, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th th Edition, Eds.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0016] Unless otherwise specified, the structures described herein are intended to encompass all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, and all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are intended as part of this disclosure. Accordingly, single stereochemical isomers of the compounds provided, as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) mixtures, are within the scope of the invention. For example, in some cases, Tables 1 and 2 show one or more stereoisomers of the compounds, and unless otherwise specified, each stereoisomer is represented individually and / or as a mixture. Unless otherwise specified, all tautomeric forms of the compounds provided are within the scope of this disclosure.

[0017] Unless otherwise specified, the structures described herein are intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C concentrated carbon or 14 Compounds having the structure of the present invention, including carbon substitution with carbon-enriched carbon, are within the scope of this disclosure.

[0018] Approximately or nearly: As used herein, the terms “nearly” or “approximately” applied to one or more values ​​of interest refer to values ​​that are close to the explicitly stated reference value. Generally, a person skilled in the art familiar with the context will understand the reasonable degree of variation that “approximately” or “approximately” encompasses in that context. For example, in some embodiments, the terms “nearly” or “approximately” may encompass a range of values ​​within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the value mentioned.

[0019] Administration: As used herein, the terms “administering” or “dosing” usually refer to the administration of a composition to a subject to achieve delivery of the composition or the drugs contained therein to a target site or site to be treated. Those skilled in the art will know the various routes that may be used for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be by eye drops, oral administration, parenteral administration, topical administration, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial infusion), oral, cutaneous (e.g., one or more of the following, or may include, local administration to the dermis, intradermal administration, interdermal administration, transdermal administration), enteral administration, intra-arterial administration, intradermal administration, intragastric administration, intrathecal administration, intramuscular administration, intranasal administration, intraperitoneal administration, subarachnoid administration, intravenous administration, intraventricular administration, administration within a specific organ (e.g., intrahepatic administration), mucosal administration, nasal administration, oral administration, rectal administration, subcutaneous administration, sublingual administration, local administration, tracheal administration (e.g., by intratracheal infusion), vaginal administration, intravitreal administration, 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 consist of only a single dose. In some embodiments, administration may include the application of a fixed number of doses. In some embodiments, administration may include intermittent administration (e.g., multiple doses spaced apart in time) and / or cyclic administration (individual doses separated by a common set of time). In some embodiments, administration may include continuous administration (e.g., perfusion) for at least a selected set of time. In some embodiments, administration may include a pre-stimulation-additional immunization protocol. The pre-stimulation-additional immunization protocol may include the administration of an initial dose of the pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine), followed by the administration of a second dose or a subsequent dose of the pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) after a certain time interval. In the case of an immunogenic composition, the pre-stimulation-additional immunization protocol may result in an enhancement of the immune response in the patient.

[0020] Aliphatic: The term "aliphatic" refers to a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is either completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is either completely saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "cycloaliphatic"), and has a single point of attachment or two or more points of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 6 aliphatic carbon atoms (e.g., C 1~6 ). In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms (e.g., C 1~5 ). In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms (e.g., C 1~4 ). In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms (e.g., C 1~3 ). In yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms (e.g., C 1~2 ). Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, and hybrids thereof. Preferred aliphatic groups are C 1~6 alkyl.

[0021] Alkyl: The term "alkyl", used alone or as part of a larger moiety, refers to an optionally substituted straight-chain or branched-chain saturated hydrocarbon group having (unless otherwise specified) 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (e.g., C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~4 , C 1~3 , or C 1~2 ). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0022] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, "alkylene" is a divalent linear or branched alkyl group. In some embodiments, "alkylene chain" is a polymethylene group, i.e., -(CH2) n - is a positive integer, for example, 1-6, 1-4, 1-3, 1-2, or 2-3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by substituents. Preferred substituents are those listed below for substituted aliphatic groups, and also those described herein. It will be understood that two substituents of an alkylene group may be combined to form a ring system. In certain embodiments, two substituents may be combined to form a 3- to 7-membered ring. The substituents may be located on the same or different atoms. The suffix "-ene" or "-enyl" is intended to refer to the bifunctional part of a group when added to a particular group herein. For example, when "-ene" or "-enyl" is added to "cyclopropyl", it becomes "cyclopropylene" or "cyclopropyrenyl", a bifunctional cyclopropyl group, for example, [ka] This is intended to refer to [something].

[0023] Alkenyl: Used alone or as part of a larger term, the term "alkenyl" has at least one double bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3The term "cycloalkenyl" refers to an optionally substituted linear, branched, or cyclic hydrocarbon group having a carbon-carbon double bond. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system having 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.

[0024] Alkynyl: Used alone or as part of a larger term, the term "alkynyl" has at least one triple bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 This refers to an optionally substituted linear or branched hydrocarbon group having ) ). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0025] Antagonist: As understood by those skilled in the art, the term “antagonist” generally refers to a drug whose presence or level is associated with a reduced level or activity of a target compared to that observed in the absence of the drug (or at different levels of the drug). In some embodiments, the antagonist is one whose presence or level correlates with a target level or activity that is equivalent to or lower than a particular reference level or activity (e.g., observed under appropriate reference conditions, e.g., a known antagonist, e.g., in the presence of a positive control). In some embodiments, the antagonist may be a direct antagonist in that it directly affects the target (e.g., by direct interaction). In some embodiments, the antagonist may be an indirect antagonist in that it indirectly affects the target by acting on, for example, a modifier of the target or some other component or entity, e.g., by interacting with it.

[0026] Aryl: The term "aryl" refers to a ring with a total of 6 to 14 members (for example, C6 to C6). 14 This refers to monocyclic and bicyclic systems having ) such that at least one ring in the system is aromatic and each ring in the system has 3 to 7 ring members. In some embodiments, the "aryl" group has a total of 6 to 12 ring members (e.g., C6 to C6). 12 ) contains. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system that may have one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, and anthrasyl. Unless otherwise specified, the "aryl" group is a hydrocarbon. In some embodiments, the "aryl" ring system is an aromatic ring (e.g., phenyl) condensed with a non-aromatic ring (e.g., cycloalkyl). Examples of condensed aryl rings include: [ka] These are some examples.

[0027] Bicyclic: The term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring, that is saturated or has one or more unsaturated units and shares one or more atoms between the two rings of the ring system. Thus, the term encompasses any acceptable ring condensation, e.g., ortho condensation or spirocyclic rings. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires one or more heteroatoms to be present in one or both of the two rings. Such heteroatoms may be present at the ring junction, are optionally substituted, and can 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, and the like. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” means any saturated or partially unsaturated bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic ring. As defined by IUPAC, a “bridge” is an unbranched chain of multiple atoms or a single atom or valence bond connecting two bridgeheads, where “bridgehead” is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is bonded to the remainder of the molecule with any substituteable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as described for aliphatic groups. In addition, or / or, any substituteable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka] These are some examples. An example of a two-ring bridge is: [ka] These are some examples.

[0028] Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained from or derived from a biological source of interest as described herein (e.g., tissue or organism or cell culture). In some embodiments, the source of interest includes organisms such as animals or humans. In some embodiments, the biological sample is or contains biological tissue or biological fluid. In some embodiments, a biological sample may be or include bone marrow; blood; blood cells; ascites; tissue or microneedle biopsy specimens; cell-containing bodily fluids; free suspended nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; lavage fluids or washing fluids such as tube lavage fluid or bronchoalveolar lavage fluid; aspirates; scrapes; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other bodily fluids, secretions, and / or excrement; and / or cells derived therefrom. In some embodiments, a biological sample is or includes cells obtained from an individual. In some embodiments, the cells obtained are or include cells derived from the individual from which the sample is obtained. In some embodiments, the sample is a “primary sample” obtained directly from a 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), surgical procedure, and collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be apparent from the context, the term “sample” refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents). For example, filtration using a semipermeable membrane. Such “processed sample” may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of specific components.

[0029] Carrier: As used herein, the term “carrier” refers to a diluent, auxiliary, excipient, or vehicle administered with a composition. In some exemplary embodiments, carriers may include sterile liquids, such as water, and oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil. In some embodiments, the carrier is or comprises one or more solid components.

[0030] Composition: Those skilled in the art will understand that the term “composition” may be used to refer to a distinct 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, or solid.

[0031] Cycloaliphatic: As used herein, the term "cycloaliphatic" means a monocyclic C that is either fully saturated or contains one or more unsaturated units. 3~8 Hydrocarbons or bicyclic carbon 6~12 This refers to hydrocarbons that are not aromatic and have a single bond site or two or more bond sites on the rest of the molecule.

[0032] Cycloalkyl: As used herein, the term “cycloalkyl” refers to a saturated monocyclic or polycyclic ring system in which approximately 3 to approximately 10 ring carbon atoms are optionally substituted. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0033] Dosage Form or Unit Dosage Form: Those skilled in the art will understand that the term “dosage form” may be used to refer to a physically separated unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or its total proportion) suitable for administration according to a dosing plan (i.e., using a therapeutic dosing plan) determined to correlate with a desired or beneficial outcome when administered to a population in question.

[0034] Dosage Plan or Treatment Plan: Those skilled in the art will understand that the terms “dosage plan” and “treatment plan” may be used to refer to a set of (typically two or more) unit doses administered individually to a subject, typically at intervals of a certain period of time. In some embodiments, a given therapeutic agent may have a recommended dosage plan that requires one or more doses. In some embodiments, the dosage plan comprises multiple doses, each of which is time-separated from the other doses. In some embodiments, the individual doses are spaced at equal intervals from one another. In some embodiments, the dosage plan comprises multiple doses, with the individual doses separated by at least two different time periods. In some embodiments, all doses in the dosage plan are the same unit dose. In some embodiments, the different doses in the dosage plan are different amounts. In some embodiments, the dosage plan comprises an initial dose of a first dose, followed by one or more additional doses of a second dose different from the first dose. In some embodiments, the dosage plan comprises an initial dose of a first dose, followed by one or more additional doses of a second dose identical to the first dose. In some embodiments, the administration plan correlates with a desired or beneficial outcome when administered to the entire relevant population (i.e., a therapeutic administration plan).

[0035] Effective dose: The term "effective dose" refers to the amount of compound sufficient to achieve a beneficial or desired outcome (e.g., therapeutic, remission, inhibitory, or preventive outcome). An effective dose may be administered in one or more doses, applications, or prescriptions and is not intended to be limited to a specific formulation or route of administration.

[0036] Excipients: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, white powder, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol.

[0037] Halogen: The term "halogen" or "halo" refers to F, Cl, Br, or I.

[0038] Heteroaliphatic: As used herein, the term “heteroaliphatic” or “heteroaliphatic group” means an optionally substituted hydrocarbon moiety, but non-aromatic, having 1 to 5 heteroatoms in addition to carbon atoms, and being linear (i.e., unbranched), branched, or cyclic (“heterocyclic”), and being fully saturated or containing one or more unsaturated units. 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, heteroaliphatic groups contain 1 to 10 carbon atoms, where 1 to 3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1 to 4 carbon atoms, where 1 to 2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In further embodiments, the heteroaliphatic group contains 1 to 3 carbon atoms, where one 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, linear or branched heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, exemplary heteroaliphatic groups with 1 to 10 atoms include: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, etc.

[0039] Heteroaryl: The terms "heteroaryl" and "heteroar-", used alone or as part of a larger term, such as "heteroaralkyl" or "heteroaralkoxy," refer to monocyclic or bicyclic rings having 5 to 10 ring atoms (e.g., 5-6 membered monocyclic heteroaryls or 9-10 membered bicyclic heteroaryls), sharing 6, 10, or 14 π electrons in a cyclic configuration, and having 1 to 5 heteroatoms in addition to the carbon atoms. Examples of heteroaryl groups, though not limited to them, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, purinyl, naphthylidinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. As used herein, the terms “heteroaryl” and “heteroar-” also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, and whose radical or bond site lies on the aromatic heterocycle (i.e., bicyclic heteroaryl rings having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranil, dibenzofuranil, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazine-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl.The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heterocyclic aromatic," and includes rings in which any of these terms are optionally substituted. Exemplary monocyclic and bicyclic heteroaryl rings include: [ka] These are some examples.

[0040] Heteroatom: As used herein, the term “heteroatom” means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen.

[0041] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocycle” are interchangeable and refer to stable 3- to 8-membered monocyclic heterocycle parts, stable 6- to 10-membered bicyclic heterocycle parts, or stable 10- to 16-membered polycyclic heterocycle parts, which are either saturated or partially unsaturated and have one or more, e.g., 1- to 4, of the above-defined heteroatoms in addition to the carbon atom. When used in relation to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). +This is possible. The heterocycle may be bonded to its pendant group by any heteroatom or carbon atom, which results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. The heterocyclyl group may be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Examples of bicyclic heterocycles include groups in which the heterocycle is fused to one or more aryl rings. Examples of bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. The bicyclic heterocycle may also be a spirocyclic system (for example, a 7- to 11-membered spirocyclic fused heterocycle having one or more heteroatoms as defined above (e.g., 1, 2, 3, or 4 heteroatoms) in addition to a carbon atom). The bicyclic heterocycle may also be a bridging ring system (for example, a 7- to 11-membered bridging heterocycle having 1, 2, or 3 bridging atoms).

[0042] Modulator: 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 may cause an increase or decrease in the magnitude of a particular activity of a certain molecule compared to the magnitude of that activity in the absence of the modulator. For example, a modulator may be an agonist or antagonist (these terms are defined herein) of a particular target. For example, in some embodiments, the modulator is an agonist. In some embodiments, the modulator is an antagonist.

[0043] Oral: As used herein, the terms “oral administration” and “administered orally” have their meanings as understood in the art and refer to the administration of a compound or composition by mouth.

[0044] Parenteral: As used herein, the terms “parenteral administration” and “administered parenterally” have their meanings as understood in the art and refer to, but are not limited to, methods of administration other than enteral and topical administration, which are usually by injection, including, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0045] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aromatic (e.g., aryl or heteroaryl) moies as defined herein.

[0046] Patient or Subject: As used herein, the terms “patient” or “subject” refer to any organism to which the provided composition is administered, or may be administered, for example, for experimental, diagnostic, preventive, 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 human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject has been administered, or is currently administered, a specific treatment for diagnosing and / or treating a disease, disorder, or condition.

[0047] 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 exists in a unit dose suitable for administration in a treatment or dosing regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, which include those suitable for: oral administration, e.g., liquid drugs (aqueous solutions or non-aqueous solutions or suspensions), tablets, e.g., those targeting oral absorption, sublingual absorption, and systemic absorption, pills, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions or sustained-release formulations; topical application, e.g., creams, ointments, or sustained-release patches, or sprays applied to the skin, lungs, or mouth; vaginal or rectal use, e.g., pessaries, creams, or foams; sublingual use; ocular use; transdermal use; or transnasal, transpulmonary, and other mucosal applications.

[0048] Pharmacologically acceptable: As used herein, the term "pharmaceutically acceptable" means a compound, substance, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic response, or other problems or complications, and that is commensurate with a reasonable benefit-to-risk ratio.

[0049] pharmaceutically acceptable salts: As used herein, the term “pharmaceutically acceptable salt” means a salt of such compound that is suitable for use in the context of a pharmaceutical, i.e., a salt that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic response, etc., within the bounds of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by 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, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanes. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates.

[0050] Furthermore, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) 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 J. 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, and their websites). These disclosures are incorporated herein by reference.

[0051] Suitable bases from which salts can be derived include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4 Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0052] Polypeptide: As used herein, the term “polypeptide” generally has its recognized meaning in the art, for example, of a polymer of at least three amino acids linked together by peptide bonds. Those skilled in the art will understand that the term “polypeptide” is intended to be broad enough to encompass not only polypeptides having the complete sequences detailed herein, but also polypeptides representing functional fragments of such complete polypeptides (i.e., fragments retaining at least one activity). Furthermore, those skilled in the art will understand that protein sequences generally tolerate some substitutions without disrupting activity. Therefore, any polypeptide that retains activity, shares at least about 30–40%, often about 50%, 60%, 70%, or more than 80% overall sequence identity with another polypeptide of the same class, and more often typically contains at least one region of very high identity, often more than 90%, or even 95%, 96%, 97%, 98%, or 99%, and typically contains at least 3–4, and often up to 20 or more, amino acids in one or more highly conserved regions, is encompassed within the relevant term “polypeptide” as used herein. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of the various amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, proteins may contain native amino acids, non-native amino acids, synthetic amino acids, and combinations thereof.

[0053] To prevent or prevent: As used herein, the term “to prevent” or “prevent” when used in relation to the onset of a disease, disorder, and / or condition means to reduce the risk of developing such disease, disorder, and / or condition, and / or to delay the onset of one or more characteristics or symptoms of such disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition is delayed for a given period of time.

[0054] Substituted or optionally substituted: As described herein, the compounds of the present invention may contain an "optionally substituted" moiety. Generally, whether followed by the term "optionally," the term "substituted" means that one or more hydrogens of a given moiety are replaced with a preferred substituent. "Substituted" applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., [ka] at least [ka] It refers to, [ka] at least [ka] (This refers to [a specific group]). Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each of its substituted positions, and if two or more positions in any given structure can be substituted with two or more substituents selected from a specified group, the substituents may be identical or different at all positions. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, means a compound that remains substantially unchanged when subjected to conditions that enable its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. 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.

[0055] A suitable monovalent substituent on the replaceable 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(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;R°-(CH2) 0~4 O(CH2) 0~1 It may be substituted with Ph;R° - CH=CHPh;R° - (CH2) 0~4 O(CH2) 0~1 -Pyridyl;-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) 0~4 SSR°;-(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 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, together with the atom(s) between them, form a 3-12 member saturated monocyclic or bicyclic ring, a partially unsaturated monocyclic or bicyclic ring, or a monocyclic or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0056] Suitable monovalent substituents on R° (or rings formed with atoms between them by the occurrence of two independent appearances of R°) are, independently, halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2, -O(HaroR ● ), -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)0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● ,-(C 1~4 (Linear or branched alkylene) C(O)OR ● , or -SSR ● And in the formula, each R ● It is either unsubstituted, or if "halo" precedes it, it is substituted with only one or more halogens, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 The ring is independently selected from a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0057] Suitable divalent substituents on the saturated carbon atoms of the "arbitrarily substituted" groups include: =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- is listed, and each R that appears independently in the formula * C may be substituted with hydrogen as defined below. 1~6 Selected from an aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to a substituted carbon adjacent to the "optionally substituted" group is -O(CR * 2) 2~3O- is mentioned, and each R that appears independently in the formula * C may be substituted with hydrogen as defined below. 1~6 The rings are selected from aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] R * Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0059] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -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 † These are listed, and in the formula, each R † C may be substituted independently with hydrogen as defined below. 1~6An aliphatic, unsubstituted -OPh, or unsubstituted 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † The two independent occurrences of , along with the atom(s) interposed between them, form an unsubstituted 3- to 12-membered saturated monocyclic or bicyclic ring, a partially unsaturated monocyclic or bicyclic ring, or a monocyclic or bicyclic aryl ring, having 0- to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0061] Low molecular weight: As used herein, the term “low molecular weight” means organic and / or inorganic compounds with a low molecular weight. Generally, “low molecular weight” refers to molecules with a size of less than about 5 kilodaltons (kD). In some embodiments, low molecular weight is less than about 4 kD, less than 3 kD, less than about 2 kD, or less than about 1 kD. In some embodiments, low molecular weight is less than about 800 daltons (D), less than about 600 D, less than about 500 D, less than about 400 D, less than about 300 D, less than about 200 D, or less than about 100 D. In some embodiments, low molecular weight is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, low molecular weight is not a polymer.

[0062] In some embodiments, the low molecular weight does not contain a polymer portion. In some embodiments, the low molecular weight is not a protein or polypeptide and / or does not contain a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, the low molecular weight is not a polynucleotide and / or does not contain a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the low molecular weight is not a polysaccharide and / or does not contain a polysaccharide. For example, in some embodiments, the low molecular weight is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, the low molecular weight is not a lipid.

[0063] In some embodiments, the small molecule is a regulator (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.

[0064] Those skilled in the art who read this disclosure will understand that certain low molecular weight compounds described herein may be provided and / or available in any of the following forms, for example: crystalline form (e.g., polymorphs, solvates, etc.), salt form, protected form, prodrug form, ester form, isomer form (e.g., optical isomers and / or structural isomers), isotopic form, etc.

[0065] Those skilled in the art will understand that certain low molecular weight compounds have a structure that allows them to exist in one or more stereoisomeric forms. In some embodiments, such low molecular weight compounds may be available in accordance with this disclosure in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers. In some embodiments, such low molecular weight compounds may be available in accordance with this disclosure in the form of a racemic mixture.

[0066] Those skilled in the art will understand that certain small molecules have a structure that allows them to exist in one or more tautomerized forms. In some embodiments, such small molecules may be utilized in accordance with this disclosure in the form of individual tautomers or in a form that interconverts between tautomerized forms.

[0067] Those skilled in the art will know that certain low molecular weight compounds can undergo isotopic substitution (for example, with respect to H). 2 H or 3 H; 12 Regarding C 11 C, 13 C, or 14 C; 14 About N 13 N or 15 N; 16 About O 17 O or 18 O; 35 Cl or 37 About Cl 36 Cl; 19 Regarding F 18 F; 127 Regarding I 131It will be understood that they have structures that enable (e.g., I). In some embodiments, such low molecules may be utilized in accordance with this disclosure in one or more isotopically modified forms or in mixtures thereof.

[0068] In some embodiments, reference to a particular low molecular weight compound may relate to a particular form of that compound. In some embodiments, a particular low molecular weight compound may be provided and / or available in salt form (e.g., an acid-added salt or a base-added salt form, depending on the compound). In some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0069] In some embodiments, if a low molecular weight compound is naturally occurring or found in nature, the compound may be provided and / or utilized in accordance with this disclosure in a form different from the form in which it is naturally occurring or found in nature. Those skilled in the art will understand that in some embodiments, a preparation of a particular low molecular weight compound containing an absolute or relative amount of the compound or a particular form of the compound that is different from the absolute or relative amount (for example, relative to another component of the preparation that contains another form of the compound) of the compound or a particular form of the compound that is present in a reference preparation of interest (e.g., a primary sample from a source of interest such as a biological or environmental source), the preparation will be different from the compound if it were present in the reference preparation or source. Accordingly, in some embodiments, for example, a preparation of a low molecular weight compound of a single stereoisomer may be considered a different form of compound from a racemic mixture of the compound; a particular salt of a low molecular weight compound may be considered a different form from another salt of the compound; a preparation containing only one form of the compound containing one conformational isomer of a double bond ((Z) or (E)) may be considered a different form of compound from one containing the other conformational isomer of the double bond ((E) or (Z)); and a preparation in which one or more atoms are different isotopes compared to those present in the reference preparation may be considered a different form.

[0070] When used in this specification, in a low molecular structure, [ka] Those skilled in the art will understand that the bond represented by this expression refers to a bond that is a single bond (e.g., a saturated bond) in some embodiments and a double bond (e.g., an unsaturated bond) in some embodiments. For example, the following structure: [ka] teeth, [ka] It is intended to encompass both.

[0071] Furthermore, those skilled in the art will understand that, when used herein, the symbols in low molecular structures are... [ka] However, they are interchangeable, and you will understand that each refers to a bond point between two atoms. Additionally or alternatively, the symbols [ka] This refers to the point of the connecting ring in the form of a spiro ring.

[0072] To treat: As used herein, the terms “to treat,” “treatment,” or “to treat” refer to any method used to partially or completely reduce, improve, alleviate, inhibit, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be applied to subjects that do not show signs of a disease, disorder, and / or condition. In some embodiments, treatment may be applied to subjects that show only the initial signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing a pathology associated with the disease, disorder, and / or condition.

[0073] Compounds for binding to p62 In certain embodiments, this disclosure provides compounds for binding to p62. In some embodiments, the compounds are bifunctional, comprising a p62-binding moiety that binds to or associates with p62, and a target-binding moiety that binds to or associates with a target, thereby promoting autophagy degradation of the target. As used herein, the moiety “associates” with the target or p62 by various chemical interactions known to those skilled in the art. For example, the moiety may associate with the target or p62 by hydrogen bonds, van der Waals forces, London dispersion forces, ionic bonds, etc. In some embodiments, the p62 binding is measured by a method described herein, for example, in Example C1. In some embodiments, the compounds for binding to p62 and the target of interest are of formula I: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, A is the part that joins or associates with p62, B is the linker part, C is the target binding site.

[0074] In some embodiments, A is a polypeptide or peptide mimetic moiety that binds to or associates with p62. In some embodiments, A is a moiety comprising two or three conjugated amino acids (e.g., standard or non-standard amino acids) linked by a peptide bond (an amide linking two consecutive amino acids from C1 of one amino acid to N2 of the other amino acid). In some embodiments, A is a peptide mimetic moiety. A peptide mimetic moiety, as used herein, is a small protein-like chain that mimics a peptide. In some embodiments, a peptide mimetic moiety comprises a modified peptide, a structural mimetic of a peptide, a peptide foldamer, a mechanism mimetic, or other structural analogue.

[0075] In some embodiments, A is the following part: [ka] And, Compounds of formula I are those of formula II-1 or II-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a)2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0076] In some embodiments, the compounds described herein are of formula II-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(Ra )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0077] In some embodiments, the compounds described herein are of formula II-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, G 2C1-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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0078] In some embodiments, A is the following part: [ka] And, Compounds of formula I are those of formula III-1 or III-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R aThese are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0079] In some embodiments, the compounds described herein are of formula III-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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 12Aryl-C0~C6 aliphatic, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0080] In some embodiments, the compounds described herein are of formula III-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R cThese are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, C is the target binding site.

[0081] The descriptions of values ​​and variable parts herein are intended to apply to all formulas provided (e.g., formulas II-1, II-2, III-1, III-2, etc.) unless otherwise specified.

[0082] As generally described herein, ring A is an optionally substituted five- or six-membered heteroaryl containing one to three 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.

[0083] In some embodiments, ring A is [ka] Selected from, in the formula, [ka] G 3 Represents the connection point to, [ka] G 2 This represents a connection point to [a specific location].

[0084] As generally described herein, G 1This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is optionally replaced with G. In some embodiments, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl or guanidine, where G 1 is one or more R b It is optionally replaced with G. In some embodiments, G 1 is one or more R b It is a 5- to 12-membered heteroaryl or 4- to 6-membered heteroring containing 1 to 4 heteroatoms selected from N, O, and S, which are optionally substituted.

[0085] In some embodiments, G 1 It is a 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and one or more R b It is optionally replaced with G. In some embodiments, G 1 It is a 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S, and one or more R b It is optionally replaced with G. In some embodiments, G 1 It is a 5-6 member unsubstituted monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, G 1 It is a 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S, and one or more R b It is replaced by G 1This is a 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more halogens, -NH2, or optionally substituted C1-C6 aliphatic atoms. In some embodiments, G 1 This refers to halogen, -NH2, or -C(NH)NR°2 or -(CH2) 0~4 A 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more C1-C6 aliphatic atoms substituted with C(O)NR°2. In some embodiments, G 1 It is a 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more of -NH2 or -CH3. In some embodiments, G 1 R b imidazolyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, or thiazolyl, substituted with one or more of the following. In some embodiments, G 1 is an imidazolyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, or thiazolyl substituted with one or more halogens, -NH2, or C1-C6 aliphatic groups. In some embodiments, G 1 is an optionally substituted imidazolyl or pyridinyl, which is substituted with one or more halogens, -NH2, or C1-C6 aliphatic atoms. In some embodiments, G 1 is an unsubstituted imidazolyl or pyridinyl. In some embodiments, G 1 This is an imidazolyl or pyridinyl compound substituted with one or more -NH2 or -CH3 groups.

[0086] In some embodiments, G 1 is one or more R b It is a 7-12 member bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, which are optionally substituted with G. In some embodiments, G 1 is one or more -N(R a)2 or optionally substituted with halogens, it is a 7-12 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, G 1 This is a 7-12 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with one or more halogens, -NH2, or optionally substituted C1-C6 aliphatic atoms. In some embodiments, G 1 This is a 7-12 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more of halogens, -NH2, or -CH3. In some embodiments, G 1 is one or more R b Benzimidazolyl, indazolyl, indolyl, or pyrrolopyridinyl are optionally substituted with G. In some embodiments, G 1 is one or more R b Benzimidazolyl or indolyl, optionally substituted with G. In some embodiments, G 1 is benzimidazolyl, indazolyl, indolyl, or pyrrolopyridinyl substituted with one or more halogens, -NH2, or C1-C6 aliphatic groups. In some embodiments, G 1 is benzimidazolyl or indolyl substituted with one or more of the following: halogen, -NH2, or C1-C6 aliphatic. In some embodiments, G 1 is benzimidazolyl, indazolyl, indolyl, or pyrrolopyridinyl substituted with one or more of -NH2 or CH3. In some embodiments, G 1 This is an optionally substituted benzimidazolyl or indolyl, which is substituted with one or more of -NH2 or -CH3 groups.

[0087] In some embodiments, G 1 It is a 4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S, and one or more R b It is optionally replaced with G. In some embodiments, G 1This is a 4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S, and is optionally substituted with one or more halogens, -NH2, or C1-C6 aliphatic atoms. In some embodiments, G 1 It is a 4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S, and optionally substituted with -NH2 or -CH3.

[0088] In some embodiments, G 1 is one or more R b C6~C arbitrarily substituted 12 It is an arrow. In some embodiments, G 1 C6~C is optionally substituted with one or more of the following: halogen, -N(R°)2, R°, -NO2, or -C(NH)N(R°)2. 12 It is an arrow. In some embodiments, G 1 C6~C, optionally substituted with halogen or -NH2. 12 It is Ariel.

[0089] In some embodiments, G 1 It is guanidine.

[0090] In some embodiments, G 1 It is -C(O)NH2.

[0091] In some embodiments, G 1 teeth, [ka] Selected from.

[0092] In some embodiments, G 1 teeth, [ka] Selected from, in the formula, [ka] This represents the connection point to part B, [ka] is part G 2 This represents a connection point to [a specific location].

[0093] In some embodiments, G 1 teeth, [ka] Selected from, in the formula, [ka] This represents the connection point to part B, [ka] is part G 2 This represents a connection point to [a specific location].

[0094] As generally described herein, G 2 C1-C6 aliphatic, -N(R a )-C1~C6 aliphatic, C1~C6 aliphatic-N(R a A 4-6 membered heteroring containing 1-3 heteroatoms selected from C1-C6 aliphatic-N, O, and S, where G 2 is one or more R b It is arbitrarily replaced.

[0095] In some embodiments, G 2 is one or more R b It is a C1-C6 aliphatic atom that is optionally substituted with G. In some embodiments, G 2 is one or more R b It is a C1-C6 alkyl group that is optionally substituted with G. In some embodiments, G 2 is -N(R a )2 is a C1-C6 alkyl group that is optionally substituted with 2. In some embodiments, G 2 is -N(R a ) is a C1-C6 alkyl substituted with 2. In some embodiments, G 2This is methylene, ethylene, propylene, or n-butylene substituted with -NH2.

[0096] In some embodiments, G 2 is one or more R b -N(R a )-C1~C6 aliphatic. In some embodiments, G 2 is one or more R b It is an aliphatic molecule with -NH-C1~C6, which is optionally substituted with G. In some embodiments, G 2 is one or more R b It is an optionally substituted -NH-C1~C6 alkyl group. In some embodiments, G 2 This is a -NH-C1~C6 alkylene that is arbitrarily substituted with C1~C6 aliphatic molecules.

[0097] In some embodiments, G 2 is one or more R b C1~C6 aliphatic-N(R) is arbitrarily substituted. a )-. In some embodiments, G 2 is one or more R b It is a C1-C6 aliphatic-NH- which is optionally substituted with G. In some embodiments, G 2 is one or more R b It is a C1-C6 alkylene-NH- which is optionally substituted with G. In some embodiments, G 2 This is a C1-C6 alkylene-NH- group that is arbitrarily substituted with C1-C6 aliphatic groups.

[0098] In some embodiments, G 2 is one or more R b It is an aliphatic molecule with an arbitrary substitution of -O-C1~C6. In some embodiments, G 2 is one or more R b These are -O-C1~C6 alkylenes that have been arbitrarily substituted.

[0099] In some embodiments, G 2 is one or more R bIt is a -C(O)-C1~C6 aliphatic molecule, which is optionally substituted with G. In some embodiments, G 2 is one or more R b It is a -C(O)-C1~C6 alkylene, which is arbitrarily substituted.

[0100] In some embodiments, G 2 is one or more R b C6~C, which are arbitrarily substituted. 12 It is aryl-C0~C6 aliphatic. In some embodiments, G 2 is one or more R b C6~C arbitrarily substituted 12 It is an arrow. In some embodiments, G 2 is one or more R b It is a phenyl that is optionally substituted with G. In some embodiments, G 2 is one or more R b C6~C, which are arbitrarily substituted. 12 It is aryl-C1~C6 aliphatic. In some embodiments, G 2 is one or more R b It is a phenyl-C1~C6 aliphatic molecule that is arbitrarily substituted with .

[0101] In some embodiments, G 2 is one or more R b It is a C1-C6 aliphatic (4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S) which is optionally substituted with. In some embodiments, G 2 is one or more -N(R a )2 is optionally substituted with (a 4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S)-C1-C6 aliphatic. In some embodiments, G 2 is one or more N(R a ) is a piperidine-C1~C6 aliphatic which is optionally substituted with 2. In some embodiments, G 2 It is a piperidine-C1~C6 aliphatic molecule optionally substituted with one or more NH2 groups.

[0102] In some embodiments, G 2is one or more R b It is a 2- to 10-membered heteroaliphatic molecule that is optionally substituted with G. In some embodiments, G 2 is one or more R b It is a -C1~C3 aliphatic -NH-C1~C3 aliphatic molecule, arbitrarily substituted with .

[0103] In some embodiments, G 2 teeth, [ka] Selected from, in the formula, [ka] In equation II-1 or II-2, -C(O)-N(R a ) represents the connection point to -, or the connection point to A in equation III-1 or III-2, [ka] G 1 This represents a connection point to [a specific location].

[0104] As described herein, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is optionally substituted with. In some embodiments (for example, some embodiments of the compounds of formula II-1 or III-1), G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-, C3~C 12A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is optionally substituted with. In some embodiments (for example, some embodiments of compounds of formula II-2 or III-2), G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C1~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S, or a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C6 aliphatic-C(O)-N, O, and S, where G 3 is one or more R c It is arbitrarily replaced.

[0105] In some embodiments, G 3 is one or more R c It is a C1-C7 aliphatic molecule that is optionally substituted with G. In some embodiments, G 3 is one or more R c It is a C1-C7 alkyl group that is optionally substituted with G. In some embodiments, G 3 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, or heptyl. In some embodiments, G 3 is one or more R c These are C1-C7 alkylenes that are optionally substituted with G. In some embodiments, G 3 is methylene, ethylene, propylene, butylene, pentylene, hexylene, or heptylene. In some embodiments, G 3 is a C1-C7 aliphatic atom that is optionally substituted with one or more of the following: optionally substituted C3-C6 cycloaliphatic atoms, -OR a , or -C(O)-OR a In some embodiments, G 3is an optionally substituted C3-C6 cycloaliphatic and an optionally substituted C1-C7 aliphatic. In some embodiments, G 3 is an arbitrarily substituted C1-C6 aliphatic and an arbitrarily substituted C1-C7 aliphatic. In some embodiments, G 3 This is a C1-C7 aliphatic molecule that is arbitrarily substituted with a C1-C6 aliphatic molecule, and this is -(CH2) 0~4 OR ° or -(CH2) 0~ It is optionally replaced with 4SR°. In some embodiments, G 3 is -OR a These are C1-C6 aliphatic atoms that have been arbitrarily substituted.

[0106] In some embodiments, G 3 is one or more R c C1~C6 aliphatic-C(O)-N(R) are arbitrarily substituted. a )-C0~C6 aliphatic. In some embodiments, G 3 is one or more R c C1~C6 aliphatic-C(O)-N(R) are arbitrarily substituted. a )-. In some embodiments, G 3 is one or more R c C1~C6 aliphatic-C(O)-N(R) are arbitrarily substituted. a )-C1~C6 aliphatic. In some embodiments, G 3 is one or more -OR a C1~C6 aliphatic-C(O)-N(R) are arbitrarily substituted. a )-C1~C6 aliphatic.

[0107] In some embodiments of formula II-1 or III-1, G 3 teeth, [ka] And in the formula, [ka] This represents the connection point to part B, [ka] In equation II-1, -C(O)-N(R a This represents the bonding point to ring A in equation III-1, and also the bonding point to ring A.

[0108] In some embodiments of formula II-1 or III-1, G 3 teeth, [ka] That is the case.

[0109] In some embodiments, G 3 is one or more R c C3~C arbitrarily substituted 12 It is cycloaliphatic. In some embodiments, G 3 is one or more R c It is a C3-C6 cycloaliphatic which is optionally substituted with. In some embodiments, G 3 is one or more R c The cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl compounds are optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0110] In some embodiments, G 3 is one or more R c It is a 4- to 9-membered heteroring containing 1 to 3 heteroatoms selected from N, O, and S, which are optionally substituted with G. In some embodiments, G 3 is one or more R c It is a 4-6 member monocyclic heterocycle containing 1-3 heteroatoms selected from N, O, and S, which are optionally substituted with G. In some embodiments, G 3 is one or more R c It is a 6-9 member bicyclic heterocycle containing 1-3 heteroatoms selected from N, O, and S, which are optionally substituted with G. In some embodiments, G 3 Each of these is one or more R c Pyrrolidine, piperazine, tetrahydropyran, or piperidine, optionally substituted with G. In some embodiments, G 3This is a 4-6 member monocyclic heterocycle containing 1-3 heteroatoms selected from N, O, and S, which are optionally substituted with C1-C6 aliphatic atoms. In some embodiments, G 3 This is a 4-6 member monocyclic heterocycle containing 1-3 heteroatoms selected from N, O, and S, which are optionally substituted with C1-C6 aliphatic atoms, and the C1-C6 aliphatic atoms are -(CH2) 0~4 C(O)NR°2 or -(CH2) 0~4 It is arbitrarily substituted with C(O)R°, where R° is -(CH2) 0~2 R ● C, which has been arbitrarily replaced by 1~6 It is a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur.

[0111] In some embodiments, G 3 is one or more R c It is a 4- to 9-membered heteroring containing 1 to 3 heteroatoms selected from C1-C6 aliphatic-C(O)-N, O, and S, which are optionally substituted with G. In some embodiments, G 3 is one or more R c It is a 4-6 member monocyclic heterocycle containing 1-3 heteroatoms selected from C1-C6 aliphatic-C(O)-N, O, and S, which are optionally substituted with G. In some embodiments, G 3 is one or more R c It is a 6-9 membered bicyclic heterocycle containing 1-3 heteroatoms selected from C1-C6 aliphatic-C(O)-N, O, and S, which are arbitrarily substituted.

[0112] In some embodiments of formula II-1 or III-1, G 3 teeth, [ka] Selected from, in the formula, [ka] This represents the connection point to part B.

[0113] In some embodiments of formula II-1 or III-1, G 3 teeth, [ka] Selected from.

[0114] In some embodiments of formula II-2 or III-2, G 3 teeth, [ka] [ka] Selected from.

[0115] In some embodiments of formula II-2 or III-2, G 3 teeth, [ka] Selected from.

[0116] As described herein, each R a R is independently selected from H and optionally substituted C1-C6 aliphatic atoms. In some embodiments, R a H is H. In some embodiments, R a These are C1-C6 aliphatic atoms that have been arbitrarily substituted.

[0117] As described herein, each R b is -N(R a )2, optionally substituted C1-C6 aliphatic and halogens are independently selected. In some embodiments, R b is -N(R a )2. In some embodiments, R b is an optionally substituted C1-C6 aliphatic. In some embodiments, R b It is a halogen.

[0118] As described herein, each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a It is selected independently of R. In some embodiments, c is an optionally substituted C1-C6 aliphatic. In some embodiments, R c is an optionally substituted C3-C6 cycloaliphatic. In some embodiments, R c This is C6~C which is arbitrarily substituted. 12 It is an arrow. In some embodiments, R c R is an optionally substituted 4- to 12-membered heteroaryl. In some embodiments, R c R is an optionally substituted 4-6 member heteroring. In some embodiments, R c is -OR a In some embodiments, R c It is -C(O)-C1~C6 aliphatic. In some embodiments, R c is -C(O)-OR a That is the case.

[0119] As described herein, B is the linker portion. In some embodiments, B is G on the other hand. 1 (In formulas II-2 and III-2) or G 3 (In formulas II-1 and III-1) is a linker portion which is a divalent portion covalently bonded to part C on the other hand. In some embodiments, B is a linker portion which is a divalent portion covalently bonded to part C on the other hand. 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(RZ )SO2(R Z )-,-SO2(R Z )N(R Z )C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)-O-, -SO-, -SO2, arbitrarily substituted C 2~30 It is an aliphatic group, where each -Cy- is independently a 3-12 membered divalent C3-C6 cycloaliphatic group that is optionally substituted, a 5-12 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, and each R Z These are independently H or C1~C 20 Aliphatic or C3-C 12 It is an optionally substituted group selected from cycloaliphatic compounds.

[0120] In some embodiments, B is optionally replaced by C2-C 10 Aliphatic group, optionally substituted 2-10 member heteroaliphatic group, -C2-C 10 Aliphatic -Cy-, or -C2~C 10 It is an aliphatic C(O)-. In some embodiments, B is optionally substituted with C2-C 10 An aliphatic group, or an optionally substituted 2-10 membered heteroaliphatic group. In some embodiments, B is an optionally substituted C2-C 10 It is an aliphatic group. In some embodiments, B is an optionally substituted 2- to 10-membered heteroaliphatic group.

[0121] In some embodiments, B is optionally replaced by C 2~30 It is an aliphatic linker. In some embodiments, B is an optionally substituted C where one or more carbons are replaced by -O- 2~30 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, in which one or more carbons are replaced by -C(O)-. 2~30 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, where one or more carbons are independently replaced by -Cy-.2~30 The linker is an aliphatic group, where -Cy- is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, B is an optionally substituted C, where one or more carbons are independently replaced by -Cy-. 2~30 It is an aliphatic linker, where -Cy- is an optionally substituted six-membered heteroaryl ring having one nitrogen heteroatom.

[0122] In some embodiments, B is an optionally substituted C, where one or more carbon atoms are independently replaced by -O- and / or -C(O)-. 2~30 It is an aliphatic linker. In some embodiments, B is a linker in which one or more carbon atoms are independently -O- and / or -N(R Z )C(O)- is replaced by any substituted C 2~30 It is an aliphatic linker, and in the formula, R Z is H. In some embodiments, B is one or more carbon atoms independently of -O- and / or -C(O)N(R) Z )- which is replaced by an arbitrarily substituted C 2~30 It is an aliphatic linker, and in the formula, R Z is H. In some embodiments, B is one or more carbon atoms independently of -N(R Z ) is replaced by C(O)- and / or -C(O)-, R Z However, H is an arbitrarily substituted C. 2~30 It is an aliphatic linker. In some embodiments, B is a linker in which one or more carbon atoms are independently -C(O)N(R Z )- and / or -C(O)- are replaced, R Z However, H is an arbitrarily substituted C. 2~30 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, where one or more carbons are independently replaced by -Cy- and / or -C(O)-. 2~30 It is an aliphatic linker, where -Cy- is a six-membered divalent heterocyclyl ring having a C6 cycloalkyl and / or two nitrogen heteroatoms.

[0123] In some embodiments, B is a molecule in which one or more carbon atoms are independently -O-, -N(R Z )C(O)-, and / or -Cy-, any substituted C 2~30 It is an aliphatic linker, where -Cy- is a 3-12 member divalent substituted heteroaryl ring having 1-4 nitrogen heteroatoms, R Z is H. In some embodiments, B is one or more carbon atoms independently of -O-, -C(O)N(R Z )-, and / or -Cy-, any substituted C 2~30 It is an aliphatic linker, where -Cy- is a 3-12 member divalent substituted heteroaryl ring having 1-4 nitrogen heteroatoms, R Z is H. In some embodiments, B is one or more carbon atoms independently of -N(R Z ) is replaced by C(O)-, -O-, and / or -C(O)-, R Z However, H is an arbitrarily substituted C. 2~30 It is an aliphatic linker. In some embodiments, B is a linker in which one or more carbon atoms are independently -C(O)N(R Z )-, -O-, and / or -C(O)- are replaced by R Z However, H is an arbitrarily substituted C. 2~30 It is an aliphatic linker.

[0124] In some embodiments, B is a molecule in which one or more carbon atoms are independently -O-, -N(R Z )C(O)-, -C(O)-, and / or -Cy-, any substituted C 2~30 It is an aliphatic linker, where -Cy- is a C6 cycloalkyl group, and R Z is H. In some embodiments, B is one or more carbon atoms independently of -O-, -C(O)N(R Z )-, -C(O)-, and / or -Cy-, any substituted C 2~30It is an aliphatic linker, where -Cy- is a C6 cycloalkyl group, and R Z H is H.

[0125] In some embodiments, B is optionally replaced by C 1~10 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, where one carbon is replaced by -C(O)-. 1~10 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, in which one or more carbons are replaced by -C(O)-. 1~10 It is an aliphatic linker. In some embodiments, B is an optionally substituted C, where two carbon atoms are replaced by -C(O)-. 1~6 It is an aliphatic linker. In some embodiments, B is a linker in which one or more carbon atoms are independently -N(R Z )C(O)- is replaced by any substituted C 1~10 It is an aliphatic linker, and in the formula, R Z is H. In some embodiments, B is one or more carbons independently of -C(O)N(R Z )- is replaced by any replaced C1~ 10 It is an aliphatic linker, and in the formula, R Z is H. In some embodiments, B is an optionally substituted C, where one carbon is replaced by -Cy-. 1~10 The linker is an aliphatic group, where -Cy- is a six-membered divalent heterocyclyl ring having one nitrogen heteroatom. In some embodiments, B is an optionally substituted C, where one carbon is replaced by -Cy-. 1~10 It is an aliphatic linker, where -Cy- is a six-membered divalent heterocyclyl ring having two nitrogen heteroatoms.

[0126] In some embodiments, B is an optionally substituted C, where two carbon atoms are replaced by -O- 1~10It is an aliphatic linker. In some embodiments, B is an optionally substituted C1~, in which one or more carbons are independently replaced by -C(O)- and / or -Cy-. 10 The linker is an aliphatic group, where -Cy- is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, B is an optionally substituted C, where two carbon atoms are independently replaced by -C(O)- and -Cy-. 1~10 The linker is an aliphatic group, where -Cy- is an optionally substituted 3-12 membered divalent heteroaryl ring having 1-4 nitrogen heteroatoms. In some embodiments, B is an optionally substituted C where two carbon atoms are independently replaced by -C(O)- and -Cy-. 1~10 The linker is an aliphatic group, where -Cy- is an optionally substituted six-membered divalent heteroaryl ring having one nitrogen heteroatom. In some embodiments, B is an optionally substituted C, where one or more carbons are independently replaced by -C(O)- and / or -Cy-. 1~10 It is an aliphatic linker, where -Cy- is an optionally substituted C7 cycloalkyl group.

[0127] In some embodiments, portion A is derived from the compounds listed in Table A below. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15] [Table 9-16] [Table 9-17]

[0128] In some embodiments, B is a linker portion selected from Table B below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, t is an integer between 1 and 20.)

[0129] In some embodiments, B is a linker portion selected from the following: [ka] (In the formula, t is an integer between 1 and 20.)

[0130] As generally defined above, C is a target-binding moiety. In some embodiments, C is a target-binding moiety that binds to a kinase, kinase fusion, protein of interest, and / or fusion protein. In some embodiments, C is a target-binding moiety that binds to ALK, BRD4, EML4, midsome (IRAK4), midsome (MALT1), FGFR, RET, HTT, tau, NLRP3 inflammasome, EGFR / RTK, androgen receptor, ACC2, KMO, IAPP, TSPO, STING, cGAS, or USP30. In some embodiments, C is a target-binding moiety that binds to ALK, midsome (IRAK4), MALT1, BRD4, FGFR, or RET.

[0131] In some embodiments, C is a target binding moiety that binds to ALK. (References: 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 Molecular Medicine 14:e14296(2022), Acta Pharmaceutica Sinica B11(2),2021,355-372, J Med It is derived from compounds described in Chem. 2016, 14; 59(7): 3392-408, or Cancer Lett. 2016, 28; 372(2): 179-86.

[0132] In some embodiments, C is a target binding moiety that binds to ALK and is derived from a compound selected from the following: [ka] [ka]

[0133] In some embodiments, C is a target binding moiety that binds to ALK, and is selected from the following: [ka] [ka] [ka]

[0134] 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 a 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 following compounds. [ka]

[0135] In some embodiments, C is a target binding moiety that binds to BRD4, and is as follows: [ka]

[0136] In some embodiments, C is a target-binding region that binds to the midsome (IRAK4). In some embodiments, C is a target binding moiety that binds to the midsome (IRAK4). (See WO2011043371, WO2019133531, WO2015068856, US20180111917, WO2019160915, WO2018098367, Bioorg Med Chem Lett 2006;16(11):2842-5, ACS MedChem Lett.,2019,10,p1081, WO2015103453, Cell ChemBio,2020,27,p11-10, WO2018060174, ACS MedChem Lett.,2021,12,p82, WO2019099926, Bioorganic & Medicinal Chemistry) It is derived from compounds described in Letters (2014), 24(9), 2066-2072, Bioorganic & Medicinal Chemistry Letters (2008), 18(11), 3211-3214, WO2021018118, or WO2022147465.

[0137] In some embodiments, C is a target binding site that binds to the midsome (IRAK4) and is derived from the following: [ka] [ka]

[0138] In some embodiments, C is a target binding site that binds to the midsome (IRAK4), and is selected from the following: [ka] [ka]

[0139] In some embodiments, C is a target-binding moiety that binds to the midsome (MALT1). In some embodiments, C is a target-binding moiety that binds to the midsome (MALT1) and is derived from compounds described in J Med Chem., 2020 Dec 10;63(23):14594-14608, J Med Chem. 2020 Dec 10;63(23):14576-14593, Cancer Cell. 2012 Dec 11;22(6):812-24, WO2020111087, or WO2018020474. In some embodiments, C is a target-binding moiety that binds to the midsome (MALT1) and is derived from the following: [ka]

[0140] In some embodiments, C is a target binding site that binds to the midsome (MALT1), selected from the following: [ka] [ka]

[0141] In some embodiments, C is a target-binding moiety that binds to FGFR. In some embodiments, C is a target-binding moiety that binds to FGFR and is derived from compounds described in 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 FGFR and is derived from: [ka]

[0142] In some embodiments, C is a target binding moiety that binds to FGFR and is selected from the following: [ka]

[0143] In some embodiments, C is a target binding moiety that binds to RET. In some embodiments, C is a target binding moiety that binds to RET and is derived from compounds described in 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 that binds to RET and is derived from: [ka]

[0144] In some embodiments, C is a target binding moiety that binds to RET, and is selected from the following: [ka]

[0145] In some embodiments, C is a target binding moiety that binds to HTT. In some embodiments, C is a target binding moiety that binds to HTT and is derived from compounds described in 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 that binds to HTT and is derived from the following: [ka] [ka]

[0146] In some embodiments, C is a target binding moiety that binds to HTT and is selected from the following: [ka] [ka] [ka]

[0147] In some embodiments, C is a target binding moiety that binds to tau. In some embodiments, C is a target binding moiety that binds to tau and is derived from compounds described in 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 that binds to tau and is derived from: [ka]

[0148] In some embodiments, C is a target binding moiety that binds to tau, and is selected from the following: [ka] [ka] [ka] [ka]

[0149] 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 a compound described in WO2019092170. In some embodiments, C is a target binding moiety that binds to the NLRP3 inflammasome and is selected from the following: [ka]

[0150] 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 the following: [ka]

[0151] In some embodiments, C is a target-binding moiety that binds to the androgen receptor. In some embodiments, C is a target-binding moiety that binds to the 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 the androgen receptor and is selected from the following: [ka]

[0152] In some embodiments, C is a target binding moiety that binds to ACC2. In some embodiments, C is a target binding moiety that binds 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 that binds to ACC2 and is derived from: [ka]

[0153] In some embodiments, C is a target binding portion that binds to ACC2, and is selected from the following: [ka]

[0154] In some embodiments, C is a target binding moiety that binds to KMO. In some embodiments, C is a target binding moiety that binds to KMO and is selected from compounds described in JMC 2017, 60, 3383-3404. In some embodiments, C is a target binding moiety that binds to KMO and is derived from the following compounds. [ka]

[0155] In some embodiments, C is a target binding moiety that binds to KMO, and is as follows: [ka]

[0156] In some embodiments, C is a target binding moiety that binds 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 that binds to IAPP and is derived from the following compounds: [ka]

[0157] In some embodiments, C is a target binding portion that binds to IAPP, and is as follows: [ka]

[0158] In some embodiments, C is a target binding moiety that binds to TSPO. In some embodiments, C is a target binding moiety that binds to TSPO and is derived from compounds described in 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 a target binding moiety derived from: [ka]

[0159] In some embodiments, C is a target binding moiety that binds to TSPO and is selected from the following: [ka]

[0160] In some embodiments, C is a target binding moiety that binds to STING. In some embodiments, C is a target binding moiety that binds 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 that binds to STING and is derived from: [ka]

[0161] In some embodiments, C is a target binding portion that binds to STING, and is selected from the following: [ka]

[0162] In some embodiments, C is a target binding moiety that binds to cGAS. In some embodiments, C is a target binding moiety that binds 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 that binds to cGAS and is derived from: [ka]

[0163] In some embodiments, C is a target binding portion that binds to cGAS, and is selected from the following: [ka]

[0164] In some embodiments, C is a target binding moiety that binds to USP30. In some embodiments, C is a target binding moiety that binds to USP30 and is derived from the compound described in WO2020212350. In some embodiments, C is a target binding moiety that binds to USP30 and is derived from the following: [ka]

[0165] In some embodiments, C is a target binding portion that binds to USP30 and is selected from the following: [ka]

[0166] In some embodiments, C is a target binding moiety that binds to p62. In some embodiments, C is a target binding moiety that binds to p62 and is derived from a compound described in WO2020022783 or Nat Commun. 2017 Jul 24;8(1):102. In some embodiments, C is a target binding moiety that binds to p62 and is selected from the following: [ka]

[0167] In some embodiments, C is a target binding moiety that binds to p62, and is selected from the following: [ka]

[0168] In some embodiments, C is replaced with halogen C1-C 20 It is aliphatic. In some embodiments, C is C1-C 20 It is an aliphatic -Cl.

[0169] In some embodiments, the compounds described herein are of formula IVa: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , R b , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0170] In some embodiments, the compounds described herein are of formula IVb: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0171] In some embodiments, the compounds described herein are of formula IVc-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G3 These are as described in the Classes and Subclasses of this Specified Specified.

[0172] In some embodiments, the compounds described herein are of formula IVc-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0173] In some embodiments, the compounds described herein are of formula IVd-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0174] In some embodiments, the compounds described herein are of formula IVd-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0175] In some embodiments, the compounds described herein are of formula IVe-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , R b , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0176] In some embodiments, the compounds described herein are of formula IVe-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0177] In some embodiments, the compounds described herein are of formula IVf: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0178] In some embodiments, the compounds described herein are of formula IVg: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0179] In some embodiments, the compounds described herein are of formula IVh: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , and G 3 This is as described in the Classes and Subclasses herein, and W 1 , W 2 , W 3 , and W 4 Each of these is N, CH, and CR. bSelected independently from, R b These are described in the Classes and Subclasses of this Specified Specified Use.

[0180] In some embodiments, the compounds described herein are of formula IVi: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which B, C, R a , R b , and G 3 These are as described in the Classes and Subclasses of this Specified Specified.

[0181] In some embodiments, the compounds described herein are of formula IVj: [ka] A compound of or a pharmaceutically acceptable salt thereof, where R a and G 3 This is as described in the Classes and Subclasses herein, and W 5 , W 6 , W 7 , and W 8 Each of these is N and CR d Selected independently from each R d H, -N(R a )2, independently selected from optionally substituted C1-C6 aliphatic, halogen, or partial BC, W 1 , W 2 , W 3 , or W 4 One of them is CR d And R d This is a subdivision of BC.

[0182] In some embodiments, compounds of formulas I to IVj are selected from Table 1 below or their pharmaceutically acceptable salts. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52

[0183] In some embodiments, the compound of formula I is selected from the following: [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14] [Table 10-15] [Table 10-16] Table 10-17 Table 10-18 Table 10-19 Table 10-20 Table 10-21 Table 10-22 Table 10-23 Table 10-24 Table 10-25 Table 10-26 Table 10-27 Table 10-28 Table 10-29 Table 10-30 Table 10-31 Table 10-32 [Table 10-33] [Table 10-34]

[0184] In some embodiments, the compound that binds to p62 is of formula X: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R cIt is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a It is selected independently of others.

[0185] In some embodiments, the compound that binds to p62 is of formula XI: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 This includes 5- to 12-membered heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6. 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 is one or more R b It is arbitrarily replaced with, 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 12Aryl-C0~C6 aliphatic, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 is one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 is one or more R c It is arbitrarily replaced with, Each R a These are independently selected from H and optionally substituted C1-C6 aliphatic atoms. Each R b is -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c These are arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a It is selected independently of others.

[0186] In some embodiments of formula X or XI, the variable parts are rings A, G 1 , G 2 , G 3 , R a , R b , and R c Any of these is as defined in the Class and Subclass with respect to Formula I herein.

[0187] In some embodiments, the compound of formula X or XI is selected from Table 2 below or its pharmaceutically acceptable salts. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16]

[0188] In some embodiments, the compounds provided are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). References to the compounds provided herein are understood to include references to their salts unless otherwise specified.

[0189] Use, formulation, and administration Pharmaceutically acceptable compositions In another embodiment, the disclosure provides compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the compositions described herein are formulated for administration to a patient requiring such composition. In some embodiments, the compositions described herein are formulated for oral administration to a patient.

[0190] According to the methods disclosed herein, compounds and compositions are administered using any amount and route of administration that is effective in treating or mitigating the severity of the disorders described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, and its mode of administration. The compounds described herein are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage.

[0191] The compositions of this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, intraperitoneally, intracisionally, orally, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0192] The sterile injectable compositions described herein may be aqueous suspensions or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable non-toxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic salines. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media.

[0193] For this purpose, any non-irritating, non-volatile oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable formulations, and similarly, naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated forms, are useful. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions, such as carboxymethylcellulose or similar dispersants. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0194] Injectable formulations can be sterilized, for example, by filtering through a bacterial collection filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other injectable sterile media before use.

[0195] To extend the effects of the compounds of this disclosure, it is often desirable to delay the absorption of the compounds by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. In this case, the absorption rate of the compound depends on its dissolution rate, which may then depend on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oily medium. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolide. The compound release rate can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0196] 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 may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorings may also be added as needed.

[0197] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is provided with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; and d) disintegrants, such as agar, calcium carbonate, and potato It is mixed with modern starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) a dissolution retarder, e.g., paraffin, f) an absorption enhancer, e.g., a quaternary ammonium compound, g) a wetting agent, e.g., cetyl alcohol and glycerol monostearate, h) an absorbent, e.g., kaolin and bentonite clay, and / or i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0198] Similar types of solid compositions can also be used as fillers for soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifiers and may be compositions that release the active ingredient(s) in a delayed manner, either only in or preferentially in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Similar types of solid compositions can also be used as fillers for soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0199] The active compound may be in a microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, sugars, capsules, pills, and granules may be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also include additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, according to conventional methods. In the case of capsules, tablets, and pills, the dosage form may also include buffers. These may optionally contain opacifiers and may be compositions that release the active ingredient(s) in a delayed manner, either only in or preferentially in a particular part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

[0200] 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, the liquid dosage form may contain, for example, water or other solvents, solvents and emulsifiers, such as inert diluents commonly used in the art, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may contain auxiliaries, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0201] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore dissolves in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0202] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore dissolves in the rectum or vaginal cavity to release the active compound.

[0203] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, such as diseases of the eyes, skin, or lower intestines. Suitable topical formulations are readily prepared for each of these areas or organs.

[0204] Topical application to the lower intestinal tract can be achieved with rectal suppositories (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0205] For topical application, the pharmaceutically acceptable compositions provided may be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0206] For intraocular use, the pharmaceutically acceptable composition provided may be formulated as a finely powdered suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline containing or not containing a preservative such as benzalkonium chloride. Alternatively, for intraocular use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum.

[0207] The pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the field of pharmaceutical formulations and may be prepared as solvents in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0208] Dosage forms for topical or transdermal administration of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredients are mixed under sterile conditions with a pharmaceutically acceptable carrier and, as necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of this disclosure. In addition, this disclosure is intended for use in transdermal patches, which have the additional advantage of providing controlled delivery of the compounds to the body. Such dosage forms can be prepared by dissolving or distributing the compounds in a suitable medium. Absorption enhancers may also be used to increase the flow of the compounds through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compounds in a polymer matrix or gel.

[0209] Diseases, disorders, and conditions This disclosure includes the insight that the compounds and compositions provided herein can be used to direct autophagy to a target. This disclosure also includes the insight that directing autophagy to a specific target may be useful in treating certain diseases, disorders, and conditions. In some embodiments, the disease, disorder, or condition 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, activated 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, cryopyrin-associated periodic fever syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, and other conditions. Supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), Ritico-Bodig disease (Guam Parkinson's dementia complex), neuronal glioma and gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-related conditions. This includes diseases, disorders, or conditions selected from neurodegenerative diseases, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ecardi-Goutier syndrome, ataxia, familial lupus frostbite, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis, frontotemporal dementia (FTLD-TDP), and amyotrophic lateral sclerosis.

[0210] In some embodiments, a specific target binding moiety (e.g., part C' in formula I above) may be selected to modulate (and thereby induce the degradation of) a selected target in order to treat a selected disease, disorder, or condition. Those skilled in the art can use known binding moieties to identify a specific binding moiety based on the desired disease, disorder, or condition to be treated.

[0211] In some embodiments, the target is lipid droplets, and the disease, disorder, or condition to be treated is selected from NASH and NAFLD.

[0212] In some embodiments, the target is COP9, and the disease, disorder, or condition is cancer.

[0213] In some embodiments, the target is MYC, and the disease, disorder, or condition is Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, lung cancer, or gastric cancer.

[0214] In some embodiments, the target is the midsome, and the disease, disorder, or condition is activated 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.

[0215] In some embodiments, the target is the inflammasome, and the disease, disorder, or condition is gout, atherosclerosis, Alzheimer's disease, type II diabetes, experimental autoimmune encephalitis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cryopyrin-associated periodic fever syndromes (CAPS), colon cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, and gastrointestinal cancer.

[0216] In some embodiments, the target is KRAS, and the disease, disorder, or condition is colorectal cancer, lung cancer, leukemia, or pancreatic cancer.

[0217] In some embodiments, the target is alpha-synuclein, and the disease, disorder, or condition is Parkinson's disease, Lewy body dementia, multiple system atrophy, or axonal dystrophy.

[0218] In some embodiments, the target is tau, and the disease, disorder, or condition is Alzheimer's disease, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), Ritico-Bodig disease (Guam Parkinson's Dementia Complex), neuronal glioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, or lipofuscinosis.

[0219] In some embodiments, the target is estrogen receptor-α, and the disease, disorder, or condition is breast cancer.

[0220] In some embodiments, the target is an androgen receptor, and the disease, disorder, or condition is prostate cancer or spinal and bulbar muscular atrophy (SBMA) / Kennedy disease.

[0221] In some embodiments, the target is KSR1, and the disease, disorder, or condition is cancer.

[0222] In some embodiments, the target is islet amyloid polypeptide (IAPP), and the disease, disorder, or condition is type II diabetes mellitus.

[0223] In some embodiments, the target is IRAK4, and the disease, disorder, or condition is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or psoriasis.

[0224] In some embodiments, the target is PINK1, and the disease, disorder, or condition is Parkinson's disease, Huntington's disease, or spinocerebellar ataxia.

[0225] In some embodiments, the target is TDP43, and the disease, disorder, or condition is familial amyotrophic lateral sclerosis or frontotemporal dementia (FTLD-TDP).

[0226] Exemplary Embodiments This disclosure provides the following non-limiting numbered embodiments. Embodiment 1. Formula I: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is A is the part that joins or associates with p62. B is the linker part, A pharmaceutically acceptable salt thereof of the compound or the compound or a pharmaceutically acceptable salt thereof, wherein C is the target binding site. The compound according to Embodiment 1, wherein Embodiment 2.A is a polypeptide or peptide mimetic moiety that binds to or associates with p62. The compound according to Embodiment 1 or 2, wherein Embodiment 3.A is a dipeptide or peptide mimetic moiety that binds to or associates with p62. Embodiment 4. The compound is of formula II-1 or II-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, G 1 However, 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, C6-C 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 However, one or more R b It is arbitrarily replaced with, G 2 is C1~C6 aliphatic, -N(R a )-C1~C6 aliphatic, C1~C6 aliphatic-N(Ra )-, -O-C1~C6 aliphatic, -C(O)-C1~C6 aliphatic, C6~C 12 Aryl-C0~C6 aliphatic, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 However, one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 However, one or more R c It is arbitrarily replaced with, Each R a However, H and any optionally substituted C1-C6 aliphatic elements are independently selected. Each R b However, -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R c However, arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, The compound according to Embodiment 1, wherein C is the target binding site. Embodiment 5. The compound is of formula III-1 or III-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G 1 However, 5- to 12-membered heteroaryls containing 1 to 6 heteroatoms selected from N, O, and S, 4- to 6-membered heterorings containing 1 to 4 heteroatoms selected from N, O, and S, C6-C 12 It is an aryl, guanidine, -C(O)NH2, or -C(NH)NH2, where G 1 However, one or more R b It is arbitrarily replaced with, G 2 is 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, 2~10-membered heteroaliphatic, or (4~6-membered heteroring containing 1~3 heteroatoms selected from N, O, and S)-C1~C6 aliphatic, where G 2 However, one or more R b It is arbitrarily replaced with, G 3 is C1~C7 aliphatic, C1~C7 aliphatic -C(O)N(R a )-C0~C6 aliphatic, C3~C 12 A 4-9 membered heteroring containing 1-3 heteroatoms selected from cycloaliphatic, N, O, and S; a 4-9 membered heteroring containing 1-3 heteroatoms selected from C1-C7aliphatic-C(O)-N, O, and S; or S(O)2, where G 3 However, one or more R c It is arbitrarily replaced with, Each R a However, H and any optionally substituted C1-C6 aliphatic elements are independently selected. Each R b However, -N(R a )2, independently selected from arbitrarily substituted C1-C6 aliphatic and halogen elements, Each R cHowever, arbitrarily substituted C1-C6 aliphatic, arbitrarily substituted C3-C6 cycloaliphatic, and arbitrarily substituted C6-C 12 Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR a , -C(O)-C1~C6 aliphatic, and -C(O)-OR a Selected independently from, B is the linker part, The compound according to Embodiment 1, wherein C is the target binding site. Embodiment 6.G 1 The compound according to Embodiment 4 or 5, wherein the compound is an optionally substituted 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O, and S. Embodiment 7.G 1 However, -N(R a The compound according to Embodiment 4 or 5, which is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more of 2 or halogens. Embodiment 8.G 1 However, one or more -N(R a The compound according to Embodiment 4 or 5, which is a 7-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, optionally substituted with 2 or a halogen. Embodiment 9. The compound according to any one of Embodiments 4 to 8, wherein the compound is a compound of formula II-1 or III-1. Embodiment 10.G 1 but, [ka] [ka] A compound selected from the compound described in Embodiment 9. Embodiment 11. The compound according to any one of Embodiments 4 to 8, wherein the compound is a compound of formula II-2 or III-2. Embodiment 12.G 1 but, [ka] Selected from, in the formula, [ka] However, this represents the connection point to part B, [ka] However, part G 2 The compound according to Embodiment 11, representing a bonding site to [a specific location]. Embodiment 13.G 2 However, it is a 4-6 membered heteroring containing 1-3 heteroatoms selected from C1-C6 aliphatic or C1-C6 aliphatic-N, O, and S, where G 2 However, one or more R b A compound according to any one of Embodiments 4 to 12, which is optionally substituted with [the specified compound]. Embodiment 14.G 2 However, one or more R b The compound according to Embodiment 13, which is a C1-C6 aliphatic atom optionally substituted with a C1-C6 aliphatic atom. Embodiment 15.G 2 However, one or more -N(R a The compound according to Embodiment 14, which is a C1-C6 aliphatic atom optionally substituted with )2. Embodiment 16.G 2 However, the compound according to Embodiment 15 is a C1-C6 aliphatic compound substituted with -NH2. Embodiment 17.G 2 The compound according to Embodiment 16, wherein the carbon atom bonded to -NH2 is a C1-C6 aliphatic atom, and the carbon atom bonded to -NH2 is in an S enantiomer configuration. Embodiment 18.G 2 However, it is a 4-6 membered heteroring containing 1-3 heteroatoms selected from C1-C6 aliphatic-N, O, and S, where G 2 However, one or more R b The compound according to Embodiment 13, which is optionally substituted with [the specified compound]. Embodiment 19.G 2The compound according to Embodiment 18, wherein the compound is a 4-6 membered heteroring containing 1-3 heteroatoms selected from -CH2-N, O, and S. Embodiment 20.G 2 but, [ka] Selected from, in the formula, [ka] However, in equation II-1 or II-2, -C(O)-N(R a ) represents the connection point to -, or the connection point to A in equation III-1 or III-2, [ka] However, G 1 A compound according to any one of embodiments 4 to 12, representing a bonding site to a compound. Embodiment 21.G 3 is C1~C7 aliphatic-C(O)N(R a A 4-7 membered heteroring containing 1-3 heteroatoms selected from N, O, and S, where G 3 However, one or more R c A compound according to any one of Embodiments 4 to 20, which is optionally substituted with. Embodiment 22.G 3 However, C1~C7 aliphatic-C(O)N(R) is arbitrarily substituted with halogens. a The compound according to Embodiment 21, which is a C1-C6 aliphatic ) or optionally substituted C1-C6 aliphatic. Embodiment 23.G 3 However, C1~C7 alkyl-C(O)N(R) is arbitrarily substituted with halogens. a The compound according to Embodiment 22, which is a C1-C6 aliphatic ) or optionally substituted C1-C6 aliphatic. Embodiment 24.G 3 but, [ka] Selected from, in the formula, [ka] The compound according to Embodiments 9, 10, or 13-20, wherein the compound represents a bonding site to part B. Embodiment 25.G 3 but, [ka] [ka] A compound selected from any one of embodiments 11 to 20. Embodiment 26.G 3 but, [ka] Selected from, in the formula, [ka] However, the compound according to Embodiment 24 represents a bonding site to part B. Embodiment 27.G 3 but, [ka] A compound selected from the compounds described in Embodiment 25. Embodiment 28. Ring A is [ka] The compound according to any one of Embodiments 5 to 27. Embodiment 29. The compound is of formula IVa: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 30. The compound is of formula IVb: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 31. The compound is of formula IVc-1: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 32. The compound is of formula IVd-1: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 33. The compound is of formula IVe-1: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 34. The compound is of formula IVf: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 35. The compound is of formula IVg: [ka] The compound according to Embodiment 4, which is a compound or a pharmaceutically acceptable salt thereof. Embodiment 36. The compound is of formula IVh: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which W 1 , W 2 , W 3 , and W 4 Each of these is N, CH, and CR. b A compound according to Embodiment 4, independently selected from the above. Embodiment 37. The compound is of formula IVi: [ka] The compound according to embodiment 4, which is a compound of or a pharmaceutically acceptable salt thereof. Embodiment 38. The compound is of formula IVj:

Chemical formula

[0227] As described in the following examples, in certain representative embodiments, the compounds are prepared by the following general procedure. While the general method illustrates the synthesis of a particular compound in this disclosure, it will be understood that the following general method and other methods known to those skilled in the art may be applied to all compounds described herein and to each of their subclasses and species. [Table 11-1] [Table 11-2] [Table 11-3]

[0228] Analytical instruments and purification NMR instrument details: Varian 400MHz, Probe 1: Auto XID, Probe 2: ATB.

[0229] LCMS equipment details: Shimadzu LCMS-2010EV system connected to SPD-M20A PDA and ELS detector (Softa Model 400). LCMS method 1 - acidic conditions Column: X-Select C18 CSH (3.0*50mm) 2.5μ; Manufacturer: Waters Mobile phase A: Water: 0.05% formic acid in acetonitrile (95:5); pH = 3.5 Mobile phase B: 0.05% formic acid in acetonitrile Column oven temperature: 50℃ Flow rate: 1.2ml / min PDA: Max plot at 210nm Gradient program: Time (minutes) A% B% 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan range: 80~2000amu Scan speed: 2000 LC-MS Method 2 - Basic Conditions Column: X-Select C18 CSH (3.0*50mm) 2.5μm; Manufacturer: Waters Mobile phase A: 5 mM ammonium bicarbonate; pH = 8.8 Mobile phase B: Acetonitrile Column oven temperature: 50℃ Flow rate: 1.2ml / min PDA: Max plot at 210nm Gradient program: Time (minutes) A% B% 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan range: 80~2000amu Scan speed: 2000 HPLC method 1 - acidic conditions Column: X-Select CSH C18 (4.6*150mm); 5μ; Manufacturer: Waters Mobile phase A: Water: 0.1% formic acid in acetonitrile (95:05); pH = 3.5 B: Acetonitrile Flow rate: 1.0mL / min PDA: Max plot at 210nm Gradient program: Time (minutes) A% B% 0.0 95 5 1.0 95 5 8.0 0 100 12.0 0 100 14.0 95 5 18.0 95 5 HPLC Method 2 - Basic Conditions Column: Xbridge C18 (4.6*150mm), 5μ; Manufacturer: Waters Mobile phase A: 0.1% NH3 in water; pH = 9.5 B: Acetonitrile Flow rate: 1.2ml / min PDA: Max plot at 210nm Gradient program: Time (minutes) A% B% 0.0 98 2 6.0 0 85 8.0 0 85 9.0 0 100 12.0 0 100 14.0 98 2 18.0 98 2

[0230] INT-1:(Z)-N 2 ,N w ,N w’ - Synthesis of Tris(tert-butoxycarbonyl)-L-arginine [ka] Step 1: (Z)-N 2 ,N w ,N w´Synthesis of Tris(tert-butoxycarbonyl)-L-arginine (INT-1)

[0231] (2S)-2-amino-5-carbamimidamidopentanoic 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 minutes. Then, Boc2O (43.30 g, 199.0 mmol) was gradually added to the mixture. The reaction mixture was stirred at room temperature for 2 days. t-BuOH (150 mL) was removed under reduced pressure, and the residue was acidified to pH=3 with citric acid. The above solution was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and removed by distillation under vacuum to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}pentanoic acid (INT-1). Yield: 7.73 g, 33%; Appearance: White solid; 1 H NMR (300 MHz, DMSO-d6) 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%;C21H 38 LCMS calculated value for N4O8: 474.27; measured value: 475.3 [M+H] + .

[0232] Synthesis of INT-2:(2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid [ka] Step 1: Synthesis of (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-icate methyl

[0233] To a solution of 3-iodopyridine-2-amine (350 mg, 1.59 mmol) in DMF (2 mL), 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}pento-4-methyl acid (540 mg, 2.38 mmol) were added. The mixed solution was stirred at 80°C for 1 hour under N2. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (EA / PE = 0%~50%) to obtain (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-icate methyl (430 mg, 1.34 mmol, 100% purity, 84.8% yield) as a yellow oil.

[0234] Step 2: Synthesis of (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}methyl pentanoate

[0235] (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-methyl (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate (2S)-5-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate (2S)-5-5-5-5-5-5-5-5-5-5-5-5-5-5-5-5

[0236] Step 3: Synthesis of (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (INT-2)

[0237] LiOH (63.3 mg, 2.64 mmol) was added to a solution of (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate methyl (430 mg, 1.32 mmol) in H2O (2 mL) and THF (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (INT-2) (408 mg, 1.31 mmol, 100% purity, 100% yield) as a yellow solid.

[0238] Synthesis of INT-3:(S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid [ka] Step 1: Synthesis of benzyl (S)-2-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate

[0239] Sodium borohydride (2.36 g, 62.6 mmol, 2.0 equivalents) was added at 0°C to a stirred solution of 5-oxopyrrolidine-1,2-dicarboxylic acid 2-benzyl 1-tert-butyl (10.0 g, 31.3 mmol, 1.0 equivalent) in tetrahydrofuran (120.0 mL) and water (20.0 mL). The mixture was stirred at 0°C for 1 hour, allowed to rise naturally to room temperature, and then stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete and a product had been formed. The reaction mixture was concentrated under reduced pressure, the residue was suspended in EA, and washed with water. The aqueous layer was extracted with EA, the combined organic extract was washed with water and brine, dried, and concentrated under reduced pressure to obtain the crude product. This was purified by flash chromatography using 0-50% EA in PE to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoate benzyl (3.96 g, 100% purity, 38% yield) as a colorless oil.

[0240] Step 2: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)benzyl pentanoate

[0241] (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoate benzyl (3.96 g, 12.2 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (40.0 mL), to which 2-nitro-1H-imidazole (2.75 g, 24.4 mmol, 2.0 equivalent), triphenylphosphine (6.39 g, 24.4 mmol, 2.0 equivalent), and diisopropyl azodicarboxylic acid (4.93 g, 24.4 mmol, 2.0 equivalent) were added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete and a product had been formed. The reaction mixture was concentrated to obtain (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanoate benzyl (13.2 g, crude product). The crude product was used directly in the next step without further purification.

[0242] Step 3: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid

[0243] (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)benzyl pentanoate (13.2 g, 31.5 mmol, crude product) was dissolved in methanol (120.0 mL), to which lithium ol (1.50 g, 63.0 mmol, 2.0 equivalents) and water (40.0 mL) were added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in water and EA, and the resulting mixture was extracted three times with EA to remove by-products from the previous reaction. The aqueous layer was acidified to pH=1 with 1N HCl (aqueous solution) and extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and removed under reduced pressure to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid (INT-3). Yield: 3.34 g, 84%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) 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 for N4O6: 328.14; measured value: 219.1 [M+H] + .

[0244] Synthesis of INT-4 and INT-9: (2S)-5-(2-amino-1H-1,3-benzodiazole-1-yl)-2-{[(tert-butoxy)carbonylamino}pentanoic acid [ka] Step 1: Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioic acid 1-benzyl 2,5-dioxopyrrolidine-1-yl

[0245] (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) from DCM (150 mL) were added, and DCC (7.27 g, 35.5 mmol) was added at 0°C. 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 reduced pressure to obtain crude (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioic acid 1-benzyl 2,5-dioxopyrrolidine-1-yl (11.5 g, 26.5 mmol, 92% purity, 83% yield) as a white solid, which was used directly in the next step.

[0246] Step 2: Synthesis of benzyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoate

[0247] In a 1 L three-necked round-bottomed container, 12.0 g (27.6 mmol) of (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioic acid 1-benzyl 2,5-dioxopyrrolidine-1-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioic acid was added in 120 mL of THF, and then the solution of NaBH4 (2.09 g, 55.2 mmol) in THF / H2O (5:1, 60 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 1.0 hour. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-hydroxypentanoate benzyl (7.40 g, 22.8 mmol, 96% purity, 90% yield) as a colorless oil.

[0248] Step 3: Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazole-1-yl)benzyl pentanoate (INT-4)

[0249] 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-hydroxypentanoate benzyl (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 reduced pressure, and the residue was purified by preparative HPLC (NH3·H2O buffer) to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazole-1-yl)pentanoate benzyl (INT-4) (2.10 g, 4.48 mmol, 95.6% purity, 72.5% yield) as a yellow solid. 17 H 22LCMS calculated value for N4O6: 378.385; measured value: 323.1 [(M-t-Bu+H) + .

[0250] Step 4: Synthesis of (2S)-5-(2-amino-1H-1,3-benzodiazol-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (INT-9)

[0251] Into a 100 mL round-bottom flask, benzyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazol-1-yl)pentanoate (2.00 g, 4.26 mmol) in MeOH (30 mL) was placed, Pd / C (455 mg, 4.26 mmol, 10%) was added at room temperature under a nitrogen atmosphere, and then the reaction mixture was degassed and purged with hydrogen three times. The resulting reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain (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 for N4O4: 348.18; measured value: 349.1 [M+H] + .

[0252] INT-5 and INT-6: Synthesis of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (INT-6)

Chemical Structure

[0253] To a solution of 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (10.0 g, 22.7 mmol) and piperazine-1-carboxylate tert-butyl (4.63 g, 24.9 mmol) in THF (200 mL), 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 at room temperature. The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature. The reaction product was quenched by adding water (100.0 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 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 reduced pressure. The residue was added to a silica gel column and eluted with petroleum ether / ethyl acetate (0% to 30% ethyl acetate) to obtain 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl]piperazine-1-carboxylate tert-butyl (11.0 g, 22.0 mmol, 90% purity, 95% yield) as a yellow solid.

[0254] Step 2: Synthesis of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonilicate (INT-6)

[0255] Next, a solution of 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazine-1-carboxylate tert-butyl (100 mg, 200 μmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 3.0 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazine-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (29.7 mg, 74.7 μmol) as a white solid (INT-6). Yield: 29.7 mg, 37.2%; Appearance: White solid; 1 H NMR (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 for N4O: 398.21; measured value: 399.3 [M+H] + .

[0256] Synthesis of INT-7:(R)-8-(4-(4-(3-aminopyrrolidine-1-yl)butanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonilicate [ka] Step 1: Synthesis of 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]methyl butanoate

[0257] To a solution of methyl 4-bromobutanoate (193 mg, 1.07 mmol) in DMF (5 mL), methyl 4-bromobutanoate (193 mg, 1.07 mmol), K2CO3 (147 mg, 1.07 mmol), and NaI (160 mg, 1.07 mmol) were added, and the mixed reaction was stirred at 80°C for 3 hours. The reaction was 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 on anhydrous sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by flash silica gel chromatography (PE / EA = 1 / 1) to obtain the product methyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoate (250 mg, 872 μmol, 90% purity, 82% yield) as a colorless oil.

[0258] Step 2: Synthesis of 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoic acid

[0259] To a solution of methyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoate (300 mg, 1.04 mmol) in THF (3 mL) / MeOH (1 mL) / H2O (1 mL), lithium ol hydrate (218 mg, 5.20 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoic acid (283 mg, 1.04 mmol, 90% purity, 100% yield) as a yellow oil.

[0260] Step 3: Synthesis of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrile

[0261] To a solution of 4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazine-1-carboxylate tert-butyl (440 mg, 882 μmol) in DCM (5 mL), TFA (71.4 μL, 882 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazine-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (330 mg, 828 μmol, 93% purity, 94% yield) as a yellow oil.

[0262] Step 4: Synthesis of N-[(3R)-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]pyrrolidine-3-yl]carbamate tert-butyl

[0263] To a solution of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrilate (350 mg, 878 μmol) in DMF (10 mL), 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoic acid (285 mg, 1.05 mmol), DIPEA (723 μL, 4.39 mmol), and HATU (497 mg, 1.31 mmol) were added, and the mixed reaction was stirred at room temperature for 4 hours. The reaction was added to water (200 mL) and extracted with EA (300 mL x 3). The organic layer was washed with water (200 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by flash silica gel chromatography (DCM / MeOH = 10 / 1) to obtain the product N-[(3R)-1-[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 tert-butyl (450 mg, 689 μmol, 100% purity, 79% yield) as a yellow solid.

[0264] Step 5: Synthesis of 8-(4-{4-[(3R)-3-aminopyrrolidine-1-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonilicate

[0265] To a solution of N-[(3R)-1-[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]tert-butyl carbamate (400 mg, 612 μmol) in DCM (5 mL), TFA (1.5 mL, 612 μmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 8-(4-{4-[(3R)-3-aminopyrrolidine-1-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile)(INT-7 (300 mg, 542 μmol, 94% purity, 89% yield) as a yellow oil. 33 H 40 LCMS calculated value for N6O2: 552.32; measured value: 553.2 [M+H] + .

[0266] Synthesis of Int-8:4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanamide)pyrrolidine-1-yl)butanoic acid [ka] Step 1: Synthesis of ethyl (R)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)butanoate

[0267] To a solution of tert-butyl N-[(3R)-pyrrolidine-3-yl]carbamate (1 g, 5.36 mmol) in DMF (10 mL), ethyl 4-bromobutanoate (1.25 g, 6.43 mmol) and K2CO3 (2.20 g, 16.0 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was added to water (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to obtain ethyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoate (1.26 g, 4.19 mmol, 100% purity, 78% yield) as a pale yellow oil.

[0268] Step 2: Synthesis of ethyl (R)-4-(3-aminopyrrolidine-1-yl)butanoate

[0269] To a solution of ethyl 4-[(3R)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidine-1-yl]butanoate (160 mg, 532 μmol) in DCM (4 mL), TFA (1 ml, 4.19 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain ethyl 4-[(3R)-3-aminopyrrolidine-1-yl]butanoate (106 mg, 529 μmol, 100% purity, 100% yield) as a pale yellow oil.

[0270] Step 3: Synthesis of 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanamide)pyrrolidine-1-yl)butanoate ethyl

[0271] To a solution of ethyl 4-[(3R)-3-aminopyrrolidine-1-yl]butanoate (106 mg, 529 μmol) in DMF (5 mL), (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid (190 mg, 581 μmol), DIPEA (343 mg, 2.64 mmol), and DEPBT (237 mg, 793 μmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to obtain ethyl 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanamide]pyrrolidine-1-yl]butanoate (170 mg, 332 μmol, 100% purity, 62% yield) as a pale yellow oil.

[0272] Step 4: Synthesis of 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanamide)pyrrolidine-1-yl)butanoic acid

[0273] To a solution of 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanamide]pyrrolidine-1-yl]ethyl butanoate (170 mg, 332 μmol) in THF (5 mL) and H2O (1 mL), LiOH (39.8 mg, 1.66 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 5-6 with 1N HCl (aqueous solution), and then extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-30%) to obtain 4-[(3R)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanamide]pyrrolidine-1-yl]butanoic acid (INT-8) (120 mg, 248 μmol, 100% purity, yield 75%) as a pale yellow oil. 21 H 34 LCMS calculated value for N6O7: 482.25; measured value: 483.1 [M+H] + .

[0274] Synthesis of INT-10:8-(4-{4-[(4R)-4-amino-3,3-dimethylpyrrolidine-1-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonilicate [ka] Step 1: Synthesis of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate

[0275] To a solution of tert-butyl N-[(3R)-4,4-dimethylpyrrolidine-3-yl]carbamate (250 mg, 1.16 mmol) and methyl 4-bromobutanoate (376 mg, 2.08 mmol) in MeCN (5 mL), DIPEA (599 mg, 4.64 mmol) was added, and the mixture was stirred at 80°C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate (300 mg, 954 μmol) as a yellow oil.

[0276] Step 2: Synthesis of 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid

[0277] To a solution of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate (300 mg, 954 μmol) in THF (5 mL) and water (2.5 mL), LiOH (45.6 mg, 1.9 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid (279 mg, 927 μmol), which was used directly in the next step.

[0278] Step 3: Synthesis of N-[(3R)-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]-4,4-dimethylpyrrolidine-3-yl]carbamate tert-butyl

[0279] To a solution of 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid (200 mg, 665 μmol), DIPEA (429 mg, 3.32 mmol), and HATU (379 mg, 997 μmol) in DMF (5 mL), 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (265 mg, 665 μmol) was added, and the mixture was stirred at room temperature for 16 hours. 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 obtain the product N-[(3R)-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]-4,4-dimethylpyrrolidine-3-yl]carbamate tert-butyl (263 mg, 386 μmol) as a yellow solid.

[0280] Step 4: Synthesis of 8-(4-{4-[(4R)-4-amino-3,3-dimethylpyrrolidine-1-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonil

[0281] To a solution of N-[(3R)-1-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-8-yl}piperazin-1-yl)-4-oxobutyl]-4,4-dimethylpyrrolidine-3-yl]carbamate tert-butyl (70 mg, 102 μmol) in DCM (3 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature for 40 minutes. After the mixture was completed, it was concentrated under reduced pressure to obtain the crude residue, which was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to obtain the product 8-(4-{4-[(4R)-4-amino-3,3-dimethylpyrrolidine-1-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (INT-10). Yield: 15 mg, 25%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.4 Hz, 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 for N6O2: 580.78; measured value: 581.1 [M+H] + .

[0282] Synthesis of INT-11:(R)-8-(4-(4-(7-amino-5-azaspiro[2,4]heptan-5-yl)butanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonilicate [ka] Step 1: Synthesis of 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]heptan-5-yl]methyl butanoate

[0283] A solution of methyl 4-bromobutanoate (300 mg, 1.65 mmol), DIEA (637 mg, 4.94 mmol), and tert-butyl N-[(7R)-5-azaspiro[2.4]heptan-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 reduced pressure to obtain methyl 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2.4]heptan-5-yl]butanoate (301 mg, 965 μmol, 86.0% purity, 59.0% yield) as a yellow oil, which was used directly in the next step.

[0284] Step 2: Synthesis of 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2,4]heptan-5-yl]butanoic acid

[0285] A solution of methyl 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2.4]heptan-5-yl]butanoate (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 reduced pressure to obtain crude 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2.4]heptan-5-yl]butanoic acid (256 mg, 860 μmol, 86.0% purity, 77.0% yield) as a yellow oil, which was used directly in the next step.

[0286] Step 3: Synthesis of N-[(7R)-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]-5-azaspiro[2,4]heptan-7-yl]carbamate tert-butyl

[0287] A mixture of 4-[(7R)-7-{[(tert-butoxy)carbonyl]amino}-5-azaspiro[2.4]heptan-5-yl]butanoic 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-carbonitrile (398 mg, 1.00 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Then, HATU (455 mg, 1.20 mmol) was added, and the reaction mixture was stirred at room temperature for 1.0 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (NH3·H2O buffer) to obtain 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]heptan-7-yl]carbamate tert-butyl (346 mg, 509 μmol, 87.0% purity, 51.0% yield) as a yellow solid.

[0288] Step 4: Synthesis of 8-(4-{4-[(7R)-7-amino-5-azapiro[2,4]heptan-5-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonilicate (INT-11)

[0289] A solution of N-[(7R)-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]-5-azaspiro[2.4]heptan-7-yl]carbamate tert-butyl (180 mg, 265 μmol) in TFA / DCM (1:1, 5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 8-(4-{4-[(7R)-7-amino-5-azaspiro[2,4]heptan-5-yl]butanoyl}piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (INT-11) (127 mg, 220 μmol, 85% purity, 83% yield) as a brown oil, which was used directly in the next step.

[0290] Synthesis of 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]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid [ka] Step 1: Synthesis of (2S)-5-(2-amino-5-bromopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-icate methyl

[0291] (2S)-2-{[(tert-butoxy)carbonyl]amino}pento-4-methyl acid (250 mg, 1.10 mmol), 5-bromo-3-iodopyridine-2-amine (273 mg, 916 μmol), Pd(PPh3)2Cl2 (128 mg, 183 μmol), and CuI (17.4 mg, 91.6 μmol) were dissolved in DMF (5 mL), to which TEA (463 mg, 4.58 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was added to water (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-5%) to obtain (2S)-5-(2-amino-5-bromopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-icate methyl (258 mg, 647 μmol, 100% purity, 71% yield) as a yellow solid.

[0292] Step 2: Synthesis of (3E)-4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopento-1-in-1-yl]pyridine-3-yl}buta-3-enoic acid

[0293] (2S)-5-(2-amino-5-bromopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pento-4-methyl (290 mg, 728 μmol), buta-3-enoic acid (155 mg, 1.81 mmol), (acetyloxy) pararadioacetate (24.4 mg, 109 μmol), and P(o-tol)3 (66.3 mg, 218 μmol) were dissolved in CH3CN (5 mL), to which TEA (367 mg, 3.63 mmol) was added at room temperature. The reaction mixture was stirred at 120 °C for 0.5 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to obtain (3E)-4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopento-1-in-1-yl]pyridine-3-yl}buta-3-enoic acid (185 mg, 458 μmol, 92% purity, 63% yield) as a brown solid.

[0294] Step 3: Synthesis of 4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridine-3-yl}butanoic acid

[0295] (3E)-4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopento-1-in-1-yl]pyridine-3-yl}buta-3-enoic acid (185 mg, 458 μmol) was dissolved in MeOH (5 mL), to which Pd / C (97.3 mg, 91.6 μmol) was added at room temperature. The reaction mixture was stirred under H2 at room temperature for 16 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridine-3-yl}butanoic acid (155 mg, 378 μmol, 85% purity, 83% yield) as a pale yellow solid.

[0296] Step 4: Synthesis of (2S)-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}methyl pentanoate

[0297] 4-{6-amino-5-[(4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentyl]pyridine-3-yl}butanoic acid (155 mg, 378 μmol) and 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrilate (150 mg, 378 μmol) were dissolved in 5 mL of DCM, to which DIPEA (242 mg, 1.88 mmol) and HATU (172 mg, 453 μmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to 20 mL of water and extracted with 3 x 20 mL of DCM. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to obtain (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]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}methyl pentanoate (103 mg, 130 μmol, 91% purity, 35% yield) as a yellow solid.

[0298] Step 5: Synthesis of (2S)-5-{2-amino-5-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid

[0299] LiOH·H2O (27.2 mg, 650 μmol) was added to a solution of (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]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}methyl pentanoate (103 mg, 130 μmol) in THF (5 mL) and H2O (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain (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]pyridine-3-yl}-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (100 mg, 128 μmol, 91% purity, 100% yield) as the Li salt, which was used in the next step without further purification.

[0300] INT-13: Synthesis of (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)piperazine-1-yl)-5-oxopentyl)-1H-imidazole-1-yl)-2-((tert-butoxycarbonyl)amino)pentanoic acid [ka] Step 1: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl

[0301] A mixture of tert-butyl (2S)-5-bromo-2-{[(tert-butoxy)carbonyl]amino}pentanoate (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 × 200 mL). The combined organic layers were washed with saturated brine (3 × 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl (4.50 g, 11.7 mmol, 90% purity, 82% yield) as a yellow solid.

[0302] Step 2: Synthesis of (2S)-5-(4-bromo-2-nitro-1H-imidazole-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate tert-butyl

[0303] A mixture of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl (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 × 100 mL). The combined organic layers were washed with saturated brine (3 × 100 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (2S)-5-(4-bromo-2-nitro-1H-imidazole-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate tert-butyl (3.00 g, 6.47 mmol, 90% purity, 65% yield) as a yellow solid.

[0304] Step 3: Synthesis of (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pent-4-enoate methyl

[0305] (2S)-5-(4-bromo-2-nitro-1H-imidazole-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoate tert-butyl (2.00 g, 4.31 mmol) and pent-4-enoate methyl (1.47 g, 12.9 mmol) were dissolved in DMF (20 mL), to which TEA (2.17 g, 21.5 mmol), Pd2(dba)3 (788 mg, 862 μmol), and P(O-Tol)3 (1.31 g, 4.31 mmol) were added. The resulting mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flashing under the following conditions (column: C18 silica gel; mobile phase: 0.1% NH4OH in H2O / MeCN, gradient from 10% to 50% over 10 minutes; detector: UV 254 nm) to obtain (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pento-4-enoic acid (1.00 g, 2.01 mmol, 90% purity, 47% yield) as a yellow oil.

[0306] Step 4: Synthesis of (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pent-4-enoic acid

[0307] LiOH (205 mg, 5.00 mmol) was added at room temperature to a stirred solution of (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pent-4-enoate methyl (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 reduced pressure to obtain the crude product (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pento-4-enoic acid (300 mg, 621 μmol, 90% purity, 62% yield) as a yellow solid.

[0308] Step 5: Synthesis of (2S)-5-(4-bromo-2-nitro-1H-imidazole-1-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid

[0309] To a solution of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrile (450 mg, 1.13 mmol) in DMF (10 mL), K2CO3 (426 mg, 3.09 mmol) was added at room temperature, and the mixture was stirred at room temperature for 15 minutes. To the above mixture, (4E)-5-{1-[(4S)-5-(tert-butoxy)-4-{[(tert-butoxy)carbonyl]amino}-5-oxopentyl]-2-nitro-1H-imidazole-4-yl}pento-4-enoic acid (500 mg, 1.03 mmol) and HATU (585 mg, 1.54 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (200 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 × 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-oxopento-1-en-1-yl]-2-nitro-1H-imidazole-1-yl}tert-butyl pentanoate (400 mg, 463 μmol, 90% purity, 50% yield) as a yellow solid.

[0310] 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-oxopento-1-en-1-yl]-2-nitro-1H-imidazole-1-yl}pentanoic acid

[0311] NaOH (18.5 mg, 463 μmol) was added at room temperature 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-oxopento-1-en-1-yl]-2-nitro-1H-imidazole-1-yl}tert-butyl pentanoate (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 reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN in water, 30% to 55% gradient over 10 minutes; 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]carbazole-8-yl}piperazin-1-yl)-5-oxopento-1-en-1-yl]-2-nitro-1H-imidazole-1-yl}pentanoic acid (INT-13). Yield: 300 mg, 90%; Appearance: Yellow solid; 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (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%;C 43 H 50 LCMS calculated value for N8O8: 806.38; measured value: 807.5 [M+H]+ .

[0312] Synthesis of INT-14:N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl [ka] Step 1: Synthesis of tert-butyl N-[(3R)-1-ethylpyrrolidine-3-yl]carbamate

[0313] To a stirred solution of N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl (4.00 g, 21.4 mmol) and bromoethane (2.78 g, 25.6 mmol) in MeCN (50 mL), K2CO3 (8.84 g, 64.1 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded N-[(3R)-1-ethylpyrrolidine-3-yl]carbamate tert-butyl (2.40 g, 11.1 mmol, 85% purity, 53% yield) as a yellow solid.

[0314] Step 2: Synthesis of (R)-1-ethylpyrrolidine-3-amine hydrochloride

[0315] A solution of tert-butyl N-[(3R)-1-ethylpyrrolidine-3-yl]carbamate (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 reduced pressure to obtain (R)-1-ethylpyrrolidine-3-amine (1.60 g, 10.6 mmol, 80% purity, crude product) as the HCl salt, as a brown solid, which was used directly in the next step.

[0316] Step 3: Synthesis of N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl

[0317] A mixture of (2S)-5-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butoxy)carbonyl]amino}pentanoic 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 minutes. Then, TCFH (1.83 g, 6.54 mmol) was added, and the reaction mixture was stirred at room temperature for 3.0 hours. The reaction product was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (10% to 40% ethyl acetate) to obtain N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (1.80 g, 3.89 mmol, 95% purity, 71% yield) as a white solid.

[0318] Step 4: Synthesis of N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (INT-14)

[0319] In a 50 mL round-bottom flask, 1.8 g (3.89 mmol) of N-[(1S)-4-{[(benzyloxy)carbonyl]amino}-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl was added in 20 mL of MeOH. Pd / C (372 mg, 3.50 mmol, 10%) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was then degassed and purged with hydrogen three times. The resulting reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-[(1S)-4-amino-1-{[(3R)-1-ethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl as a white solid (INT-14). Yield: 1.20 g, 94%; 1 H 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 for N4O3: 328.25; measured value: 329.1 [M+H] + .

[0320] Synthesis of INT-15:8-[4-(4-aminobutanoyl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonilicate [ka] Step 1: Synthesis of N-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]carbamate tert-butyl

[0321] A mixture of 9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-5H,6H,11H-benzo[b]carbazole-3-carbonitrilate (500 mg, 1.25 mmol), 4-{[(tert-butoxy)carbonyl]amino}butanoic acid (254 mg, 1.25 mmol), and DIEA (483 mg, 3.75 mmol) in DMF (10 mL) was stirred at room temperature for 10 minutes. Then, HATU (570 mg, 1.50 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (NH3·H2O buffer) to obtain N-[4-(4-{3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazol-8-yl}piperazin-1-yl)-4-oxobutyl]carbamate tert-butyl (690 mg, 1.18 mmol, 98.0% purity, 95.0% yield) as a white solid.

[0322] Step 2: Synthesis of 8-[4-(4-aminobutanoyl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonilicate (INT-15)

[0323] A solution of tert-butyl 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 reduced pressure to obtain 8-[4-(4-aminobutanoyl)piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile as the 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 for N5O2: 483.26; measured value: 484.3 [M+H] + .

[0324] Synthesis of INT-16:(R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphan-15-carbonitrile (INT-16) [ka] Step 1: Synthesis of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine

[0325] To a stirred solution of (1S)-1-(5-fluoro-2-iodophenyl)ethanol (200 g, 751 mmol, 1.00 equivalent), 2-aminopyridine-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), DIAD (228 g, 1.13 mol, 1.50 equivalent) was added dropwise at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 12 hours under an N2 atmosphere. The reaction was quenched with H2O (100 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (0-50% ethyl acetate) to obtain 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine (220 g, 57%) as a yellow oil.

[0326] Step 2: Synthesis of methyl 2-[(1R)-1-[(2-aminopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate

[0327] 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) were dissolved in MeOH (8.00 L), to which Pd(dppf)Cl2 (44.9 g, 61.4 mmol, 0.1 equivalent) was added in a pressurized tank. The mixture was purged three times with carbon monoxide, and then pressurized to 20.0 psi at 100°C for 12 hours using carbon monoxide. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (0-50% ethyl acetate) to obtain methyl 2-[(1R)-1-[(2-aminopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate (220 g, 86%) as a green oil.

[0328] Step 3: Synthesis of 2-[(1R)-1-[(2-amino-5-bromopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate methyl

[0329] To a stirred solution of methyl 2-[(1R)-1-[(2-aminopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate (120 g, 413 mmol, 1.00 equivalent) in MeCN (1.00 L), NBS (88.3 g, 496 mmol, 1.20 equivalent) was added dropwise at 0°C under N2. The resulting mixture was stirred at 0-10°C under an N2 atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1.00 L). The mixture was basicized to pH 8-9 with saturated NaHCO3 solution. The resulting mixture was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (0-30% ethyl acetate) to obtain methyl 2-[(1R)-1-[(2-amino-5-bromopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate (60.0 g, 33%) as a yellow solid.

[0330] Step 4: Synthesis of (R)-2-(1-((2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)oxy)ethyl)-4-fluorobenzoate methyl

[0331] 2-[(1R)-1-[(2-amino-5-bromopyridine-3-yl)oxy]ethyl]-4-fluorobenzoate methyl (60.0 g, 163 mmol, 1.00 equivalent), KOAc (39.9 g, 406 mmol, 2.50 equivalents), and bis(pinacolate)diborone (49.5 g, 195 mmol, 1.20 equivalents) were dissolved in dioxane (600 mL), to which Pd(dppf)Cl2 (13.2 g, 16.3 mmol, 0.100 equivalent) was added. After stirring at 80°C for 16 hours under a nitrogen atmosphere, the mixture was allowed to cool to room temperature and used directly in the next step.

[0332] Step 5: Synthesis of 2-[(1R)-1-([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazole-4-yl)pyridine-3-yl]oxyethyl]-4-fluorobenzoate methyl

[0333] To the mixture from the previous step, tert-butyl N-[(5-cyano-4-iodo-1H-pyrazole-3-yl)methyl]-N-methylcarbamate (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 at room temperature. After stirring at 100°C for 16 hours under a nitrogen atmosphere, the mixture was allowed to cool 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 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (0-80% ethyl acetate) to obtain 2-[(1R)-1([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazole-4-yl)pyridine-3-yl]oxyethyl]-4-methyl fluorobenzoate (25.0 g, 31%) as a yellow solid.

[0334] Step 6: Synthesis of 2-[(1R)-1[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-3-yl)oxy]ethyl]-4-fluorobenzoate methyl

[0335] A stirred solution of 2-[(1R)-1-([2-amino-5-(3-([(tert-butoxycarbonyl)(methyl)amino]methyl-5-cyano-1H-pyrazole-4-yl)pyridine-3-yl]oxyethyl]-4-fluorobenzoic acid (25.0 g, 47.7 mmol, 1.00 equivalent) in HCl (gas) (4 M, 250 mL) in 1,4-dioxane. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product, 2-[(1R)-1[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-3-yl)oxy]ethyl]-4-fluorobenzoate methyl (18.0 g, 71%), as the HCl salt, was obtained as a pale yellow solid and was used directly in the next step without further purification.

[0336] Step 7: Synthesis of 2-[(1R)-1[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-3-yl)oxy]ethyl]-4-fluorobenzoic acid

[0337] To a stirred solution of methyl 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-3-yl)oxy]ethyl]-4-fluorobenzoate (18.0 g, 42.4 mmol, 1.00 equivalent) in MeOH (100 mL) and H2O (50 mL), NaOH (5.09 g, 127 mmol, 3.00 equivalent) was gradually added at room temperature. The resulting mixture was stirred at 40°C for 3 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure to obtain the crude product 2-[(1R)-1[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-3-yl)oxy]ethyl]-4-fluorobenzoic acid (13.0 g, 56%) as a pale yellow solid, which was used directly in the next step.

[0338] Step 8: Synthesis of (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphan-15-carbonitrili (PH-CSM-INT-10 / CSM-2362073(INT-16))

[0339] To a stirred solution of 2-[(1R)-1-[(2-amino-5-(3-cyano-5-[(methylamino)methyl]-2H-pyrazole-4-ylpyridine-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), PyBOP (24.7 g, 47.5 mmol, 1.50 equivalent) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then subjected to reverse-phase flash chromatography under the following conditions. Purified by Phi: Column: C18 silica gel; Mobile phase: MeCN in H2O (0.01% TFA), 30% to 55% gradient over 15 mins; Detector: UV 254 nm. (R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphan-15-carbonitrile (PH-CSM-INT-10 / CSM-2362073(INT-16)). 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 for C20H17FN6O2: 392.14; Actual value: 393.2 [M+H]+.

[0340] Step 9: Synthesis of N-[(5-cyano-4-iodo-1H-pyrazole-3-yl)methyl]-N-methylcarbamate tert-butyl (INT-17)

[0341] To a stirred solution of N-[(5-cyano-1H-pyrazole-3-yl)methyl]-N-methylcarbamate tert-butyl (45.0 g, 190 mmol, 1.00 equivalent) in MeCN (400 mL), NIS (42.9 g, 190 mmol, 1.00 equivalent) was gradually added at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was eluted with ethyl acetate / petroleum ether (0-50% ethyl acetate) and purified by silica gel column chromatography to obtain N-[(5-cyano-4-iodo-1H-pyrazole-3-yl)methyl]-N-methylcarbamate tert-butyl (INT-17) (40.0 g, 52%) as a yellow solid.

[0342] Synthesis of INT-18:(R)-26-amino-55-fluoro-4,7-dimethyl-6-oxo-11-(piperidine-4-ylmethyl)-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphan-15-carbonitrile [ka] Step 1: Synthesis of (R)-4-((26-amino-15-cyano-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctafan-11-yl)methyl)piperidine-1-carboxylate tert-butyl

[0343] 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)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphan-15-carbonitride (300 mg, 764 μmol), 4-(hydroxymethyl)piperidine-1-carboxylate tert-butyl (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 under a nitrogen atmosphere at 0°C for 3 hours. The reaction product was quenched with H2O (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. 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)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctafan-11-yl)methyl)piperidine-1-carboxylate tert-butyl (200 mg, 339 μmol, 80% purity, 44% yield) as a yellow oil. 1 H 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 for FN7O4: 589.28; measured value: 590.3 [M+H] + .

[0344] INT-19: Synthesis of 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ka] Step 1: Synthesis of (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxypropa-2-ethyl ethoxypropa-2-enoate

[0345] 5.00 g, 32.0 mmol of ethyl 3-cyclopropyl-3-oxopropanoate and 9.48 g, 64.0 mmol of (diethoxymethoxy)ethane in 60 mL of Ac2O were placed in a 250 mL three-necked round-bottom container at room temperature. The resulting mixture was stirred overnight at 130 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxypropa-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.

[0346] Step 2: Synthesis of 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylate ethyl

[0347] A solution of (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-ethoxypropa-2-enoate ethyl (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 allowed to cool to room temperature, filtered, and the filter cake was washed with Et2O (3 × 30 mL). The resulting mixture was concentrated under reduced pressure to obtain 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylate ethyl (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).

[0348] Step 3: Synthesis of 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (INT-19)

[0349] 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 × 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 LC-MS calculated value for H8ClN3O2: 237.03; measured value: 238.1 [M+H] + .

[0350] Synthesis of INT-20:1-(2-{4-[(3R)-3-aminopyrrolidine-1-yl]butoxy}-5-chloropyridine-3-yl)-3-{2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}urea [ka] Step 1: Synthesis of 4-[(5-chloro-3-nitropyridine-2-yl)oxy]butan-1-ol

[0351] To a solution of tert-butyl N-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yl)carbamate (2.16 g, 5.67 mmol) and butane-1,4-diol (2.33 g, 25.9 mmol) in DMF (10.0 mL), t-BuOK (2.90 g, 25.9 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was warmed to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain 4-[(5-chloro-3-nitropyridine-2-yl)oxy]butan-1-ol (2.56 g, 10.4 mmol, 86% purity, 40% yield) as a brown oil.

[0352] Step 2: Synthesis of 4-[(5-chloro-3-nitropyridine-2-yl)oxy]butanal

[0353] A solution of 4-[(5-chloro-3-nitropyridine-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 allowed to cool to room temperature and filtered. The filtered cake was washed with MeCN (3 × 30 mL), and the filtrate was concentrated under reduced pressure to obtain crude 4-[(5-chloro-3-nitropyridine-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.

[0354] Step 3: Synthesis of N-[(3R)-1-{4-[(5-chloro-3-nitropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl

[0355] 4-[(5-chloro-3-nitropyridine-2-yl)oxy]butanal (1.80 g, 7.35 mmol) and N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl (1.36 g, 7.35 mmol) were dissolved in MeOH (30 mL) and 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 reduced pressure. The residue was purified by silica gel chromatography (petroleum / ethyl acetate = 1:1) to obtain N-[(3R)-1-{4-[(5-chloro-3-nitropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl (1.20 g, 2.89 mmol, 92% purity, 40% yield) as a brown solid.

[0356] Step 4: Synthesis of N-[(3R)-1-{4-[(3-amino-5-chloropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl

[0357] In a 250 mL round-bottom flask, 1.00 g, 2.41 mmol of N-[(3R)-1-{4-[(5-chloro-3-nitropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl was added in 20 mL of MeOH. Runney nickel (282 mg, 4.82 mmol) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was then degassed and purged with hydrogen three times. The resulting reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-[(3R)-1-{4-[(3-amino-5-chloropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl (725 mg, 1.88 mmol, 85% purity, 78% yield) as an off-white solid.

[0358] Step 5: Synthesis of N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}carbamoyl)amino]pyridine-2-yl}oxy)butyl]pyrrolidine-3-yl]carbamate tert-butyl

[0359] In a 40 mL four-necked round-bottom container, 2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-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, and the mixture was stirred at room temperature for 30 minutes. Then, N-[(3R)-1-{4-[(3-amino-5-chloropyridine-2-yl)oxy]butyl}pyrrolidine-3-yl]carbamate tert-butyl (500 mg, 1.29 mmol) was added, and the reaction mixture was stirred at 100 °C for 4.0 hours. The mixture was allowed to cool to room temperature, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether:ethyl acetate = 1:1 to obtain N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}carbamoyl)amino]pyridine-2-yl}oxy)butyl]pyrrolidine-3-yl]carbamate tert-butyl (113 mg, 183 μmol, 76% purity, 14% yield) as a brown solid.

[0360] Step 6: Synthesis of 1-(2-{4-[(3R)-3-aminopyrrolidine-1-yl]butoxy}-5-chloropyridine-3-yl)-3-{2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}urea (INT-20)

[0361] A solution of N-[(3R)-1-[4-({5-chloro-3-[({2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}carbamoyl)amino]pyridine-2-yl}oxy)butyl]pyrrolidine-3-yl]carbamate tert-butyl (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 reduced pressure to obtain 1-(2-{4-[(3R)-3-aminopyrrolidine-1-yl]butoxy}-5-chloropyridine-3-yl)-3-{2-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine-6-yl}urea (INT-20) (103 mg, 199 μmol, 88% purity, 94% yield) as a brown oil.

[0362] Synthesis of INT-21 and INT-22:(2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoic acid methyl (INT-22) [ka] Step 1: Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]carbamate tert-butyl

[0363] A mixture of (2S)-5-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (2.1 g, 5.73 mmol), 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-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 minutes. Then, HATU (2.61 g, 6.87 mmol) was added, and the reaction mixture was stirred at room temperature for 1.0 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (50% to 80% ethyl acetate) to obtain N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]carbamate tert-butyl (2.00 g, 4.19 mmol, 95% purity, 73% yield) as a white solid.

[0364] Step 2: Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-aminobutyl]carbamate tert-butyl (INT-21)

[0365] To a solution of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(benzyloxy)carbonyl]amino}butyl]carbamate tert-butyl (2.0 g, 4.19 mmol) in MeOH (20 mL), Pd / C (445 mg, 4.19 mmol, 10%) was added in a 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 3 hours, and then concentrated under reduced pressure to obtain N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-aminobutyl]carbamate tert-butyl (1.40 g, 4.08 mmol, 90% purity, 95% yield) as a colorless oil.

[0366] Step 3: Synthesis of (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoate methyl

[0367] In a 100 mL three-necked round-bottom container, tert-butyl N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-aminobutyl]carbamate (900 mg, 2.62 mmol), methyl (2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate (884 mg, 3.93 mmol), DIEA (1.01 g, 7.86 mmol), and 1,4-dioxane (10.0 mL) were placed at room temperature. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere (1 atm). The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: Aqueous phase of 0.05% ammonia in acetonitrile, 60% to 80% gradient over 20 minutes; Detector: UV 254 nm. (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoic acid methyl (1.00 g, 1.82 mmol, 90% purity, 69% yield) was obtained as a yellow solid.

[0368] Step 4: Synthesis of 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)methyl propanoate

[0369] (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoic acid methyl (600 mg, 1.09 mmol) was added to a solution of Pd / C (115 mg, 1.09 mmol, 10%) in MeOH (12.0 mL) in a 50 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 2 hours, and then concentrated under reduced pressure to obtain methyl 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)propanoate (450 mg, 865 μmol, 85% purity, 79% yield) as a yellow oil.

[0370] Step 5: Synthesis of 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazole-5-yl}methyl propanoate

[0371] 3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-aminophenyl)methyl propanoate (400 mg, 769 μmol), carbononitol bromide (488 mg, 4.61 mmol), and EtOH (8.0 mL) were placed in a 50 mL round-bottom container. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: Aqueous phase of 0.05% ammonia in acetonitrile, gradient from 40% to 70% over 20 minutes; Detector: UV 254 nm. 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazole-5-yl}methyl propanoate (250 mg, 459 μmol, 80% purity, 59% yield) was obtained as a white solid.

[0372] Step 6: Synthesis of (2E)-3-(4-{[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]amino}-3-nitrophenyl)prop-2-enoic acid methyl (INT-22).

[0373] 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-benzodiazole-5-yl}propanoate (240 mg, 440 μmol) in THF:H2O (2:1, 4.8 mL), LiOH (18.4 mg, 1.76 mmol) was added 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 precipitated solid was collected by filtration and washed with water (50 mL). This yielded 3-{1-[(4S)-4-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(tert-butoxy)carbonyl]amino}butyl]-2-amino-1H-1,3-benzodiazole-5-yl}propanoic acid (INT-22). Yield: 210 mg, 90.1%; Appearance: White solid; 1 H 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 for N6O6: 530.29; measured value: 531.2 [M+H] + .

[0374] 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]docosa-1(22),2,5,10(15),11,13,18,20-octaen-3-carbonitrile (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 Synthesis of docosa-1(22),2(6),3,10(15),11,13,18,20-octaene-3-carbonitrili (INT-24) [ka] 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 docosa-1(22),2,5,10(15),11,13,18,20-octaene-3-carbonitrili

[0375] In a 40 mL vial, add (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 , 15Docosa-1(22),2,5,10(15),11,13,18,20-octaen-3-carbonitrile (200 mg, 509 μmol), 1,6-dibromohexane (246 mg, 1.01 mmol), K2CO3 (280 mg, 2.03 mmol), and MeCN (4.0 mL) were added. The resulting reaction mixture was heated to 60°C for 3.0 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: Aqueous phase of 0.05% ammonia in acetonitrile, gradient from 70% to 100% over 20 minutes; Detector: UV 254 nm. (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 ]docosa-1(22)(2,5,10(15),11,13,18,20-octaen-3-carbonitride)(INT-23)(150 mg, 270 μmol, 90% purity, 53% yield) as a white solid, 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 Docosa-1(22),2(6),3,10(15),11,13,18,20-octaen-3-carbonitrile (INT-24) (70.0 mg, 126 μmol, 89% purity, 25% yield) was obtained as a white solid.

[0376] Synthesis of INT-25: 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (INT-25) [ka] Step 1: Synthesis of 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl

[0377] A mixture of 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (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) at room temperature in MeCN (20 mL), along with the reaction mixture, was stirred at 80 °C for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (2.30 g, 6.96 mmol, 85.0% purity, 53.2% yield) as a yellow solid.

[0378] Step 2: Synthesis of 5-{[(1R)-1-(2-{[(2S)-1-{[(tert-butoxy)carbonyl]amino}propan-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl

[0379] A mixture of 5-{[(1R)-1-(5-fluoro-2-hydroxyphenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (2.30 g, 6.96 mmol), N-[(2R)-2-hydroxypropyl]carbamate tert-butyl (1.82 g, 10.4 mmol), and PPh3 (2.72 g, 10.4 mmol) in THF (20 mL) and DCM (20 mL) at 0°C. Then, DTBAD (2.39 g, 10.4 mmol) was added to the above mixture at 0°C under a nitrogen atmosphere, 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 5-{[(1R)-1-(2-{[(2S)-1-{[(tert-butoxy)carbonyl]amino}propan-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (1.60 g, 3.28 mmol, 90.0% purity, 50.5% yield) as a yellow oil.

[0380] Step 3: Synthesis of 5-{[(1R)-1-(2-{[(2S)-1-aminopropane-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (INT-25)

[0381] A mixture of 5-{[(1R)-1-(2-{[(2S)-1-{[(tert-butoxy)carbonyl]amino}propan-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (1.60 g, 3.28 mmol) in HCl / dioxane (20 mL, 4 M) at room temperature was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 5-{[(1R)-1-(2-{[(2S)-1-aminopropan-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylate methyl (1.40 g, 3.61 mmol, crude product) as the HCl salt as a yellow solid, which was used directly in the next step.

[0382] 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 Synthesis of docosa-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetic acid [ka] 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 docosa-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetate

[0383] (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 , 15 A mixture of docosa-1(22),2,5,10(15),11,13,18,20-octaen-3-carbonitrile (400 mg, 1.01 mmol), K2CO3 (418 mg, 3.03 mmol), 2-tert-butyl bromoacetate (294 mg, 1.51 mmol), and DMF (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water, 30% to 70% gradient over 20 minutes; detector: UV 254 nm. This revealed 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 ]docosa-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]tert-butyl acetate (200 mg, 394 μmol, 85% purity, 39% yield) was obtained as a yellow solid, and (R)-2-(26-amino-13-cyano-55-fluoro-4,7-dimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,5)-pyrazola-5(1,2)-benzenacyclooctafan-11-yl)tert-butyl acetate (90 mg, 184 μmol, 85% purity, 18% yield) was obtained as a yellow solid.

[0384] 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 docosa-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetic acid (INT-26)

[0385] 2-[(16R)-19-amino-3-cyano-13-fluoro-8,16-dimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0] in TFA:DCM (1:1, 2mL) 2 , 6 .0 10 , 15 A solution of tert-butyl 1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetate (200 mg, 394 μmol) was stirred at room temperature for 12.0 hours. The resulting mixture was concentrated under reduced pressure to obtain the TFA salt 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]docosa-1(22),2,5,10(15),11,13,18,20-octaen-4-yl]acetic acid (170 mg, 377 μmol, crude product) was obtained as a yellow oil and used directly in the next step.

[0386] Synthesis of INT-27:(R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2,4]heptan-5-yl)hexanoic acid [ka] Step 1: Synthesis of methyl (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2,4]heptan-5-yl)hexanoate

[0387] A stirred solution at room temperature in MeCN (5 mL) containing tert-butyl N-[(7R)-5-azaspiro[2.4]heptan-7-yl]carbamate (500 mg, 2.35 mmol), methyl 6-bromohexanoate (491 mg, 2.35 mmol), and K2CO3 (972 mg, 7.05 mmol). The resulting mixture was stirred at 80°C for 2 hours. The mixture was allowed to cool to room temperature. The residue was purified by reverse-phase flash under the following conditions (column: C18 silica gel; mobile phase: 0.1% NH4OH in H2O / MeCN, gradient from 10% to 60% over 12 minutes; detector: UV254nm) to obtain (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptan-5-yl)hexanoate methyl (780 mg, 2.29 mmol, 91.2% purity, 97.5% yield) as a yellow solid.

[0388] Step 2: Synthesis of (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2,4]heptan-5-yl)hexanoic acid (INT-27)

[0389] To a solution of methyl (R)-6-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptan-5-yl)hexanoate (780 mg, 2.29 mmol) in THF:H2O (2:1, 16 mL), NaOH (274 mg, 6.86 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1.0 hour. 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]heptan-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 for N2O4: 326.22; measured value: 327.1 [M+H] + .

[0390] Synthesis of INT-28:4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid [ka] Step 1: Synthesis of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate

[0391] In a 50 mL round-bottomed container, tert-butyl hydrochloride N-[(3R)-4,4-dimethylpyrrolidine-3-yl]carbamate (200 mg, 797 μmol), methyl 4-bromobutanoate (25 mg, 1.19 mmol), K2CO3 (329 mg, 2.39 mmol), and MeCN (4 mL) were placed. The resulting mixture was stirred at 80°C for 5.0 hours under a nitrogen atmosphere. The mixture was allowed to cool 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 on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate methyl (210 mg, 667 μmol, 70% purity, 84% yield) as a yellow oil. Step 2: Synthesis of 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid (INT-28)

[0392] A mixture of methyl 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoate (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 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (NH3·H2O buffer) to obtain 4-[(4R)-4-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylpyrrolidine-1-yl]butanoic acid (100 mg, 332 μmol, 75% purity, 85% yield) as a white solid.

[0393] Example A1: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-guanidinopentanamide (A-1) [ka] Step 1: Synthesis of (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl

[0394] AcCl (2.50 g, 32.1 mmol) was added at 0°C to a stirred solution of N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl (5.00 g, 26.8 mmol) and pyridine (6.34 g, 80.3 mmol) in DCM (50 mL). After the 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 phase was washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and diluted with petroleum ether:ethyl acetate = 1:2 to obtain N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate tert-butyl (4.59 g, 20.1 mmol, 90% purity, 75% yield) as a white solid.

[0395] Step 2: Synthesis of (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one

[0396] A solution of tert-butyl N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate (5.10 g, 22.3 mmol) in TFA (50 mL) was stirred at room temperature for 2.0 hours. The resulting mixture was concentrated under reduced pressure to obtain the crude product 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-1-one (2.97 g, 23.1 mmol, crude product) as a brown oil, which was then used as the TFA salt.

[0397] Step 3: Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}butyl]carbamate tert-butyl

[0398] HATU (399 mg, 1.05 mmol) was added at -40°C to a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}pentanoic acid (500 mg, 1.05 mmol), 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-1-one (134 mg, 1.05 mmol), and DIEA (134 mg, 1.05 mmol) in DCM (10 mL). After 2.0 hours, the reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH3·H2O buffer) to obtain N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}butyl]carbamate tert-butyl (424 mg, 725 μmol, 90% purity, 69% yield) as a pale yellow solid.

[0399] Step 4: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-guanidinopentanamide (A-1)

[0400] To 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 tert-butyl (450 mg, 769 μmol) in dioxane (5 mL), HCl / dioxane (2 M in dioxane, 3.8 mL, 7.68 mmol) was added dropwise, and the mixture was stirred at room temperature for 3.0 hours. The resulting mixture was concentrated under reduced pressure to obtain (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-carbamimidopentanamide as the HCl salt (A-1). Yield: 99.9 mg, 45.8%; Appearance: Brown semi-solid; 1H 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 for N6O2: 284.20; measured value: 285.20 [M+H] + .

[0401] The following examples were prepared using standard chemical procedures and techniques similar to those used in the preparation of the previous example. The analytical data are shown in the table below. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10] [Table 12-11] [Table 12-12] [Table 12-13] [Table 12-14]

[0402] Example A2: Scheme 3: Synthesis of (S)-2-amino-5-guanidino-N-((S)-1-(methylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)pentanamide (A-23) [ka] Step 1: Synthesis of (S)-(1-(methylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)carbamate tert-butyl

[0403] A solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(oxan-4-yl)propanoic 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 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to obtain N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamate tert-butyl (200 mg, 0.698 mmol, 80% purity, 95% yield) as a white solid.

[0404] Step 2: Synthesis of (S)-2-amino-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide hydrochloride

[0405] A solution of tert-butyl N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamate (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 the crude product (2S)-2-amino-N-methyl-3-(oxan-4-yl)propenamide (80.0 mg, 359 μmol, 80% purity, 98% yield) as a white solid, which was used directly in the next step without further purification.

[0406] Step 3: Synthesis of N-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}butyl]amino})methylidene]carbamate tert-butyl

[0407] (2S)-2-amino-N-methyl-3-(oxan-4-yl)propanamide hydrochloride (70 mg, 0.314 mmol), (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}pentanoic acid (INT-1) (123 mg, 0.261 mmol), HATU (119 mg, 0.314 mmol), and DIEA (167 mg, 1.30 mmol) were mixed in DMF (1 mL) and 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-(oxan-4-yl)ethyl]carbamoyl}butyl]amino}) methylidene]carbamate tert-butyl (60.0 mg, 0.933 mmol, 92% purity, 29% yield) as a white solid.

[0408] Step 4: Synthesis of (S)-2-amino-5-guanidino-N-((S)-1-(methylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)pentanamide (A-23)

[0409] A solution of N-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}butyl]amino})methylidene]carbamate tert-butyl (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 obtain (2S)-2-amino-5-carbamimidamide-N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]pentanamide as the HCl salt (A-23). Yield: 15.0 mg, 56%; Appearance: White solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.72 (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 for N6O3: 342.24; measured value: 343.3 [M+H] + .

[0410] Example A3: Synthesis of (2S,3S)-2-((S)-2-amino-3-(6-aminopyridine-3-yl)propanamide)-N,3-dimethylpentanamide (A-24) [ka] Step 1: Synthesis of methyl (S)-3-(6-aminopyridine-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate

[0411] 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 minutes. The reaction mixture was allowed to cool to room temperature. TMS-Cl (29.9 mg, 276 μmol) was added to the mixture, and the mixture was stirred vigorously for another 30 minutes. 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 hours. Next, the reaction mixture was allowed to stand for another 30 minutes, and the supernatant was transferred by 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 hours. After pouring into water, the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (2 × 50 mL), dried on sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain (2S)-3-(6-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propanoate methyl (650 mg, 2.20 mmol) as a white solid.

[0412] Step 2: Synthesis of (S)-3-(6-aminopyridine-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0413] A solution of methyl (2S)-3-(6-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propanoate (640 mg, 2.16 mmol) in THF (5 mL) and H2O (1 mL) was mixed with LiOH (258 mg, 10.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 5-6 with 1 N HCl (aqueous solution), concentrated under reduced pressure to obtain a residue, which was purified using reverse Combi Flash (registered trademark) (Biotage, 130 g Agela C18, MeCN / H2O (0.5% FA)) to obtain (2S)-3-(6-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propanoate as a white solid (300 mg, 1.06 mmol).

[0414] Step 3: Synthesis of ((S)-3-(6-aminopyridine-3-yl)-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate tert-butyl

[0415] (2S)-3-(6-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}propanoic acid (270 mg, 959 μmol), (2S,3S)-2-amino-N,3-dimethylpentanamide (115 mg, 797 μmol), and DIPEA (514 mg, 3.98 mmol) were dissolved in DMF (5 mL), to which DEPBT (261 mg, 876 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified using reverse Combi Flash (registered trademark) (Biotage, 10g Agela C18, MeCN / H2O (0.1% NH4HCO3)) to obtain N-[(1S)-2-(6-aminopyridine-3-yl)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}ethyl]carbamate tert-butyl (40.0 mg, 98.1 μmol) as a white solid.

[0416] Step 4: Synthesis of (2S,3S)-2-((S)-2-amino-3-(6-aminopyridine-3-yl)propanamide)-N,3-dimethylpentanamide

[0417] A solution of N-[(1S)-2-(6-aminopyridine-3-yl)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}ethyl]carbamate tert-butyl (120 mg, 294 μmol) in 4 M HCl (1,4-dioxane solution) (5 mL) was stirred at room temperature for 1 hour. 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 obtain (2S,3S)-2-[(2S)-2-amino-3-(6-aminopyridine-3-yl)propanamide]-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 for N5O2: 307.20; measured value: 308.4 [M+H] + .

[0418] Example A4: Synthesis of (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-(2-aminopyridine-3-yl)pentanamide (A-25) [ka] Step 1: Synthesis of tert-butyl N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate

[0419] To a solution of tert-butyl N-[(3R)-pyrrolidine-3-yl]carbamate (200 mg, 1.07 mmol) in DCM (5 mL), TEA (324 mg, 3.21 mmol) and acetyl chloride (125 mg, 1.60 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash silica gel chromatography (MeOH / DCM = 0%~5%) to obtain tert-butyl N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate (200 mg, 0.88 mmol, 100% purity, 81.9% yield) as a colorless oil.

[0420] Step 2: Synthesis of 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-1-one

[0421] To a solution of tert-butyl N-[(3R)-1-acetylpyrrolidine-3-yl]carbamate (200 mg, 0.88 mmol) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-1-one (112 mg, 0.88 mmol, 100% purity, 100% yield) as a colorless oil.

[0422] Step 3: Synthesis of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-(2-aminopyridine-3-yl)butyl]carbamate tert-butyl

[0423] To a solution of 1-[(3R)-3-aminopyrrolidine-1-yl]ethane-1-one (50 mg, 0.39 mmol) in DMF (5 mL), DIPEA (152 mg, 1.17 mmol), (2S)-5-(2-aminopyridine-3-yl)-2-{[(tert-butoxy)carbonyl]amino}pentanoic acid (INT-2) (120 mg, 0.39 mmol), and DEPBT (139 mg, 0.47 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with anhydrous sodium sulfate and filtered. 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-aminopyridine-3-yl)butyl]carbamate tert-butyl (60.0 mg, 0.14 mmol, 100% purity, 36.8% yield) as a yellow solid.

[0424] Step 4: Synthesis of (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-(2-aminopyridine-3-yl)pentanamide (A-25)

[0425] To a solution of N-[(1S)-1-{[(3R)-1-acetylpyrrolidine-3-yl]carbamoyl}-4-(2-aminopyridine-3-yl)butyl]carbamate tert-butyl (40 mg, 0.10 mmol) in DCM (2 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the 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, acidic method) to obtain (2S)-N-[(3R)-1-acetylpyrrolidine-3-yl]-2-amino-5-(2-aminopyridine-3-yl)pentanamide (A-25). Yield: 15.4 mg, 50.6%; Appearance: White solid; Yield: 16.0 mg, 50.6%; Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) 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 = 6.8 Hz, 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 for N5O2: 319.41, measured value: 320.2 [M+H] + .

[0426] The following examples were prepared using standard chemical procedures and techniques similar to those used in the preparation of the previous example. The analytical data are shown in the table below. [Table 13]

[0427] Example A5: Synthesis of (2S,3S)-2-((S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridine-3-yl)propanamide)-N,3-dimethylpentanamide (A-27) and (2S,3S)-2-((R)-2-amino-3-(1H-pyrrolo[2,3-b]pyridine-3-yl)propanamide)-N,3-dimethylpentanamide (A-28) [ka] Step 1: Synthesis of 3-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0428] To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.07 mmol) in dichloromethane (5 mL), tosyl chloride (966 mg, 5.07 mmol), 4-dimethylaminopyridine (619 mg, 5.07 mmol), and triethylamine (513 mg, 5.07 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. 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 on anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (SiO2, petroleum ether / siRNA = 10 / 3) to obtain 3-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.56 mmol, 100% purity, 56% yield) as a white solid.

[0429] Step 2: Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]propanoate methyl

[0430] 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 minutes. The reaction mixture was allowed to cool to room temperature. Chlorotrimethylsilane (29 mg, 272 μmol) was added to the mixture, and the mixture was stirred vigorously for another 30 minutes. Methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-iodopropionate (1.11 g, 3.40 mmol) in DMF (5 mL) was added to the reaction mixture, and it was then stirred at room temperature for 2 hours. Next, the reaction mixture was allowed to stand for another 30 minutes, and the supernatant was transferred by syringe to 3-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.70 mmol), tris(dibenzylideneacetone)dipalladium (92.4 mg, 101 μmol), and X-Phos (96.7 mg, 203 μmol). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (20 mL), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (SiO2, petroleum ether / alkyl = 10 / 7) to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]propanoate methyl (450 mg, 950 μmol, 87% purity, 56% yield) as a white solid.

[0431] Step 3: Synthesis of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]propanoic acid

[0432] (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propanoate methyl (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 hour. The reaction mixture was concentrated to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propanoic acid (436 mg, 948 μmol, 100% purity, 100% yield) as a white solid.

[0433] Step 4: Synthesis of N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]ethyl]carbamate tert-butyl

[0434] (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propanoic acid (450 mg, 979 μmol) was dissolved in N,N-dimethylformamide (10 mL) to which DEPBT (583 mg, 1.95 mmol), N,N-diisopropylethylamine (126 mg, 979 μmol), and (2S,3S)-2-amino-N,3-dimethylpentanamide (210 mg, 1.46 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with  (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (SiO2, petroleum ether / ethyl 5 / 4) to obtain N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]ethyl]carbamate tert-butyl (380 mg, 648 μmol, 89% purity, 66% yield) as a yellow solid.

[0435] Step 5: Synthesis of N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1H-pyrrolo[2,3-b]pyridine-3-yl}ethyl]carbamate tert-butyl

[0436] To a solution of N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]ethyl]carbamate tert-butyl (450 mg, 768 μmol) in methanol (5 mL), potassium carbonate (530 mg, 3.84 mmol) was added. The resulting mixture was stirred at 65°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1H-pyrrolo[2,3-b]pyridine-3-yl}ethyl]carbamate tert-butyl (330 mg, 764 μmol, 100% purity, 99% yield) as a white solid.

[0437] Step 6: Synthesis of (2S,3S)-2-[(2S)-2-amino-3-{1H-pyrrolo[2,3-b]pyridine-3-yl}propanamide]-N,3-dimethylpentanamide (16.5 mg, 49.7 μmol) and (2S,3S)-2-[(2R)-2-amino-3-{1H-pyrrolo[2,3-b]pyridine-3-yl}propanamide]-N,3-dimethylpentanamide

[0438] To a solution of N-[(1S)-1-{[(1S,2S)-2-methyl-1-(methylcarbamoyl)butyl]carbamoyl}-2-{1H-pyrrolo[2,3-b]pyridine-3-yl}ethyl]carbamate tert-butyl (100 mg, 231 μmol), HCl-dioxane (729 mg, 20.0 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The pH was adjusted to 7-8 with NH4OH and filtered. The reaction mixture was concentrated and purified by preparative HPLC (ACN / H2O / 0.5%NH4HCO3) to obtain the crude product, which was then fed into SFC (mobile phase: CO2 / EtOH [1%NH3 (7M 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 (2S,3S)-2-[(2S)-2-amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanamide]-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, 5.2 Hz, 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 for N5O2: 331.20; measured value: 332.4 [M+H] +) and (2S,3S)-2-[(2R)-2-amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanamide]-N,3-dimethylpentanamide (A-28) (Yield: 39.8 mg, 52%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) 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 = 2.8 Hz, 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 for N5O2: 331.20; measured value: 332.4 [M+H] + ) was obtained.

[0439] The following examples were prepared using standard chemical procedures and techniques similar to those used in the preparation of the previous example. The analytical data are shown in the table below. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10]

[0440] Example A6: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((R)-1,4,4-trimethylpyrrolidine-3-yl)pentanamide (A-39) [ka] Step 1: Synthesis of (R)-(1,4,4-trimethylpyrrolidine-3-yl)carbamate tert-butyl

[0441] To a solution of tert-butyl N-[(3R)-4,4-dimethylpyrrolidine-3-yl]carbamate (200 mg, 933 μmol) in MeOH (5 mL), paraformaldehyde (419 mg, 4.66 mmol) and NaBH4 (175 mg, 2.79 mmol) were added at room temperature. The reaction mixture was stirred at 40 °C for 2 hours. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl N-[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamate (150 mg, 656 μmol, 100% purity, 70% yield) as a colorless oil.

[0442] Step 2: Synthesis of (R)-1,4,4-trimethylpyrrolidine-3-amine

[0443] To a solution of tert-butyl N-[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamate (150 mg, 656 μmol) in DCM (5 mL), TFA (1 ml, 6.56 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain (3R)-1,4,4-trimethylpyrrolidine-3-amine (84.0 mg, 655 μmol, 100% purity, 100% yield) as a pale yellow oil.

[0444] Step 3: Synthesis of ((S)-5-(2-nitro-1H-imidazole-1-yl)-1-oxo-1-(((R)-1,4,4-trimethylpyrrolidine-3-yl)amino)pentan-2-yl)carbamate tert-butyl

[0445] (3R)-1,4,4-trimethylpyrrolidine-3-amine (50 mg, 389 μmol) in DMF (5 mL) was mixed with (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid (INT-3) (127 mg, 389 μmol), DEPBT (139 mg, 466 μmol), and DIPEA (50.5 mg, 389 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, concentrated, and purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to obtain N-[(1S)-4-(2-nitro-1H-imidazole-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (70.0 mg, 159 μmol, 100% purity, 41% yield) as a pale yellow oil.

[0446] Step 4: ((S)-5-(2-amino-1H-imidazole-1-yl)-1-oxo-1-(((R)-1,4,4-trimethylpyrrolidine-3-yl)amino)pentan-2-yl) tert-butyl carbamate (A-39)

[0447] To a solution of N-[(1S)-4-(2-nitro-1H-imidazole-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (100 mg, 228 μmol) in MeOH (5 mL), Pd / C (36.2 mg, 342 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain N-[(1S)-4-(2-amino-1H-imidazole-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (93.0 mg, 227 μmol, 100% purity, 99% yield) as a pale yellow oil.

[0448] Step 5: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((R)-1,4,4-trimethylpyrrolidine-3-yl)pentanamide

[0449] To a solution of N-[(1S)-4-(2-amino-1H-imidazole-1-yl)-1-{[(3R)-1,4,4-trimethylpyrrolidine-3-yl]carbamoyl}butyl]carbamate tert-butyl (93 mg, 227 μmol) in DCM (5 mL), TFA (1 ml, 227 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated. The residue was dissolved in MeOH, adjusted to pH 9 with NH3 / MeOH, and then purified by preparative HPLC (by 0.1% NH4OH) to obtain (2S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-[(3R)-1,4,4-trimethylpyrrolidine-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, 5.0 Hz, 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 for N6O: 308.43; measured value: 309.3 [M+H]+.

[0450] Example A7: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-imidazole-1-yl)pentanamide (A-40) [ka] Step 1: Synthesis of (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl

[0451] To a solution of (R)-pyrrolidine-3-ylcarbamate tert-butyl (2 g, 10.7 mmol) in DCM (50 mL), acetyl chloride (1.67 g, 21.4 mmol) and triethylamine (2.16 g, 21.4 mmol) were added at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (MeOH / DCM = 0-4%) to obtain (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl (2.4 g, 10.6 mmol, 100% purity, 99% yield) as a white solid.

[0452] Step 2: Synthesis of (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one hydrochloride

[0453] A solution of (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl (2.4 g, 10.5 mmol) in 4 M HCl (50 mL) in MeOH was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one hydrochloride (1.72 g, 10.4 mmol, 100% purity, 100% yield) as a white solid. The crude product was used directly in the next step without further purification.

[0454] Step 3: Synthesis of (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate methyl

[0455] (S)-2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (2.58 g, 9.90 mmol) was dissolved in DMF (30 mL) and (R)-1-(3-aminopyrrolidine-1-yl)ethane-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) were added at room temperature. The mixture was stirred at room temperature for 10 hours. The mixture was quenched with water and extracted with EA. The organic layer was collected, washed with water, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (MeOH / DCM = 0-4%) to obtain (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-methyl oxopentanoate (1.50 g, 4.03 mmol, 100% purity, 41% yield) as a colorless oil.

[0456] Step 4: Synthesis of (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid

[0457] (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate methyl (1.50 g, 4.03 mmol) was dissolved in THF (30 mL), to which LiOH (106 mg, 4.43 mmol) and H2O (10 mL) were added at room temperature. The mixture was stirred at room temperature for 10 hours. The mixture was quenched with 1 M HCl and extracted with EA. The organic layer was concentrated under reduced pressure to obtain (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (1.30 g, 3.63 mmol, 100% purity, 90% yield) as a white solid. The crude product was used directly in the next step without further purification.

[0458] Step 5: Synthesis of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-hydroxy-1-oxopentan-2-yl)carbamate tert-butyl

[0459] A stirred solution of (S)-5-(((R)-1-acetylpyrrolidine-3-yl)amino)-4-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (500 mg, 1.39 mmol) in DCM (10 mL) was mixed with BH3 (4 mL, 1 M in THF) at 0°C. The mixture was stirred at 0°C for 0.5 hours. The mixture was quenched with MeOH and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (MeOH / DCM = 0-4%) to obtain ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-hydroxy-1-oxopentan-2-yl)carbamate tert-butyl (125 mg, 363 μmol, 100% purity, 26% yield) as a colorless oil.

[0460] Step 6: Synthesis of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl

[0461] A solution of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-hydroxy-1-oxopentan-2-yl)carbamate tert-butyl (125 mg, 363 μmol) in THF (8 mL) was added to PPh3 (190 mg, 726 μmol), 2-nitro-1H-imidazole (82 mg, 726 μmol), and DIAD (146 mg, 726 μmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with water and extracted with EA. The organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (MeOH / DCM = 0-4%) to obtain ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (85 mg, 193 μmol, 100% purity, 53% yield) as a colorless oil.

[0462] Step 7: Synthesis of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl

[0463] ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (85 mg, 193 μmol) was dissolved in MeOH (30 mL) and 10% Pd / C (30 mg) was added by RT. The mixture was stirred at room temperature under an H2 atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (79 mg, 192 μmol, 100% purity, 100% yield) as a colorless oil. The crude product was used directly in the next step without further purification.

[0464] Step 8: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-imidazole-1-yl)pentanamide

[0465] A solution of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-imidazole-1-yl)-1-oxopentan-2-yl) tert-butyl carbamate (79 mg, 193 μmol) in HCl (20 mL, 4 M in dioxane) was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The residue was purified by preparative HPLC (ACN / water / 0.1% NH4OH) to obtain (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-imidazole-1-yl)pentanamide (A-40). Yield: 33.1 mg, 52%; Appearance: colorless oil; 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J1= 7.2, J2= 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 24 LCMS calculated value for N6O2: 308.39; measured value: 309.4 [M+H] + .

[0466] The following examples were prepared using standard chemical procedures and techniques similar to those used in the preparation of the previous example. The analytical data are shown in the table below. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6]

[0467] Example A8: Synthesis of (2S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]pentanamide (A-52) [ka] Step 1: Synthesis of N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamate tert-butyl

[0468] (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(oxan-4-yl)propanoic acid (100 mg, 365 μmol), methylamine hydrochloride (29.5 mg, 438 μmol), and DIPEA (140 mg, 1.09 mmol) were dissolved in DMF (5 mL), to which HATU (180 mg, 474 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (20 mL) and extracted with EA (30 mL x 3). The organic layer was washed with water (20 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to obtain N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamate tert-butyl (92.0 mg, 321 μmol, 100% purity, 88% yield) as a pale yellow oil.

[0469] Step 2: Synthesis of (2S)-2-amino-N-methyl-3-(oxan-4-yl)propanamide

[0470] A solution of tert-butyl N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamate (92 mg, 321 μmol) in HCl (4 M) (5 mL) in dioxane was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain (2S)-2-amino-N-methyl-3-(oxan-4-yl)propanamide (59.2 mg, 317 μmol, 100% purity, 99% yield) as a pale yellow oil.

[0471] Step 3: Synthesis of N-[(1S)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}-4-(2-nitro-1H-imidazole-1-yl)butyl]carbamate tert-butyl

[0472] (2S)-2-amino-N-methyl-3-(oxan-4-yl)propanamide (59 mg, 316 μmol), (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid, INT-3 (124 mg, 379 μmol), and DEPBT (113 mg, 379 μmol) were dissolved in DMF (5 mL) to which DIPEA (122 mg, 948 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (20 mL) and extracted with EA (30 mL x 3). The organic layer was washed with water (20 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to obtain N-[(1S)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}-4-(2-nitro-1H-imidazole-1-yl)butyl]carbamate tert-butyl (105 mg, 211 μmol, 100% purity, 67% yield) as a colorless oil.

[0473] Step 4: Synthesis of N-[(1S)-4-(2-amino-1H-imidazole-1-yl)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}butyl]carbamate tert-butyl

[0474] To a solution of N-[(1S)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}-4-(2-nitro-1H-imidazole-1-yl)butyl]carbamate tert-butyl (105 mg, 211 μmol) in MeOH (5 mL), Pd / C (10 mg) was added at room temperature. The reaction mixture was stirred under H2 at room temperature for 1 hour. The reaction mixture was filtered and concentrated to obtain N-[(1S)-4-(2-amino-1H-imidazole-1-yl)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}butyl]carbamate tert-butyl (98.0 mg, 210 μmol, 100% purity, 100% yield) as a pale yellow solid.

[0475] Step 5: Synthesis of (2S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]pentanamide

[0476] To a solution of N-[(1S)-4-(2-amino-1H-imidazole-1-yl)-1-{[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]carbamoyl}butyl]carbamate tert-butyl (98 mg, 210 μmol) in DCM (5 mL), TFA (1 mL, 210 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 7-8 with NH3 in MeOH, concentrated, and the residue was obtained. This residue was further purified by preparative HPLC (ACN / water / 0.1% FA) to obtain (2S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-[(1S)-1-(methylcarbamoyl)-2-(oxan-4-yl)ethyl]pentanamide (A-52). Yield: 7.8 mg, 9.2%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) 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 for N6O3: 366.24; measured value: 367.4 [M+H] + .

[0477] Example A9: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-2-methyl-N-((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)pentanamide (A-53) [ka] Step 1: Synthesis of ((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl

[0478] (2S,3S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-methylpentanoic acid (300 mg, 848 μmol) was dissolved in DMF (3 mL), to which DEPBT (301 mg, 1.01 mmol), DIEA (735 μL, 4.23 mmol), and methanamine hydrochloride (68.1 mg, 1.01 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water was then added to the mixture, and the precipitate was collected by filtration to obtain ((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (228 mg, 622 μmol, 100% purity, 73.5% yield) as a pale yellow solid.

[0479] Step 2: Synthesis of (2S,3S)-2-amino-N,3-dimethylpentanamide

[0480] A mixture of ((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (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 SiO (2 × 10 mL). The aqueous phase was concentrated to obtain (2S,3S)-2-amino-N,3-dimethylpentanamide (88.8 mg, 615 μmol, 100% purity, 99% yield) as a colorless oil.

[0481] Step 3: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoate tert-butyl

[0482] (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-2-methylpent-4-enoic acid (1 g, 2.84 mmol) was dissolved in DCM (40 mL) and 2,2,2-trichloroethaneimide tert-butyl (2.46 g, 11.3 mmol) was added. The mixture was stirred at 35°C for 3 days. The mixture was then concentrated, and the residue was purified by silica gel column (PE: Depositphotos = 30:1) to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoic acid tert-butyl (980 mg, 2.40 mmol, 100% purity, 85% yield) as a colorless oil.

[0483] Step 4: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoate tert-butyl

[0484] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoate tert-butyl (190 mg, 466 μmol) was added to a solution in THF (10 mL) at 0°C with 9-BBN (3.72 mL, 1.86 mmol). 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 (25.7 mmol) was then added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was then diluted with RINKAN (35 mL) and washed with brine (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (PE / SiO=2 / 1) to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoate tert-butyl (173 mg, 406 μmol, 100% purity, 87% yield) as a colorless oil.

[0485] Step 5: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl

[0486] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-hydroxy-2-methylpentanoate tert-butyl (173 mg, 406 μmol), 2-nitro-1H-imidazole (55.0 mg, 487 μmol), and PPh3 (170 mg, 649 μmol) were dissolved in THF (2 mL) to which DIAD (127 μL, 649 μmol) was added at 0°C. The mixture was stirred overnight at room temperature. The mixture was then concentrated. The residue was purified by silica gel column (PE:SiO=2:1) ​​to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl (170 mg, 326 μmol, 100% purity, 80.5% yield) as a white solid.

[0487] Step 6: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid

[0488] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoate tert-butyl (170 mg, 326 μmol) in DCM (1.5 mL) was mixed with TFA (0.5 mL, 6.72 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid (150 mg, 322 μmol, 100% purity, 99% yield) as a white solid, which was used directly in the next step without purification.

[0489] Step 7: Synthesis of ((S)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl

[0490] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-5-(2-nitro-1H-imidazole-1-yl)pentanoic acid (90 mg, 193 μmol) was dissolved in DMF (3 mL) and DEPBT (69.0 mg, 231 μmol), DIEA (100 μL, 579 μmol), and (2S,3S)-2-amino-N,3-dimethylpentanamide (139 mg, 965 μmol) were added. The mixture was stirred overnight at room temperature. The mixture was then diluted with ELISA (30 mL) and washed with brine (3 × 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (DCM / MeOH=20 / 1) to obtain ((S)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (37.0 mg, 62.6 μmol, 100% purity, 32% yield) as an off-white solid.

[0491] Step 8: Synthesis of ((S)-5-(2-amino-1H-imidazole-1-yl)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl

[0492] ((S)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (37 mg, 62.6 μmol) was dissolved in MeOH (3 mL) and Pd / C (6.63 mg, 62.6 μmol) was added. The mixture was stirred at room temperature under H2 (1 atm) for 1 hour. The mixture was then filtered. The filtrate was concentrated to obtain ((S)-5-(2-amino-1H-imidazole-1-yl)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (32.0 mg, 57.0 μmol, 100% purity, 91% yield) as a light brown solid.

[0493] Step 9: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-2-methyl-N-((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)pentanamide (A-53)

[0494] A solution of ((S)-5-(2-amino-1H-imidazole-1-yl)-2-methyl-1-(((2S,3S)-3-methyl-1-(methylamino)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl)carbamate (9H-fluoren-9-yl)methyl (32 mg, 57.0 μmol) in dimethylamine (3 mL, 57.0 μmol) was stirred at room temperature for 1 hour. The mixture was then concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH:NH3=30:1:0.1) to obtain the crude product, which was further purified by preparative HPLC (ACN / water / 0.1%NH4HCO3) to obtain (S)-2-amino-5-(2-amino-1H-imidazole-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 oil; 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 for N6O2: 338.24; measured value: 339.2 [M+H]+.

[0495] Example A10: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)pentanamide (A-54) [ka] Step 1: Synthesis of ((S)-1-(((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl

[0496] A solution of 4-((R)-3-((S)-2-((tert-butoxycarbonyl)amino)-5-(2-nitro-1H-imidazole-1-yl)pentanamide)pyrrolidine-1-yl)butanoic acid (60 mg, 124 μmol), 1-methylpiperazine (25 mg, 248 μmol), 1-[(dimethylamino)(dimethylimino)methyl]-3-oxo-2H,3H-3λ5-[1,2,3]triazolo[5,4-b]pyridine-3-illium-2-oid·hexafluoro-λ5-phosphanuiid (94 mg, 248 μmol), and N,N-diisopropylethylamine (48 mg, 372 μmol) in DMF (3 mL) was stirred at RT for 3 hours. The reaction mixture was added to water and extracted with ethyl acetate (3 mL x 3). The organic layer was washed with water (2 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by flash chromatography (MeOH / DCM = 0-6%) to obtain ((S)-1-(((R)-1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (66 mg, 116 μmol, 94% purity, 94% yield) as a colorless oil.

[0497] Step 2: Synthesis of ((S)-5-(2-amino-1H-imidazole-1-yl)-1-(((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-1-oxopentan-2-yl)carbamate tert-butyl

[0498] ((S)-1-(((R)-1-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-5-(2-nitro-1H-imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (46 mg, 81 μmol) was added by RT to a solution in MeOH (3 mL). 10% Pd / C (14 mg) was added by RT. The reaction mixture was stirred under H2 for 2 hours. The reaction mixture was filtered and concentrated to obtain ((S)-5-(2-amino-1H-imidazole-1-yl)-1-(((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-1-oxopentan-2-yl) tert-butyl carbamate (58 mg, 108 μmol, 90% purity, 96% yield) as a yellow solid, which was used directly in the next step without further purification.

[0499] Step 3: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)pentanamide

[0500] ((S)-5-(2-amino-1H-imidazole-1-yl)-1-(((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)amino)-1-oxopentan-2-yl) tert-butyl carbamate (58 mg, 108 μmol) was dissolved in DCM (3 mL) and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative HPLC (ACN / water / 0.1% NH3·H2O) to obtain (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((R)-1-(4-(4-methylpiperazine-1-yl)-4-oxobutyl)pyrrolidine-3-yl)pentanamide (A-54). Yield: 33.4 mg, 71%; Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (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 for N4O2S: 434.59; measured value: 435.3 [M+H] + .

[0501] Example A11: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-benzo[d]imidazole-1-yl)pentanamide (A-55) [ka] Step 1: Synthesis of (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl

[0502] To a solution of N-[(3R)-pyrrolidine-3-yl]carbamate tert-butyl (300 mg, 1.61 mmol) in DCM (3 mL), acetyl chloride (252 mg, 3.22 mmol) and TEA (325 mg, 3.22 mmol) were added at 0°C. The resulting mixture was stirred at 0°C for 3 hours. 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 flash chromatography (MeOH / DCM = 0-6%) to obtain (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl (265 mg, 1.16 mmol, 100% purity, 72% yield) as a white solid.

[0503] Step 2: Synthesis of (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one

[0504] To a solution of (R)-(1-acetylpyrrolidine-3-yl)carbamate tert-butyl (175 mg, 766 μmol) in DCM (4 mL), TFA (2 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain crude (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one (98 g, 432 μmol, 100% purity, 56% yield) as a yellow oil.

[0505] Step 3: Synthesis of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl

[0506] (R)-1-(3-aminopyrrolidine-1-yl)ethane-1-one (50 mg, 390 μmol) was dissolved in DMF (2 mL) and (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-(2-nitro-1H-1,3-benzodiazole-1-yl)pentanoic acid (147 mg, 390 μmol), DEPBT (175 mg, 585 μmol), and DIPEA (252 mg, 1.95 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EA (60 mL x 3). The organic layer was concentrated. The residue was purified by flash chromatography (MeOH / DCM = 0-6%) to obtain ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (100 mg, 204 μmol, 100% purity, 53% yield) as a green oil.

[0507] Step 4: Synthesis of ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl

[0508] (S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-nitro-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (100 mg, 204 μmol) was dissolved in MeOH (3 mL) and 10% Pd / C (33 mg) was added. The reaction mixture was stirred under H2 for 2 hours. The reaction mixture was filtered and concentrated to obtain crude ((S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (94 mg, 204 μmol) as a green oil, which was used directly in the next step without further purification.

[0509] Step 5: Synthesis of (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-benzo[d]imidazole-1-yl)pentanamide

[0510] (S)-1-(((R)-1-acetylpyrrolidine-3-yl)amino)-5-(2-amino-1H-benzo[d]imidazole-1-yl)-1-oxopentan-2-yl)carbamate tert-butyl (94 mg, 204 μmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (ACN / water / 0.1% FA) to obtain (S)-N-((R)-1-acetylpyrrolidine-3-yl)-2-amino-5-(2-amino-1H-benzo[d]imidazole-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, HPLC purity: 98.2%;C 18 H 26 LCMS calculated value for N6O2: 358.45; measured value: 359.2 [M+H] + .

[0511] The following examples were prepared using standard chemical procedures and techniques similar to those used in the preparation of the previous example. The analytical data are shown in the table below. [Table 16]

[0512] Example A12: Synthesis of (S)-2-amino-5-(2-amino-1H-imidazole-1-yl)-N-((S)-1-(5-(methoxymethyl)-1,3,4-oxadiazole-2-yl)-2,2-dimethylpropyl)pentanamide (A-57) [ka...

Claims

1. Formula I: 【Chemistry 282】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is A is the part that joins or associates with p62. B is the linker part, A pharmaceutically acceptable salt thereof of the compound or the compound or a pharmaceutically acceptable salt thereof, wherein C is the target binding site.

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

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

4. The compound is of formula II-1 or II-2: 【Chemistry 283】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, G １ However, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, a 4- to 6-membered heteroring containing 1 to 4 heteroatoms selected from N, O, and S, C ６ ~C １２ Aryl, guanidine, -C(O)NH ２ , or -C(NH)NH ２ And here, G １ However, one or more R ｂ It is arbitrarily replaced with, G ２ is C １ to C ６ aliphatic, -N(R ａ )-C １ to C ６ aliphatic, C １ to C ６ aliphatic -N(R ａ )-, -O-C １ to C ６ aliphatic, -C(O)-C １ to C ６ aliphatic, C ６ to C １２ aryl-C ０ to C ６ aliphatic, a 2- to 10-membered heteroaliphatic, or (a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S)-C １ to C ６ aliphatic, where G ２ is optionally substituted with one or more R ｂ s, G ３ However, C １ ~C ７ aliphatic, C １ ~C ７ Aliphatic -C(O)N(R ａ )-C ０ ~C ６ aliphatic, C ３ ~C １２ Cycloaliphatic, 4-9 membered heterorings containing 1-3 heteroatoms selected from N, O, and S, C １ ~C ７ A 4- to 9-membered heteroring containing 1 to 3 heteroatoms selected from aliphatic-C(O)-N, O, and S, or S(O) ２ And here, G ３ However, one or more R ｃ It is arbitrarily replaced with, Each R ａ However, H and any substituted C １ ~C ６ Selected independently from aliphatic species, Each R ｂ However, -N(R ａ ) ２ , arbitrarily substituted C １ ~C ６ Selected independently from aliphatic and halogens, Each R ｃ However, C is arbitrarily substituted. １ ~C ６ Aliphatic, arbitrarily substituted C ３ ~C ６ Cycloaliphatic, optionally substituted C ６ ~C １２ Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR ａ , -C(O)-C １ ~C ６ Aliphatic and -C(O)-OR ａ Selected independently from, B is the linker part, The compound according to claim 1, wherein C is the target binding site.

5. The compound is of formula III-1 or III-2: 【Chemistry 284】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is an optionally substituted 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G １ However, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, a 4- to 6-membered heteroring containing 1 to 4 heteroatoms selected from N, O, and S, C ６ ~C １２ Aryl, guanidine, -C(O)NH ２ , or -C(NH)NH ２ And here, G １ However, one or more R ｂ It is arbitrarily replaced with, G ２ is C １ -C ６ aliphatic, -N(R ａ )-C １ -C ６ aliphatic, C １ -C ６ aliphatic -N(R ａ )-, -O-C １ -C ６ aliphatic, -C(O)-C １ -C ６ aliphatic, C ６ -C １２ aryl-C ０ -C ６ aliphatic, 2- to 10-membered heteroaliphatic, or (4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S)-C １ -C ６ aliphatic, where G ２ is optionally substituted with one or more R ｂ s, G ３ is C １ to C ７ aliphatic, C １ to C ７ aliphatic-C(O)N(R ａ )-C ０ to C ６ aliphatic, C ３ to C １２ a 4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, cycloaliphatic, C １ to C ７ aliphatic-C(O)-a 4- to 9-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, or S(O) ２ and where G ３ is optionally substituted with one or more R ｃ ​ Each R ａ However, H and any substituted C １ ~C ６ Selected independently from aliphatic species, Each R ｂ However, -N(R ａ ) ２ , arbitrarily substituted C １ ~C ６ Selected independently from aliphatic and halogens, Each R ｃ However, C is arbitrarily substituted. １ ~C ６ Aliphatic, arbitrarily substituted C ３ ~C ６ Cycloaliphatic, optionally substituted C ６ ~C １２ Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR ａ , -C(O)-C １ ~C ６ Aliphatic and -C(O)-OR ａ Selected independently from, B is the linker part, The compound according to claim 1, wherein C is the target binding site.

6. G １ The compound according to claim 4 or 5, wherein the compound is an optionally substituted 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

7. G １ However, -N(R ａ ) ２ The compound according to claim 4 or 5, or a 5- to 6-membered heteroaryl compound comprising 1 to 3 heteroatoms selected from N, O, and S, which are optionally substituted with one or more halogens.

8. G １ However, one or more -N(R ａ ) ２ The compound according to claim 4 or 5, or a 7-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, which are optionally substituted with halogens.

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

10. G １ but, 【Chemistry 285-1】 【Chemistry 285-2】 A compound according to claim 9, selected from the above.

11. The compound according to any one of claims 4 to 8, wherein the compound is a compound of formula II-2 or III-2.

12. G １ but, 【Chemistry 286】 Selected from, in the formula, 【Chemistry 287】 However, this represents the connection point to part B, 【Chemical 288】 However, part G ２ The compound according to claim 11, representing a bonding site to

13. G ２ However, C １ ~C ６ Aliphatic, or C １ ~C ６ A 4-6 membered heteroring containing 1-3 heteroatoms selected from aliphatic-N, O, and S, where G ２ However, one or more R ｂ The compound according to any one of claims 4 to 12, which is optionally substituted with

14. G ２ However, one or more R ｂ C arbitrarily replaced by １ ~C ６ The compound according to claim 13, which is aliphatic.

15. G ２ However, one or more -N(R ａ ) ２ C arbitrarily replaced by １ ~C ６ The compound according to claim 14, which is aliphatic.

16. G ２ However, -NH ２ C replaced by １ ~C ６ The compound according to claim 15, which is aliphatic.

17. G ２ However, -NH ２ C replaced by １ ~C ６ It is aliphatic, -NH ２ The compound according to claim 16, wherein the carbon atoms bonded to it are in an S enantiomer configuration.

18. G ２ However, C １ ~C ６ A 4-6 membered heteroring containing 1-3 heteroatoms selected from aliphatic-N, O, and S, where G ２ However, one or more R ｂ The compound according to claim 13, which is optionally substituted with

19. G ２ However, -CH ２ The compound according to claim 18, which is a 4-6 membered heteroring containing 1-3 heteroatoms selected from -N, O, and S.

20. G ２ but, 【Chemistry 289】 Selected from, in the formula, 【Chemistry 290】 However, in formula II-1 or II-2, -C(O)-N(R ａ ) represents the connection point to -, or the connection point to A in formula III-1 or III-2, 【Chemistry 291】 However, G １ A compound according to any one of claims 4 to 12, representing a bonding site to a compound.

21. G ３ However, C １ ~C ７ Aliphatic -C(O)N(R ａ )-, or a 4- to 7-membered heteroring containing 1 to 3 heteroatoms selected from N, O, and S, where G ３ However, one or more R ｃ The compound according to any one of claims 4 to 20, which is optionally substituted with

22. G ３ However, C is arbitrarily substituted with halogen. １ ~C ７ Aliphatic -C(O)N(R ａ ) or optionally replaced C １ ~C ６ The compound according to claim 21, which is aliphatic.

23. G ３ However, C is arbitrarily substituted with halogen. １ ~C ７ Alkyl-C(O)N(R) ａ ) or optionally replaced C １ ~C ６ The compound according to claim 22, which is aliphatic.

24. G ３ but, 【Chemistry 292】 Selected from, in the formula, 【Chemistry 293】 The compound according to claim 9, 10, or 13-20, wherein the compound represents a bonding site to part B.

25. G ３ but, 【Chemistry 294-1】 【Chemistry 294-2】 A compound according to any one of claims 11 to 20, selected from the above.

26. G ３ but, 【Chemistry 295】 Selected from, in the formula, 【Chemistry 296】 The compound according to claim 24, wherein the bond site to portion B is represented.

27. G ３ but, 【Chemistry 297】 A compound according to claim 25, selected from the above.

28. Ring A is 【Chemistry 298】 The compound according to any one of claims 5 to 27.

29. The aforementioned compound is of formula IVa: 【Chemistry 299】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound is of formula IVb: [Chemical 300] The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound is of formula IVc-1: 【Chemical 301】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

32. The aforementioned compound is of formula IVd-1: 【Chemical 302】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

33. The aforementioned compound is of formula IVe-1: 【Chemical 303】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

34. The aforementioned compound is given by formula IVf: 【Chemical 304】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

35. The aforementioned compound is of formula IVg: 【Chemical 305】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

36. The aforementioned compound has the formula IVh: 【Chemical 306】 A compound of or a pharmaceutically acceptable salt thereof, where W １ , W ２ , W ３ , and W ４ Each of these is N, CH, and CR ｂ A compound according to claim 4, independently selected from the above.

37. The aforementioned compound is of formula IVi: 【Chemical 307】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt thereof.

38. The aforementioned compound is of formula IVj: 【Chemical 308】 A compound of or a pharmaceutically acceptable salt thereof, where W ５ , W ６ , W ７ , and W ８ Each of them is N and CR ｄ Selected independently from each R ｄ However, H, -N(R ａ ) ２ , arbitrarily substituted C １ ~C ６ Independently selected from aliphatic, halogen, or partial B-C, W １ , W ２ , W ３ , or W ４ One of them is CR ｄ And R ｄ The compound according to claim 4, wherein it is a partial B-C.

39. The linker has one or more carbon atoms, which are arbitrarily and independently -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-, -SO ２ The arbitrarily replaced C is replaced by ２～３０ The aliphatic group is an optionally substituted 3-12 membered divalent heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered divalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, or an optionally substituted C ３ ~C ６ Cycloalkyl or optionally substituted C ６ ~C １２ It is an aryl, and each R Ｚ However, independently, H or C １ ~C ２０ Aliphatic or C ３ ~C １２ The compound according to any one of claims 1 to 38, wherein the group is optionally substituted with a group selected from cycloaliphatic groups.

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

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

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

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

44. A method for treating a target disease, disorder, or condition, comprising administering a compound according to any one of claims 1 to 42 or a pharmaceutical composition according to claim 43.

45. The aforementioned diseases, disorders, or conditions include 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, activated 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, cryopyrin-associated periodic fever syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, and progressive The method according to claim 44, selected from supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), Ritico-Bodig disease (Guam Parkinson's dementia complex), neuronal glioma and ganglion cell tumor, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ecardi-Goutier syndrome, ataxia, familial lupus frostbite, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis, frontotemporal dementia (FTLD-TDP), and ALS.

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

47. A compound according to any one of claims 1 to 42 or a pharmaceutical composition according to claim 43 for use in pharmaceuticals.

48. Use of a compound according to any one of claims 1 to 42 or a pharmaceutical composition according to claim 43 in the treatment of a disease, disorder, or condition.

49. The aforementioned diseases, disorders, or conditions include 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, activated 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, cryopyrin-associated periodic fever syndrome, Parkinson's disease, Lewy body dementia, multiple system atrophy, axonal dystrophy, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, The use according to claim 48, which is progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), Ritico-Bodig disease (Guam Parkinson's dementia complex), neuronal glioma and ganglion cell tumor, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, spinal and bulbar muscular atrophy (SBMA) / Kennedy disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Ecardi-Goutier syndrome, ataxia, familial lupus frostbite, Huntington's disease, spinocerebellar ataxia, familial amyotrophic lateral sclerosis, frontotemporal dementia (FTLD-TDP), and ALS.

50. Formula X: 【Chemical 309】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is G １ However, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, a 4- to 6-membered heteroring containing 1 to 4 heteroatoms selected from N, O, and S, C ６ ~C １２ Aryl, guanidine, -C(O)NH ２ , or -C(NH)NH ２ And here, G １ However, one or more R ｂ It is arbitrarily replaced with, G ２ However, C １ ~C ６ Aliphatic, -N(R ａ )-C １ ~C ６ aliphatic, C １ ~C ６ Aliphatic-N(R ａ )-,-O-C １ ~C ６ Aliphatic, -C(O)-C １ ~C ６ aliphatic, C ６ ~C １２ Aryl-C ０ ~C ６ Aliphatic, 2-10 membered heteroaliphatic, or (4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S)-C １ ~C ６ It is aliphatic, and here, G ２ However, one or more R ｂ It is arbitrarily replaced with, G ３ However, C １ ~C ７ aliphatic, C １ ~C ７ Aliphatic -C(O)N(R ａ )-C ０ ~C ６ aliphatic, C ３ ~C １２ Cycloaliphatic, 4-9 membered heterorings containing 1-3 heteroatoms selected from N, O, and S, C １ ~C ７ A 4- to 9-membered heteroring containing 1 to 3 heteroatoms selected from aliphatic-C(O)-N, O, and S, or S(O) ２ And here, G ３ However, one or more R ｃ It is arbitrarily replaced with, Each R ａ However, H and any substituted C １ ~C ６ Selected independently from aliphatic species, Each R ｂ However, -N(R ａ ) ２ , arbitrarily substituted C １ ~C ６ Selected independently from aliphatic and halogens, Each R ｃ However, C is arbitrarily substituted. １ ~C ６ Aliphatic, arbitrarily substituted C ３ ~C ６ Cycloaliphatic, optionally substituted C ６ ~C １２ Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR ａ , -C(O)-C １ ~C ６ Aliphatic and -C(O)-OR ａ A compound or a pharmaceutically acceptable salt thereof, independently selected from the above.

51. Formula XI: 【Chemical 310】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is Ring A is an optionally substituted 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S. G １ However, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, a 4- to 6-membered heteroring containing 1 to 4 heteroatoms selected from N, O, and S, C ６ ~C １２ Aryl, guanidine, -C(O)NH ２ , or -C(NH)NH ２ And here, G １ However, one or more R ｂ It is arbitrarily replaced with, G ２ However, C １ ~C ６ Aliphatic, -N(R ａ )-C １ ~C ６ aliphatic, C １ ~C ６ Aliphatic-N(R ａ )-,-O-C １ ~C ６ Aliphatic, -C(O)-C １ ~C ６ aliphatic, C ６ ~C １２ Aryl-C ０ ~C ６ Aliphatic, 2-10 membered heteroaliphatic, or (4-6 membered heteroring containing 1-3 heteroatoms selected from N, O, and S)-C １ ~C ６ It is aliphatic, and here, G ２ However, one or more R ｂ It is arbitrarily replaced with, G ３ However, C １ ~C ７ aliphatic, C １ ~C ７ Aliphatic -C(O)N(R ａ )-C ０ ~C ６ aliphatic, C ３ ~C １２ Cycloaliphatic, 4-9 membered heterorings containing 1-3 heteroatoms selected from N, O, and S, C １ ~C ７ A 4- to 9-membered heteroring containing 1 to 3 heteroatoms selected from aliphatic-C(O)-N, O, and S, or S(O) ２ And here, G ３ However, one or more R ｃ It is arbitrarily replaced with, Each R ａ However, H and any substituted C １ ~C ６ Selected independently from aliphatic species, Each R ｂ However, -N(R ａ ) ２ , arbitrarily substituted C １ ~C ６ Selected independently from aliphatic and halogens, Each R ｃ However, C is arbitrarily substituted. １ ~C ６ Aliphatic, arbitrarily substituted C ３ ~C ６ Cycloaliphatic, optionally substituted C ６ ~C １２ Aryl, optionally substituted 4- to 12-membered heteroaryls, optionally substituted 4- to 6-membered heterorings, -OR ａ , -C(O)-C １ ~C ６ Aliphatic and -C(O)-OR ａ A compound or a pharmaceutically acceptable salt thereof, independently selected from the above.

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

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