Compound Library

Abstract

To provide a compound library having structural diversity, and a method of producing the same and a screening method.SOLUTION: A library includes a compound of 1×102-1×108. The compound includes a structure of (first CB)-(first L)-(second CB), in which a first core block (first CB), a first linker (first L) and a second core block (second CB) are bonded by covalent bonding. The library includes two or more kinds of the first CB, two or more kinds of the first L, and two or more kinds of the second CB. The library is composed of one or two or more mixtures containing a compound of 1×102-1×105.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001]

[0001] This disclosure relates to a compound library having structural diversity, a method for producing the same, and a screening method, etc. [Background technology]

[0002]

[0002] In pharmaceutical development, the search for novel compounds with the desired pharmacological activity plays an important role. Expanding libraries of compounds with structural diversity and developing screening methods are key technologies for obtaining hit compounds (hit generation) (Non-Patent Documents 1 and 2). As a method for searching for new compounds from known compounds, the concept of scaffold hopping (identifying compounds that possess both "isofunctional molecular structures" and "significantly different molecular backbones" relative to the parent compound) was proposed in 1999 (Non-Patent Document 30) and has been widely accepted and used in the field of medicinal chemistry (Non-Patent Document 31).

[0003]

[0003] Looking at the properties of compounds, much of the drug discovery to date has emphasized the concept of the Rule of 5, proposed in 1998, and has been carried out within the range of molecular weight less than 500. On the other hand, in recent years, examples have been reported of drugs that can act as oral agents or intracellular targets even outside the range of the Rule of 5 (most of which have molecular weights exceeding 500), and attention is being drawn to drug discovery beyond the Rule of 5 (Non-Patent Literature 27). It has been pointed out that compounds within the Rule of 5 range may not be able to obtain sufficient affinity for proteins against tough targets (a general term for drug targets characterized by not having deep holes to which small molecules can bind; for example, protein-protein interaction inhibition, RNA-protein interaction inhibition, nucleic acid-nucleic acid interaction inhibition, etc.), which have been difficult to target with conventional small molecule drug discovery (Non-Patent Literature 28). In addition, the relationship between the stericity of molecules and the success rate in clinical trials (Non-Patent Literature 29) has attracted attention, and methods for supplying sterically rich compound libraries are also being considered important.

[0004]

[0004] Thus, there is a strong demand for the provision of a group of compounds with new properties, and hit generation and scaffold hopping methods that evaluate using a large number of new compounds are indispensable. There are two methods for actually performing evaluation using compounds: (a) using an existing compound library, and (b) constructing a new compound library and performing evaluation.

[0005] (a) High-throughput screening (HTS) libraries are one example, and for a long time they have played a central role as a method for obtaining hit compounds (Non-Patent Literature 3). The expansion of HTS libraries has been strongly influenced by the rule of 5 proposed by Lipinski, and most of them have been carried out within a certain range (for example, molecular weight not exceeding 500) (Non-Patent Literature 4). In addition, methods for obtaining hit compounds using fragment-based drug discovery (FBDD) have also been used (Non-Patent Literature 5), and the acquisition of hit compounds leading to drug discovery has been reported for multiple target molecules (Non-Patent Literature 6). However, due to the small molecular weight of the fragment compounds used, the affinity of the obtained hit compounds is weak, and growing and linking approaches are necessary to improve activity (Non-Patent Literature 7). Structural information of the target molecule is indispensable for significantly increasing activity, and this method is not suitable for target molecules for which structural information is unavailable (Non-Patent Literature 2). For target molecules for which structural information is available, an approach is used that utilizes computational methods to search for the optimal linker to link the fragments together (Non-Patent Literature 8).

[0006] (b) One method for expanding the compound library is a peptide library using amino acids as building blocks (Non-Patent Literature 9). The linking mechanism of each building block is limited to amide bonds formed by amidation reactions, and the building blocks used are also limited to amino acids.

[0007]

[0005] Combinatorial chemistry in the 1990s utilized chemical reactions other than amidation reactions and attracted considerable attention as a promising method for discovering new drugs. On the other hand, when considering the structural diversity of library compounds, each library was a structurally homogeneous library, where building blocks were linked around a common structure (scaffold) (Non-Patent Literature 10). In contrast, structurally heterogeneous libraries have been reported to be libraries that can increase the structural diversity of compounds because the compounds constituting the library do not have a specific common structure (scaffold) and are constructed by sequentially linking building blocks (Non-Patent Literature 11, Non-Patent Literature 12). However, it has been pointed out that a common point in these conventional compound library constructions is that they focus on the number of compounds and the synthesis period, and therefore utilize chemical reactions that can be carried out with simple operations for library construction (Non-Patent Literature 13) and use building blocks that do not utilize protecting groups (Non-Patent Literature 14).

[0008]

[0006] Looking at compound library construction methods from another perspective, they can be broadly classified into parallel synthesis methods and mixture-based synthesis methods. Examples of libraries that synthesize thousands of compounds by parallel synthesis have been reported (Patent Documents 1 and 2), but mixture-based synthesis is considered a methodology that can synthesize more compounds in a shorter period of time (Non-Patent Document 10). On the other hand, when supplying a library using mixtures, it is necessary to select a method (decoding) to identify compounds that have binding activity with the target molecule during screening.

[0009] One example of library synthesis using mixtures is DNA-encoded library technology (DELT), which utilizes building blocks not limited to amino acids (Non-Patent Literature 16). DELT is characterized by the use of DNA tags for decoding compounds that have binding activity to target molecules. Decoding with DNA tags means that the sequence information of each library compound correctly indicates the structural information of each library compound in a one-to-one relationship. Therefore, the DNA tag needs to be bound to the same molecule as the library compound (for example, Non-Patent Literature 20, Non-Patent Literature 21). Although the DNA tag plays a role in decoding, because the DNA tag exists in the same molecule as the library compound, the reaction conditions of the chemical reactions that can be used for library synthesis are restricted. As a result, the range of compounds that can be synthesized is limited (Non-Patent Literature 17). Furthermore, it has been reported that damage to the DNA tag occurs depending on the chemical reaction used (Non-Patent Literature 18). Damage to this DNA tag prevents the correct decoding of compounds that bind to the target molecule, and it has been reported that DELT libraries actually experience an increase in false negatives at scales of 10^8 or more (Non-Patent Literature 19).

[0010]

[0007] Another decoding method known is the use of AS-MS (Affinity Selection Mass Spectrometry) to screen molecules that have binding activity with a target molecule (Non-Patent Literature 22). This method does not require labeling or immobilization and is recognized as an unbiased assay method because it screens compounds using affinity with the target molecule, and it is also possible to identify allosteric inhibitors. Examples of using AS-MS include screening existing compounds that exist as single compounds by mixing them (Non-Patent Literature 23 and 24), and examples of its use for derivative evaluation rather than hit generation (Non-Patent Literature 25 and 26), and its usefulness as a method for screening compounds has been recognized. There are also reports of screening libraries synthesized by reagent mixture synthesis (one of the mixture-based methods, a method that uses a mixture of multiple building blocks to be bound) with AS-MS (Non-Patent Literature 25), but this has been limited to the use of structurally homogeneous libraries centered on scaffold structures.

[0011] There is a need for new compound libraries with structural diversity that can be used in drug development, but there is room for improvement in various aspects of establishing such compound libraries. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1]

[0008] JP2019-527672(A) [Patent Document 2] JP2020-524701(A) [Non-patent literature]

[0013] [Non-Patent Document 1]

[0009] Ruiwu Liu et al., Combinatorial chemistry in drug discovery. Current Opinion in Chemical Biology 2017, 38:117-126. [Non-Patent Document 2] Joerg Holenz, Patrick Stoy., Advances in Lead Generation. Bioorganic & Medicinal Chemistry Letters 29 (2019) 517-524. [Non-Patent Document 3] R. Macarron et al., Impact of high-throughput screening in biomedical research. Nature Reviews Drug Discovery volume 10, pages 188-195(2011). [Non-Patent Document 4] MJ Wigglesworth et al., Increasing the delivery of next generation therapeutics from high throughput screening libraries. Current Opinion in Chemical Biology 2015, 26:104-110. [Non-Patent Document 5] PJ Hajduk et al., A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews Drug Discovery volume 6, pages 211-219(2007). [Non-Patent Document 6] G. Chessari et al., From fragment to clinical candidate-a historical perspective. Drug Discovery Today, Volume 14, Issues 13-14, July 2009, Pages 668-675 [Non-Patent Document 7] A. Bancet. et al., Fragment Linking Strategies for Structure-Based Drug Design., J. Med. Chem. 2020, 63, 20, 11420-11435 [Non-Patent Document 8] F. Imrie et al., Deep Generative Models for 3D Linker Design., J. Chem. Inf. Model. 2020, 60, 4, 1983-1995. [Non-Patent Document 9] R. Liu et al., Combinatorial peptide library methods for immunobiology research., Experimental Hematology 31 (2003) 11-30. [Non-Patent Document 10] The “One-Bead-One-Compound” Combinatorial Library Method. Chem. Rev. 1997, 97, 2, 411-448. [Non-Patent Document 11] Structurally homogeneous and heterogeneous synthetic combinatorial libraries., Molecular Diversity volume 1, pages149-164(1996) [Non-Patent Document 12] R. Severinsen et al., Library of Biphenyl Privileged Substructures using a Safety-Catch Linker Approach., J. Chem. Inf. Model. 2020, 60, 4, 1983-1995 [Non-Patent Document 13] Drug Discovery Chemistry, Tokyo Kagaku Dojin, ISBN 978-4-8079-0584-3, p. 186 [Non-Patent Document 14] The Practice of Medicinal Chemistry, p. 483 [Non-Patent Document 15] Richard A. Houghten et al., Mixture-Based Synthetic Combinatorial Libraries., J. Med. Chem. 1999, 42, 19, 3743-3778. [Non-Patent Document 16] Robert A. Goodnow et al., DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nature Reviews Drug Discovery volume 16, pages131-147(2017). [Non-Patent Document 17] Kin-Chun Luk, Alexander Lee Satz, DNA-Compatible Chemistry. A Handbook for DNA-Encoded Chemistry 67-98. [Non-Patent Document 18] Marie L. Malone, Brian M. Paegel, What is a “DNA-Compatible” Reaction? ACS Combinatorial Science 2016, 18, 4, 182-187. [Non-Patent Document 19] A. Satz et al., Analysis of Current DNA Encoded Library Screening Data Indicates Higher False Negative Rates for Numerically Larger Libraries. ACS Comb. Sci. 2017, 19, 4, 234-238. Non-Patent Document 20 C. S. Kollmann et al., Application of encoded library technology (ELT) to a protein-protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists. Bioorg. Med. Chem. 22 (2014) 235. Non-Patent Document 21 Y. C. Chen et al., C-N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis. Bioconjugate Chem. 2020, 31, 3, 770-780. Non-Patent Document 22 D. A. Annis, et al., Affinity selection-mass spectrometry screening techniques for small molecule drug discovery. Current Opinion in Chemical Biology 2007,11:518-526. Non-Patent Document 23 J. Qian et al., Discovery of novel inhibitors of Bcl-xL using multiple high-throughput screening platforms. Analytical Biochemistry 328 (2004) 131-138. Non-Patent Document 24 K. M. Comess, et al., Kinase Drug Discovery by Affinity Selection / Mass Spectrometry (ASMS): Application to DNA Damage Checkpoint Kinase Chk1. Journal of Biomolecular Screening 11(7); 2006, 755-764. Non-Patent Document 25 D. A. Annis, et al., An affinity selection-mass spectrometry method for the identification of small molecule ligands from self-encoded combinatorial libraries: Discovery of a novel antagonist of E. coli dihydrofolate reductase. International Journal of Mass Spectrometry 238 (2004) 77-83. Non-Patent Document 26 B. R. Lahue et al., Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors. Bioorganic & Medicinal Chemistry Letters 19 (2009) 3405. Non-Patent Document 27 BC Doak, J. Kihlberg, Drug discovery beyond the rule of 5 - Opportunities and challenges. Expert Opinion on Drug Discovery, (2017), 12:2, 115-119. [Non-Patent Document 28] H. Lu et at., Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials, Sig Transduct Target Ther 5, 213 (2020). https: / / doi.org / 10.1038 / s41392-020-00315-3. [Non-Patent Document 29] F. Lovering et al., Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 21, 6752-6756. [Non-Patent Document 30] G. Schneider et al., “Scaffold‐Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening. Angew. Chem. Int. Ed., 38 (1999), pp. 2894-2896. [Non-Patent Document 31] H. Sun et at., Classification of scaffold-hopping approaches. Drug Discovery Today Volume 17, Issues 7-8, April 2012, Pages 310-32 [Overview of the Initiative] [Problems that the invention aims to solve]

[0014]

[0010] In order to obtain a true hit compound for a target molecule, a method of synthesizing the compounds that make up the library as a mixture is advantageous from the viewpoint of compound synthesis efficiency. On the other hand, when synthesizing the compounds that make up the library as a mixture, ensuring the diversity and quality of the compounds is important.

[0015]

[0011] We will now discuss the diversity of library compounds. The vast majority of conventional compound libraries have been composed of groups of compounds with defined scaffolds (Structurally Homogeneous Library). By attaching a group of building blocks with common reactive functional groups to a given scaffold, diversity of pharmacophores arises from the structural diversity of the building blocks. Furthermore, structural diversity is generated by the combination of pharmacophores at multiple locations. In other words, attention has been focused only on the structural diversity of pharmacophores derived from the structure of the building blocks. To put it another way, the diversity of the linking parts (linkers) that connect the building blocks has not been given attention.

[0016]

[0012] Compound libraries that include diversity not only in building blocks but also in the bonding modes connecting them allow for diversity in the stereochemistry of pharmacophores (i.e., the distances and angles between each functional group forming the pharmacophore), and also offer the potential for acquiring affinity with target molecules through linkers. Therefore, libraries that allow for the free selection of core blocks containing functional groups that form pharmacophores, as well as the free selection of linkers between them, are highly valuable as they enable a significant expansion of structural diversity. Despite this value, libraries that use multifunctional building blocks with two or more reactive functional groups and consider the diversity of linkers have not been fully utilized. For example, although structurally heterogeneous libraries are constructed by solid-phase synthesis, the use of multifunctional building blocks is limited, and although multiple bonding modes are used at a single bonding site, their application is limited to the capping of a specific type of reactive functional group (introduction of building blocks to the molecular ends) (Non-Patent Literature 12). DELT using multiple linkers during the introduction of building blocks within a molecule has been reported (Non-Patent Literature 21), but quality issues, which will be discussed later, remain.

[0017]

[0013] When a hit compound is obtained by FBDD, the compound generally has weak affinity to the target molecule, so growing and linking approaches are taken to improve its activity. However, in the process of the linking approach, which is expected to yield a more active compound, there are challenges in searching for a highly active compound while fully taking into account the diversity of linkers and core blocks that form the pharmacophore. Specifically, many linking approaches optimize the linker and binding while keeping the type of core block that forms the pharmacophore fixed (Non-Patent Document 7, Non-Patent Document 8), so they cannot be said to explore a wide range.

[0018]

[0014] Furthermore, when searching for new compounds based on known compounds using the scaffold hopping method, the optimal stereochemistry of each pharmacophore is likely to differ for each backbone (scaffold). For this reason, it is desirable to be able to search for diverse core blocks and diverse linkers simultaneously, but there are challenges in general methods to achieve this, and even when advanced computational methods are used, the search for linkers and bonds is limited to keeping the type of core block fixed (Non-Patent Literature 8).

[0019]

[0015] In other words, a methodology that broadly explores the range of combinations of core block and linker diversity is what is needed in hit generation, scaffold hopping, and FBDD drug discovery.

[0020] On the other hand, when synthesizing library compounds with a mixture, no purification operations other than solid-phase extraction, liquid-liquid extraction, vacuum distillation, or removal using solid-phase reagents are performed to remove reagents. Therefore, if unintended reactions proceed when the building blocks are joined together, the proportion of unintended compounds increases, and the assay is performed without their removal. This problem is exacerbated when reactions are carried out with many compounds and functional groups present, and the yield of the target compound decreases significantly.

[0021]

[0016] Conventional libraries, in pursuit of library size, include a large number of compounds in a single reaction space. For example, in peptide libraries formed solely of amide bonds, more than 100,000 compounds are included in a single reaction space for synthesis (Non-Patent Literature 15). However, despite using only amide bonds, there are many sequences that cannot be synthesized, resulting in false negatives and making it difficult to obtain information about the affinity of the designed compound to the target. Furthermore, contamination from impurities resulting from reactions other than the intended one, or from unreacted synthetic intermediates, is unavoidable, and as a result, false positives due to unintentionally produced compounds cannot be eliminated.

[0022]

[0017] In the case of DELT with a DNA tag, the DNA tag itself can also react, so in addition to the generation of impurities in the target compound, damage to the DNA tag can occur. In other words, not only is the yield of the target compound reduced, but the DNA itself, which codes for the structural information of the compound, is also damaged, leading to false negatives in which the hit compound cannot be identified.

[0023] Furthermore, in synthesis methods utilizing mixtures, the building blocks added to the reaction system are mixed and then added to the substrate. This difference in the reactivity of the building blocks can lead to variations in the yield of the resulting compounds, and when assaying the mixture, concentration differences between compounds can easily occur. While methods to adjust the number of moles of building blocks added are conceivable, it is not practical to compare the reactivity of the building blocks used beforehand. This makes reaction control difficult, and the quality of the resulting mixture cannot be guaranteed.

[0024]

[0018] Furthermore, there are challenges in terms of utilizing protecting groups. Conventional libraries avoid the use of protecting groups because they focus on simplifying synthesis, but as a result, the diversity of functional groups contained in the target compound is limited.

[0025] As described above, conventional libraries that synthesize library compounds as mixtures have the following drawbacks: (a) a large number of compounds per flask, (b) limitations on available reactions and damage to DNA tags due to the presence of DNA tags, (c) difficulty in reaction control due to being a mixture, and (d) insufficient utilization of protecting groups. As a result, the quality of compounds included in the mixture cannot be guaranteed. Conventional technology has not yet resolved the above technical challenges, and it has not yet reached a point where compound libraries prepared using mixtures can be prepared with diverse linkers connecting the core blocks.

[0026] In other words, there has never been an example of a library construction methodology that pursues structural diversity while simultaneously ensuring quality. This invention was made in light of the circumstances described above, and aims to provide a compound library containing diverse bonding modes, and a method for producing the same. [Means for solving the problem]

[0027]

[0019] The inventors have conceived of a mixture and parallel library, which allows for the rapid synthesis of large quantities of compounds (e.g., 1 million or more) as a quality-assured mixture by limiting the number of compounds included in a single reaction space and increasing the number of flasks (for example, 1000 or more libraries each containing 1000 compounds). In other words, the inventors conceived of a method that ensures quality in a single small group of reaction spaces, while simultaneously achieving diversity of compounds by arranging these reaction spaces in parallel. Based on this concept, it becomes possible to ensure quality even when supplying groups of 1 million or more compounds.

[0028]

[0020] As one specific method for constructing a library based on this idea, we have found the following. Molecules are constructed using multifunctional building blocks, each containing two or more reactive functional groups. Unlike many conventional libraries, the core block of the building block containing reactive functional groups is not limited to a specific scaffold. By linking one reactive functional group of the first building block (first BB) to a solid-phase reagent, a solid-phase supported reagent containing the other reactive functional group can be prepared. From this group of solid-phase reagents, those with a common reactive functional group on the first building block to be used in the reaction in the next step are uniformly mixed. This mixture is then divided into multiple containers, and a different second building block is reacted in each container to prepare a solid-phase reagent in which the first BB and second BB are linked via a first linker (first L). Again, those with a common reactive functional group on the second building block to be used in the reaction in the next step are uniformly mixed and then divided into multiple containers. By repeating these processes the required number of times and then cleaving from the solid phase, it is possible to provide a group of compounds that exhibit exponential diversity within the same flask, while simultaneously having diversity in the core block and linker.

[0029]

[0021] By performing this series of operations as a single unit, and similar operations separately in another group of building blocks, it is possible to increase the diversity of compounds while ensuring the quality of the compounds prepared in a single flask.

[0030] Furthermore, various protecting groups can be utilized in preparing libraries that simultaneously achieve the aforementioned bonding diversity and quality assurance. Specifically, by utilizing protecting groups, it is possible to avoid side reactions during bond formation, realize bonding diversity by exposing the functional groups used at any step, and include any hydrogen bond-donating group in the target compound.

[0031]

[0022] In one aspect of the present invention, a method for producing a compound library is provided, and as a result of diligent study, it has been confirmed in practice that this method can significantly improve the diversity of molecules through the combination of core blocks and linkers, and that it is possible to construct a library that guarantees the quality of the compounds constituting the library (presence or absence of each compound, their relative abundance, and the presence or absence of impurities). Furthermore, it has been confirmed that a hit compound that can specifically bind to a target molecule can be obtained from this library. Based on these findings, the present invention has been completed as a practical method for improving the efficiency of screening for any target molecule. In one aspect of the present invention, the following invention is provided.

[0032]

[0023] [A1] 1 x 10 2 ~1 × 10 8 A library containing compounds of the following: The compound has the following structure in which a first core block (first CB), a first linker (first L), and a second core block (second CB) are covalently linked: (1st CB) - (1st L) - (2nd CB) Includes, The U library includes two or more types of first CBs, two or more types of first Ls, and two or more types of second CBs. The aforementioned library is 1 × 10 2 ~1 × 10 5 A mixture comprising one or more of the above-mentioned compounds, The aforementioned library.

[0033]

[0024] [A2] The compound further has the following structure in which a second linker (second L) and a third core block (third CB) are covalently linked: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) Includes, The library described in [A1], wherein the library includes two or more types of second Ls and two or more types of third CBs.

[0034] [A3] The aforementioned compound further has the following structure in which the third linker (third L) and the fourth core block (fourth CB) are linked via covalent bonds: (First CB)-(First L)-(Second CB)-(Second L)-(Third CB)-(Third L)-(Fourth CB); or, (First CB)-(First L)-(Second CB)(-(Third L)-(Fourth CB))-(Second L)-(Third CB); comprising, The library according to [A1] or [A2], wherein the aforementioned library comprises two or more types of the third L, and two or more types of the fourth CB.

[0035]

[0025] [A4] The library according to any one of [A1] to [A3], wherein the aforementioned compound does not comprise an oligonucleotide tag. [A5] The library according to any one of [A1] to [A4], wherein the first L, the second L, and the third L each independently comprise a structure selected from the group consisting of amide, sulfonamide, acylsulfonamide, amino, ether, thioether, ester, ketone, sulfone, single bond, ethyne-1,2-diyl (-C≡C-), and nitrogen-containing 5-membered heteroarylene.

[0036]

[0026] [A6] The first L, the second L, and the third L are independently, -C(=O)-NR 1 - -NR 1 -C(=O)- -SO2-NR 1 - -NR 1 -SO2- -SO2-NR 1 -C(=O)- -C(=O)-NR 1 -SO2- -NR 1 - -O- -S- -C(=O)-O- -O-C(=O)- -C(=O)- -SO2- -C≡C- -CHR 2 - single bond

[0037] [ka]

[0038] [In the formula, R 1 and R 2 These are, independently, hydrogen atoms, or C 1-6 It is alkyl. A library listed in any of the cells [A1] to [A5], represented by the formula selected from the following.

[0039]

[0027] [A7] The library according to [A5] or [A6], wherein the single bond is a carbon-nitrogen single bond or a carbon-carbon single bond. [A8] A library according to any one of [A1] to [A7], wherein 1L, 2L, and 3L are formed by reactions independently selected from the group consisting of amidation, sulfonamidation, acylsulfonamidation, reductive amination, etherification, thioetherification, esterification, O-alkylation, N-alkylation, ketone bond formation reactions, carbon-nitrogen bond formation reactions, carbon-carbon bond formation reactions, and nitrogen-containing 5-membered heteroarylene bond formation reactions.

[0040] [A9] A library according to any one of [A1] to [A8], wherein 1L, 2L, and 3L are formed by reactions independently selected from the group consisting of amidation, sulfonamidation, acylsulfonamidation, reductive amination, O-alkylation, and carbon-carbon bond formation reactions.

[0041]

[0028] [A10] The library according to any one of [A7] to [A9], wherein the carbon-nitrogen bond formation reaction is an aromatic nucleophilic substitution reaction and / or a Buchwald-Hartwig coupling, and the carbon-carbon bond formation reaction is a Suzuki coupling, a Negishi coupling, a Stile coupling and / or a Sonogashira coupling.

[0042] [A11] A library containing 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more compounds, as described in any of [A1] to [A9]. [A12] 1 x 10 7 Below, 5 x 10 6 Below, 1 x 10 6 Below, 5 x 10 5 Below, 1 x 10 5 The following libraries, as described in any of [A1] to [A11], include compounds with values ​​of 50,000 or less, 20,000 or less, 10,000 or less, 8,000 or less, 7,000 or less, 6,000 or less, 5,000 or less, 4,000 or less, 3,000 or less, 2,000 or less, 1,500 or less, or 1,200 or less.

[0043]

[0029] [A13] Compounds that make up the compound library 1) The standard deviation of the clogp value calculated for each compound is 1.2 or higher, 1.3 or higher, 1.4 or higher, or 1.5 or higher; 2) The variance of the clogp values ​​calculated for each compound is 1.5 or higher, 1.75 or higher, 2.0 or higher, or 2.5 or higher; 3) The median Fsp3 value calculated for each compound as [(number of sp3 carbon atoms in the molecule) / number of non-hydrogen atoms in the molecule] is 0.10 or greater, 0.15 or greater, 0.20 or greater, 0.25 or greater, or 0.30 or greater; 4) The standard deviation of the molecular weight calculated for each compound is 25 or greater, 50 or greater, or 75 or greater; 5) The median number of hydrogen bond-accepting groups for each compound is 2–30, 3–20, or 3–18; 6) The difference between the compound with the most hydrogen bond-donating groups and the compound with the fewest is 0-10, 0-8, or 1-5; and 7) The variance of the tPSA / Topological Polar Surface Area calculated for each compound is 20 or greater, 25 or greater, 30 or greater; and 8) The median Tanimoto Similarity (ECFP_6: Extended-connectivity fingerprints up to 6 bonds distinguishable at the atomic level, for example, the value calculated by ECFP_6 using Dassault Systèmes' Pipeline Pilot 2017HF2) calculated for each compound is 0.98 or less, 0.95 or less, 0.90 or less, 0.85 or less, or 0.80 or less; 9) The median Tanimoto Similarity (ECFP_6: Extended-connectivity fingerprints of up to 6 bonds distinguishable at the atomic level, calculated using ECFP_6, for example, Dassault Systèmes' Pipeline Pilot 2017HF2) calculated for each compound must be 0.50 or higher, 0.55 or higher, 0.60 or higher, 0.65 or higher, 0.70 or higher, or 0.75 or higher; A library listed in any of [A1] to [A12] that satisfies one or more of the following conditions.

[0044]

[0030] [A14] The library is 1 × 10 2 ~1 × 10 5 A library described in any of [A1] to [A13], manufactured as a mixture of the compounds. [A15] Select one, two, or all of the group consisting of the first CB, the second CB, and the third CB, 1) A library as described in any of [A1] to [A14], in which the total number of carbon atoms, nitrogen atoms, and oxygen atoms contained in the constituent atoms is 1 or more and 18 or less, 2 or more and 17 or less, 3 or more and 16 or less, 4 or more and 15 or less, 5 or more and 14 or less, or 6 or more and 13 or less.

[0045]

[0031] [A16] One, two, or all of the first CB, second CB, and third CB selected from the group, each having at least one annular structure. The library listed in any of [A1] to [A15].

[0046] [A17] Select one, two, three, or all of the group consisting of the 1st CB, 2nd CB, 3rd CB, and 4th CB, 1) A library as described in any one of the items [A1] to [A16], wherein the total number of carbon atoms, nitrogen atoms, and oxygen atoms contained in the constituent atoms is 1 or more and 18 or less, 2 or more and 17 or less, 3 or more and 16 or less, 4 or more and 15 or less, 5 or more and 14 or less, or 6 or more and 13 or less.

[0047]

[0032] [A18] A library according to any of [A1] to [A17], comprising at least one annular structure for one, two, three, or all of the group consisting of the first CB, second CB, third CB, and fourth CB.

[0048]

[0033] [A19] The library according to any one of [A1] to [A18], wherein the ratio (compound A / compound B) of the compound present in the mixture in the largest molar amount (compound A) to the compound present in the smallest molar amount (compound B) in the compound constituting the library is 500 or less, 400 or less, 300 or less, 200 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 10 or less, 5 or less, 4 or less, 3 or less, or 2 or less.

[0049] [A20] A library according to any one of [A1] to [A19], wherein 80% or more of the compounds constituting the library are detected by retention time and mass-to-charge ratio (m / z) in a liquid chromatograph-mass spectrometer (LC-MS).

[0050] [A21] A library according to any one of [A1] to [A20], wherein 90% or more of the compounds constituting the library are detected by retention time and mass-to-charge ratio (m / z) in a liquid chromatograph-mass spectrometer (LC-MS).

[0051] [A22] The library according to any one of [A1] to [A21], wherein 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or 96% or more of the compounds constituting the library are detected by retention time and mass-to-charge ratio (m / z) in a liquid chromatograph-mass spectrometer (LC-MS).

[0052] A library assembly containing 200 or more compounds, prepared by combining two or more libraries described in any of [A23], [A1], or [A22].

[0034] [B1] A method for screening compounds that bind to a target molecule, (1) Provide a library as described in any of [A1] to [A23]; (2) Contacting each of the one or more mixtures constituting the library with a target molecule; (3) Identifying compounds that bind to the target molecule. The method, including the method described above.

[0053]

[0035] [B2] The method according to [B1], wherein the target molecule is a protein, nucleic acid, polypeptide, or glycan. [B3] The method according to [B1] or [B2], wherein the identification of compounds that bind to the target molecule is performed by AS-MS.

[0054]

[0036] [B4] The method according to any one of [B1] to [B3], wherein the mixture comprises compounds in the order of 100-50000, 100-10000, 200-5000, 400-3000, or 600-1500.

[0055] [B5] A method according to any of [B1] to [B4], which involves screening a mixture of 2-100,000, 2-50,000, 2-20,000, 2-10,000, 2-5,000, or 2-2,500 contained in the library.

[0056]

[0037] A method for manufacturing a library, (a) Prepare a support carrier (first BB support carrier) on which the first building blocks (first BB) are covalently linked, where the first BB support carrier is made up of na types of first building blocks (first BB1 to first BB1 na ) containing a solid phase support (1st BB 1-na (Carrier) and the first BB 1-na First BB of the support carrier 1-na Each portion has a reactive functional group for forming a bond with the second building block (second BB), and the first BB 1-na The reactive functional groups contained in the support are one type or two or more types. (b) 1st BB 1-na A mixture of supporters sharing a common reactive functional group is prepared, and each mixture is reacted with one type of second building block introduction reagent (second BB introduction reagent) or a mixture of two or more types of second BB introduction reagents to prepare a supporter in which the second BB is covalently linked to the first BB (second BB-first BB supporter). The supporter obtained here contains nb types of second building blocks (second BB1 to second BB1). nb ) including the carrier (2nd BB 1-nb -1st BB 1-na (Supporting carrier) and 2BB1 introduction reagent ~ 2BB nb If any of the induction reagents are in the first bar 1-na It reacts with each reactive functional group of the support to form the first linker (first L). (e) Cutting off the compound from the solid support The method comprising, wherein na is an integer of 2 or more, nb is an integer of 2 or more, and the resulting compound library contains 100 or more compounds as a mixture.

[0057]

[0038] In [C2](b), the first BB 1-na The method according to [C1], wherein a mixture of support carriers having common reactive functional groups is prepared, and each mixture is reacted with one of nb types of second BB introducing reagents.

[0058] [C3] 2nd BB 1-nb -1st BB 1-naEach support has a reactive functional group capable of linking with the third building block (third BB), and each first BB 1-na Part or Second BB 1-nb The reactive functional group contained in the portion is of one or more types, and further (c) 2nd BB 1-nb -1st BB 1-na A mixture of supporters sharing a common reactive functional group is prepared, and each mixture is reacted with one type of third building block introduction reagent (third BB introduction reagent) or a mixture of two or more types of third BB introduction reagents to prepare a supporter in which the third BB is covalently linked to the first BB or second BB (third BB-second BB-first BB supporter, or second BB-(third BB-)first BB supporter). The supporter obtained here contains nc types of third building blocks (third BB1 to third BB nc ) including the carrier (3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier, or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na (Supporting carrier) and 3BB1 introduction reagent ~ 3BB nc If any of the induction reagents are in BB 2 1-nb -1st BB 1-na It reacts with each reactive functional group of the support to form a second linker (second L). The method according to [C1] or [C2], wherein nc is an integer of 2 or more, and there are two or more types of first or second linkers in the compounds included in the library.

[0059]

[0039] In [C4](c), the resulting support carrier is the third BB 1-nc -2nd BB 1-nb -1st BB 1-na The method described in [C3], which is a support carrier. [C5] 3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB1-na Each support has a reactive functional group for forming a bond with the fourth building block (fourth BB), and each first BB 1-na Part, 2nd BB 1-nb Part, or the 3rd BB 1-nc The reactive functional group contained in the portion is of one type or two or more types, and further (d) 3BB 1-nc -2nd BB 1-na -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na A mixture of supporters sharing a common reactive functional group is prepared, and each mixture is reacted with one type of fourth building block introduction reagent (fourth BB introduction reagent) or a mixture of two or more types of fourth BB introduction reagents to prepare a support in which the fourth BB is covalently linked to the third BB, second BB, or first BB. The support obtained here is a mixture of nd types of fourth building blocks (fourth BB1 to fourth BB1). nd ) is a carrier containing the 4th BB1 introduction reagent ~ 4th BB nd If any of the induction reagents are in the 3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na It reacts with each reactive functional group of the support to form a third linker. The method according to any of [C1] to [C4], wherein nd is an integer of 2 or more, and the first, second, or third linkers of the compounds included in the library are two or more types.

[0060]

[0040] The carrier obtained in [C6](d) is 4th BB 1-nd -3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Carrier; support; 4th BB 1-nd -(3rd BB 1-nc -) 2nd BB 1-nb-1stBB 1-na supported carrier; 3rdBB 1-nc -2ndBB 1-nb -(4thBB 1-nd -)1stBB 1-na supported carrier; 4thBB 1-nd -3rdBB 1-nc -(2ndBB 1-nb -)1stBB 1-na supported carrier; or 4thBB 1-nd -2ndBB 1-nb -(3rdBB 1-nc -)1stBB 1-na supported carrier The method according to [C5], which is

[0061]

[0041] The supported carrier obtained in [C7](d) is 4thBB 1-nd -3rdBB 1-nc -2ndBB 1-nb -1stBB 1-na supported carrier; The method according to [C5] or [C6], which is

[0062] [C8] The first linker and the second linker 1-1) the first linker is two or more types; 1-2) the second linker is two or more types; and 1-3) the first linker or the second linker is three or more types; satisfy one or more of the conditions, or.

[0063] The first linker, the second linker and the third linker 2-1) the first linker is two or more types; 2-2) the second linker is two or more types; 2-3) the third linker is two or more types; 2-4) the first linker, the second linker or the third linker is three or more types; satisfy one or more of the conditions, the method according to any one of [C1] to [C7].

[0064]

[0042] [C9] na is an integer between 2 and 1000, nb is an integer between 2 and 1000, and either na or nb is an integer of 3 or greater; or A method according to any of [C1] to [C8], wherein na is an integer between 2 and 1000, nb is an integer between 2 and 1000, nc is an integer between 2 and 1000, and any one of na, nb, or nc is an integer of 3 or greater.

[0065]

[0043] [C10] First BB1 introduction reagent ~ First BB na One of the introduction reagents, the first BB introduction reagent, is reacted with a solid support to introduce the first BB into the solid support, and the resulting first BB-supported support is used to introduce the first BB 1-na A method for preparing a support carrier, according to any of [C1] to [C9].

[0066] [C11] 1st BB1 introduction reagent ~ 1st BB na A mixture of 2-na types of the introduction reagents for the first BB is reacted with a solid support to introduce the first BB into the solid support. 1-na A method for preparing a support carrier, according to any of [C1] to [C10].

[0067]

[0044] [C12] 1st BB 1-na First BB of the support carrier 1-na Each portion has one reactive functional group to form a bond with the second building block (second BB), and / or the second BB 1-nb -1st BB 1-na Second BB of the support carrier 1-nb The method according to any of [C1] to [C11], wherein each portion has one reactive functional group for forming a bond with the third building block (third BB).

[0068] [C13] 1st BB 1-na First BB of the support carrier 1-na Each portion has one reactive functional group to form a bond with the second building block (second BB), and / or the second BB 1-nb-1st BB 1-na First BB of the support carrier 1-na The method according to any of [C1] to [C11], wherein each portion has one reactive functional group for forming a bond with the third building block (third BB).

[0069]

[0045] [C14] The method according to any one of [C1] to [C13], further comprising a deprotection step, a protection step, or a derivatization step of the reactive functional group. [C15] The method according to [C14], further comprising the step of washing the solid support with a solution mixed with an acidic component after the deprotection step of the reactive functional group.

[0070] [C16] The method according to [C15], wherein the above acidic component is an acidic compound with a pKa of 0 to 10 in water.

[0046] [C17] The method according to [C15] or [C16], wherein the above acidic component is at least one selected from the group consisting of 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ethyl (hydroxyimino)cyanoethyl acetate (Oxyma), and 4-nitrophenol.

[0071] [C18] The method according to any one of [C15] to [C17], wherein the functional group produced by the deprotection step of the reactive functional group is either a carboxyl or a hydroxyl substituted on an aromatic ring.

[0072]

[0047] The method according to any one of [C1] to [C18], further comprising the step of linking two crosslinkable groups present in the [C19] molecule to obtain a cyclic compound. The method according to any one of [C1] to [C19], further comprising modifying the functional groups contained in the compound cleaved from the solid support in step [C20](e).

[0073] [C21] The method according to [C20], wherein the functional group is a functional group produced by cleaving a compound from a solid support. [C22] The above modification is hydroxy or carboxyl C 1-6 A method of alkylation, either involving [C20] or [C21].

[0074]

[0048] [C23] In (b) above, in a first BB support where the conversion rate of the reaction between the second BB introducing reagent and the reactive functional groups of the first BB is less than 100%, the further comprises reacting a different second BB introducing reagent with higher reactivity with the remaining reactive functional groups of the first BB, and / or In (c) above, in a second-to-first-to-third-BB support where the conversion rate of the reaction between the third-to-third-BB introducing reagent and the reactive functional group is less than 100%, the further method includes reacting a different third-to-third-BB introducing reagent with a higher reactivity with the remaining reactive functional group, and / or In the above (d), in a third BB-second BB-first BB support or second BB-(third BB-)first BB support where the conversion rate of the reaction between the fourth BB introducing reagent and the reactive functional group is less than 100%, the method further includes reacting a different fourth BB introducing reagent with higher reactivity with the remaining reactive functional group. The method described in any of [C1] to [C22].

[0075]

[0049] [C24] The method according to any one of [C1] to [C23], wherein one or more compounds included in the library include a UV tag. [C25] The aforementioned UV tag is given by Equation 1:

[0076] [ka]

[0077] [In the formula, ring A is selected from benzene, naphthalene, anthracene, and biphenyl; The benzene, the naphthalene, the anthracene, and the biphenyl are halogen atoms, nitro, cyano, carboxy, sulfoxy, -COR 1 , -OR 1 , -NR 1 R 2 ,-CONR1 R 2 , or -SO2NR 1 R 2 It may be substituted with one to three identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (It may form a heterocycle with an alkyl or a linked nitrogen atom, and X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O- that is bonded to the building block.) The method described in [C24], which has a structure represented by [C24].

[0078]

[0050] [C26] The UV tag is defined by formula 2 or formula 3:

[0079] [ka]

[0080] (In the formula, X is a divalent group selected from the group consisting of -CONH-, -NHCO-, -CH2O- and -O-, which is bonded to the building block, and Y and Z are hydrogen atoms, halogens, nitro, cyano, carboxy, sulfoxyl, -COR 1 , -OR 1 , -NR 1 R 2 ,-CONR 1 R 2 , or -SO2NR 1 R 2 It may be substituted with one to three identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (An alkyl group or two of them together may form a heterocycle.) The method described in [C24], which has a structure represented by [C24].

[0081]

[0051] [C27] The UV tag is given by formula 3:

[0082] [ka]

[0083] (In the formula, X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O- that is bonded to the building block, and Y and Z represent hydrogen atoms, halogen atoms, nitro, cyano, carboxy, sulfoxyl, -COR 1 , -OR 1 , -NR 1 R 2 , -CO-NR 1 R 2 , or -SO2-NR 1 R 2 It may also be substituted with 1 to 3 identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (An alkyl group or two of them together may form a heterocycle.) The method described in [C24], which has a structure represented by [C24].

[0084]

[0052] [C28] The UV tag is given by formula 4:

[0085] [ka]

[0086] (In the formula, X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O-, and is bonded to the building block, R 1 and R 2 Each is independently C 1-6 (They may form heterocycles together with alkyl groups or the nitrogen atoms to which they are linked.) The method described in [C24], which has a structure represented by [C24].

[0087]

[0053] [C29] The method according to any one of [C1] to [C28], wherein the compound included in the library does not contain an oligonucleotide tag. [C30] The method according to any one of [C1] to [C23] and [C29], wherein the compound contained in the library does not contain a UV tag.

[0088] [C31] Further steps: 1) A step to obtain a solid-phase support obtained in any of the steps; 2) A step of cleaving the intermediate compound from the solid support obtained in step 1); and 3) A step of analyzing the intermediate compound; Optionally, a step of analyzing the compound excised in step (e). A method that includes any of the methods described in [C1] to [C30].

[0089]

[0054] [C32] The method according to [C31], wherein the analysis is performed using a liquid chromatogram. [C33] The method according to any one of [C1] to [C32], wherein 1L, 2L, 3L, and 4L are formed by a reaction independently selected from the group consisting of amidation, sulfonamidation, acylsulfonamidation, reductive amination, etherification, thioetherification, esterification, O-alkylation, N-alkylation, ketone bond formation reaction, carbon-nitrogen bond formation reaction, carbon-carbon bond formation reaction, and nitrogen-containing 5-membered heteroarylene formation reaction.

[0090]

[0055] [C34] The method according to any one of [C1] to [C33], wherein 1L, 2L, 3L and 4L comprises structures independently selected from the group consisting of amides, sulfonamides, acylsulfonamides, aminos, ethers, thioethers, esters, ketones, sulfones, single bonds, etyn-1,2-diyl (-C≡C-), and nitrogen-containing 5-membered heteroarylenes.

[0091] [C35] The method according to any of [C1] to [C34], wherein the carbon-nitrogen bond formation reaction is an aromatic nucleophilic substitution reaction and / or a Buchwald-Hartwig coupling, and the carbon-carbon bond formation reaction is a Suzuki coupling, Negishi coupling, Stile coupling and / or Sonogashira coupling.

[0092]

[0056] [C36] The method according to any one of [C1] to [C35], wherein the obtained library comprises 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more compounds.

[0093] [C37] The resulting compound library is 1 × 10 8 Below, 1 x 10 7 Below, 5 x 10 6 Below, 1 x 10 6 The method according to any of [C1] to [C36], including compounds with a concentration of 500,000 or less, 100,000 or less, 50,000 or less, 20,000 or less, 10,000 or less, 8,000 or less, 7,000 or less, 6,000 or less, 5,000 or less, 4,000 or less, 3,000 or less, 2,000 or less, 1,500 or less, or 1,200 or less.

[0094]

[0057] [C38] A library according to any one of [C1] to [C37] in which the manufacture of 90% or more of the target compounds whose synthesis is set as compounds constituting the library has been confirmed.

[0095] [C39] A library according to any of [A1] to [C38], wherein the manufacture of 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or 96% or more of the target compounds whose synthesis has been set as compounds constituting the library has been confirmed.

[0096] [C40] Confirmation of synthesis by retention time and mass-to-charge ratio (m / z) using liquid chromatography-mass spectrometry (LC-MS), as described in [C38] or [C39].

[0058] [C41] The method according to any of [C1] to [C37], wherein the obtained library is one of the libraries described in any of [A1] to [A23].

[0097] This includes combining a compound library prepared by any of the methods described in [C42][C1]~[C40], 1 × 10 2 ~1 × 10 8 , 3 x 10 2 ~1 × 10 8 , 1 x 10 2 ~1 × 10 7 , or 5×10 2 ~1 × 10 6 A method for producing a compound library assembly containing the compound.

[0098]

[0059] A method for forming a carbon-carbon bond by a Suzuki coupling reaction, wherein a leaving group X is placed on the carbon atom of an aromatic ring. 8 The process involves reacting a compound V having said leaving group with a boron atom-containing compound W having a boron atom linked to a carbon atom, which is capable of forming a carbon-carbon bond by substitution with the leaving group, in the presence of an organic base and a palladium catalyst comprising at least one selected from the group consisting of 1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane palladium Buchwald fourth-generation catalyst precursor (meCgPPh Pd G4) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) ((dtbpf)PdCl2). X 8 is a halogen atom or -O-SO2-R 5 And; R 5 C may be substituted with one or more fluorine atoms. 1-6 Alkyl, or C1 or more fluorine atoms or C1 which may be substituted with fluorine atoms 1-6 A phenyl that may be substituted with an alkyl group; The method wherein the compound V is a resin for solid-phase synthesis, or the boron atom-containing compound W is a resin for solid-phase synthesis.

[0099]

[0060] [D2] The method according to [D1], wherein the organic base is selected from the group consisting of organic bases whose conjugate acid pKa in acetonitrile is 23 or more, and two or more different bases may be used.

[0100] [D3] The method according to either [D1] or [D2], wherein the organic base is selected from the group consisting of amidines, guanidines, and phosphazenes.

[0061] [D4] The organic bases are 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]deca-5-ene (MTBD), and 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(P2Et), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 A method according to any of [D1] to [D3], selected from the group consisting of -catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), and tert-butylimino-tri(pyrrolidino)phosphorane (BTPP).

[0101]

[0062] [D5] The method according to any one of [D1] to [D4], wherein the organic base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG). [D6] Compound V, the solid-phase synthesis resin, has compound Va in its side chain via a decomposable linker, Compound Va is X 8 -Ar 8 A method according to any of [D1] to [D5], comprising a compound represented by as part of its chemical structure.

[0102]

[0063] [D7] Said X 8However, the method described in any of [D1] to [D6], wherein the atom is a halogen atom. [D8] Said X 8 However, the method described in any of [D1] to [D7], wherein the atom is a bromine atom.

[0103] [D9] The above Ar 8 The method according to any one of [D1] to [D8], wherein each of the following may be independently selected from the group consisting of phenyl, naphthyl, pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triaryl, pyrimidyl, pyrazinyl, pyridadinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothiophenyl, benzofuranil, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, and imidazopyridyl, and each may be substituted.

[0104]

[0064] [D10] The Ar 8 The method according to any one of [D1] to [D9], wherein the substituted members are selected from the group consisting of phenyl and pyridyl, and each may be substituted. [D11] The solid-phase synthesis resin has a boron atom-containing compound Wa in its side chain via a decomposable linker. Boron atom-containing compound Wa, X 9 -Ar 9 or X 9 -CR 6 R 7 R 8 It is a compound having a boron atom-containing group that is linked to a carbon atom by a boron atom, represented as [formula]. X 9 is -B(-OR 10 )(-OR 11 ), -BF3K, or (a), (b), (c), or (d) below

[0105] [ka]

[0106] And M is lithium, sodium, or potassium. R 10 and R 11 Each of these is independently a hydrogen atom, or C 1-6 Alkoxy or C 6-10 C may be substituted with aryl. 1-6 Alkyl, or R 10 and R 11 Together with the intervening oxygen and boron atoms, it forms a 5-8 member saturated or unsaturated ring, and this ring is C 1-6 Alkyl alkyl group, C 1-6 Alkoxy and C 6-10 They may be substituted with one or more substituents selected from aryl groups. Ar 9 C 6-10 A 5-10 membered heteroaryl containing an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkoxy)carbonyl, (C 1-6 Alkoxy)carbonylamino, (C 1-6 Alkyl)carbonylamino, (C 6-10 aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C 1-6 Alkyl)amino, 4-8 membered cyclic amino, aminocarbonyl, (C 1-6 Alkyl)aminocarbonyl, di(C 1-6 It may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl groups. R 6 , R 7 and R 8 Each is independently a hydrogen atom, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C3-8 Cycloalkyl, C 7-14 Aralquil, (C 1-6 Alkyl)carbonyl, (C 6-10 aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N, and S, C 6-10 A 5-10 membered heteroaryl containing an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkoxy)carbonyl, (C 1-6 Alkoxy)carbonylamino, (C 1-6 Alkyl)carbonylamino, (C 6-10 aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C 1-6 Alkyl)amino, 4-8 membered cyclic amino, and aminocarbonyl, (C 1-6 Alkyl)aminocarbonyl, di(C 1-6 The method according to any one of [D1] to [D10], which may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl.

[0107]

[0065] [D12] The boron atom-containing compound Wa is X 9 -Ar 9 And, Ar 9 C 6-10 A 5-10 membered heteroaryl containing an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkoxy)carbonyl, (C 1-6 Alkoxy)carbonylamino, (C 1-6 Alkyl)carbonylamino, (C 6-10aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C 1-6 Alkyl)amino, 4-8 membered cyclic amino, aminocarbonyl, (C 1-6 Alkyl)aminocarbonyl, di(C 1-6 The method according to any one of [D1] to [D11], which may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl.

[0108]

[0066] The method according to any one of [D1] to [D12], wherein the reaction is carried out in the presence of a solvent. [D14] The solvent may be selected from the group consisting of halogenated solvents, nitrile solvents, amide solvents, ether solvents, and aromatic hydrocarbon solvents, and two or more may be used, as described in [D13].

[0109]

[0067] [D15] The solvent may be selected from the group consisting of ether-based solvents, and two or more may be used, as described in [D13]. [D16] The method according to [D15], wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,3-dioxolane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and 4-methyltetrahydropyran, and two or more of these are used.

[0110]

[0068] [D17] The method according to [D15], wherein the ether solvent is tetrahydrofuran. [D18] The method according to any of [D1] to [D17], wherein the reaction is carried out at a reaction temperature of 0°C to 100°C.

[0111] [D19] The method according to [D18], wherein the reaction temperature is 20°C to 90°C, 40°C to 80°C, 50°C to 70°C, or 55°C to 65°C.

[0069] [D20] The method according to any one of [D1] to [D19], wherein the solid-phase synthesis resin is bonded to compound Va via a linker containing a benzyl ether structure, or to boron atom-containing compound Wa via a linker containing a benzyl ether structure.

[0112] [D21] The method according to [D20], wherein the benzyl ether structure is as follows.

[0113] [ka]

[0114]

[0070] [D22] The method according to any one of [D1] to [D21], wherein the reaction is carried out in a mixture containing a solid-phase synthesis resin having two or more different compounds Va in their side chains as a substrate.

[0115] [D23] The method according to any one of [D1] to [D22], wherein the reaction is carried out in a mixture containing a solid-phase synthesis resin as a substrate, wherein the reaction is carried out in a mixture containing two or more different boron atom-containing compounds Wa in the side chains.

[0116]

[0071] [D24] The method according to any one of [D1] to [D23], wherein the mixture contains as a substrate a solid-phase synthesis resin to which two or more different compounds Va are bonded, or a solid-phase synthesis resin to which two or more different boron atom-containing compounds Wa are bonded, and the compounds Va or boron atom-containing compounds Wa bonded to each resin are the same.

[0117] [D25] A method for producing compounds constituting a compound library, comprising a method for forming a carbon-carbon bond by the method described in any one of [D1] to [D24]. [Effects of the Invention]

[0118]

[0072] This specification provides a library composed of compounds having diversity in chemical structure. Furthermore, it provides assay methods using the library and methods for producing the library. [Brief explanation of the drawing]

[0119] [Figure 1]

[0073] Figure 1 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 3. [Figure 2] Figure 2 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 4. [Figure 3] Figure 3 shows the X-ray crystal structure (6QGG) of the complex of Bcl-2 protein and ABT-737 analog registered in the PDB (Protein Data Bank), and the chemical structure of the ABT-737 analog. [Figure 4] Figure 4 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 8. [Figure 5A] Figure 5A shows the process name, mixture name, and library number for library synthesis in Example 8. In Figures 5A, 5B, and 5C, the process name is written above the horizontal line, and the mixture name is written inside the rectangle. In Figures 5A, 5B, and 5C, the process name and mixture name are written without the library number "2-1-". For example, "h01" represents process "2-2-h01", and "h01A01-0" represents mixture "2-1-h01A01-0". [Figure 5B] Figure 5B is a portion of Figure 5 showing the process name, mixture name, and library number for library synthesis in Example 8. [Figure 5C] Figure 5C is a portion of Figure 5 showing the process name, mixture name, and library number for library synthesis in Example 8. [Figure 6]Figure 6 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 9. [Figure 7A] Figure 7A shows the process name, mixture name, and library number for library synthesis in Example 9. In Figures 7A, 7B, and 7C, the process name is written above the horizontal line, and the mixture name is written inside the rectangle. In Figures 7A, 7B, and 7C, the process name and mixture name are written without the library number "2-2-". For example, "h01" represents process "2-2-h01", and "a1B01-0" represents mixture "2-2-a1B01-0". [Figure 7B] Figure 7B is a portion of Figure 7 showing the process name, mixture name, and library number for library synthesis in Example 9. [Figure 7C] Figure 7C is a portion of Figure 7 showing the process name, mixture name, and library number for library synthesis in Example 9. [Figure 8] Figure 8 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 10 (case 1). [Figure 9] Figure 9 shows the "diversity of core blocks" and "diversity of linkers" included in the library synthesized in Example 10 (case 2). [Figure 10] Figure 10 shows the process name, mixture name, and library number for library synthesis in Example 10 (case 1). The process name is written above the horizontal line in Figure 10, and the mixture name is written inside the rectangle. In Figure 10, the process name and mixture name are written without the library number "4-1-". For example, "a1B01" represents process "4-1-a1B01", and "a1B01-0" represents mixture "4-1-a1B01-0". [Figure 11]Figure 11 shows the process name, mixture name, and library number for library synthesis in Example 10 (case 2). The process name is written above the horizontal line in Figure 11, and the mixture name is written inside the rectangle. In Figure 11, the process name and mixture name are written without the library number "4-2-". For example, "a1B05" represents process "4-2-a1B05", and "a1B05-0" represents mixture "4-1-a1B05-0". [Modes for carrying out the invention]

[0120]

[0074] In this specification, "C 1-6 "Alkyl" refers to a monovalent group derived by removing one hydrogen atom from a linear or branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0121] In this specification, "C 3-7 "Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0122]

[0075] In the present invention, "C 6-10 "Aryl" refers to a monovalent aromatic hydrocarbon ring group. 6-10 Examples of aryl compounds include phenyl, 1-naphthyl, and 2-naphthyl.

[0123] In this specification, "halogen atom" means a fluorine atom, chlorine atom, bromine atom, iodine atom, etc. In the present invention, when the halogen atom is a substituent such as an aryl or heteroaryl group, preferred halogen atoms include fluorine, chlorine, and bromine atoms. In the present invention, when the halogen atom is a substituent of an alkyl group or a group containing an alkyl group as part thereof (such as an alkoxy, alkenyl, or alkylthio group), a preferred halogen atom includes fluorine. Specific examples of groups having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.

[0124]

[0076] In one aspect of the present invention, a library is provided comprising compounds having a predetermined chemical structure. The number of compounds comprising the library is not particularly limited insofar as they can be subjected to screening, and the number of compounds may be, for example, 1 × 10 2 ~1 × 10 8 , 3 x 10 2 ~1 × 10 7 , 5×10 2 ~1 × 10 6 Other examples are also acceptable. Here, the number of compounds refers to the number of compounds that differ in chemical structure, and tautomers, etc., are considered to be the same compound. On the other hand, positional isomers, stereoisomers, and other compounds that differ in chemical structure are considered to be separate compounds. Compounds containing isotopes in ratios significantly different from their natural abundance can be considered as compounds.

[0125] Examples of lower limits for the number of compounds constituting the library include 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more. Furthermore, an upper limit for the number of compounds is 1 × 10⁻¹⁰. 8 Below, 1 x 10 7 Below, 5 x 10 6 Below, 1 x 10 6Examples include 500,000 or less, 100,000 or less, 50,000 or less, 20,000 or less, 10,000 or less, 8,000 or less, 7,000 or less, 6,000 or less, 5,000 or less, 4,000 or less, 3,000 or less, 2,000 or less, 1,500 or less, or 1,200 or less.

[0126]

[0077] The compounds constituting the library are not particularly limited as long as they are compounds that can exist stably under the screening conditions. The compounds may be prepared by synthesis, or some may be obtained by purchase. In one embodiment, the compounds are composed of atoms selected from hydrogen, carbon, oxygen, nitrogen, sulfur, halogen, and phosphorus atoms. In another embodiment, the compounds are composed only of atoms selected from hydrogen, carbon, oxygen, nitrogen, sulfur, halogen (e.g., fluorine, chlorine, bromine, iodine) and phosphorus atoms. The compounds constituting the library are not particularly limited, but have molecular weights in the range of, for example, 200 to 3000, specifically 300 to 2000, more specifically 300 to 1800, and even more specifically 400 to 1800. In one aspect of the present invention, the standard deviation of the molecular weights of the compounds constituting the library is not particularly limited, but is for example, 25 or more, specifically 50 or more, and more specifically 75 or more. The compounds that make up the library are not particularly limited, but for example, they may contain 7 to 200 carbon atoms, specifically 11 to 130, more specifically 11 to 120; for example, 0 to 40 nitrogen atoms, specifically 2 to 27, more specifically 2 to 24; and for example, 0 to 30 oxygen atoms, specifically 2 to 20, more specifically 2 to 18. The amount of each compound that makes up the library is not particularly limited as long as it is usable for screening, and each compound may be in the range of, for example, 0.001 to 50,000 μg, specifically 0.1 to 40,000 μg, more specifically 1 to 30,000 μg. In one embodiment of the present invention, the ratio (compound A / compound B) of the compound present in the mixture in the largest molar amount (compound A) to the compound present in the smallest molar amount (compound B) is 500 or less, 400 or less, 300 or less, 200 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 10 or less, 5 or less, 4 or less, 3 or less, or 2 or less.

[0127]

[0078] With respect to the compounds that make up the library, the number of compounds contained in one mixture is not particularly limited as long as it is applicable to screening, for example, 100 to 100,000, 100 to 10,000, or 100 to 5,000 different compounds may be contained in the mixture.

[0128] In one aspect of the present invention, the compounds constituting the library are contained in a mixture. The mixture is not particularly limited, as long as it can be used for screening using a mixture of sample compounds, and may be a concentrated mixture of compounds or a solution diluted with a solvent or the like. The mixture may be prepared by mixing individually synthesized or obtained compounds, or a mixture obtained as a product by a chemical reaction using the mixture as a substrate may be used. In one aspect of the present invention, the library is prepared as a mixture of different compounds, for example, 100 to 100,000, 100 to 10,000, or 100 to 5,000.

[0129]

[0079] In one aspect of the present invention, parameters relating to the properties of each compound constituting the library (e.g., clogp, topological polar surface area (tPSA), etc.) may be calculated, and the calculation of these parameters can be carried out by methods commonly used by those skilled in the art to which the present invention belongs. For example, clogp and topological polar surface area (tPSA) can be calculated for each compound using ADMET predicto. In one aspect of the present invention, the standard deviation of the clogp values ​​of the compounds constituting the library is, for example, 1.2 or more, specifically 1.3 or more, more specifically 1.4 or more, and still more specifically 1.5 or more. In yet another aspect of the present invention, the variance of the tPSA values ​​of the compounds constituting the library is, for example, 20 or more, specifically 25 or more, and more specifically 30 or more.

[0130]

[0080] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of sp3 carbon atoms in their chemical structure. Here, sp3 carbon atoms mean carbon atoms in which all bonds are single bonds. In one embodiment, the median value of [(number of sp3 carbon atoms in the molecule) / number of atoms other than hydrogen in the molecule] calculated for each compound is, for example, 0.1 or more, specifically 0.15 or more, more specifically 0.2 or more, even more specifically 0.25 or more, and most specifically 0.3 or more.

[0131]

[0081] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of oxygen atoms contained in their chemical structure. Here, oxygen atoms mean all oxygen atoms contained in the chemical structure of the compound, and include oxygen atoms contained in hydroxyl groups, ether structures, carbonyl groups, etc. In one embodiment, the number of oxygen atoms contained in the chemical structure of each compound is, for example, in the range of 0 to 30, specifically 2 to 20, and more specifically 2 to 18. In another embodiment, the value of [(number of oxygen atoms contained in the molecule) / number of atoms other than hydrogen contained in the molecule] calculated for each compound is, for example, in the range of 0 to 0.20, specifically 0.01 to 0.20, more specifically 0.03 to 0.17, and even more specifically 0.06 to 0.14.

[0132]

[0082] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of nitrogen atoms contained in their chemical structure. Here, nitrogen atoms mean all nitrogen atoms contained in the chemical structure of the compound, and include nitrogen atoms contained in amino groups, intraring nitrogen atoms such as pyridine rings, amide groups, imino groups, etc. In one embodiment, the number of nitrogen atoms contained in the chemical structure of each compound is, for example, in the range of 0 to 40, specifically 2 to 27, and more specifically 2 to 24. In another embodiment, the value of [(number of nitrogen atoms contained in the molecule) / number of atoms other than hydrogen contained in the molecule] calculated for each compound is, for example, in the range of 0 to 0.2, specifically 0 to 0.18, and more specifically 0.05 to 0.18.

[0133]

[0083] In one embodiment, the total number of oxygen and nitrogen atoms contained in the chemical structure of each compound is, for example, in the range of 1 to 70, specifically 2 to 60, and more specifically 2 to 40. In another embodiment, the value of [(number of oxygen and nitrogen atoms contained in the molecule) / number of atoms other than hydrogen contained in the molecule] calculated for each compound is, for example, in the range of 0.01 to 0.35, specifically 0.02 to 0.3, and more specifically 0.01 to 0.27.

[0134]

[0084] In one embodiment, the total number of atoms other than carbon and hydrogen atoms in the chemical structure of each compound is, for example, in the range of 1 to 85, specifically 2 to 56, and more specifically 3 to 50. In another embodiment, the value of [(number of atoms other than carbon and hydrogen atoms in the molecule) / number of atoms other than hydrogen in the molecule] calculated for each compound is, for example, in the range of 0.05 to 0.45, specifically 0.05 to 0.4, and more specifically 0.1 to 0.4.

[0135]

[0085] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of basic nitrogen atoms contained in their chemical structure. Here, basic nitrogen atoms refer to nitrogen atoms contained in a basic compound such that the pKb of the compound in water is, for example, 14 or less, more specifically 13.5 or less, and more specifically 13 or less. In one embodiment, the number of basic nitrogen atoms in the compounds constituting the library is, for example, in the range of 0 to 30, more specifically 0 to 20, and more specifically 0 to 18.

[0136]

[0086] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of hydrogen bond-donating groups contained in their chemical structure. Here, a hydrogen bond-donating group is a group that has a hydrogen atom bonded by a covalent bond and can produce a non-covalent attractive interaction with a lone pair of electrons such as nitrogen, oxygen, sulfur, fluorine, or a π-electron system located nearby. The hydrogen atom of the group is not particularly limited as long as the electronegativity of the atom to which it is bonded is higher than that of the hydrogen atom, for example, a group having a hydrogen atom bonded to an atom such as an oxygen atom, nitrogen atom, sulfur atom, or phosphorus atom. In one embodiment, the number of hydrogen bond-donating groups in the compounds constituting the library is, for example, in the range of 0 to 20, specifically 0 to 15, and more specifically 0 to 10. In another embodiment, the difference between the compound with the most hydrogen bond-donating groups and the compound with the fewest is, for example, 1 or more, specifically 2 or more, and more specifically 3 or more.

[0137]

[0087] In one aspect of the present invention, the compounds constituting the library can be characterized by the number of hydrogen bond accepting groups contained in their chemical structure. Here, a hydrogen bond accepting group is a group having a lone pair of electrons, such as nitrogen, oxygen, sulfur, fluorine, or a π-electron system, which can produce a non-covalent attractive interaction with a nearby covalently bonded hydrogen atom. The lone pair of electrons possessed by the group is not particularly limited as long as it is a group that can exist stably, and examples include carbonyl groups such as ketone groups, ester groups, or amide groups, ether groups, amino groups, imino groups, cyano groups, sulfoxide groups, and sulfone groups. In one embodiment, the number of hydrogen bond accepting groups in the compounds constituting the library is, for example, in the range of 0 to 40, specifically 0 to 30, and more specifically 0 to 20. In another embodiment, the difference between the compound with the most hydrogen bond donating groups and the compound with the fewest is, for example, 1 or more, specifically 2 or more, and more specifically 3 or more.

[0138]

[0088] In one aspect of the present invention, the compounds constituting the library have a chemical structure in which a first core block (first CB), a first linker (first L), and a second core block (second CB) are covalently linked, as shown in the following formula: (1st CB) - (1st L) - (2nd CB) It is represented by and is characterized by sharing the above chemical structure. Here, the first CB and the second CB are any chemical structure containing at least one atom, and are not particularly limited as long as they are substructures of the compound. The first CB and the second CB may be any chemical structure as long as they form a compound different from the other compounds constituting the library, for example, the first CB and the second CB may have the same chemical structure. The first CB and the second CB may also contain as substitutions the chemical structures identified as the third core block (third CB) and / or the fourth core block (fourth CB) as described later. Here, the first L is not particularly limited as long as it is any chemical structure linking the first CB and the second CB, for example, it may be a direct bond (single bond, double bond, triple bond).

[0139]

[0089] In one aspect of the present invention, the compounds constituting the library have the following structure in which a first CB, a first L, a second CB, a second linker (second L), and a third core block (third CB) are covalently linked: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) The compound is characterized by containing the following. Here, the first CB, first L, and second CB have already been described. The third CB is any chemical structure containing at least one atom, and is not particularly limited as long as it is a substructure of the compound. The third CB may be any chemical structure as long as it forms a compound different from the other compounds constituting the library, for example, it may be the same chemical structure as the first CB and / or the second CB. The first CB, second CB, and third CB may also contain as substitution the chemical structure identified as the fourth core block (fourth CB) as described later. Here, the second L is not particularly limited as long as it is any chemical structure linking the second CB and the third CB, for example, it may be a direct bond (single bond, double bond, triple bond).

[0140]

[0090] In one aspect of the present invention, the compounds constituting the library have the following structure in which a first CB, a first L, a second CB, a second L, a third CB, a third linker (third L), and a fourth core block (fourth CB) are covalently linked: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) - (3rd L) - (4th CB); or (1st CB) - (1st L) - (2nd CB) (- (3rd L) - (4th CB)) - (2nd L) - (3rd CB); It is characterized by containing the above. In the second of the above formulas, -(1st L)-(1st CB), -(2nd L)-(3rd CB), and -(3rd L)-(4th CB) all mean that they are linked to the 2nd CB. In one embodiment, the compounds represented by the above two formulas are included in the range of compounds represented by (1st CB)-(1st L)-(2nd CB) above.

[0141]

[0091] Here, the first CB, first L, second CB, second L, and third CB have already been described. The fourth CB is any chemical structure containing at least one atom, and is not particularly limited as long as it is a substructure of the compound. The third CB may be any chemical structure as long as it forms a compound different from the other compounds constituting the library, for example, it may be the same chemical structure as the first CB and / or the second CB. The first CB, second CB, and third CB may also contain as substitution the chemical structure identified as the fourth core block (fourth CB) as described later. Here, the second L is not particularly limited as long as it is any chemical structure linking the second CB and the third CB, for example, it may be a direct bond (single bond, double bond, triple bond).

[0142]

[0092] In one embodiment, the following formula is added to one mixture: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) - (3rd L) - (4th CB); and (1st CB) - (1st L) - (2nd CB) (- (3rd L) - (4th CB)) - (2nd L) - (3rd CB); The compound is represented by the following formula. In another embodiment, a mixture contains the following: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) - (3rd L) - (4th CB); or (1st CB) - (1st L) - (2nd CB) (- (3rd L) - (4th CB)) - (2nd L) - (3rd CB); The compound is represented by one of the following: In another embodiment, a mixture contains a compound represented by the following formula: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) - (3rd L) - (4th CB); It includes compounds represented by [the formula shown].

[0143]

[0093] The first CB, second CB, third CB, and fourth CB may further have a fifth core block (-(4L)-(5CB)) linked via a fourth linker. In a compound having the group -(4L)-(5CB), the fourth L and fifth CB may have the chemical structures specified herein as first L, second L, and third L, and first CB, second CB, third CB, and fourth CB, respectively. The compound may further have a sixth core block (-(5L)-(6CB)) linked via a fifth linker. Compounds having the groups -(4L)-(5CB) and -(5L)-(6CB) can be synthesized by sequentially introducing each of the groups according to the method described herein.

[0144]

[0094] In one embodiment of the present invention, the compounds constituting the library are characterized in that they do not contain a tag for decoding. The tag for decoding is not particularly limited as long as it can be used to identify the structure of the compound, and examples include oligonucleotide tags. A DNA-encoded library (DEL) is known as a library having a tag for decoding. In one embodiment, the library of the present invention does not contain a library encoded by oligonucleotides, such as DEL.

[0145]

[0095] In one aspect of the present invention, linkers contained in the compound, for example, 1L, 2L, and 3L, include structures independently selected from the group consisting of amides, sulfonamides, acylsulfonamides, aminos, ethers, thioethers, esters, ketones, sulfones, single bonds, ethyne-1,2-diyl (-C≡C-), and nitrogen-containing 5-membered heteroarylenes. In one embodiment, 1L, 2L, and 3L are independently, -C(=O)-NR 1 - -NR 1 -C(=O)- -SO2-NR 1 - -NR 1 -SO2- -SO2-NR 1 -C(=O)- -C(=O)-NR 1 -SO2- -NR 1 - -O- -S- -C(=O)-O- -OC(=O)- -C(=O)- -SO2- -C≡C- -CHR 2 - single bond

[0146] [ka]

[0147] [In the formula, R 1 and R 2 These are, independently, hydrogen atoms, or C 1-6 It is alkyl. It is represented by an equation selected from the following. Here, a single bond is either a carbon-nitrogen single bond or a carbon-carbon single bond.

[0148]

[0096] In one aspect of the present invention, the linker described above is derived from a chemical structure resulting from covalently linking two core blocks selected from each core block, for example, 1st CB, 2nd CB, 3rd CB, and 4th CB, by a reaction involving reactive functional groups. In one embodiment, 1L, 2L, and 3L are formed by a reaction independently selected from the group consisting of amidation, sulfonamidation, acylsulfonamidation, reductive amination, etherification, thioetherification, esterification, O-alkylation, N-alkylation, ketone bond formation reactions, carbon-nitrogen bond formation reactions, carbon-carbon bond formation reactions, and nitrogen-containing 5-membered heteroarylene cyclization. Here, the carbon-nitrogen bond formation reaction is, for example, an aromatic nucleophilic substitution reaction and / or a Buchwald-Hartwig coupling, and the carbon-carbon bond formation reaction is, for example, a Suzuki coupling, a Negishi coupling, a Stile coupling, and / or a Sonogashira coupling.

[0149]

[0097] In one aspect of the present invention, the compounds constituting the library are compounds comprising 1CB to 3CB and 1L and 2L, and at least one, at least two, or all of the compounds selected from the group consisting of 1CB, 2CB, and 3CB are characterized in that the total number of carbon atoms, nitrogen atoms, and oxygen atoms is 2 to 17, 3 to 16, 4 to 15, 5 to 14, or 6 to 13, respectively. In one aspect of the present invention, all compounds constituting the library satisfy the above conditions.

[0150]

[0098] In one aspect of the present invention, the compounds constituting the library are compounds comprising 1CB to 3CB and 1L and 2L, and at least one, at least two, or all of the compounds selected from the group consisting of 1CB, 2CB, and 3CB are characterized in that the total number of carbon atoms, nitrogen atoms, and oxygen atoms is 1 or more and 18 or less, respectively. In one aspect of the present invention, all compounds constituting the library satisfy the above condition.

[0151]

[0099] In one embodiment of the present invention, the compounds constituting the library are compounds comprising 1CB to 3CB and 1L and 2L, and at least one, at least two, or all of the compounds selected from the group consisting of 1CB, 2CB, and 3CB contain at least one or two cyclic structures. In one embodiment of the present invention, all compounds constituting the library satisfy the above condition.

[0152]

[0100] In one aspect of the present invention, the compounds constituting the library are compounds comprising 1CB to 4CB and 1L to 3L, characterized in that at least one, at least two, at least three or all of 1CB, 2CB, 3CB, and 4CB have a total number of carbon atoms, nitrogen atoms, and oxygen atoms of 2 to 17, 3 to 16, 4 to 15, 5 to 14, or 6 to 13, respectively. In one aspect of the present invention, all compounds constituting the library satisfy the above conditions.

[0153]

[0101] In one aspect of the present invention, the compounds constituting the library are compounds comprising 1CB to 4CB and 1L to 3L, characterized in that at least one, at least two, at least three or all of 1CB, 2CB, 3CB, and 4CB have a total number of carbon atoms, nitrogen atoms, and oxygen atoms of 1 to 18 each. In one aspect of the present invention, all compounds constituting the library satisfy the above condition.

[0154]

[0102] In one aspect of the present invention, the compounds constituting the library are compounds comprising 1CB to 4CB and 1L to 3L, characterized in that at least one, at least two, at least three or all of 1CB, 2CB, 3CB, and 4CB contain at least one or two cyclic structures. In one aspect of the present invention, all compounds constituting the library satisfy the above condition.

[0155]

[0103] In one aspect of the present invention, 1 × 10 2 ~1 × 10 8 A library comprising the compound, wherein the library comprises two or more types of first CB, two or more types of first L, and two or more types of second CB; two or more types of first CB, two or more types of first L, two or more types of second CB, two or more types of second L, and two or more types of third CB; or two or more types of first CB, two or more types of first L, two or more types of second CB, two or more types of second L, two or more types of third CB, two or more types of third L, and two or more types of fourth CB. In one aspect of the present invention, the total number of types of first L, second L, and third L is 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more. In another aspect of the present invention, the total number of types of first L, second L, and third L is 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 20, or 8 to 15.

[0156]

[0104] In one aspect, the present invention provides the following: 1 x 10 2 ~1 × 10 8 A library containing the compound, the compound comprising the library has the following structure in which the first CB, first L, second CB, second L, and third CB are covalently linked: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) It includes, and the total number of types of 1st L and 2nd L is 3 or more, and the total number of types of 1st CB, 2nd CB, and 3rd CB is 6 or more, and 1 × 10 2 ~1 × 10 5 The library is composed of one or more mixtures containing the aforementioned compounds, wherein 90% or more of the compounds constituting the library are detected by retention time and mass-to-charge ratio (m / z) in a liquid chromatograph-mass spectrometer (LC-MS).

[0157]

[0105] In one aspect, the present invention provides the following: 1 x 10 2 ~1 × 10 4A library containing the compound, the compound comprising the library has the following structure in which the 1st CB, 1st L, 2nd CB, 2nd L, 3rd CB, 3rd L, and 4th CB are covalently linked: (1st CB) - (1st L) - (2nd CB) - (2nd L) - (3rd CB) - (3rd L) - (4th CB) It includes, and the total number of types of 1st L, 2nd L, and 3rd L is 5 or more, and the total number of types of 1st CB, 2nd CB, 3rd CB, and 4th CB is 8 or more, and 1 × 10 2 ~5×10 3 The library is composed of one or more mixtures containing the aforementioned compounds, wherein 95% or more of the compounds constituting the library are detected by retention time and mass-to-charge ratio (m / z) in a liquid chromatograph-mass spectrometer (LC-MS).

[0158]

[0106] Two or more of the above libraries may be prepared, and these may be combined to form a library assembly. That is, in one aspect of the present invention, a library assembly is provided which is prepared by combining two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twenty or more, thirty or more, forty or more, fifty or more, or one hundred or more libraries. In one aspect, the library assembly may contain, for example, 200 or more, 300 or more, 400 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 2000 or more, 4000 or more, 100000 or more, or 100000 or more compounds. In one aspect of the present invention, the individual libraries constituting the above library assembly may be mixtures of compounds.

[0159]

[0107] Screening can be performed using the library described herein. That is, in one aspect of the present invention, a method is provided for screening compounds that bind to a target molecule, the method (1) To provide the library described herein; (2) Contacting each of the one or more mixtures constituting the library with a target molecule; (3) Identifying compounds that bind to the target molecule. It is characterized by including.

[0160]

[0108] Here, the target molecule is not particularly limited as long as it is a molecule that can be targeted in drug discovery, for example, proteins, nucleic acids, polypeptides, glycans, etc. Specifically, examples include enzymes, G protein-coupled receptors, ion channels, transporters, nuclear receptors, etc. Specific examples of target molecules include Bcl-2, IL-6, A2aR, NMDA-type glutamate receptors, estrogen receptors, etc.

[0161]

[0109] The method for identifying compounds that bind to target molecules is not particularly limited as long as it is a method known to those skilled in the art in the field to which the present invention belongs, but it is preferable that the method is capable of identifying the chemical structure of the compounds that bind to the target molecule. Examples include methods using AS-MS (Affinity Selection Mass Spectrometry), methods using SPR (Surface Plasmon Resonance), methods using X-ray crystal structure analysis, and methods using cryo-electron microscopy, with a preferred example being the method using AS-MS. The method using AS-MS can be carried out, for example, by the method described in Current Opinion in Chemical Biology 2007, 11:518-526, and can be carried out using, for example, a 96-well MacroSpin column, P-2 Material (Harvard, 74-5655), Panquish UHPLC (Thermo Fisher Scientific), etc.

[0162]

[0110] Examples of the number of compounds contained in the mixture include 100-50000, 100-10000, 200-5000, 400-3000, or 600-1500. The number of mixtures to be screened is not particularly limited and may be just one mixture. Examples of lower limits include 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, or 100 or more. Examples of upper limits include 100000 or less, 50000 or less, 20000 or less, 10000 or less, 5000 or less, 3000 or less, 2000 or less, or 1000 or less. For example, screening may be performed on each of the mixtures with 1-5000, 1-3000, 2-2000, or 2-1500 compounds.

[0163]

[0111] In one aspect of the present invention, a method for manufacturing a library, wherein (a)na types of first building block introduction reagents (first BB introduction reagents) are used to introduce a support carrier (first BB) to which the first BBs are covalently linked. 1-na (b) Prepare a support carrier, (b) 1st BB 1-na (e) preparing a mixture of supporters that share a common reactive functional group, reacting each mixture with one type of second building block introduction reagent (second BB introduction reagent) or a mixture of two or more types of second BB introduction reagents to prepare a supporter in which nb types of second BBs are covalently linked to the first BB (second BB-first BB supporter), and (e) cleaving the compound from the solid support, and the second BB 1-nb -1st BB 1-na Compounds represented by can be obtained as a mixture of some or all of them, and a library can be constructed using these compounds. 2nd BB 1-nb -1st BB 1-na The compound represented by na is a first BB support carrier introduction reagent (first BB 1-na (Introduction reagent) and nb type second BB introduction reagent (second BB 1-nb This includes a group of compounds comprising up to Na × nb elements or a portion thereof, produced from a supported carrier introduction reagent, and a group of compounds obtained by further modifying said group.

[0164]

[0112] Here, na is an integer greater than or equal to 2, 3, 4, or 5, and nb is an integer greater than or equal to 2, 3, 4, or 5. The resulting compound library may contain a mixture of 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more compounds.

[0165]

[0113] Regarding (a) above, the first BB support carrier is a first building block of type na (first BB 1-na ) a solid-phase carrier (1st BB) that supports 1-na (Carrier) and the first BB 1-na First BB of the support carrier 1-na Each portion has a reactive functional group for forming a bond with the second building block (second BB). First BB 1-na The reactive functional groups contained in the support are one type, two or more types, or three or more types. (First BB) 1-na The support carrier is the 1st BB1 introduction reagent ~ 1st BB na Each of the introduction reagents is used to react the solid support with one type of first BB introduction reagent, and the first BB1 supported support ~ first BB na Each of the supporting carriers is obtained as one type of first BB supporting carrier, and these are used to make a mixture of the first BB supporting carriers (first BB 1-na A support carrier can be obtained. Alternatively, a mixture of the first BB introduction reagent (for example, the first BB 1-na The mixture of introducing reagents is reacted with a solid support to obtain the first BB 1-na A mixture of the support carriers can be used in (b). In one embodiment, a mixture of a portion of the first BB introduction reagent can be used to introduce the first BB 1-na It may also be obtained as a mixture of some of the supporting materials, and can be selected based on the type of reactive functional group of the first BB introduction reagent included in the mixture.

[0166]

[0114] Regarding (b) above, the carrier obtained here is nb types of second building blocks (2nd BB1 to 2nd BB nb ) including the carrier (2nd BB 1-nb -1st BB 1-na(Supporting carrier) and 2BB1 introduction reagent ~ 2BB nb If any of the induction reagents are in the first bar 1-na It reacts with each reactive functional group of the support to form the first linker (first L).

[0167]

[0115] The solid support that can be used in the method for manufacturing the library described herein is not particularly limited as long as it is a commonly used one. Examples include CTC resin, Trt resin, SASRIN resin, Rink amide resin, Merrifield resin, Wang resin, 2-(4-bromomethylphenoxy)ethyl polystyrene, as well as solid supports having any functional group such as a carboxyl group, amino group, aminomethyl group, hydroxyl group, or hydroxymethyl group on the polystyrene. Furthermore, any linker can be used to covalently connect the support and the first BB, and the design may allow for cleavage between the linker and the first BB. The support is not particularly limited, but in addition to polystyrene, examples include PEG (polyethylene glycol).

[0168]

[0116] The conditions for the reaction between the first BB and the solid support can be appropriately set by a person skilled in the art based on methods described in public literature, etc. Regarding (e) above, the reaction conditions for cleaving the compound from the solid support can be appropriately set by those skilled in the art based on the chemical structure of the solid support used. Reagents used for cleavage include, for example, hydrochloric acid, carboxylic acids such as trifluoroacetic acid (TFA), fluoroalcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP), as well as Brønsted acids with a pKa of 10 or less in water, or any Lewis acid. In one embodiment, the compound cleaved from the solid support is obtained as a mixture.

[0169]

[0117] In one aspect of the present invention, a method for manufacturing a library, comprising (a), (b), and (e), wherein the second BB 1-nb -1st BB1-na Each support has a reactive functional group capable of linking with the third building block (third BB), and each first BB 1-na Part or Second BB 1-nb The reactive functional group contained in the portion is one type, two or more types, or three or more types, and furthermore (c) second BB 1-nb -1st BB 1-na A method is provided which involves preparing a mixture of support carriers that share a common reactive functional group, and reacting each mixture with one type of third building block introduction reagent (third BB introduction reagent) or a mixture of two or more types of third BB introduction reagents to prepare a support carrier in which the third BB is covalently linked to the first BB or second BB (third BB-second BB-first BB support carrier, or second BB-(third BB-)first BB support carrier).

[0170]

[0118] Here, regarding (c), the resulting support carrier is an nc type third building block (3BB1 to 3BB nc ) including the carrier (3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier, or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na (Supporting carrier) and 3BB1 introduction reagent ~ 3BB nc If any of the induction reagents are in BB 2 1-nb -1st BB 1-na The compounds react with each reactive functional group of the support to form a second linker (second L). Here, nc is an integer of 2 or greater, 3 or greater, 4 or greater, or 5 or greater, and the compounds in the library have two or more types of first or second linkers.

[0171]

[0119] (c) in the second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na The support carrier is the 3rd BB 1-nc The part goes through the second linker to the first BB 1-na It has a structure that is linked to a portion, for example, a reactive functional group protected by a protecting group is the first BB1-na It exists in the second BB 1-nb After introducing the part, the protection of the unit is removed, and the 3rd BB 1-nc The reactive functional group of the introduction reagent can be introduced by forming a second linker. In one embodiment, the support obtained in (c) is a third BB 1-nc -2nd BB 1-nb -1st BB 1-na It is a support carrier, and the second BB 1-nb -1st BB 1-na Second BB of the support carrier 1-nb Each portion has one reactive functional group for forming a bond with the third building block (third BB).

[0172]

[0120] In one aspect of the present invention, a method for manufacturing a library, comprising (a), (b), (c), and (e), wherein the third BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na Each support has a reactive functional group for forming a bond with the fourth building block (fourth BB), and each first BB 1-na Part, 2nd BB 1-nb Part, or the 3rd BB 1-nc The reactive functional group contained in the portion is one type, two or more types, or three or more types, and furthermore (d) the third BB 1-nc -2nd BB 1-na -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na A method is provided which involves preparing a mixture of support carriers that share a common reactive functional group, and reacting each mixture with one type of fourth building block introduction reagent (fourth BB introduction reagent) or a mixture of two or more types of fourth BB introduction reagents to prepare a support carrier in which the fourth BB is covalently linked to the third BB, second BB, or first BB.

[0173]

[0121] Here, the carrier obtained in (e) is a fourth building block of type nd (4BB1 to 4BB nd ) is a carrier containing the 4th BB1 introduction reagent ~ 4th BB nd If any of the induction reagents are in the 3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Supporting carrier or second BB 1-nb -(3rd BB 1-nc -)1st BB 1-na The fourth linker (BB) is introduced by reacting with each reactive functional group of the support to form a third linker. The reactive functional groups that form the third linker and the fourth linker introduction reagent may have protecting groups, in which case deprotection is performed before the reaction with the fourth linker introduction reagent. Here, nd is an integer of 2 or greater, 3 or greater, 4 or greater, or 5 or greater, and the compounds in the library have two or more types of first, second, or third linkers.

[0174] The carrier obtained in (d) is 4th BB 1-nd -3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na Carrier; support; 4th BB 1-nd -(3rd BB 1-nc -) 2nd BB 1-nb -1st BB 1-na Carrier; support; 3rd BB 1-nc -2nd BB 1-nb -(4th BB) 1-nd -)1st BB 1-na Carrier; support; 4th BB 1-nd -3rd BB 1-nc -(2nd BB) 1-nb -)1st BB 1-na Carrier; or 4th BB 1-nd -2nd BB 1-nb -(3rd BB 1-nc -)1st BB 1-na Carrier In one embodiment, the support obtained in (d) may be a mixture of two or more support units represented by the above formula. In one embodiment, the support obtained in (d) is the 4th BB 1-nd -3rd BB 1-nc -2nd BB 1-nb -1st BB 1-na It is a carrier or support.

[0175]

[0122] In one aspect of the library manufacturing method of the present invention, the first linker and the second linker are 1-1) The first linker consists of two or more types, three or more types, or four or more types; 1-2) The second linker is of two or more types, three or more types, or four or more types; and 1-3) The first or second linker consists of three or more types, four or more types, or five or more types; It is characterized by satisfying one or more of the following conditions. In another aspect, the first linker, the second linker and the third linker are 2-1) The first linker consists of two or more types, three or more types, or four or more types; 2-2) The second linker consists of two or more types, three or more types, or four or more types; 2-3) There are two or more types of third linkers, three or more types, or four or more types; and 2-4) The first linker, second linker, or third linker consists of three or more types, four or more types, or five or more types; It is characterized by satisfying one or more of the following conditions.

[0176]

[0123] In one embodiment of the present invention, na is an integer between 2 and 1000, nb is an integer between 2 and 1000, and either na or nb is an integer of 3 or more. In one embodiment of the present invention, na is an integer between 2 and 1000, nb is an integer between 2 and 1000, nc is an integer between 2 and 1000, and either na, nb, or nc is an integer of 3 or more.

[0177] The method according to any of [C1] to [C33], wherein the resulting library contains 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more compounds. In one aspect of the present invention, the number of compounds contained in a library obtained by the library synthesis method can be exemplified with upper limits of 800 or less, 1000 or less, 1200 or less, 1500 or less, 1700 or less, 2000 or less, 2500 or less, 3000 or less, 4000 or less, 5000 or less, 6000 or less, 7000 or less, 8000 or less, 10000 or less, 20000 or less, 50000 or less, or 100000 or less, and with lower limits of 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or 1000 or more.

[0178]

[0124] In one aspect of the present invention, the library synthesis method may further include a deprotection and / or protection step of the reactive functional group. In one embodiment, after the deprotection step of the reactive functional group, impurities can be removed from the support by washing with a solution mixed with an acidic component. As the acidic component, an acidic compound having a pKa of 0 to 10 in water can be used. Examples of the acidic component include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ethyl (hydroxyimino)cyanoethyl acetate (Oxyma), and 4-nitrophenol. The functional group produced by the deprotection step of the reactive functional group is not particularly limited as long as it is a group having appropriate reactivity, and may be, for example, a carboxyl or a hydroxyl substituted on an aromatic ring.

[0179]

[0125] In one aspect of the present invention, the library synthesis method may further include a step of linking two crosslinkable groups present in the molecule to obtain a cyclic compound. The cyclization step can be performed, for example, after the compound has been cleaved from the solid support. Alternatively, it can be performed on the solid support before cleavage (also called cyclization on resin or cyclization on resin). Examples of the two crosslinkable groups present in the molecule include a combination of a carboxyl group and an amino group, a combination of a carboxyl group and a hydroxyl group, a combination of an acetylene group and an azide group, a combination of alkenes in which any substituent is substituted at any position, and a combination of thiol groups. In one embodiment, the cyclization step can be performed using a mixture of the obtained compounds as a substrate after the compound has been cleaved from the solid support.

[0180]

[0126] In one aspect of the present invention, the library synthesis method may further include modifying (or sometimes referred to as derivatizing) the functional groups contained in the compounds in the obtained library. The functional groups to be modified are not particularly limited, but examples include hydroxyl groups, carboxyl groups, amino groups, etc. Examples of functional groups obtained by modification include ethers, amides, esters, sulfonamides, acylsulfonamides, etc. The steps required for modifying the functional groups may be a single step or multiple steps. In one embodiment, the functional group is a functional group produced by cleaving a compound from a solid support, and an example of the modification is a hydroxyl or carboxyl C 1-6 Alkylation is one example.

[0181]

[0127] While a 100% conversion rate is preferred for the reaction between the building block introducing reagent and the reactive functional group, reactions that do not necessarily reach 100% are also conceivable. In one embodiment of the present invention, in (b) above, in a first BB support where the conversion rate of the reaction between the second BB introducing reagent and the reactive functional group of the first BB is less than 100%, the present invention further includes reacting a different second BB introducing reagent with higher reactivity with the remaining reactive functional group of the first BB. In another embodiment of the present invention, in (c) above, in a second BB-first BB support where the conversion rate of the reaction between the third BB introducing reagent and the reactive functional group is less than 100%, the present invention further includes reacting a different third BB introducing reagent with higher reactivity with the remaining reactive functional group. In yet another embodiment of the present invention, in (d) above, in a third BB-second BB-first BB support or second BB-(third BB-)first BB support where the conversion rate of the reaction between the fourth BB introducing reagent and the reactive functional group is less than 100%, the present invention further includes reacting a different fourth BB introducing reagent with a higher reactivity with the remaining reactive functional group.

[0182]

[0128] In one aspect of the present invention, one or more compounds in the library, for example all of the compounds, may or may not contain a UV tag. If one or more compounds in the library, for example all of the compounds, contain a UV tag, the UV tag may be, for example, formula 1:

[0183] [ka]

[0184] [In the formula, ring A is selected from benzene, naphthalene, anthracene, and biphenyl; The benzene, the naphthalene, the anthracene, and the biphenyl are halogen atoms, nitro, cyano, carboxy, sulfoxy, -COR 1 , -OR 1 , -NR 1 R 2 ,-CONR 1 R 2 , or -SO2NR 1 R2 It may be substituted with one to three identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (It may form a heterocycle with an alkyl or a linked nitrogen atom, and X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O- that is bonded to the building block.) The group of the structure represented by can be introduced into the compound.

[0185]

[0129] As a UV tag, use formula 2 or formula 3:

[0186] [ka]

[0187] (In the formula, X is a divalent group selected from the group consisting of -CONH-, -NHCO-, -CH2O- and -O-, which is bonded to the building block, and Y and Z are hydrogen atoms, halogens, nitro, cyano, carboxy, sulfoxyl, -COR 1 , -OR 1 , -NR 1 R 2 ,-CONR 1 R 2 , or -SO2NR 1 R 2 It may be substituted with one to three identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (An alkyl group or two of them together may form a heterocycle.) A group of the structure represented by may be introduced into the compound.

[0188]

[0130] In one embodiment, as a UV tag, Equation 3:

[0189] [ka]

[0190] (In the formula, X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O- that is bonded to the building block, and Y and Z represent hydrogen atoms, halogen atoms, nitro, cyano, carboxy, sulfoxyl, -COR 1 , -OR 1 , -NR 1 R 2 , -CO-NR 1 R 2 , or -SO2-NR 1 R 2 It may also be substituted with 1 to 3 identical or different groups selected from the group consisting of R 1 and R 2 Each is independently C 1-6 (An alkyl group or two of them together may form a heterocycle.) A group of the structure represented by may be introduced into the compound.

[0191]

[0131] In one embodiment, the UV tag is given by formula 4:

[0192] [ka]

[0193] (In the formula, X represents one selected from the group consisting of -CONH-, -NHCO-, -CH2O-, and -O-, and is bonded to the building block, R 1 and R 2 Each is independently C 1-6 (They may form heterocycles together with alkyl groups or the nitrogen atoms to which they are linked.) A group of the structure represented by may be introduced into the compound.

[0194]

[0132] In one embodiment of the present invention, the compounds included in the library are characterized in that they do not include either a UV tag or an oligonucleotide tag, or neither.

[0195] In one aspect of the present invention, the compounds constituting the library include UV tags, which can be used for the analysis of intermediate compounds in the solid-phase synthesis of the compounds. In one embodiment, the method for producing the library further includes: 1) A step to obtain a support carrier obtained in any of the steps; 2) A step of cleaving the intermediate compound from the support obtained in step 1); and 3) A step of analyzing the intermediate compound; In addition, optionally, a step of analyzing the compound excised in step (e), This includes the analysis of intermediate compounds. The results obtained from the analysis of intermediate compounds can be used to optimize the reaction conditions of solid-phase reactions, thereby enabling the production of high-quality libraries. In one embodiment, the analysis can be performed using a liquid chromatogram.

[0196]

[0133] In one aspect of the present invention, the first, second, third, and fourth linkers formed in the method for producing the library are exemplified by chemical structures formed by reactions independently selected from the group consisting of amidation, sulfonamidation, acylsulfonamidation, reductive amination, etherification, thioetherification, esterification, O-alkylation, N-alkylation, carbon-nitrogen bond formation reactions, carbon-carbon bond formation reactions, and nitrogen-containing five-membered heteroarylene formation reactions. In one embodiment, the first, second, third, and fourth linkers include structures independently selected from the group consisting of amides, sulfonamides, acylsulfonamides, aminos, ethers, thioethers, esters, ketones, sulfones, single bonds, ethyne-1,2-diyl (-C≡C-), and nitrogen-containing five-membered heteroarylenes.

[0197]

[0134] In one aspect of the present invention, the method for manufacturing the library can be used for manufacturing the library described in any of [A1] to [A23]. In one embodiment, the first linker, second linker, third linker and fourth linker formed in the method for manufacturing the library correspond to the first linker, second linker, third linker and fourth linker formed in the method for manufacturing the library as defined above, for example, the product obtained by cleaving a compound from a 3BB-2BB-1BB support or a 2BB-(3BB-)1BB support corresponds to (1CB)-(1L)-(2CB)-(2L)-(3CB) or (3CB)-(2L)-(1CB)-(1L)-(2CB).

[0198]

[0135] The following is an example of a method for forming the linker that connects the core blocks. However, the method and structure are not limited to those described. Reagents (bases, coupling agents, catalysts, ligands, etc.) may be used individually, or multiple reagents having the same function may be used in combination simultaneously (for example, DIPEA and potassium phosphate as bases). The equivalent amounts of reagents shown below represent how many times more moles of the reagent are used relative to the total number of moles of functional groups used for linker formation in each compound of the solid-phase mixture. For example, if it is written as 10 equivalents, it means that 10 times the number of moles of the reagent are used relative to the total number of moles of functional groups used for linker formation in each compound of the solid-phase mixture. Unless otherwise specified, if the reaction conditions are described for the case where A contains a solid-phase support, the same reaction conditions (type of reagent, type of solvent, reaction temperature, reaction time, etc.) can be used for the case where B contains a solid-phase support. In this case, the equivalent amount of the substrate on the liquid phase side can be appropriately set by those skilled in the art, for example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the substrate on the solid phase side.

[0199]

[0136] Unless otherwise specified, the reaction time can be set as appropriate by those skilled in the art. For example, the reaction time can be determined or confirmed by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by some method to predict the time based on the study results, or by cutting off part of the product from the solid support.

[0200]

[0137] In the following formula, A and B each represent core blocks to which reactive functional groups are linked, and each core block may be further linked to another core block via a linker. In addition, either A or B contains a solid support.

[0201]

[0138]

[0202] [ka]

[0203] [In the formula, R1 is a hydrogen atom, or C which may have substituents] 1-6 It is alkyl and may form a ring with the bonded nitrogen atom and B. The amide bond, acting as a linker, can be formed by the reaction of a carboxylic acid or its derivative with an amine.

[0204]

[0139] In the above formula, if A includes a solid support, the reactive functional group X linked to A is a hydroxyl or halogen atom. If X is hydroxyl, an amide bond as a linker can be formed by using a condensing agent and reacting it with an amine containing an amino group linked to B. Here, the condensing agent is not particularly limited as long as it is commonly available, but for example, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1,1'-carbonyldi(1,2,4-triazole), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium Hexafluorophosphate, (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, [ethylcyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate, 2-chloro-4,5-dihydro-1,3-dimethyl-1H-hexafluorophosphate imidazolium, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate, isobutyl chlorocarbonate, triphosgene, diphenyl phosphate azide, propylphosphonic anhydride, cyanurate chloride, 2-chloro-4,6-Dimethoxytriazine 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, trifluoromethanesulfonic acid (4,6-dimethoxy-1,3,5-triazine-2-yl)-(2-octoxy-2-oxoethyl)dimethylammonium, 2-methyl-6-nitrobenzoic anhydride, 2-chloro-1-methylpyridinium iodide, 2-fluoro-1-methylpyridinium p-toluenesulfonate, N-ethynyl-N,4-dimethylbenzenesulfonylformamide, 1-chloro-N,N,2-trimethyl-1-propenylamine, etc. can be used. The equivalent amount of the condensing agent used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the carboxylic acid containing A. The number of equivalent amounts of the amine used can be appropriately determined by those skilled in the art. For example, relative to a carboxylic acid containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0205]

[0140] R1 in the above formula is as already defined. Preferred examples of R1 include a hydrogen atom and a C atom which may have substituents. 1-6 Examples of aromatic rings that may have substituents, such as alkyl, methyl, and ethyl, include benzene and ethylpyridine.

[0206]

[0141] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Lumorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isopropyl acetate) In addition to butyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, limonene, etc. can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, -20 to 200°C, 0 to 150°C, 0 to 100°C, 0 to 80°C, or 10 to 80°C. A base may be used if necessary, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, K2HPO. 4、 KHCO3, Na2HPO 4、 NaHCO3, sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc. can be used as bases. The number of equivalent amounts of base used can be appropriately determined by those skilled in the art. For example, for a carboxylic acid containing A, the amount can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The reaction time can be appropriately determined by those skilled in the art. The reaction time can be determined or confirmed by the reaction time required in a model experiment, or by excising the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by conventional workup methods.

[0207]

[0142] When X is a halogen atom, specific examples include a chlorine atom or a fluorine atom. The reaction between the acid halide and the amine may be carried out in the presence of a base, or using two or more equivalents of the amine. Suitable bases include pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, K2HPO 4、 KHCO3, Na2HPO 4、 Examples include NaHCO3, sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, and the like. The number of equivalents of the base used can be appropriately set by a person skilled in the art. For example, relative to an acid halide containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The number of equivalents of the amine used can be appropriately set by a person skilled in the art. For example, relative to an acid halide containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0208] R in the above formula 1 This is as already defined. 1 Preferred examples include hydrogen atoms, C 1-6Examples of alkyl groups include methyl and ethyl.

[0143] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Myrmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid) In addition to isobutyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, and limonene can also be used.The reaction temperature can be set as appropriate by those skilled in the art, for example, -80 to 150°C, -80 to 100°C, -80 to 80°C, -40 to 80°C, or 0 to 80°C.

[0209]

[0144] The acid halide used in the reaction may be prepared from the corresponding carboxylic acid within the reaction system. The reagents used are not particularly limited as long as they are commonly available, but for example, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, sulfuryl chloride, (chloromethylene)dimethyliminium chloride (Vilsmeier reagent), 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez reagent), chloro-N,N,N',N'-bis(tetramethylene)formamidinium tetrafluoroboric acid, PyClU, PipClU, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), and fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH) can be used. When using thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, sulfuryl chloride, etc., an amide solvent such as DMF may be present. If necessary, a base may be used, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, K2HPO 4、 KHCO3, Na2HPO 4、NaHCO3, sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc. can be used as bases.The above reaction can use any solvent, and is not particularly limited, but examples include halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Myrmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid) In addition to isobutyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, and limonene can also be used.The reaction temperature can be appropriately set by those skilled in the art, for example, -40 to 150°C, -40 to 100°C, -40 to 80°C, -20 to 80°C, or 0 to 80°C. The number of equivalents of reagents and bases used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 20 equivalents, 1 to 15 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to a carboxylic acid containing A. The number of equivalents of amines used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 20 equivalents, 1 to 15 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to a carboxylic acid containing A. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0210]

[0145] In the above formula, when B contains a solid support, the reactive functional group X linked to A is a hydroxyl or halogen atom. When X is hydroxyl, an amide bond as a linker can be formed by using a condensing agent and reacting it with an amine containing an amino group linked to B. The reagents and other reaction conditions used here are the same as when A contains a solid support. When a condensing agent is used, the equivalent amount can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. When a condensing agent is used, the equivalent amount of carboxylic acid used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. If A is an acid halide, the number of equivalents of the base used can be appropriately determined by a person skilled in the art. For example, relative to an amine containing B, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The number of equivalents of the acid halide used can be appropriately determined by a person skilled in the art. For example, relative to an amine containing B, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The reaction time can be appropriately determined by a person skilled in the art. For example, it can be the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method from the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0211]

[0146]

[0212] [ka]

[0213]

[0147] [wherein, R 1 C may have hydrogen atoms and substituents. 1-6It is alkyl and may form a ring with the bonded nitrogen atom and A. Sulfonamide bonds, which act as linkers, can be formed by the reaction of amines with sulfonyl halides or their derivatives.

[0214]

[0148] In the above formula, if A includes a solid support, the reactive functional group X linked to B is a halogen atom, such as a chlorine atom or a fluorine atom, and a sulfonamide bond as a linker can be formed by reacting it with an amine containing an amino group linked to A using a base. Here, the base is not particularly limited as long as it can be used normally, but for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, K2HPO 4、 KHCO3, Na2HPO 4、 Sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, tetrabutylammonium fluoride, cesium fluoride, sodium phosphate, lithium t-pentoxide, methyllithium, NaBHT, etc. can be used.

[0215]

[0149] The number of equivalent amounts of sulfonyl halides used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to an amine containing A. The number of equivalent amounts of bases used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to an amine containing A.

[0216]

[0150] The above reaction can use a solvent and is not particularly limited, but examples include halogenated solvents such as DCM, chloroform, DCE, and carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, and tetraglyceride; ketone solvents such as acetone, MEK, MIBK, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, and diethyl ketone; urea solvents such as TMU, DMI, and DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, and NBP; and sulfoxy solvents such as DMSO. In addition to sulfonate solvents such as diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethylsulfone, and ethyl isopropyl sulfone, ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, and methyl propionate, aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, and pyridine, carbonate solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate, as well as solvents such as acetonitrile and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used.

[0217]

[0151] The reaction temperature can be set appropriately by those skilled in the art, for example, -20 to 100°C, 0 to 60°C, or 0 to 30°C. Additives may be used if necessary, for example, NMI, DMAP, HOAt, oxyma, pentafluorophenol, pyridine N-oxide, NaI, etc. can be used as additives. The number of equivalents of additives used can be set appropriately by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing A. The reaction time can be set appropriately by those skilled in the art, for example, the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method from the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a part of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0218]

[0152] In the above formula, if B contains a solid support, the reactive functional group X linked to B is a halogen atom. X may be prepared from hydroxyl. In this case, the reagent is not particularly limited as long as it is commonly available, but for example, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosgene, etc., can be used. An amide solvent such as DMF may also be present. The reagents and other reaction conditions used here are the same as when A contains a solid support. For example, if A is an amine, the number of equivalents of the base used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonic acid halide containing B. The number of equivalents of the amine used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonic acid halide containing B. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0219]

[0153]

[0220] [ka]

[0221] [In the formula, R 2 C may have hydrogen atoms and substituents. 1-6 It is alkyl and may form a ring with the bonded nitrogen atom, sulfur atom, and B. Acyl sulfonamide bonds, which act as linkers, can be formed by the reaction of a carboxylic acid or its derivative with a sulfonamide.

[0222]

[0154] In the above formula, if A includes a solid support, the reactive functional group X linked to A is hydroxyl, and by using a condensing agent and reacting it with an amine containing an amino group linked to B, an acylsulfonamide can be formed as a linker. Here, the coupling agent is not particularly limited as long as it is one that can be used normally, but for example, a combination of a carbodiimide coupling agent such as DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and an activator such as HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), HOOBT (3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine), oxyma (cyano(hydroxyimino)ethyl acetate), HATU (O-(7-aza-1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate), HCTU (O-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TBTU (N,N,N',Uronium salt-based condensing agents such as N'-tetramethyl-O-(benzotriazole-1-yl)uronium tetrafluoroborate, COMU ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate), BOP (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, PyAOP ((7-azabenzotriazole-1-yloxy)trispirolidinophosphonium hexafluorophosphate), PyBOP (1H-benzotriazole-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate), PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate), and PyOxim ([ethylcyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium). Phosphonium salt-based condensing agents such as hexafluorophosphate, 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez reagent), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), PyCIU (N,N,N',N'-bis(tetramethylene)chloroformamidinium hexafluorophosphate), BTFFH (fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate), TFFH (fluoro-N,N,N',N'-tetramethylamidinium Formamidinium salt-based condensing agents such as hexafluorophosphate, TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), PyClU (1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate), PipClU (chlorodipiperidinocarbenium hexafluorophosphate), as well as CDI (N,N'-carbonyldiimidazole), CDT (1,1'-carbonyldi(1,2,4-triazole)), DMT-MM (4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride), CIP (2-chloro-4,5-dihydro-1,You can use 3-dimethyl-1H-hexafluorophosphate imidazolium), isobutyl chlorocarbonate, triphosgene, diphenyl phosphate azide, propylphosphonic anhydride, cyanuric acid chloride, 2-chloro-4,6-dimethoxytriazine 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, trifluoromethanesulfonic acid (4,6-dimethoxy-1,3,5-triazine-2-yl)-(2-octoxy-2-oxoethyl)dimethylammonium, 2-methyl-6-nitrobenzoic anhydride, 2-chloro-1-methylpyridinium iodide, 2-fluoro-1-methylpyridinium p-toluenesulfonate, N-ethynyl-N,4-dimethylbenzenesulfonylformamide, 1-chloro-N,N,2-trimethyl-1-propenylamine, etc.

[0223]

[0155] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, dig (e.g., methyl triglycerides, tetraglycerides), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formylmolamide) (Sulfoline), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate) In addition to solvents such as ethanol, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), solvents such as acetonitrile, silene, and limonene can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, 0-25°C, 0-50°C, 0-80°C, -20-80°C, -20-140°C, or 0-140°C. A base may be used if necessary, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, K2HPO. 4、 KHCO3, NaHCO3, Na2HPO 4、 Sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium, tetrabutylammonium fluoride, cesium fluoride, sodium phosphate, lithium t-pentoxide, methyllithium, etc. can be used as bases, and these bases can be used in combination.

[0224]

[0156] The equivalent amount of the condensing agent used can be appropriately set by a person skilled in the art. For example, relative to the carboxylic acid containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The equivalent amount of the base used can be appropriately set by a person skilled in the art. For example, relative to the carboxylic acid containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The equivalent amount of the sulfonamide containing B used can be appropriately set by a person skilled in the art. For example, relative to the carboxylic acid containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0225]

[0157] R in the above formula 1 This is as already defined. 1 Preferred examples include hydrogen atoms, C 1-6 Examples of alkyl groups include methyl and ethyl.

[0158] In addition, X may be a halide, and may be prepared in the reaction system from the corresponding carboxylic acid (X = hydroxyl). The reagents used are not particularly limited as long as they are commonly available, but for example, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, sulfuryl chloride, (chloromethylene)dimethyliminium chloride (Vilsmeier reagent), 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez reagent), chloro-N,N,N',N'-bis(tetramethylene)formamidinium tetrafluoroboric acid, PyClU, PipClU, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), and fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH) can be used. When using thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, sulfuryl chloride, etc., an amide solvent such as DMF may be present. If necessary, a base may be used, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, K2HPO 4、 KHCO3, Na2HPO 4、NaHCO3, sodium tetraborate, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, LiHMDS, NaHMDS, KHMDS, HMDS, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc. can be used as bases.The above reaction can use any solvent, and is not particularly limited, but examples include halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Myrmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid) In addition to isobutyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, and limonene can also be used.The reaction temperature can be appropriately set by those skilled in the art, for example, -40 to 150°C, -40 to 100°C, -40 to 80°C, -20 to 80°C, or 0 to 80°C. The number of equivalents of reagents and bases used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 20 equivalents, 1 to 15 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to the carboxylic acid containing A. The number of equivalents of sulfonamide containing B used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 20 equivalents, 1 to 15 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to the carboxylic acid containing A. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0226]

[0159] In the above formula, if B contains a solid support, the reactive functional group X linked to A is a halide (specifically a chlorine atom or a fluorine atom) or a hydroxyl group. In the case of a hydroxyl group, an acylsulfonamide can be formed as a linker by using a condensing agent and reacting it with a sulfonamide containing an amino group linked to B. The acylsulfonamide formation reaction can be carried out using the reagents and reaction conditions already described. When a base is used, the equivalent amount can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonamide containing B. The equivalent amount of the condensing agent used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonamide containing B. The number of equivalents of carboxylic acid or acid halide containing A used can be appropriately determined by those skilled in the art. For example, relative to a sulfonamide containing B, the amount can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The reaction time can be appropriately determined by those skilled in the art. For example, it can be the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method based on the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0227]

[0160]

[0228] [ka]

[0229] [In the formula, R 3 C may have hydrogen atoms and substituents. 1-6 It is alkyl and may form a ring with the bonded nitrogen atom and B.

[0161] The amine bond as a linker can be formed by an aromatic nucleophilic substitution reaction using an aryl halide or its derivative with an amine, a catalytic coupling reaction using a metal catalyst, or a nucleophilic substitution reaction using an alkyl halide, hydroxyalkyl halide or its derivative with an amine. The reaction described above results in -NR 3 A linker represented by - can be formed. Furthermore, it can also be formed by the reaction of a primary or secondary amide with an aryl halide or its derivative, a nucleophilic substitution reaction using a primary or secondary amide with an alkyl halide or hydroxyalkyl derivative, a reaction of a primary or secondary sulfonamide with an aryl halide or its derivative, or a nucleophilic substitution reaction using a primary or secondary sulfonamide with an alkyl halide or hydroxyalkyl derivative.

[0230]

[0162] In the above formula, if A includes a solid support, and A-X is an aryl halide or a derivative thereof, the reactive functional group X linked to A is a group derived from a halogen or a hydroxyl group. Examples of groups derived from a hydroxyl group include methanesulfonyl group, trifluoromethanesulfonyl group, nonafluorobutanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, and 2,4-dinitrobenzenesulfonyl group. AX can be reacted with an amine linked to B in the presence of a base.Here, the base is not particularly limited as long as it is one that can be used normally, but for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, etc.), fluoride Cesium fluoride, potassium fluoride, LiOtBu, NaOtBu, KOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium hydride, potassium hydride, lithium hydride, sodium amide, lithium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, hexamethyldisilazane, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride Lithium chloride complexes, methyllithium, butyllithium, pyridine, alkyl-substituted pyridines (2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, etc.), DMAP, N,N-dimethylaniline, N-methylmorpholine, triethylamine, DIPEA, DBU, DBN, MTBD, TMG, BTMG, P1tBu, BEMP, BTPP, P2Et, P2tBu, NMI, sodium tetraborate, 1,8-bis(dimethylamino)naphthalene, N,N-dimethylaniline, tetrabutylammonium fluoride, etc. can be used. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of B-containing amine used can be appropriately set by those skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0231]

[0163] R in the above formula 3 This is as already defined. 3 Preferred examples include hydrogen atoms, and C which may have substituents. 1-6 Examples of alkyl groups include methyl and ethyl groups, and aromatic rings which may have substituents, such as benzene and pyridine. Examples of ring structures formed with the bonded nitrogen atom and B include pyrrolidine, piperidine, piperazine, and morpholine, and examples of heterocyclic aromatic amines include pyrrole, imidazole, pyrazole, indole, and benzimidazole.

[0232]

[0164] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME ( (Cyclopentyl methyl ether), isosorbide dimethyl ether, diglyceride, triglyceride, tetraglyceride, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyl (e.g., urea), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formylmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl methyl (Sulfone, sulfolane, 3-methylsulfolane, ethylmethylsulfone, ethylisopropylsulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc.), aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,In addition to solvents such as 2-dichlorobenzene, benzene, tetralin, pyridine, and quinoline, alcoholic solvents (ethanol, isopropanol, tert-butanol, tert-amyl alcohol, etc.) and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, methylcyclohexane, etc.), acetonitrile, water, dimethylacetal, dimethyl sulfate, silene, and limonene can also be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, 0 to 150°C, 10 to 120°C, 20 to 100°C, 20 to 80°C, or 20 to 60°C. If necessary, metal catalysts may be used, for example, for palladium, for example, palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl) palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II). For nickel, for example, NiCl2, ( Nickel(II) chloride, Ni(COD)2 (bis(1,5-cyclooctadiene)nickel(O)), etc., and for copper, for example, copper(I) oxide (Cu2O), copper(I) iodide (CuI), copper(I) bromide (CuBr), copper(I) chloride (CuCl), copper acetate (Cu(OAc)2), bis(acetylacetonato)copper(II) (Cu(acac)2), and copper(I) 2-thiophenecarboxylate (CuTc) can be used as metal catalysts.

[0233]

[0165] Ligands may be used if necessary, and examples of palladium ligands include trialkylphosphines (Cy3 (tricyclohexylphosphine), P(tBu)3 (tri-tert-butylphosphine), cataCXium A (di(1-adamantyl)-n-butylphosphine), (tBu)2PMe (di-tert-butylmethylphosphine), P(Ad)3 (tri(1-adamantyl)phosphine), neopentyl(tBu)2P (di-tert-butylneopentylphosphine), etc.), triarylphosphines (PPh3 (triphenylphosphine), etc.), dialkylbiarylphosphines (XPhos (2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl), S Phos(2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclohexyl Phosphino-2',6'-bis(N,N-dimethylamino)biphenyl), DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me 4tBuXPhos(2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos(2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl),BippyPhos (5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole), AdBippyPhos (5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole), etc.), dialkylmonoarylphosphines (APhos, ((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine)(tBu)2PPh, MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine), etc.), bidentate phosphine ligands (dppf (1,1′-bis(diphenylphosphino)ferrocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis Ligands such as (diphenylphosphino)-1,1'-binaphthyl, XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos ((R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), NHC ligands (IPr (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr (1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)) can be used. Furthermore, the above ligands and palladium catalyst precursors may also be used, for example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1, etc.), Buchwald second-generation catalyst precursors (G2) (XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, APhos Pd G2, (tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2,cataCXium A Pd G2, XantPhos Pd G2, etc.), Buchwald 3rd generation catalyst precursor (G3) (XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, (tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd G3, (tBu)2PMe Pd G3, Neopentyl(tBu)2P Pd G3, dppf Pd G3, dtbpf Buchwald 4th generation catalyst precursor (G4) (XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhosPd G4, APhos Pd G4, PCy3Pd G4, P(tBu)3Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.), palladium(O) complexes (tetrakistriphenylphosphine palladium(O), bis(tricyclohexylphosphine)palladium(O), bis(tri-tert-butylphosphine)palladium(O), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.), phosphine π-allyl palladium catalyst (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)),SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhos Pd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphin)]palladium(II)), P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphin)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphin(chloro)(clotyl)palladium(II)), [BINAP Pd(allyl)]Cl[XantPhos Pd(allyl)]Cl (allyl[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride), PEPPSI catalysts (Pd-PEPPSI IPr, Pd-PEPPSI SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI IPent, etc.), (NHC)Pd(allyl)Cl catalysts (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II),[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc., and NHC-Pd naphthoquinone catalysts (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(O) dimer, etc.) can be used as precursors for palladium catalysts.

[0234]

[0166] Examples of copper ligands include diamine ligands such as ditert-butylbipyridine (dtBBPy(4,4′-di-tert-butyl-2,2′-dipyridyl)), dimethylethylenediamine (DMEDA(N,N′-dimethylethylenediamine)), cyclohexyldimethylethylenediamine (CyDMEDA(trans-N,N′-dimethylcyclohexane-1,2-diamine)), and 1,10-phenanthroline (Phen); amino acid ligands such as N,N'-dimethylglycine, sarcosine (N-methylglycine), L-proline, 4-hydroxy-L-proline, pyrrole-2-carboxylic acid, and pipecolic acid; and diamide ligands such as N 1 -(2-methyl-1-naphthalenyl)-N 2 -(phenylmethyl)ethanediamide, N 1 ,N 2 -Bis(phenylmethyl)ethanediamine, N 1 ,N 2 -Bis(2,6-dimethylphenyl)ethanediamine, N 1 ,N 2 -Bis(2-furanylmethyl)ethanediamine, N 1 ,N 2 -Bis(2,4,6-trimethoxyphenyl)ethanediamine, N 1 ,N 2Ligands such as -bis(5-methyl[1,1'-biphenyl]-2-yl)-ethanediamide, [(2,6-dimethylphenyl)amino](oxo)acetic acid (DMPAO), N,N'-bis(furan-2-ylmethyl)oxalamide (BFMO), N,N'-bis(2,4,6-trimethoxyphenyl)-oxalamide (BTMPO), N-[1,1'-biphenyl]-2-yl1H-indole-2-carboxamide, 1,1,1-trifluoro-3-phenyl-2-(1H-pyrrole-2-yl)propan-2-ol, or 2-methyl-8-hydroxyquinoline can be used. When using a metal catalyst, the equivalent amount of the metal catalyst to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a catalyst precursor, the equivalent amount of the catalyst precursor to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0235]

[0167] In the above formula, if B includes a solid support and A-X are aryl halides or their analogs, aromatic nucleophilic substitution reactions with amines and catalytic coupling reactions using metal catalysts can be carried out using the reagents and reaction conditions already described. When a base is used, the equivalent amount can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. The equivalent amount of AX used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. When using a metal catalyst, the equivalent amount of the metal catalyst can be appropriately set by a person skilled in the art. For example, relative to an amine containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand used can be appropriately set by a person skilled in the art. For example, relative to an amine containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a catalyst precursor, the equivalent amount of the catalyst precursor used can be appropriately set by a person skilled in the art. For example, relative to an amine containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0236]

[0168] In the above formula, when A-X is an alkyl halide, a hydroxyalkyl group or an analogue thereof, the reactive functional group X linked to A is a leaving group, for example, a group derived from a halogen or a hydroxyl group. Examples of groups derived from a hydroxyl group include methanesulfonyl group, trifluoromethanesulfonyl group, nonafluorobutanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, and 2,4-dinitrobenzenesulfonyl group. By reacting with an amine linked to B in the presence of a base, -NR is obtained. 3 A linker can be formed represented by -.

[0237]

[0169] Here, the bases are not particularly limited as long as they are commonly available, but examples include sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), sodium hydride, potassium hydride, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, BEMP, BTPP, P2Et, P2tBu, potassium phosphate, LiOtBu, NaOtBu, KOtBu, LiHMDS, NaHMDS, KHMDS, HMDS, pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, sodium phosphate, K2HPO 4、 KHCO3, Na2HPO 4、 Sodium tetraborate, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc. can be used. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of B-containing amine used can be appropriately set by those skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0238]

[0170] R in the above formula 3 This is as already defined. 3 Preferred examples include hydrogen atoms, and C which may have substituents. 1-6 Examples of alkyl groups include methyl and ethyl groups, and aromatic rings which may have substituents, such as benzene and pyridine. Examples of ring structures formed with the bonded nitrogen atom and B include pyrrolidine, piperidine, piperazine, and morpholine, and examples of heterocyclic aromatic amines include pyrrole, imidazole, pyrazole, indole, and benzimidazole.

[0239]

[0171] The above reaction can use a solvent and is not particularly limited, but examples include halogenated solvents such as DCM, chloroform, DCE, and carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, and tetraglyceride; urea solvents such as TMU, DMI, and DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, and NBP; and DMSO. In addition to sulfonate solvents, sulfone solvents such as diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethylsulfone, and ethyl isopropyl sulfone, aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, and pyridine, carbonate solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate, as well as solvents such as acetonitrile and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, -20 to 120°C, -20 to 80°C, 0 to 80°C, or 0 to 60°C. Additives may be used if necessary; for example, 12-crown-4, 15-crown-5, 18-crown-6, HMPA, TMEDA, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, and tetrabutylammonium bisulfate can be used as additives. After the reaction is complete, the desired compound can be obtained by conventional workup methods.

[0240]

[0172] In the above formula, if B contains a solid support and A-X is an alkyl halide, hydroxyalkyl or its analogue, the nucleophilic substitution reaction with an amine can be carried out using the reagents and reaction conditions already described. When a base is used, the equivalent amount can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. The equivalent amount of AX used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B.

[0241]

[0173]

[0242] [ka]

[0243] [In the formula, R 1 C may have hydrogen atoms and substituents. 1-6 It is alkyl and may form a ring with the bonded nitrogen atom, carbonyl carbon atom, and A. The amide bond acting as a linker can also be formed by the reaction of a primary or secondary amide with an aryl halide or its derivative.

[0244]

[0174] In the above formula, if A includes a solid support, and if it is a derivative in which an amide is linked to A via a carbonyl group, an amide bond as a linker can be formed by using a base to react with BX, which is a halogen or hydroxyl group derivative of the reactive functional group X linked to B. Here, the base is not particularly limited as long as it can be used normally, but for example, NaOtBu, KOtBu, K2CO3, Cs2CO3, K3PO4, NaOH, NaOPh, KOPh, NaBHT, DBU, TEA, TMG, BTMG, MTBD, BTPP, P1tBu, P2Et, P2tBu, LiHMDS, NaHMDS, KHMDS, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, phosphoric acid Potassium, LiOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc. can be used. The number of equivalents of BX used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents for an amide containing A. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents for an amide containing A.

[0245]

[0175] The above reaction can use a solvent and is not particularly limited, but for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, 4-methyltetrahydropyran, diglyme, triglyceride, tetraglyceride, etc.), amide solvents (N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA), N-ethylpyrrolidone (NEP), N-methyl A variety of solvents can be used, including tylpyrrolidone (NBP), sulfoxide solvents (dimethyl sulfoxide (DMSO), methylphenyl sulfoxide), urea solvents (1,3-dimethyl-2-imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)), and alcohol solvents (tBuOH, tAmOH). A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, 0-200°C, 0-150°C, or 20-150°C. The temperature can be 40-120°C or 60-100°C. If necessary, a metal catalyst may be used. For example, palladium salts such as PdCl2, Pd(OAc)2, and Pd2(dba)3-CHCl3, as well as nickel salts such as NiCl2 (nickel(II) chloride) and Ni(COD)2 (bis(1,5-cyclooctadiene)nickel(O)), copper salts such as CuI, CuBr, CuCl, Cu(OAc)2, copper(II) oxide, and copper(I) oxide, and iron(III) chloride can be used as metal catalysts. If necessary, a ligand may be used. For example, tri Alkylphosphines (tBu3P (tri-tert-butylphosphine), Cy3P (tricyclohexylphosphine), tBu2MeP (di-tert-butylmethylphosphine)), biaryldialkylphosphines (XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), tBuXPhos (2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl), Me4tBuXPhos (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-Triisopropyl-1,1′-biphenyl), RuPhos(2-Dicyclohexylphosphino-2′,6′-Diisopropoxybiphenyl), BrettPhos(2-(Dicyclohexylphosphino)-3,6-Dimethoxy-2',4',6'-Triisopropyl-1,1'-biphenyl), tBuBrettPhos(2-(Di-tert-butylphosphino)-2',4',6'-Triisopropyl-3,6-Dimethoxy-1,1'-biphenyl), AdBrettPhos(2-(Di-1-adamantylphosphino) Fino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AlPhos(di-1-adamantyl(4"-butyl-2",3",5",6"-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-meth-terphenyl)phosphine), triarylphosphine (e.g., JackiePhos(bis(3,5-bis(trifluoromethyl)phenyl)(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine)), bisphosphine (For example, DPPF (1,1'-bis(diphenylphosphino)ferrocene), DtBPF (1,1'-bis(di-tert-butylphosphino)ferrocene), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)), as well as N-heterocyclic carbene derivatives (for example, IPr (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr (1,3-bis(2,6- Diamines such as di-i-propylphenyl)imidazolidine-2-ylidene, IMes (1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene), and diamines (e.g., dtBBPy (4,4′-di-tert-butyl-2,2′-dipyridyl), DMEDA (N,N′-dimethylethylenediamine), CyDMEDA (trans-N,N′-dimethylcyclohexane-1,2-diamine), Phen (1,10-phenanthroline, etc., can be used as ligands. Alternatively, metal ligand complexes may be used as catalysts, such as Buchwald catalyst precursors like XPhos Pd G1-4, Xantphos Pd G3,4, tBuBrettPhos Pd G4, AlPhos Pd G6 Br (CAS: 2097600-15-0), or NHC-Pd complexes like PEPPSI-IPr, [(NHC)Pd(allyl)Cl] (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II)) can be used as catalysts. When using a metal catalyst, the equivalent amount of the metal catalyst to be used can be appropriately set by a person skilled in the art. For example, with respect to an amide containing A, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand to be used can be appropriately set by a person skilled in the art. For example, with respect to an amide containing A, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a metal ligand complex, the equivalent amount of the metal ligand complex to be used can be appropriately determined by those skilled in the art. For example, for an amide containing A, the equivalent amounts can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The reaction time can be appropriately determined by those skilled in the art. For example, it can be the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate or a similar substrate, or the time that can be predicted by some method from the study results, or the reaction completion time can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0246]

[0176] After the reaction is complete, the target compound can be obtained by a standard post-treatment method. In the above formula, if B includes a solid support, the reaction between a primary or secondary amide containing A and an aryl halide or its derivative (BX) can be carried out using the reagents and reaction conditions already described. Here, the equivalent amount of primary or secondary amide containing A used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to BX. The equivalent amount of base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to BX. When using a metal catalyst, the equivalent amount of the metal catalyst to be used can be appropriately set by a person skilled in the art. For example, relative to BX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand to be used can be appropriately set by a person skilled in the art. For example, relative to BX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a metal ligand composite, the equivalent amount of the metal ligand composite to be used can be appropriately set by a person skilled in the art. For example, relative to BX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0247]

[0177]

[0248] [ka]

[0249] [In the formula, R 1 C may have hydrogen atoms and substituents. 1-6 It is alkyl and may form a ring with the bonded nitrogen atom, sulfur atom, and B. Sulfonamide bonds acting as linkers can also be formed by the reaction of a primary or secondary sulfonamide with an aryl halide or its derivatives.

[0250]

[0178] In the above formula, if A includes a solid support, and A-X is an aryl halide or a derivative thereof, the reactive functional group X linked to A is a halogen or a hydroxyl group derivative, and a sulfonamide bond as a linker can be formed by reacting it with a compound containing a sulfonamide group linked to B using a base. Here, the bases used are not particularly limited as long as they are commonly available, but examples include NaOtBu, KOtBu, K2CO3, Cs2CO3, K3PO4, NaOH, NaOPh, KOPh, NaBHT, DBU, TEA, TMG, BTMG, MTBD, BTPP, P1tBu, P2Et, P2tBu, LiHMDS, NaHMDS, KHMDS, potassium hydride, sodium hydride, lithium hydride, sodium amide, lithium amide, KOH, NaOH, LiOH, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, LiOtBu, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium Chloride complexes, N,N-dimethylaniline, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, etc., can be used.

[0251]

[0179] The above reaction can use solvents and is not particularly limited, but examples include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, 4-methyltetrahydropyran, diglyme, triglyceride, tetraglyceride, etc.), amide solvents (N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA), N-ethylpyrrolidone (NEP), N-butylpyrrolidone (NBP), etc.), sulfoxide solvents (dimethyl sulfoxide (DMSO), methylphenyl sulfoxide), urea solvents (1,3-dimethyl-2-imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)), and alcohol solvents (tBuOH, tAmOH). A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set appropriately by those skilled in the art, for example, 0-150°C, 20-150°C, 40-120°C, or 60-100°C. If necessary, a metal catalyst may be used, for example, palladium salts such as PdCl2, Pd(OAc)2, and Pd2(dba)3-CHCl3, as well as nickel salts such as NiCl2 (nickel(II) chloride) and Ni(COD)2 (bis(1,5-cyclooctadiene)nickel(O)), and copper salts such as CuI, CuBr, CuCl, Cu(OAc)2, copper(II) oxide, and copper(I) oxide can be used as metal catalysts. Ligands may be used if necessary, for example, trialkylphosphines (tBu3P (tri-tert-butylphosphine), Cy3P (tricyclohexylphosphine), tBu2MeP (di-tert-butylmethylphosphine)), biaryldialkylphosphines (XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), Me4tBuXPhos (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl), RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos(2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6- Dimethoxy-1,1'-biphenyl), BippyPhos (5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole), AdBippyPhos (5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole)), AlPhos (di-1-adamantyl(4”-butyl-2”,3”,5”,6”-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-meth-terphenyl)phosphine), triarylphosphines (e.g.) For example, JackiePhos (bis(3,5-bis(trifluoromethyl)phenyl)(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine)), bisphosphines (e.g., DPPF (1,1'-bis(diphenylphosphino)ferrocene), DtBPF (1,1'-bis(di-tert-butylphosphino)ferrocene), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)), as well as N- Heterocyclic carbene derivatives (e.g., IPr (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr (1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene), etc.) and diamines (e.g., dtBBPy (4,4′-di-tert-butyl-2,2′-dipyridyl), DMEDA (N,The ligands can be N'-dimethylethylenediamine, CyDMEDA (trans-N,N'-dimethylcyclohexane-1,2-diamine), Phen (1,10-phenanthroline), etc. Alternatively, metal ligand complexes can be used as catalysts, such as Buchwald catalyst precursors like XPhos Pd G1~4, Xantphos Pd G3,4, tBuBrettPhos Pd G4, AlPhos Pd G6 Br (CAS: 2097600-15-0), or PEPPSI-IPr, [(NHC)Pd(allyl)Cl] (allyl[1,3-bis(2,NHC-Pd complexes such as 6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II) can be used as catalysts. Here, the equivalent amount of sulfonamide containing B used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to an aryl halide or its derivative (AX) containing A. The equivalent amount of base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to an aryl halide or its derivative (AX) containing A. When using a metal catalyst, the equivalent amount of the metal catalyst to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a metal ligand composite, the equivalent amount of the metal ligand composite to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0252]

[0180] When B in the above formula includes a solid support, the reaction between an aryl halide containing A or its derivative (AX) and a primary or secondary sulfonamide containing B can be carried out using the reagents and reaction conditions already described. Here, the number of equivalents of the aryl halide containing A or its derivative (AX) used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonamide containing B. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the sulfonamide containing B. When using a metal catalyst, the equivalent amount of the metal catalyst to be used can be appropriately set by a person skilled in the art. For example, relative to a sulfonamide containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount of the ligand to be used can be appropriately set by a person skilled in the art. For example, relative to a sulfonamide containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using metal ligand complexes, the equivalent amount of the metal ligand complex to be used can be appropriately determined by those skilled in the art. For example, relative to a sulfonamide containing B, the equivalent amounts can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0253]

[0181]

[0254] [ka]

[0255] [In the formula, R 4 C may have hydrogen atoms and substituents. 1-6 It is an alkyl group, and may form a ring with the bonded carbon atoms and A, R 3 C may have hydrogen atoms and substituents. 1-6It is alkyl and may form a ring with the bonded nitrogen atom and B. Amine bonds, acting as linkers, can also be formed by reductive amination reactions using aldehydes and amines, or ketones and amines.

[0256]

[0182] In the above formula, if A includes a solid support, the reactive functional group linked to A is -C(=O)-R 4 In R 4 is C 1-6 Alkyl, C 6-10 Aryl, 5-10 member heteroaryl, C 3-7 Selected from cycloalkyl groups. For example, the group -C(=O)-R 4 A is formyl or acetyl. A carbon-nitrogen single bond can be formed by reacting B with an amine containing an amino group that links to B using a reducing agent. The reducing agent is not particularly limited as long as it is commonly available, but pyridineborane, 2-picolineborane, tert-butylamineborane, dimethylsulfideborane, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, tetramethylammonium triacetoxyborohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, triethylsilane, phenylsilane, phenyldimethylsilane, etc. The number of equivalents of the reducing agent used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the aldehyde containing A. The equivalent amount of amine containing B used can be appropriately set by those skilled in the art. For example, relative to the aldehyde containing A, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0257]

[0183] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butylmethyl ether) (Cyclopentyl methyl ether, CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, diglycerides, triglycerides, tetraglycerides, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropylene urea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formylmolate) A variety of solvents can be used, including foline, NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc., sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethylisopropyl sulfone, etc.), aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), and alicol solvents (methanol, ethanol). A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, 0-200°C, 20-200°C, 20-150°C, 40-150°C, or 60-150°C. If necessary, an acid may be used, for example, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. can be used as the acid.If necessary, Lewis acids may be used, for example, zinc chloride, titanium tetrachloride, titanium trichloride, boron trifluoride-ethyl ether complex, tetraethyl orthotitanate, tetraisopropyl orthotitanate, nickel chloride, lithium chloride, etc. can be used as Lewis acids. When using an acid, the equivalent amount of the acid used can be appropriately set by a person skilled in the art, for example, 0.01 to 100 equivalents, 0.01 to 75 equivalents, 0.01 to 50 equivalents, 0.01 to 30 equivalents, 0.1 to 30 equivalents, or 0.1 to 10 equivalents relative to an aldehyde containing A. When using a Lewis acid, the equivalent amount of the Lewis acid used can be appropriately set by a person skilled in the art, for example, 0.01 to 100 equivalents, 0.01 to 75 equivalents, 0.01 to 50 equivalents, 0.01 to 30 equivalents, 0.1 to 30 equivalents, or 0.1 to 10 equivalents relative to an aldehyde containing A. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0258]

[0184] When B in the above formula contains a solid support, the reaction can be carried out using the reagents and reaction conditions already described. Here, the number of equivalents of the aldehyde or ketone containing A used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. The number of equivalents of the reducing agent can also be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the amine containing B. When an acid is used, the number of equivalents of the acid used can be appropriately set by a person skilled in the art, for example, 0.01 to 100 equivalents, 0.01 to 75 equivalents, 0.01 to 50 equivalents, 0.01 to 30 equivalents, 0.1 to 30 equivalents, or 0.1 to 10 equivalents relative to the amine containing B. When using Lewis acids, the equivalent amount of Lewis acid to be used can be appropriately determined by those skilled in the art. For example, relative to an amine containing B, the amount can be 0.01 to 100 equivalents, 0.01 to 75 equivalents, 0.01 to 50 equivalents, 0.01 to 30 equivalents, 0.1 to 30 equivalents, or 0.1 to 10 equivalents.

[0259]

[0185]

[0260] [ka]

[0261] The ether linker can be formed by the reaction of a hydroxyaryl with an alcohol, or by the reaction of an aryl halide or its derivative with a hydroxyaryl or alcohol, or by the reaction of a hydroxyaryl or alcohol with an alkyl halide.

[0262]

[0186] In the above formula, if A includes a solid support and A-X is a hydroxyaryl group, the reactive functional group X linked to A is a hydroxyl group, and an ether bond as a linker can be formed by reacting an azodicarboxylic acid derivative with a phosphine or a cyanomethylenephosphorane derivative with an alcohol in which the reactive functional group Y linked to B is a hydroxyl group. Here, the azodicarboxylic acid derivative is not particularly limited as long as it is commonly available, but for example, diethyl azodicarboxylic acid (DEAD), bis(2,2,2-trichloroethyl) azodicarboxylic acid, N,N,N',N'-tetramethylazodicarboxamide (TMAD), di-tert-butyl azodicarboxylic acid, dimethyl azodicarboxylic acid, dimethyl azodicarboxylic acid, dibenzyl azodicarboxylic acid, dibenzyl azodicarboxylic acid, diisopropyl azodicarboxylic acid (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazosin-2,5-dione (DHTD)azodicarboxylic acid bis(2-methoxyethyl) can be used. The phosphine used is not particularly limited as long as it is commonly available, but for example, triphenylphosphine (TPP), tributylphosphine (TBP), 4-(dimethylamino)phenyldiphenylphosphine, isopropyldiphenylphosphine, phenoxydiphenylphosphine, tri-n-octylphosphine, diphenyl-2-pyridylphosphine, tri-tert-butylphosphine, dicyclohexylphenylphosphine, tricyclohexylphosphine, trihexylphosphine, etc. can be used. The cyanomethylenephosphorane derivative is not particularly limited as long as it is commonly available, but for example, cyanomethylenetributylphosphorane (CMBP), cyanomethylenetrimethylphosphorane (CMMP), etc. can be used. The number of equivalents of alcohol containing B used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.When using azodicarboxylic acid derivatives, the equivalent amount of the azodicarboxylic acid derivative to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. When using phosphine, the equivalent amount of phosphine to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. When using cyanomethylenephosphorane derivatives, the equivalent amount of cyanomethylenephosphorane derivative to be used can be appropriately set by a person skilled in the art. For example, relative to AX, it can be 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0263]

[0187] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Lumorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isopropyl acetate) In addition to butyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, limonene, etc. can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set appropriately by those skilled in the art, for example, -20 to 200°C, 0 to 150°C, 0 to 120°C, or 0 to 100°C. The reaction time can be set appropriately by those skilled in the art, for example, by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0264]

[0188] After the reaction is complete, the target compound can be obtained by a standard post-treatment method. In the above formula, if B contains a solid support and A-X is a hydroxyaryl group, the reactive functional group X linked to A is a hydroxyl group. The formation of an ether linkage as a linker can be achieved by reacting an alcohol in which the reactive functional group Y linked to B is a hydroxyl group with an azodicarboxylic acid derivative and phosphine or a cyanomethylenephosphorane derivative, using the reagents and reaction conditions already described. When using an azodicarboxylic acid derivative, the equivalent amount can be appropriately set by those skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the alcohol containing B. When using phosphine, the equivalent amount can be appropriately set by those skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the alcohol containing B. When using cyanomethylenephosphorane derivatives, the equivalent amount can be appropriately set by those skilled in the art. For example, relative to an alcohol containing B, it can be 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The equivalent amount of AX used can be appropriately set by those skilled in the art. For example, relative to an alcohol containing B, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0265] In the above formula, if A includes a solid support and A-X is an aryl halide or its derivative, the reactive functional group X linked to A is a halogen or a hydroxyl group derivative, and by using a base to react with a hydroxyaryl or alcohol in which the reactive functional group Y linked to B is a hydroxyl group, an ether bond as a linker can be formed. Here, the base is not particularly limited as long as it is commonly available, but examples include sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), LiOtBu, NaOtBu, KOtBu, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide Methyllithium, butyllithium, pyridine, alkyl-substituted pyridines (2,6-lutidine, DTBP, DTBMP, etc.), DMAP, N,N-dimethylaniline, N-methylmorpholine, triethylamine, DIPEA, DBU, DBN, MTBD, TMG, BTMG, P1tBu, BEMP, BTPP, P2Et, P2tBu, NMI, lithium hydride, sodium amide, lithium amide, sodium tetraborate, 1,8-bis(dimethylamino)naphthalene, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, tetrabutylammonium fluoride, cesium fluoride, silver oxide, silver carbonate, etc. can be used.

[0266]

[0189] The above reaction can use a solvent and is not particularly limited, but examples include halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether (Tel, diglyme, triglyceride, tetraglyceride, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formylmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate) In addition to propyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene,Limonene and other solvents can be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set appropriately by those skilled in the art, for example, 0-140°C, 20-110°C, or 40-80°C. If necessary, a metal catalyst may be used, for example, palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl) palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), etc. If necessary, a ligand may be used, for example, trialkylphosphine (PCy3 (tricyclohexylphosphine), P(tBu)3 (tri-tert-butylphosphine), cataCXium A (di(1-adamantyl)-n-butylphosphine), (tBu)2PMe (di-tert-butylmethylphosphine), P(Ad)3, neopentyl(tBu)2P (di-tert-butylneopentylphosphine), etc.), triarylphosphine (PPh3 (triphenylphosphine), etc.), dialkylbiarylphosphine (XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), Brett Phos, tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine),Me4tBuXPhos (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl), tBuBrettPhos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos (2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), etc., dialkylmo Noarylphosphines (APhos ((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine), (tBu)2PPh (di-tert-butylphenylphosphine), MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine), etc.), bidentate phosphine ligands (dppf (1,1'-bis(diphenylphosphino)ferrocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphine) (1,3-)-1,1'-binaphthyl), XantPhos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos((R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), etc.), NHC ligand (IPr(1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr(1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes(1,3- Ligands such as bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent(1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene), BippyPhos(5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole), and AdBippyPhos(5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipirazole) can be used. Alternatively, the above ligands may be used with palladium catalyst precursors, for example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1,Buchwald second-generation catalyst precursors (G2) (e.g., RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1), Buchwald second-generation catalyst precursors (G2) (e.g., XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, APhos Pd G2, (tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2, cataCXium A Pd G2, XantPhos Pd G2), Buchwald third-generation catalyst precursors (G3) (e.g., XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd Buchwald 4th generation catalyst precursor (G4) (XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhos Pd G4, APhos Pd G4, PCy3Pd G4, P(tBu)3 Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.), palladium(O) complexes (tetrakistriphenylphosphine palladium(O),Bis(tricyclohexylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.), phosphine π-allyl palladium catalysts (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhosPd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphin)]palladium(II)), P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphin)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphin(chloro)(clotyl)palladium(II)), [BINAPPd(allyl)]Cl((R)-BINAPPd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene]palladium(II) chloride),[XantPhos Pd(allyl)]Cl(allyl[4,5-bis(diphenylphos, Pd-PEPPSI catalyst (Pd-PEPPSI IPr, Pd-PEPPSI SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI Electropalladium catalyst precursors such as IPent, (NHC)Pd(allyl)Cl catalysts (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc.), and NHC-Pd naphthoquinone catalysts (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(O) dimer, etc.) can be used. The equivalent amount of hydroxyaryl or alcohol containing B used can be appropriately determined by those skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0267]

[0190] The number of equivalents of the base to be used can be appropriately set by a person skilled in the art. For example, with respect to AX, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0268] The equivalent weight of the metal catalyst used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0269]

[0191] The equivalent number of ligands used can be appropriately set by a person skilled in the art. For example, with respect to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0270] The equivalent amount of the palladium catalyst precursor used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0271]

[0192] After the reaction is complete, the target compound can be obtained by a standard workup method. In the above formula, if B includes a solid support and A-X are aryl halides or their analogs, the reactive functional group X linked to A is a halogen or hydroxyl group derivative, and the ether bond as a linker can be formed by reacting it with a hydroxyaryl or alcohol in which the reactive functional group Y linked to B is a hydroxyl group using a base, as described with the reagents and reaction conditions already stated. Here, when using a base, the equivalent amount can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the hydroxyaryl or alcohol containing B. The equivalent amount of AX used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the hydroxyaryl or alcohol containing B. When using a metal catalyst, the equivalent amount can be appropriately set by a person skilled in the art. For example, relative to a hydroxyaryl or alcohol containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a ligand, the equivalent amount can be appropriately set by a person skilled in the art. For example, relative to a hydroxyaryl or alcohol containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. When using a catalyst precursor, the equivalent amount can be appropriately set by a person skilled in the art. For example, relative to a hydroxyaryl or alcohol containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0272] In the above formula, if A includes a solid support and A-X is a hydroxyaryl or alcohol, the reactive functional group X linked to A is a hydroxyl group, and by using a base to react with an alkyl halide where the reactive functional group Y linked to B is a halogen, or with an alkylating agent where Y is a hydroxyl group derivative, an ether bond as a linker can be formed. Here, the base is not particularly limited as long as it is commonly available, but examples include pyridine, 2,6-lutidine, 2,4,6-collidine, pyridine derivatives such as DTBP and DTBMP, as well as tertiary amines such as triethylamine, DIPEA, and 4-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), sodium hydride, potassium hydride, DBU, DBN, MTBD, BTMG, 1,8-bis(dimethylamino)naphthalene, BEMP, BTPP, P2Et, P2tBu, potassium phosphate, LiOtBu, NaOtBu, KOtBu, LiHMDS, NaHMDS, KHMDS, HMDS, triethylamine, DIPEA, 4-methylmorpholine, lithium hydride, sodium amide, lithium amide, sodium phosphate, potassium phosphate, KHCO3, Na2HPO 4、 Sodium tetraborate, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, lithium diisopropylamide, lithium dicyclohexylamide, 2,2,6,6-tetramethylpiperidinyl lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex, N,N-dimethylaniline, P1-tBu, P2tBu, butyllithium, methyllithium, tetrabutylammonium fluoride, cesium fluoride, silver oxide, silver carbonate, etc. can be used.

[0273]

[0193] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents such as DCM, chloroform, DCE, carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, tetraglyceride; ketone solvents such as acetone, MEK, MIBK, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone; urea solvents such as TMU, DMI, DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, NBP A variety of solvents can be used, including sulfoxide solvents such as DMSO, ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, and methyl propionate, sulfone solvents such as diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, and ethyl isopropyl sulfone, aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, and pyridine, as well as carbonate solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate, and solvents such as acetonitrile and limonene. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, 0 to 120°C, 20 to 100°C, or 20 to 60°C. Additives may be used if necessary, for example, Ag2O, 12-crown-4, 15-crown-5, 18-crown-6, HMPA, TMEDA, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, and tetrabutylammonium bisulfate can be used as additives.The equivalent amount of alkylating agent, which is an alkyl halide or hydroxyl group derivative containing B, can be appropriately set by a person skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of base used can be appropriately set by a person skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of additive used can be appropriately set by a person skilled in the art. For example, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method. In the above formula, if B contains a solid support and A-X is a hydroxyaryl or alcohol, the reactive functional group X linked to A is a hydroxyl group, and the ether bond as a linker can be formed by reacting it with an alkyl halide in which the reactive functional group Y linked to B is a halogen, or an alkylating agent in which Y is a hydroxyl group derivative, using a base, by the reagents and reaction conditions already described. Here, when a base is used, the equivalent amount can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the alkyl halide or alkylating agent containing B. The equivalent amount of AX used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the alkyl halide or alkylating agent containing B.

[0274]

[0194]

[0275] [ka]

[0276] A carbon-carbon single bond acting as a linker can be formed, for example, by the reaction of an aryl halide with a boron derivative or a zinc derivative.

[0195] In the above formula, if A includes a solid support, the reactive functional group X linked to A is a halogen or -O-SO2-R 5 And; R 5 C may be substituted with one or more fluorine atoms. 1-6 Alkyl, or C1 or more fluorine atoms or C1 which may be substituted with fluorine atoms 1-6The phenyl, which may be substituted with an alkyl group, can form a carbon-carbon single bond as a linker by reacting it with a boronic acid analog in which the reactive functional group Y linked to B is a boron derivative, or with an alkylborane reagent derived from a carbon-carbon terminal double bond, using a metal catalyst. The equivalent amounts of the boronic acid derivative and alkylborane reagent used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. Here, the metal catalyst is not particularly limited as long as it is commonly available, but for example, palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl) palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II) can be used. If necessary, ligands may also be used, for example, trialkylphosphine (PCy(tricyclohexylphosphine), P(tBu)3(tri-tert-butylphosphine), cataCXium A (di(1-adamantyl)-n-butylphosphine), (tBu)2PMe (di-tert-butylmethylphosphine), P(Ad)3, neopentyl(tBu)2P (di-tert-butylneopentylphosphine), etc.), triarylphosphine (PPh3 (triphenylphosphine), etc.), dialkylbiarylphosphine (XPhos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphine-2',6'- Dimethoxybiphenyl), RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl),DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me4tBuXPhos(2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tetramethyl (Diisopropyl-1,1'-biphenyl), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos(2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), etc.), Dialkylmonoarylphosphine (APhos((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine), tBu)2PPh MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine), bidentate phosphine ligands (dppf (1,1′-bis(diphenylphosphino)ferrocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos ((R)-1-[(Sp)-2-(dicyclohexylphosph Ligands such as sphino(ferrocenyl)ethyldi-tert-butylphosphine), NHC ligands (IPr(1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr(1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes(1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent(1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)) can be used. Alternatively, the above ligands and palladium catalyst precursors may be used.For example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1, etc.), Buchwald second-generation catalyst precursors (G2) (XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, APhos Pd G2, tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2, cataCXium A Pd G2, XantPhos Pd G2, etc.), Buchwald third-generation catalyst precursors (G3) (XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, (tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd G3, tBu)2PMe Pd G3, neopentyl tBu)2P Pd G3, dppf Pd G3, dtbpf Pd G3, BINAP Pd G3, XantPhos Pd G3, Josiphos Pd G3), Buchwald 4th generation catalyst precursor (G4) (XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhos Pd G4, APhos Pd G4, PCy3Pd G4, P(tBu)3Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.),Palladium(0) complexes (tetrakistriphenylphosphine palladium(0), bis(tricyclohexylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.), phosphine π-allyl palladium catalysts (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhosPd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphine)]palladium(II)), P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphine)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphine(chloro)(clotyl)palladium(II)),[BINAP Pd(allyl)]Cl((R)-BINAP Pd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene]palladium(II) chloride), [XantPhos Pd(allyl)]Cl(ally[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride), etc., PEPPSI catalyst (Pd-PEPPSI IPr, Pd-PEPPSI SIPr((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene), (NHC)Pd(allyl)Cl catalysts (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc.), NHC-Pd naphthoquinone catalysts (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(O) dimer, etc.) can be used as precursors for palladium catalysts. The equivalent weight of the metal catalyst used can be appropriately set by a person skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX. The equivalent weight of the ligand used can be appropriately set by a person skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX. The equivalent weight of the catalyst precursor used can be appropriately set by a person skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, or 0.01 to 5 equivalents relative to AX. The quantity can be 0.01 to 3 equivalents.

[0277]

[0196] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Lumorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isopropyl acetate) In addition to butyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, limonene, etc. can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, 0 to 200°C, 0 to 140°C, 10 to 100°C, or 20 to 60°C. If necessary, a base may be used. For example, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), NaOtBu, KOtBu, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine, DIPEA, DBU, DBN, MTBD, TMG, BTMG, P1tBu, BEMP, BTPP, P2Et, P2tBu, sodium tetraborate, 1,8-bis(dimethylamino)naphthalene, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, tetrabutylammonium fluoride, cesium fluoride, etc. can be used as a base. The number of equivalent amounts of base used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The reaction time can be appropriately set by those skilled in the art. For example, it can be the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method based on the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0278]

[0197] In the above formula, X, the reactive functional group linked to A, is a halogen or -O-SO2-R 5 And; R 5 C may be substituted with one or more fluorine atoms. 1-6 Alkyl, or C1 or more fluorine atoms or C1 which may be substituted with fluorine atoms 1-6The phenyl, which may be substituted with an alkyl group, can form a carbon-carbon single bond as a linker by reacting it with a compound in which the reactive functional group Y linked to B is a zinc derivative, using a metal catalyst. The number of equivalents of the zinc derivative used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. Here, the metal catalyst is not particularly limited as long as it is commonly usable, but for example, palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl) palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), etc. can be used. Ligands may be used if necessary, for example, trialkylphosphines (PCy3 (tricyclohexylphosphine), P(tBu)3 (tri-tert-butylphosphine), cataCXium A (di(1-adamantyl)-n-butylphosphine), (tBu)2PMe (di-tert-butylmethylphosphine), P(Ad)3 (tri(1-adamantyl)phosphine), neopentyl(tBu)2P (di-tert-butylneopentylphosphine), etc.), triarylphosphines (PPh3 (triphenylphosphine), etc.), dialkylbiarylphosphines (XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphate) (Phino-2',6'-dimethoxybiphenyl), RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl),DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me4tBuXPhos(2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl (tBu)2PPh(di-tert-butylphosphin), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos(2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), etc., dialkylmonoarylphosphin (APhos((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphin), (tBu)2PPh(di-tert-butylphosphin) (Phenylephosphine), MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine, etc.), bidentate phosphine ligands (dppf (1,1′-bis(diphenylphosphino)ferrocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos ((R)-1-[(Sp)-2-(disic Ligands such as (e.g., lohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphin), NHC ligands (IPr(1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr(1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes(1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent(1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)) can be used. Alternatively, the above ligands and palladium catalyst precursors may be used.For example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1, etc.), Buchwald second-generation catalyst precursors (G2) (XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, APhos Pd G2, (tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2, cataCXium A Pd G2, XantPhos Pd G2, etc.), Buchwald third-generation catalyst precursors (G3) (XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, (tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd G3, (tBu)2PMe Pd G3, neopentyl (tBu)2P Pd G3, dppf Pd G3, dtbpf Pd G3, BINAP Pd G3, XantPhos Pd G3, Josiphos Pd G3, etc.), Buchwald fourth-generation catalyst precursors (G4) (XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhos Pd G4, APhos Pd G4, PCy3Pd G4, P(tBu)3Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.),Palladium(0) complexes (tetrakistriphenylphosphine palladium(0), bis(tricyclohexylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.), phosphine π-allyl palladium catalysts (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhosPd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphine)]palladium(II)), P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphine)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphine(chloro)(clotyl)palladium(II)),[BINAP Pd(allyl)]Cl((R)-BINAP Pd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene]palladium(II) chloride), [XantPhos Pd(allyl)]Cl(ally[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride), etc., PEPPSI catalyst (Pd-PEPPSI IPr, Pd-PEPPSI SIPr((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI Electropalladium catalyst precursors such as IPent, (NHC)Pd(allyl)Cl catalysts (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc.), and NHC-Pd naphthoquinone catalysts (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(O) dimer, etc.) can be used. The equivalent weight of the metal catalyst used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The equivalent weight of the ligand used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The equivalent weight of the catalyst precursor used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0279]

[0198] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Lumorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isopropyl acetate) In addition to butyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, limonene, etc. can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set appropriately by those skilled in the art, for example, -40 to 100°C, -20 to 70°C, or 20 to 60°C. The reaction time can be set appropriately by those skilled in the art, for example, by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0280]

[0199] However, when applying the carbon-carbon single bond formation reaction to the production of compound libraries, it was found that cleavage from the solid phase also occurs depending on the type of palladium catalyst mentioned above. If the substrate in the solid phase is less reactive and / or the reagent is less reactive, a long reaction time may be required to complete the reaction, and the progress of cleavage from the solid phase can significantly affect the yield in the solid-phase reaction. To solve this problem, we investigated conditions under which cleavage from the solid phase does not occur and the carbon-carbon single bond formation reaction proceeds. We found that when meCgPPhPdG4 and (dtbpf)PdCl2 are used as palladium catalysts, there is no cleavage from the solid phase and the Suzuki coupling reaction can be performed in high yield. By using these conditions in the synthesis of compound libraries, cleavage from the solid phase can be suppressed even if a reaction delay occurs due to some factor, and a high yield can be achieved. This method enables improved reaction robustness and yield for the purpose of supplying "high-quality" mixture libraries.

[0281]

[0200]

[0282] [ka]

[0283] The ethyn-1,2-diyl bond, which acts as a linker, can be formed by the reaction of an aryl halide with an acetylene derivative.

[0201] In the above formula, if A includes a solid support, the reactive functional group X linked to A is a halogen, and by using a metal catalyst to react with a compound in which the reactive functional group Y linked to B is an acetylene derivative, an ethyne-1,2-diyl group as a linker can be formed. The equivalent amount of the acetylene derivative used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. Here, the metal catalyst is not particularly limited as long as it is one that can be used normally, but examples include palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl) palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II). For copper, examples include copper(I) oxide (Cu2O), copper(II) oxide, copper(I) iodide (CuI), copper(I) bromide (CuBr), copper(I) chloride (CuCl), copper acetate (Cu(OAc)2), copper sulfate, and Ullmann. η-type conditions (e.g., a metal catalyst such as copper(II) acetate in an aprotic solvent such as DMF) and Buchwald-type conditions (e.g., alkali metal carbonates such as cesium carbonate; BINAP; palladium catalysts such as Pd2(dba)3 and Pd(OAc)2) can be used. The number of equivalents of the metal catalyst used can be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX.

[0284]

[0202] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Myrmorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid) Isobutyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, tetralin, pyridine, quinoline, etc.), alcoholic solvents (ethanol, isopropanol, tert-butanol, tert-amyl alcohol, triethanolamine, etc.), hydrocarbon solvents (hexane, pentane, heptane, cyclohexane,In addition to methylcyclohexane, acetonitrile, water, silene, and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, 0-140°C, 5-120°C, 10-100°C, or 20-80°C. Ligands may be used if necessary, for example, trialkylphosphines (PCy3 (tricyclohexylphosphine), P(tBu)3 (tri-tert-butylphosphine), cataCXium) can be used as ligands for palladium. A(di(1-adamantyl)-n-butylphosphine), (tBu)2PMe(di-tert-butylmethylphosphine), P(Ad)3(tri(1-adamantyl)phosphine), neopentyltBu)2P, etc.), triarylphosphine (PPh3(triphenylphosphine), etc.), dialkylbiarylphosphine (XPhos, SPhos(2-dicyclohexylphosphine-2',6'-dimethyl) Xybiphenyl), RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclo Hexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3- Methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me4tBuXPhos(2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl),AdBrettPhos(2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), BippyPhos(5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipirazole), AdBippyPhos(5-[di(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'H-[1, 4′]bipirazole) etc.), dialkylmonoarylphosphine (APhos((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine), (tBu)2PPh(di-tert-butylphenylphosphine), MorDalPhos(2-morpholinophenyldi(1-adamantyl)phosphine) etc.), bidentate phosphine ligand (dppf(1,1′-bis(diphenylphosphino)ferrocene), dt bpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos ((R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), etc.), NHC ligand (IP Ligands such as r(1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene), SIPr(1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes(1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), and IPent(1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)) can be used. Furthermore, the above ligands and palladium catalyst precursors may also be used, for example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1, etc.), Buchwald second-generation catalyst precursors (G2) (XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2,DavePhos Pd G2, APhos Pd G2, (tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2, cataCXium A Pd G2, G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, (tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd G3, (tBu)2PMe Pd G3, neopentyl(tBu)2P Pd G3, dppf Pd G3, dtbpf Pd G3, BINAP Pd G3, G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhos Pd G4, APhos Pd G4, PCy3Pd G4, P(tBu)3Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.), palladium(O) complexes (tetrakistriphenylphosphine palladium(O), bis(tricyclohexylphosphine)palladium(O), bis(tri-tert-butylphosphine)palladium(O), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.),Phosphine π-allyl palladium catalyst (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhos Pd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphine)]palladium(II)), P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphine)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphine(chloro)(clotyl)palladium(II)), [BINAP Pd(allyl)]Cl((R)-BINAP Pd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphine)-1,1'-binaphthalene]palladium(II) chloride), [XantPhos Pd(allyl)]Cl(ally[4,5-bis(diphenylphosphine)-9,9-dimethylxanthene]palladium(II) chloride), etc., PEPPSI catalyst (Pd-PEPPSI IPr, Pd-PEPPSI SIPr, Pd-PEPPSI IPent, etc.(NHC)Pd(allyl)Cl catalyst (allyl[1,3-bis(2,6-diisopropylphenyl), [Imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc., and NHC-Pd naphthoquinone catalysts (such as 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(O) dimer) can be used as precursors to palladium catalysts. Examples of copper ligands include diamine ligands such as ditert-butylbipyridine (dtBBPy(4,4′-di-tert-butyl-2,2′-dipyridyl)), dimethylethylenediamine (DMEDA(N,N′-dimethylethylenediamine)), cyclohexyldimethylethylenediamine (CyDMEDA(trans-N,N′-dimethylcyclohexane-1,2-diamine)), and 1,10-phenanthroline (Phen); amino acid ligands such as N,N'-dimethylglycine, sarcosine (N-methylglycine), L-proline, 4-hydroxy-L-proline, and 6-methylpicolinic acid; and diamide ligands such as N 1 -(2-methyl-1-naphthalenyl)-N 2 -(phenylmethyl)ethanediamide, N 1 ,N 2 -Bis(phenylmethyl)ethanediamine, N 1 ,N 2 -Bis(2,6-dimethylphenyl)ethanediamine, N 1 ,N 2 -Bis(2-furanylmethyl)ethanediamine, N 1 ,N 2 -Bis(2,4,6-trimethoxyphenyl)ethanediamine, N 1 ,N 2Ligands such as bis(5-methyl[1,1'-biphenyl]-2-yl)-ethanediamide, [(2,6-dimethylphenyl)amino](oxo)acetic acid (DMPAO), N-[1,1'-biphenyl]-2-yl 1H-indole-2-carboxamide, or 2-methyl-8-hydroxyquinoline can be used. The equivalent weight of the ligand used can be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX. When using a catalyst precursor, the equivalent amount of the catalyst precursor can be appropriately set by those skilled in the art. For example, relative to AX, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. If necessary, a base may be used, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), cesium fluoride, potassium fluoride, LiOtBu, NaOtBu, KOtBu, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide Potassium bis(trimethylsilyl)amide, lithium diisopropylamide, methyllithium, butyllithium, pyridine, alkyl-substituted pyridines (2,6-lutidine, DTBP, DTBMP, DMAP, etc.), N,N-dimethylaniline, N-methylmorpholine, triethylamine, DIPEA, diethylamine, dimethylamine, diisopropylamine, dibutylamine, piperidine, morpholine, methylamine, ethylamine, isopropylamine, butylamine, DBU, DBN, MTBD, TMG, BTMG, P1tBu, BEMP, BTPP, P2Et, P2tBu, etc. can be used as bases.Additives may be used if necessary, and zinc, zinc chloride, zinc bromide, zinc iodide, zinc acetate, zinc trifluoromethanesulfonate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, etc., can be used as additives. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The number of equivalents of the additive used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The reaction time can be appropriately set by those skilled in the art, for example, the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method from the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained using a standard workup method.

[0285]

[0203]

[0286] [ka]

[0287] Ester bonds, which act as linkers, can be formed by the reaction of a carboxylic acid or its derivative with an alcohol.

[0204] In the above formula, if A includes a solid support, the reactive functional group X linked to A is hydroxyl, and by using a condensing agent and reacting it with an alcohol containing a hydroxyl group linked to B, an ester bond as a linker can be formed. The number of equivalents of the alcohol containing B used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. Here, the condensing agent is not particularly limited as long as it is commonly available, but for example, combinations of carbodiimide-based condensing agents such as DCC, DIC, N,N′-di-tert-butylcarbodiimide, EDCI, EDCI·HCl and activators such as HOAt, HOBt, oxyma, uronium salt-based condensing agents such as HATU, TATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide tetrafluoroborate), COMU, PyBOP (1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate), PyOxim ([ethylcyano(hydroxyimino)acetate-O 2Phosphonium salt condensing agents such as tri-1-pyrrolidinylphosphonium hexafluorophosphate, formamidinium salts such as TCFH (chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate), PyClU (1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate), PipClU (chlorodipiperidinocarbenium hexafluorophosphate), and CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate). Salt-based condensing agents, acid anhydrides such as 3-pyridinecarboxylic acid anhydride, 2-methyl-6-nitrobenzoic acid anhydride, 4-trifluoromethylbenzoic acid anhydride, and 2-fluoro-6-(trifluoromethyl)benzoic acid anhydride, acid chlorides such as isobutyl chloroformate, 4-nitrophenyl chloroformate, 4-nitrobenzyl chloroformate, and 2,4,6-trichlorobenzoyl chloride, phosgene derivatives such as triphosgene, and carbodiimidazole derivatives such as 1,1'-carbonyldiimidazole can be used. The equivalent amount of condensing agent used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0288]

[0205] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents such as DCM, chloroform, DCE, carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, tetraglyceride; ketone solvents such as acetone, MEK, MIBK, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone; urea solvents such as TMU, DMI, DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, NBP; sulfoxide solvents such as DMSO; diphenyl In addition to sulfone-based solvents such as yl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methyl sulfolane, ethyl methyl sulfone, and ethyl isopropyl sulfone; ester-based solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, and methyl propionate; aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, pyridine, and pyridine; carbonate-based solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate; and other solvents such as acetonitrile and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, 0 to 100°C, 20 to 80°C, or 20 to 50°C. If necessary, bases may be used, such as pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, NMI, DMAP, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, K2HPO 4、Potassium bicarbonate, Na2HPO4, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, etc., can be used as bases. The number of equivalents of the base used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0289]

[0206] After the reaction is complete, the target compound can be obtained by a standard post-treatment method. In the above formula, the reactive functional group X linked to A is hydroxyl, and an ether linker can be formed by reacting an azodicarboxylic acid derivative with a phosphine or a cyanomethylenephosphorane derivative with an alcohol containing a hydroxyl group linked to B. The equivalent amount of the alcohol containing B used can be appropriately set by those skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. Here, the azodicarboxylic acid derivative is not particularly limited as long as it is commonly available, but for example, diethyl azodicarboxylic acid (DEAD), bis(2,2,2-trichloroethyl) azodicarboxylic acid, N,N,N′,N′-tetramethylazodicarboxamide (TMAD), di-tert-butyl azodicarboxylic acid, dimethyl azodicarboxylic acid, dibenzyl azodicarboxylic acid, diisopropyl azodicarboxylic acid (DIAD), 1,1′-(azodicarbonyl)dipiperidine (ADDP), N,N,N′,N′-tetraisopropylazodicarboxamide (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazosin-2,5-dione (DHTD), and bis(2-methoxyethyl) azodicarboxylic acid can be used. As for phosphines, there are no particular limitations as long as they are commonly used, but for example, triphenylphosphine (TPP), tributylphosphine (TBP), 4-(dimethylamino)phenyldiphenylphosphine, isopropyldiphenylphosphine, phenoxydiphenylphosphine, tri-n-octylphosphine, diphenyl-2-pyridylphosphine, tri-tert-butylphosphine, dicyclohexylphenylphosphine, tricyclohexylphosphine, and trihexylphosphine can be used. As for cyanomethylenephosphoran derivatives, there are no particular limitations as long as they are commonly used, but for example, cyanomethylenetributylphosphoran (CMBP) and cyanomethylenetrimethylphosphoran (CMMP) can be used.The equivalent amount of the azodicarboxylic acid derivative used can be appropriately set by a person skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of phosphine used can be appropriately set by a person skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. When using a cyanomethylenephosphorane derivative, the equivalent amount of the cyanomethylenephosphorane derivative used can be appropriately set by a person skilled in the art, for example, 1 to 150 equivalents, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0290]

[0207] The above reaction can use a solvent and is not particularly limited, but examples include halogenated solvents such as DCM, chloroform, DCE, and carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, and tetraglyceride; ketone solvents such as acetone, MEK, MIBK, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, and diethyl ketone; urea solvents such as TMU, DMI, and DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, and NBP; sulfoxide solvents such as DMSO; methyl acetate, ethyl acetate, and propyl acetate. In addition to ester solvents such as isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, and methyl propionate, sulfone solvents such as diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethylsulfone, and ethyl isopropyl sulfone, aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, and pyridine, hydrocarbon solvents such as hexane, pentane, heptane, and cyclohexane, as well as carbonate solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate, and solvents such as acetonitrile and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be appropriately set by those skilled in the art, for example, -20 to 150°C, 0 to 120°C, or 20 to 100°C. The reaction time can be appropriately set by those skilled in the art. For example, it can be determined by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0291]

[0208]

[0292] [ka]

[0293] In addition to the methods described above, ester bonds acting as linkers can also be formed by the reaction of a carboxylic acid or its derivative with an alkyl halide.

[0209] In the above formula, if A includes a solid support, the reactive functional group X linked to A is hydroxyl, and by using a base, an ester bond as a linker can be formed by reacting it with an alkyl halide in which the reactive functional group Y linked to B is a halogen, or with an alkylating agent in which Y is a hydroxyl group derivative. The equivalent amount of alkylating agent containing B used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX.

[0294]

[0210] Here, the base is not particularly limited as long as it is normally usable, but for example, alkylpyridine derivatives such as 2,6-lutidine and 2,4,6-collidine, as well as tertiary amines such as triethylamine, DIPEA, and 4-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), lithium hydride, sodium hydride, potassium hydride, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, BEMP, BTPP, P2Et, P2tBu, potassium phosphate, sodium phosphate, LiOtBu, NaOtBu, KOtBu, LiHMDS, NaHMDS, KHMDS, HMDS, etc. can be used. The number of equivalent amounts of base used can be appropriately determined by those skilled in the art. For example, for a carboxylic acid containing A, the amount can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents.

[0295] The above reaction can use solvents and is not particularly limited, but for example, halogenated solvents such as DCM, chloroform, DCE, carbon tetrachloride; ether solvents such as diethyl ether, diisopropyl ether, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME, TBME, CPME, diisopropyl ether, isosorbide dimethyl ether, diglyme, triglyceride, tetraglyceride; ketone solvents such as acetone, MEK, MIBK, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone; urea solvents such as TMU, DMI, DMPU; amide solvents such as DMF, DMA, NFM, NMP, NEP, NBP; DM In addition to sulfoxide solvents such as SO, ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone), pentyl acetate, and methyl propionate, sulfone solvents such as diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, and ethyl isopropyl sulfone, aromatic solvents such as anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, and pyridine, carbonate solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate, as well as solvents such as acetonitrile and limonene can be used. A single solvent may be used, or a mixture of multiple solvents may be used. Additives may be used if necessary, for example, Ag2O, 12-crown-4, 15-crown-5, 18-crown-6, HMPA, TMEDA, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide can be used as additives. When additives are used, the equivalent amount of the additive can be appropriately set by those skilled in the art, for example, 0.01 to 100 equivalents, 0.01 to 75 equivalents, 0.01 to 50 equivalents, 0.01 to 30 equivalents, 0.1 to 30 equivalents, or 0.1 to 10 equivalents relative to AX.The reaction temperature can be set appropriately by those skilled in the art, for example, -20 to 150°C, 0 to 120°C, 20 to 100°C, or 20 to 60°C. The reaction time can be set appropriately by those skilled in the art, for example, by the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or by predicting the time based on the study results using some method, or by determining or confirming the end of the reaction by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0296]

[0211]

[0297] [ka]

[0298] The sulfone bond acting as a linker can be formed, for example, by the reaction of an aryl halide or its derivative with an alkyl halide or its derivative and sulfur dioxide or a sulfur dioxide equivalent. In the above formula, if A includes a solid support, the reactive functional group X linked to A is a halogen or -O-SO2-R 5 And; R 5 C may be substituted with one or more fluorine atoms. 1-6 Alkyl, or C1 or more fluorine atoms or C1 which may be substituted with fluorine atoms 1-6 A phenyl which may be alkyl-substituted, and using a metal catalyst, the reactive functional group Y linked to B is halogen or -O-SO2-R 5A sulfone bond acting as a linker can be formed by reacting a hydroxyalkyl derivative with sulfur dioxide or a sulfur dioxide equivalent. The sulfur dioxide equivalent is not particularly limited as long as it is commonly available, but for example, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, sulfur dioxide 1-methylpyrrolidine adduct, potassium pyrosulfite, etc., can be used. The equivalent amount of the alkyl halide or derivative containing B used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to AX. The equivalent amount of sulfur dioxide or sulfur dioxide equivalent used can be appropriately set by a person skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to AX. The metal catalyst is not particularly limited as long as it is one that can be used normally, but examples of catalysts that can be used include palladium acetate, Pd(dba)2, Pd2(dba)3, Pd2(dba)3CHCl3, allyl palladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl)palladium chloride dimer, and (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II). Ligands may be used if necessary, for example, trialkylphosphines (PCy (tricyclohexylphosphine), P(tBu)3 (tri-tert-butylphosphine), cataCXium A (di(1-adamantyl)-n-butylphosphine), (tBu)2PMe (di-tert-butylmethylphosphine), P(Ad)3, neopentyl(tBu)2P (di-tert-butylneopentylphosphine), etc.), triarylphosphines (PPh3 (triphenylphosphine), etc.), dialkylbiarylphosphines (XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl),BrettPhos(2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), DavePhos(2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), RockPhos(2-di(tert-butyl) Phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me4tBuXPhos(2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl), tBuBrettPhos(2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-di Methoxy-1,1'-biphenyl), AdBrettPhos (2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), etc.), dialkylmonoarylphosphine (APhos ((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine), tBu)2PPh, MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine), etc.), bidentate phosphine ligand (dppf (1,1'-bis(diphenylphosphino) Ferocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), Josiphos ((R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), NHC ligand (IPr (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene),SIPr (1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene), IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)) can be used as ligands. Furthermore, the above ligands and palladium catalyst precursors may also be used, for example, Buchwald first-generation catalyst precursors (G1) (XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, tBuXPhos Pd G1, etc.), Buchwald second-generation catalyst precursors (G2) (XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, APhos Pd G2, tBu)2PPh Pd G2, MorDalPhos Pd G2, PCy3Pd G2, P(tBu)3Pd G2, cataCXium A Pd G2, XantPhos Pd Buchwald third generation catalyst precursors (G3) (XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, RockPhos Pd G3, Me4tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, APhos Pd G3, (tBu)2PPh Pd G3, MorDalPhos Pd G3, PCy3Pd G3, P(tBu)3Pd G3, cataCXium A Pd G3, tBu)2PMe Pd G3, neopentyl tBu)2P Pd G3, dppf Pd G3, dtbpf Pd G3, BINAP Pd G3, XantPhos Pd G3, Josiphos Pd G3, etc.), Buchwald fourth-generation catalyst precursors (G4) (XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, tBuBrettPhos Pd G4,APhos Pd G4, PCy3Pd G4, P(tBu)3Pd G4, cataCXium A Pd G4, dppf Pd G4, BINAP Pd G4, XantPhos Pd G4, etc.), dichloropalladium(II) complexes (Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, (APhos)2PdCl2, etc.), palladium(O) complexes (tetrakistriphenylphosphine palladium(O), bis(tricyclohexylphosphine)palladium(O), bis(tri-tert-butylphosphine)palladium(O), etc.), palladium(I) halide complexes (bromo(tri-tert-butylphosphine)palladium(I) dimer, iod(tri-tert-butylphosphine)palladium(I) dimer, etc.), phosphine π-allyl palladium catalysts (XPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(clotyl)Cl(chloro(clotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos Pd(clotyl)]OTf(clotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf(allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhosPd(clotyl)Cl(chloro(clotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphin)]palladium(II)),P(Cy)3Pd(clotyl)Cl(chloro(clotyl)(tricyclohexylphosphine)palladium(II)), [P(tBu)3]Pd(clotyl)Cl(tri-tert-butylphosphine(chloro)(clotyl)palladium(II)), [BINAP Pd(allyl)]Cl((R)-BINAP Pd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene]palladium(II) chloride), [XantPhos Pd(allyl)]Cl(ally[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride), etc., PEPPSI catalyst (Pd-PEPPSI IPr, Pd-PEPPSI SIPr((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), Pd-PEPPSI IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene), (NHC)Pd(allyl)Cl catalyst (allyl[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinilidene]chloropalladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]chloro[3-phenylallyl]palladium(II), etc.), NHC-Pd naphthoquinone catalyst (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(0, Dimers, etc., can be used as precursors for the palladium catalyst. The equivalent weight of the metal catalyst used can be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX. The equivalent weight of the ligand used can be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX. The equivalent weight of the catalyst precursor used can be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to AX.

[0299]

[0212] The above reaction can use a solvent and is not particularly limited, but for example, halogenated solvents (DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), carbon tetrachloride, etc.), ether solvents (diethyl ether, diisopropyl ether, THF (tetrahydrofuran), 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether, di (Glymm, triglycerides, tetraglycerides, etc.), ketone solvents (acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, diethyl ketone, etc.), urea solvents (TMU (N,N,N',N'-tetramethylurea), DMI (1,3-dimethyl-2-imidazolidinone), DMPU (N,N'-dimethylpropyleneurea), etc.), amide solvents (DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formamide) (Lumorpholine), NMP (N-methyl-2-pyrrolidone), NEP (N-ethyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone), formamide, etc.), sulfoxide solvents (DMSO (dimethyl sulfoxide), methylphenyl sulfoxide, etc.), sulfone solvents (diphenyl sulfone, dimethyl sulfone, diethyl sulfone, sulfolane, 3-methylsulfolane, ethylmethyl sulfone, ethyl isopropyl sulfone, etc.), ester solvents (methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isopropyl acetate) In addition to butyl, GVL (γ-valerolactone), pentyl acetate, methyl propionate, etc., aromatic hydrocarbon solvents (anisole, toluene, xylene, chlorobenzene, bromobenzene, ethylbenzene, nitrobenzene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene, etc.), carbonate solvents (dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc.), and hydrocarbon solvents (hexane, pentane, heptane, cyclohexane, etc.), acetonitrile, silene, limonene, etc. can also be used.A single solvent may be used, or a mixture of multiple solvents may be used. The reaction temperature can be set as appropriate by those skilled in the art, for example, 0 to 200°C, 0 to 140°C, 10 to 100°C, or 20 to 60°C. If necessary, a base may be used. For example, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, etc.), NaOtBu, KOtBu, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine, DIPEA, DBU, DBN, MTBD, TMG, BTMG, P1tBu, BEMP, BTPP, P2Et, P2tBu, sodium tetraborate, 1,8-bis(dimethylamino)naphthalene, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, tetrabutylammonium fluoride, etc. can be used as a base. The number of equivalent amounts of base used can be appropriately set by those skilled in the art. For example, relative to AX, it can be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents. The reaction time can be appropriately set by those skilled in the art. For example, it can be the time required to reach a sufficient conversion rate in a study experiment (also called a model experiment) using the substrate in question or a similar substrate, or the time that can be predicted by some method based on the study results, or the end of the reaction can be determined or confirmed by cleaving the product from a portion of the solid support. After the reaction is complete, the target compound can be obtained by a normal workup method.

[0300]

[0213] When B in the above formula contains a solid support, the reaction can be carried out using the reagents and reaction conditions already described. Here, the equivalent amount of aryl halide containing A used can be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the alkyl halide containing B. The equivalent amount of sulfur dioxide or sulfur dioxide equivalent can also be appropriately set by those skilled in the art, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to the alkyl halide containing B. The equivalent amount of metal catalyst used can also be appropriately set by those skilled in the art, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the alkyl halide containing B. The equivalent weight of the ligand to be used can be appropriately set by a person skilled in the art. For example, relative to an alkyl halide containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The equivalent weight of the catalyst precursor to be used can be appropriately set by a person skilled in the art. For example, relative to an alkyl halide containing B, it can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents.

[0301]

[0214]

[0302] [ka]

[0303]

[0215] The thioether bond as a linker can be formed by an aromatic nucleophilic substitution reaction using an aryl halide or its derivative with a thiol, a catalytic coupling reaction using a metal catalyst, or a nucleophilic substitution reaction using an alkyl halide, a hydroxyalkyl halide or its derivative with a thiol.

[0304] In the above formula, if A includes a solid support and A-X is an aryl halide or a derivative thereof, the reactive functional group X linked to A is a halogen or a group derived from a hydroxyl group. Examples of groups derived from a hydroxyl group include methanesulfonyl group, trifluoromethanesulfonyl group, nonafluorobutanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, and 2,4-dinitrobenzenesulfonyl group. Ax can be reacted with a thiol linked to B in the presence of a base. Here, the base is not particularly limited as long as it is one that can be used normally, but for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tetraalkylammonium hydroxide (tetramethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, etc.), ces...

Claims

1. A method for forming a carbon-carbon bond by the Suzuki coupling reaction, wherein a leaving group X is placed on the carbon atom of the aromatic ring. ８ Compound V having the leaving group and a boron atom-containing compound W in which a boron atom is linked to a carbon atom and capable of carbon-carbon bond formation reaction by substitution with the leaving group are used to form 1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane. Palladium Buchwald fourth-generation catalyst precursor (meCgPPh Pd G4) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)((dtbpf)PdCl ２ The process involves reacting a palladium catalyst containing at least one selected from the group consisting of ) in the presence of an organic base, X ８ is a halogen atom or -O-SO ２ -R ５ And; R ５ C may be substituted with one or more fluorine atoms. １－６ Alkyl, or C1 or more fluorine atoms or C1 which may be substituted with fluorine atoms １－６ Phenyl may be substituted with alkyl; 1) The compound V is a compound supported on a solid-phase synthesis resin, or 2) The boron atom-containing compound W is a compound supported on a solid-phase synthesis resin. 1) If the compound V is a compound supported on a solid-phase synthesis resin, the solid-phase synthesis resin has compound Va in its side chain via a decomposable linker, Compound Va contains X ８ -Ar ８ the compound represented by in a part of its chemical structure, The boron atom-containing compound W is X ９ -Ar ９ or X ９ -CR ６ R ７ R ８ It is a compound having a boron atom-containing group that is linked to a carbon atom by a boron atom, represented as [formula]. 2) When the boron atom-containing compound W is a compound supported on a solid-phase synthesis resin, the solid-phase synthesis resin has a boron atom-containing compound Wa in its side chain via a decomposable linker, Boron atom-containing compound Wa, X ９ -Ar ９ or X ９ -CR ６ R ７ R ８ It is a compound having a boron atom-containing group that is linked to a carbon atom by a boron atom, represented as [formula]. The compound V is X ８ -Ar ８ It is a compound represented by the following: Here, X ９ is -B(-OR １０ ) (- OR １１ ), -BF ３ K, or (a), (b), (c), or (d) below 【Chemistry 1】 And M is lithium, sodium, or potassium. R １０ and R １１ Each of these is independently a hydrogen atom, or C １－６ Alkoxy or C ６－１０ C may be substituted with aryl. １－６ Alkyl, or R １０ and R １１ Together with the intervening oxygen and boron atoms, it forms a 5-8 member saturated or unsaturated ring, and this ring is C １－６ alkyl group, C １－６ Alkoxy and C ６－１０ They may be substituted with one or more substituents selected from aryl groups. The Ar 8 may be independently selected from the group consisting of phenyl, naphthyl, pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triaryl, pyrimidyl, pyrazinyl, pyridadinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothiophenyl, benzofuranil, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, and imidazopyridyl, and each of these may be substituted. Ar ９ C ６－１０ A 5- to 10-membered heteroaryl comprising an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C １－６ Alkyl, C １－６ Alkoxy, (C １－６ Alkoxy) carbonyl, (C １－６ Alkoxy) carbonylamino, (C １－６ Alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C) １－６ Alkyl)amino, 4-8 membered cyclic amino, aminocarbonyl, (C １－６ Alkyl)aminocarbonyl, di(C １－６ It may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl groups. R ６ , R ７ and R ８ Each is independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－８ Cycloalkyl, C ７－１４ Aralkil, (C １－６ (Alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N, and S, C ６－１０ A 5- to 10-membered heteroaryl comprising an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C １－６ Alkyl, C １－６ Alkoxy, (C １－６ Alkoxy) carbonyl, (C １－６ Alkoxy) carbonylamino, (C １－６ Alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C) １－６ Alkyl)amino, 4-8 membered cyclic amino, and aminocarbonyl, (C １－６ Alkyl)aminocarbonyl, di(C １－６ The method, wherein the molecule may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl groups.

2. The method according to claim 1, wherein the organic base is selected from the group consisting of organic bases whose conjugate acid pKa in acetonitrile is 23 or higher, and two or more different bases may be used.

3. The method according to either claim 1 or 2, wherein the organic base is selected from the group consisting of amidines, guanidines, and phosphazenes.

4. The aforementioned organic bases are 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]deca-5-ene (MTBD), and 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ. ５ ,4λ ５ -Catenadi(phosphazene)(P2Et),1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ The method according to any one of claims 1 to 3, selected from the group consisting of -catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphoran (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), and tert-butylimino-tri(pyrrolidino)phosphoran (BTPP).

5. The method according to any one of claims 1 to 4, wherein the organic base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG).

6. The aforementioned X ８ The method according to claim 1, wherein the atom is a halogen atom.

7. The aforementioned X ８ The method according to any one of claims 1 or 6, wherein the atom is a bromine atom.

8. The Ar ８ The method according to any one of claims 1 to 7, wherein the member selected from the group consisting of phenyl and pyridyl may be substituted in any one of the claims 1 to 7.

9. The boron atom-containing compound Wa is X ９ -Ar ９ And, Ar ９ C ６－１０ A 5- to 10-membered heteroaryl comprising an aryl or one or more ring heteroatoms independently selected from O, N, and S, each of which is a fluorine atom, cyano, or C １－６ Alkyl, C １－６ Alkoxy, (C １－６ Alkoxy) carbonyl, (C １－６ Alkoxy) carbonylamino, (C １－６ Alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C １－６ Alkyl)amino, 4-8 membered cyclic amino, aminocarbonyl, (C １－６ Alkyl)aminocarbonyl, di(C １－６ The method according to claim 1, which may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl and 4- to 8-membered cyclic aminocarbonyl groups.

10. The method according to any one of claims 1 and 6 to 8, wherein the reaction is carried out in a mixture containing a solid-phase synthesis resin having two or more different compounds Va in its side chain as a substrate.

11. The method according to any one of claims 1 or 9, wherein the reaction is carried out in a mixture containing a solid-phase synthesis resin as a substrate, the solid-phase synthesis resin containing two or more different boron atom-containing compounds Wa in its side chains.

12. The method according to any one of claims 6 to 11, wherein the solid-phase synthesis resin is bonded to compound Va via a linker containing a benzyl ether structure, or to boron atom-containing compound Wa via a linker containing a benzyl ether structure.

13. The benzyl ether structure is as follows: 【Chemistry 2】 The method according to claim 12.

14. A method for producing compounds constituting a compound library, comprising a method for forming a carbon-carbon bond by the method described in any one of claims 1 to 13.

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