Bifunctional compounds for the degradation of BTK via the ubiquitin-proteasome pathway

Abstract

This disclosure relates to compounds useful for degrading BTK via the ubiquitin protein degradation pathway. This specification also provides pharmaceutically acceptable compositions comprising such compounds, and methods for using these compositions in the treatment of various diseases, conditions, or disorders. [Solution] A method for treating or preventing an autoimmune disease or cancer in a subject requiring such treatment, comprising the step of orally administering a certain amount of a bifunctional compound to the subject, wherein the bifunctional compound can induce proteolysis of Bruton's tyrosine kinase, and the amount is effective in treating or preventing an autoimmune disease or cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Application No. 62 / 943,720 filed on 4 December 2019 and U.S. Provisional Application No. 63 / 010,524 filed on 15 April 2020, and incorporates International Application PCT / US2019 / 56112 filed on 14 October 2019, each of which is incorporated in whole by reference.

[0002]

[0002] This disclosure describes how to degrade targeted Bruton's tyrosine kinase (BTK). This invention provides novel bifunctional compounds for this purpose, and methods for treating diseases regulated by BTK. [Background technology]

[0003]

[0003] B cell receptor (BCR) signaling regulates B cell development, as well as mature B cell activation, signaling, and survival. Misregulation of the BCR signaling pathway is associated with signs of many diseases related to B cell function, and targeting B cells and BCR signaling has clear therapeutic potential (Woyach et al.; Blood, 120(6); 1175-1184, (2012). For example, B cell depletion by monoclonal antibodies targeting CD20 is B It has a significant impact on the treatment of cellular malignancies, autoimmune diseases, and inflammatory diseases (Cang et al.; J Hematolo Oncol. 5;64, 2012).

[0004]

[0004] BTK is a member of the TEC family of kinases and is an important signaling hub in the BCR pathway. Mutations in BTK cause X-linked agammaglobulinemia (XLA), in which B cell maturation is impaired and immunoglobulin production is reduced. (Hendriks et al.; Expert Opin Ther Targets 15;1002-1021, 2011). B cell signals Due to its central role in signal transduction and function, BTK is an attractive therapeutic target for B-cell malignancies, as well as autoimmune and inflammatory diseases. Ibrutinib, a covalent inhibitor of BTK, is used in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. To treat MCL (mammary leukemia) and other B-cell malignancies, as well as graft-versus-host disease (GvHD) It is approved (Miklos et al.; Blood, 120(21); 2243-2250, 2017). Currently, ibrutinib and second-generation BTK inhibitors are being investigated for oncological and immunological indications, such as rheumatoid arthritis (Akinleye et al.; J of Hematolo Oncol. 6: 59, 2013; Liu et al.; J Pharm). and Exper Ther. 338(1): 154-163. 2011; Di Paolo et al.; Nat Chem Biol. 7(1): 41-50, 2011).

[0005]

[0005] As an alternative to stoichiometric inhibition, proteolysis of BTK can have dramatic consequences for B cell function by effectively blocking BCR signaling. By removing the BTK protein, BTK kinase activity, as well as any protein interaction or scaffold function of BTK, will be eliminated. Specific degradation of BTK can be achieved by promoting BTK ubiquitination and proteasomal degradation by recruiting BTK to a ubiquitin ligase using heterobifunctional small molecules. Thalidomide derivatives such as lenalidomide or pomalidomide can be used to recruit potential substrates to cereblon (CRBN), a component of the ubiquitin ligase complex. This unique therapeutic approach may present a mechanism of action for interfering with BTK activity and BCR signaling that differs from the mechanism of stoichiometric BTK inhibition. Furthermore, this degradation approach can effectively target the C481S mutant of BTK, which is clinically observed. This is a known effect and leads to resistance to inhibition by ibrutinib (Woyach et al.; Blood, 120(6): 1175-1184, 2012). [Overview of the project] [Problems that the invention aims to solve]

[0006]

[0006] Currently, there is still a need for a bifunctional molecule that can induce in vivo proteolysis of BTK via the ubiquitin proteolysis pathway. [Means for solving the problem]

[0007]

[0007] Provided herein is a method using a bifunctional compound that induces proteolysis of BTK via the ubiquitin proteolysis pathway.

[0008]

[0008] In one embodiment, the foregoing provides a method for treating or preventing cancer in a subject in need. These methods include the step of orally administering to a subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, this amount is effective for treating or preventing cancer.

[0009]

[0009] In another embodiment, methods for degrading Bruton's tyrosine kinase in a subject requiring such degradation are provided herein. These methods include the step of orally administering to a subject an amount of a bifunctional compound capable of inducing proteolytic degradation of Bruton's tyrosine kinase. In a particular embodiment, this amount is effective in degrading Bruton's tyrosine kinase in the subject.

[0010]

[0010] In another embodiment, methods for preventing B cell activation in subjects requiring it are provided herein. These methods include the step of orally administering to a subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, this amount is effective in preventing B cell activation.

[0011]

[0011] In another embodiment, methods for degrading mutant Bruton's tyrosine kinases are provided herein. These methods include contacting cells expressing mutant Bruton's tyrosine kinases with an amount of a bifunctional compound that can induce proteolysis of Bruton's tyrosine kinases. In certain embodiments, this amount is effective in degrading mutant Bruton's tyrosine kinases. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481 mutant. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481S mutant.

[0012]

[0012] In these methods, the bifunctional compound comprises a moiety capable of specifically binding BTK and further comprises a moiety capable of mobilizing a ubiquitin ligase to degrade BTK. Specific compounds are described herein. These compounds can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions. [Brief explanation of the drawing]

[0013] [Figure 1]

[0013] This figure shows the degradation of BTK by the compounds specified herein in B lymphoma cell lines and primary human B cells. [Figure 2]

[0014] This figure shows the degradation of wild-type BTK and ibrutinib-resistant C481S BTK by the compounds described herein. [Figure 3]

[0015] This figure demonstrates the highly selective degradation of BTK by the compounds described herein. [Figure 4]

[0016] This figure demonstrates the increased viability of C481S BTK cells that showed increased sensitivity to the compounds described herein compared to ibrutinib. [Figure 5]

[0017] This figure demonstrates that the compounds described herein prevent B cell activation. [Figure 6]

[0018] This figure demonstrates dose-proportional degradation of BTK in splenocytes after oral administration of the compounds described herein to mice. [Figure 7]

[0019] This figure demonstrates a dose- and time-proportional decrease in BTK in circulating B cells after oral administration of the compounds described herein. [Figure 8]

[0020] This figure demonstrates the antitumor activity of the compounds specified herein after oral administration of the compounds to mice in xenograft models of tumors and ibrutinib-resistant tumors. [Figure 9]

[0021] This figure demonstrates the degradation of the BTK neosubstrate Aiolos. [Figure 10A]

[0022] This figure shows the effects of compounds 73, 72, 121, and 44, as well as the control compound, on neosubstrate and ITK or BTK levels in MOLT4 cells after 24 hours. [Figure 10B] This figure shows the effects of compounds 73, 72, 121, and 44, as well as the control compound, on neosubstrate and ITK or BTK levels in TMD8 cells after 24 hours. [Figure 11A]

[0023] This figure shows the effects of compounds 44, 72, and 149, as well as the control compound, on CRBN neosubstrate and ITK levels in MOLT4 cells. [Figure 11B] This figure shows the effects of compounds 44, 72, and 149, as well as the control compound, on CRBN neosubstrate and ITK levels in TMD8 cells. [Figure 12]

[0024] This figure shows the effects of compounds 130, 149, and 44 on ITK levels and IMiD activity. [Figure 13A]

[0025] This figure shows the degradation of TEC by a chimeric target molecule (CTM) in K562 cells. [Figure 13B] This figure shows the degradation of TEC by a chimeric target molecule (CTM) in K562 cells. [Figure 13C] This figure shows the degradation of TEC by a chimeric target molecule (CTM) in K562 cells. [Figure 13D] This figure shows the degradation of TEC by a chimeric target molecule (CTM) in K562 cells. [Modes for carrying out the invention]

[0014]

[0026] Provided herein is a method using a bifunctional compound that induces proteolysis of Bruton's tyrosine kinase (BTK) via the ubiquitin proteolysis pathway. be.

[0015]

[0027] When used herein, unless otherwise specified, the following definitions shall apply: definition

[0016]

[0028] For the purposes of this specification, chemical elements are identified according to the Periodic Table, CAS edition, Handbook of Chemistry and Physics, 75th Ed. Furthermore, general principles of organic chemistry are identified according to "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced This information is contained in "Organic Chemistry," 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and is incorporated herein by reference.

[0017]

[0029] As described herein, a “protecting group” is a part or functional group that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. This refers to a protective group. Standard protecting groups are described in Wuts and Greene: "Greene's Protective Groups in Organic Synthesis," 4th Ed, Wuts, PGM and Greene, TW, Wiley-Interscience, New York: 2006.

[0018]

[0030] As described herein, the compounds herein may be optionally substituted with one or more substituents, such as those generally illustrated herein or those exemplified by certain classes, subclasses and species in the specification.

[0019]

[0031] As used herein, the terms "hydroxyl" or "hydroxy" refer to the -OH moiety.

[0020]

[0032] As used herein, the term “aliphatic” encompasses the terms alkyl, alkenyl, and alkynyl, which are optionally substituted for each other as described below.

[0021]

[0033] As used herein, the “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 carbon atoms (e.g., 1 to 8, 1 to 6, or 1 to 4). The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. Alkyls include halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), heteroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaloyl, acyl (e.g., (aliphatic) carbonyl, (alicyclic) carbonyl or (heteroalicyclic) carbonyl), nitro, cyano, and amides (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl It may be substituted with one or more substituents such as (i.e., optionally substituted) hydroxy, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl, amino (e.g., aliphatic amino, alicyclic amino, or heteroalicyclic amino), sulfonyl (e.g., aliphatic-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, alicyclic oxy, heteroalicyclic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Some examples of substituted alkyls include, but are not limited to, carboxyalkyls (such as HOOC-alkyls, alkoxycarbonylalkyls, and alkylcarbonyloxyalkyls), cyanoalkyls, hydroxyalkyls, alkoxyalkyls, acylalkyls, aralkyls, (alkoxyaryl)alkyls, (sulfonylamino)alkyls (such as (alkyl-SO2-amino)alkyls), aminoalkyls, amidealkyls, (alicyclic)alkyls, or haloalkyls.

[0022]

[0034] As used herein, the “alkenyl” group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. Like alkyl groups, alkenyl groups may be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. Alkenyl groups can be halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), and hexenyl groups. Teroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaloyl, acyl (e.g., (aliphatic) carbonyl, (alicyclic) carbonyl or (heteroalicyclic) carbonyl), nitro, cyano, amide (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl) It may be optionally substituted with one or more substituents such as (bonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, alicyclic amino, heteroalicyclic amino, or aliphatic sulfonylamino), sulfonyl (e.g., alkyl-SO2-, alicyclic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, alicyclic oxy, heteroalicyclic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Some examples of substituted alkenyls include, but are not limited to, cyanoalkenyls, alkoxyalkenyls, acylalkenyls, hydroxyalkenyls, aralkenyls, (alkoxyaryl)alkenyls, (sulfonylamino)alkenyls (such as (alkyl-SO2-amino)alkenyls), aminoalkenyls, amidealkenyls, (alicyclic)alkenyls, or haloalkenyls.

[0023]

[0035] As used herein, the “alkynyl” group refers to an aliphatic carbon group having 2 to 8 carbon atoms (e.g., 2 to 12, 2 to 6, or 2 to 4) and at least one triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups include aroyl, heteroaloyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl (e.g., aliphatic sulfanyl or alicyclic sulfanyl), sulfinyl (e.g., aliphatic sulfinyl or alicyclic sulfinyl), sulfonyl (e.g., aliphatic-SO2-, aliphatic-amino-SO2-, or alicyclic-SO2-), amide (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, aryl It may be optionally substituted with one or more substituents such as (alkaline carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, or heteroarylaminocarbonyl), urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, alicyclic, heteroalicyclic, aryl, heteroaryl, acyl (e.g., (alicyclic)carbonyl or (heteroalicyclic)carbonyl), amino (e.g., aliphatic amino), sulfoxy, oxo, carboxy, carbamoyl, (alicyclic)oxy, (heteroalicyclic)oxy, or (heteroaryl)alkoxy.

[0024]

[0036] As used herein, “amide” encompasses both “aminocarbonyl” and “carbonylamino.” These terms, when used alone or in combination with another group, are -N(R) when used at the end of a group. X )-C(O)-RY or -C(O)-N(R X )2 and when used internally -C(O)-N(R X )- or -N(R X )-C(O)- and the like refer to an amide group, wherein R X and R Y may be aliphatic, alicyclic, aryl, araliphatic, heterocyclic, heteroaryl, or heteroaraliphatic. Examples of amide groups include alkyl amides (such as alkylcarbonylamino or alkylaminocarbonyl, etc.), (heterocyclic) amides, (heteroaralkyl) amides, (heteroaryl) amides, (heterocycloalkyl) alkyl amides, aryl amides, aralkyl amides, (cycloalkyl) alkyl amides, or cycloalkyl amides.

[0025]

[0037] As used herein, the "amino" group refers to -NR X R Y wherein R X and R Y are each independently hydrogen (H or -H), aliphatic, alicyclic, (alicyclic) aliphatic, aryl, araliphatic, heterocyclic, (heterocyclic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (alicyclic) carbonyl, ((alicyclic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocyclic) carbonyl, ((heterocyclic) aliphatic) carbonyl, (heteroaryl) carbonyl, or (heteroaraliphatic) carbonyl, each of which is defined herein and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), this is represented by -NR X - wherein R X has the same meaning as previously defined.

[0026]

[0038] As used herein, the “aryl” group, when used alone or as part of a larger phrase such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl), and tricyclic (e.g., fluorenyltetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems, where the monocyclic ring system is aromatic, or at least one ring of the bicyclic or tricyclic ring system is aromatic. Examples of bicyclic and tricyclic groups include benzo-condensed 2- or 3-membered carbocyclic rings. For example, a benzo-condensed group may have two or more C 4~8 Examples include phenyl condensed with a carbocyclic moiety. Aryls are aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (aroliphatic)oxy; (heteroaroliphatic)oxy; aroyl; heteroaloyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzo-condensed bicyclic or tricyclic aryl); nitro; carboxy; amide; acyl (e.g., (aliphatic)carbonyl; (alicyclic)carbonyl; ((lipid The compounds are optionally substituted with one or more substituents, including cyclic (aliphatic) carbonyl; (aroliphatic) carbonyl; (heteroalicyclic) carbonyl; ((heteroalicyclic) aliphatic) carbonyl; or (heteroaroliphatic) carbonyl); sulfonyl (e.g., aliphatic-SO2- or amino-SO2-); sulfinyl (e.g., aliphatic-S(O)- or alicyclic-S(O)-); sulfanyl (e.g., aliphatic-S-); cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, the aryl group may be unsubstituted.

[0027]

[0039] Non-limiting examples of substituted aryls include haloaryls (e.g., mono-, di-(p,m-dihaloaryls, etc.), and (trihalo)aryls); (carboxy)aryls (e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls, and (alkoxycarbonyl)aryls); (amide)aryls (e.g., (aminocarbonyl)aryls, (((alkylamino)alkyl)aminocarbonyl)aryls, (alkylcarbonyl)aminoaryls, (arylaminocarbonyl)aryls, and (((heteroaryl)amino)carbonyl)aryls); aminoaryls (e.g., ((alkylsulfonyl)amino)aryls or ((dialkyl)amino)aryls); (cyanoalkyl)aryls; (alkoxy)aryls; (sulfamoyl)aryls Examples include aryl (e.g., (aminosulfonyl)aryl); (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heteroalicyclic)-o-(alkyl))aryl.

[0028]

[0040] As used herein, "aromatic aliphatic" such as "aralkyl" group refers to an aliphatic group substituted with an aryl group (e.g., C 1~4 This refers to alkyl groups. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an aromatic aliphatic group, such as an aralkyl group, is benzyl.

[0029]

[0041] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group (e.g., C 1~4 This refers to alkyl groups. Both "alkyl" and "aryl" are defined previously. An example of an aralkyl group is benzyl. Aralkyl groups include aliphatic groups (e.g., alkyl, alkenyl, or alkynyl, including haloalkyls such as carboxyalkyl, hydroxyalkyl, or trifluoromethyl), alicyclic groups (e.g., cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, and It is optionally substituted with one or more substituents such as mid (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino), cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0030]

[0042] As used herein, “bicyclic ring system” includes a 6-12 (e.g., 8-12 or 9, 10 or 11) member structure that forms two rings, wherein the two rings share at least one atom in common (e.g., two atoms in common). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0031]

[0043] As used herein, the “alicyclic” group includes the “cycloalkyl” group and the “cycloalkenyl” group, which are optionally substituted as described below.

[0032]

[0044] As used herein, the “cycloalkyl” group refers to a saturated carbocyclic, monocyclic, or bicyclic (condensed or crosslinked) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cuvir, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, Examples include bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0033]

[0045] As used herein, the “cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0034]

[0046] Cycloalkyl or cycloalkenyl groups include phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (aroliphatic)oxy, (heteroaroliphatic)oxy, aroyl, heteroaloyl, amino, amide (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (aroliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or ( They may be optionally substituted with one or more substituents such as heteroaroliphatic (carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (aroliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaroliphatic)carbonyl), cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkyl-SO2- and aryl-SO2-), sulfinyl (e.g., alkyl-S(O)-), sulfanyl (e.g., alkyl-S-), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0035]

[0047] As used herein, the term “heteroalicyclic” encompasses heterocycloalkyl and heterocycloalkenyl groups, each optionally substituted as described below.

[0036]

[0048] As used herein, the “heterocycloalkyl” group refers to a 3- to 10-membered monocyclic or bicyclic (condensed, cross-linked, or spiro) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms are heteroatoms (e.g., nitrogen (N), oxygen (O), sulfur (S), or a combination thereof). Non-limiting examples of heterocycloalkyl groups include piperidyl, piperadyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl, octahydroclomenyl, octahydrothioclomenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydr Lobenzo[b]thiophenyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, decahydro-2,7-naphthyridine, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-pyrrolo[3,4-b]pyridine, and 2,6-dioxa-tricyclo[3.3.1.0 3,7 Nonyl is one example. Monocyclic heterocycloalkyl groups can condense with the phenyl moiety to form structures such as tetrahydroisoquinoline, which can be classified as heteroaryls.

[0037]

[0049] As used herein, the “heterocycloalkenyl” group refers to a monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds and one or more of the ring atoms being heteroatoms (e.g., N, O, or S). Monocyclic and bicyclic heteroalicyclic structures are numbered according to standard chemical nomenclature.

[0038]

[0050] Heterocycloalkyl or heterocycloalkenyl groups include phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (aroliphatic)oxy, (heteroaroliphatic)oxy, aroyl, heteroaloyl, amino, amide (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (aroliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or It may be optionally substituted with one or more substituents such as (hetero-aroliphatic)carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (aroliphatic)carbonyl, (hetero-alicyclic)carbonyl, ((hetero-alicyclic)aliphatic)carbonyl, or (hetero-aroliphatic)carbonyl), nitro, cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0039]

[0051] As used herein, the “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, one or more of which are heteroatoms (e.g., N, O, S, or a combination thereof), and in which the monocyclic ring system is aromatic, or in which at least one of the rings of a bicyclic or tricyclic ring system is aromatic. Examples of heteroaryl groups include benzo-condensed ring systems having 2 to 3 rings. For example, examples of benzo-condensed groups include benzos (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl) condensed with one or two 4 to 8-membered heteroalicyclic moieties. Some examples of heteroaryls are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, prill, cinnolyl, quinolyl, quinazolyl, phthalazyl, quinazolyl, quinoxalil, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthilidyl. Other examples of heteroaryls include 1,2,3,4-tetrahydroisoquinoline and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0040]

[0052] Examples of monocyclic heteroaryls include, but are not limited to, furyl, thiophen-yl, 2H-pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-planyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0041]

[0053] Examples of bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indazolyl, benzimimidazyl, benzthiazolyl, prinyl, 4H-quinolidyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthylidyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0042]

[0054] Heteroaryls include aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (aroliphatic)oxy; (heteroaroliphatic)oxy; aroyl; heteroaloyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amide; acyl (e.g., aliphatic carbonyl; (alicyclic) carbonyl) ;((alicyclic)aliphatic)carbonyl;(aroliphatic)carbonyl;(heteroalicyclic)carbonyl;((heteroalicyclic)aliphatic)carbonyl;or(heteroaroliphatic)carbonyl);sulfonyl (e.g., aliphatic sulfonyl or aminosulfonyl);sulfinyl (e.g., aliphatic sulfinyl);sulfanyl (e.g., aliphatic sulfanyl);nitro;cyano;halo;hydroxy;mercapto;sulfoxy;urea;thiourea;sulfamoyl;sulfamide;or carbamoyl; and other substituents, optionally substituted with one or more substituents. Alternatively, heteroaryls may be unsubstituted.

[0043]

[0055] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls (e.g., mono- and di-(halo)heteroaryls); (carboxy)heteroaryls (e.g., (alkoxycarbonyl)heteroaryls); cyanoheteroaryls; aminoheteroaryls (e.g., ((alkylsulfonyl)amino)heteroaryls, and ((dialkyl)amino)heteroaryls); (amide)heteroaryls (e.g., aminocarbonylheteroaryls, ((alkylcarbonyl)amino)heteroaryls, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heteroalicyclic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls); (cyanoalkyl)heteroaryls; (alkoxy)heteroaryls; (sulfamoyl) Examples include heteroaryls (e.g., (aminosulfonyl) heteroaryls); (sulfonyl) heteroaryls (e.g., (alkylsulfonyl) heteroaryls); (hydroxyalkyl) heteroaryls; (alkoxyalkyl) heteroaryls; (hydroxy) heteroaryls; ((carboxy)alkyl) heteroaryls; (((dialkyl)amino)alkyl) heteroaryls; (heteroalicyclic) heteroaryls; (alicyclic) heteroaryls; (nitroalkyl) heteroaryls; (((alkylsulfonyl)amino)alkyl) heteroaryls; ((alkylsulfonyl)alkyl) heteroaryls; (cyanoalkyl) heteroaryls; (acyl) heteroaryls (e.g., (alkylcarbonyl) heteroaryls); (alkyl) heteroaryls; or (haloalkyl) heteroaryls (e.g., trihaloalkyl heteroaryls).

[0044]

[0056] As used herein, "hetero-aromatic aliphatic" (hetero-aralkyl group, etc.) refers to an aliphatic group substituted with a heteroaryl group (e.g., C 1~4 This refers to alkyl groups. "Aliphatic," "alkyl," and "heteroaryl" are defined previously.

[0045]

[0057] As used herein, the term "heteroaralkyl" group is a heteroaryl group. Substituted alkyl group (e.g., C 1~4 This refers to alkyl groups. Both "alkyl" and "heteroaryl" are defined first. Heteroaryl groups include alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, It is optionally substituted with one or more substituents such as alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0046]

[0058] As used herein, “cyclic moiety” and “cyclic group” refer to monocyclic, bicyclic, and tricyclic ring systems, including alicyclic, heteroalicyclic, aryl, or heteroaryl ring systems, which have already been defined.

[0047]

[0059] As used herein, “crosslinked bicyclic ring system” refers to a bicyclic heteroalicyclic ring system or a bicyclic alicyclic ring system in which the rings are crosslinked. Examples of crosslinked bicyclic ring systems include adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3,7 Examples include nonyl compounds, but are not limited to these. Crosslinked bicyclic ring systems include alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, It may be optionally substituted with one or more substituents such as alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0048]

[0060] As used herein, the "acyl" group is a formyl group or R X -C(O)- (also called alkylcarbonyl, such as alkyl-C(O)-), and in the formula, R X The terms "and alkyl" have already been defined. Acetyl and pivaloyl are examples of acyl groups.

[0049]

[0061] As used herein, “alloyl” or “heteroalloyl” refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of aloyl or heteroalloyl are optionally substituted as already defined herein.

[0050]

[0062] As used herein, the term "alkoxy" group refers to an alkyl-O- group, and "alkyl" is already defined herein.

[0051]

[0063] As used herein, the "carbamoyl" group refers to the structure -O-CO-NR X R Y or -NR X -CO-OR Z This refers to a group having R, in the formula X and R Y This has been defined earlier, R Z It may be aliphatic, aryl, aromaticaliphatic, heteroalicyclic, heteroaryl, or heteroaroliphatic.

[0052]

[0064] As used herein, the term "carboxyl" group refers to -COOH when used as a terminal group, or to -OC(O)- or -C(O)O- when used as an internal group.

[0053]

[0065] As used herein, ester means -COOR when used as a terminal group. X It refers to, or when used as an internal group, -COOR X - refers to, and in the formula, R X This has already been defined.

[0054]

[0066] As used herein, "formate" refers to -OC(O)H.

[0055]

[0067] As used herein, acetate refers to -OC(O)R X It refers to, and in the formula, R X This has already been defined.

[0056]

[0068] As used herein, the term "haloaliphatic" group refers to an aliphatic group substituted with one to three halogens. For example, the term haloalkyl includes the group -CF3.

[0057]

[0069] As used herein, the "mercapto" or "sulfhydryl" group refers to the -SH group.

[0058]

[0070] As used herein, the "sulfo" group, when used at the terminal, refers to -SO3H or -SO3R. X It refers to -S(O)3- when used internally.

[0059]

[0071] As used herein, the "sulfamide" group, when used at the terminal, refers to the structure-NR X -S(O)2-NR Y R Z This refers to -NR when used internally. X -S(O)2-NR Y - refers to, and in the formula, R X , R Y , and R Z This has already been defined.

[0060]

[0072] As used herein, the "sulfamoyl" group refers to the structure-OS(O)2-NR Y R Z It refers to, and in the formula, R Y and R Z This has already been defined.

[0061]

[0073] As used herein, the "sulfonamide" group, when used at the terminal, refers to the structure -S(O)2-NR X R Y Or -NR X -S(O)2-R ZIt refers to, or when used internally, -S(O)2-NR X -or -NR X -S(O)2- refers to the formula, and in the formula, R X , R Y , and R Z This has already been defined.

[0062]

[0074] As used herein, the "sulfanyl" group is -SR when used at the terminal. X It refers to -S- when used internally, and in formulas, R X This has been defined previously. Examples of sulfanils include aliphatic-S-, alicyclic-S-, and aryl-S-.

[0063]

[0075] As used herein, the "sulfinyl" group means when used at the terminal. -S(O)-R X It refers to -S(O)- when used internally, and in the formula, R X This has been defined previously. Examples of sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (alicyclic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heteroalicyclic-S(O)-, and heteroaryl-S(O)-.

[0064]

[0076] As used herein, the "sulfonyl" group, when used at the terminal, is -S(O)2-R X It refers to -S(O)2- when used internally, and in the formula, R X These have been defined previously. Examples of sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (alicyclic (aliphatic))-S(O)2-, alicyclic-S(O)2-, heteroalicyclic-S(O)2-, heteroaryl-S(O)2-, and (alicyclic (amide (aliphatic)))-S(O)2-.

[0065]

[0077] As used herein, the "sulfoxy" group, when used at the terminal, is -OS(O)-R X or -S(O)-ORX It refers to -OS(O)- or -S(O)-O- when used internally, and in formulas, R X This has already been defined.

[0066]

[0078] As used herein, the terms "halogen" or "halo" group refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0067]

[0079] As used herein, the term "carboxyl" encompasses "alkoxycarbonyl," which refers to groups such as alkyl-OC(O)-, either alone or in combination with another group.

[0068]

[0080] As used herein, “alkoxyalkyl” refers to alkyl groups such as alkyl-O-alkyl-, where alkyl is defined previously.

[0069]

[0081] As used herein, "carbonyl" refers to -C(O)-.

[0070]

[0082] As used herein, "oxo" refers to =O.

[0071]

[0083] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(R P )2 is given, and in the formula, R P These are aliphatic, alkoxy, aryloxy, heteroaryloxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryl, heteroaryl, alicyclic, or amino compounds.

[0072]

[0084] As used herein, "aminoalkyl" means structure (R X ) refers to 2N-alkyl-.

[0073]

[0085] As used herein, "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0074]

[0086] As used herein, the "urea" group refers to the structure -NR X -CO-NR Y R Z and the "thiourea" group, when used at the ends, refers to the structure -NR X -CS-NR Y R Z and when used internally, -NR X -CO-NR Y - or -NR X -CS-NR Y -, where R X , R Y , and R Z are as previously defined.

[0075]

[0087] As used herein, the "guanidine" group refers to the structure -N=C(N(R X R Y ))N(R X R Y ) or -NR X -C(=NR X )NR X R Y , where R X and R Y are as previously defined.

[0076]

[0088] As used herein, the term "amidino" refers to the structure -C=(NR X )N(R X R Y ), where R X and R Y are as previously defined.

[0077]

[0089] As used herein, the term "vicinal" generally refers to substituents being located on a group containing two or more carbon atoms and these substituents being attached to adjacent carbon atoms.

[0078]

[0090] As used herein, the term "geminal" generally refers to substituents being disposed on a group containing two or more carbon atoms, with these substituents being bonded to the same carbon atom.

[0079]

[0091] The terms "at the terminus" and "internally" refer to the position of a group within a substituent. When a group is present at the terminus of a substituent and is not further bonded to the remainder of the chemical structure, the group is at the terminus. Carboxyalkyl (i.e., R X O(O)C-alkyl) is an example of a carboxy group used at the terminus. When a group is present within the center or terminus of a substituent of a chemical structure, the group is internally. Alkyl carboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkyl carboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0080]

[0092] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., an alkyl group, an alkenyl group, or an alkynyl group). A straight-chain aliphatic chain has the structure -[CH2] v -, where v is from 1 to 12. A branched aliphatic chain is a straight-chain aliphatic chain substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ] v -, where each Q is independently hydrogen (H or -H) or an aliphatic group, provided that Q is an aliphatic group in at least one case. The term "aliphatic chain" includes alkyl chains, alkenyl chains, and alkynyl chains, and alkyl, alkenyl, and alkynyl are as previously defined.

[0081]

[0093] The phrase “optionally substituted” is used interchangeably in this specification with the phrase “substituted or unsubstituted.” As described herein, the compounds herein may be optionally substituted with one or more substituents, for example, as generally shown earlier or exemplified by certain classes, subclasses, and species described herein. As described herein, the variables R, R are included in formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), (K), (M), (X), (I), (IA), (IB), (II), (II-A), (II-B), (III), and (IV) described herein. 1 , R 2 , L, Y and Z, as well as other variables, include certain groups such as alkyl and aryl. Unless otherwise specified, variables R, R 10 , R A , R 1 , R 2 L, L 1 , D, W, E, V, G, Y, and Z, and other variables contained therein, each particular group may be optionally substituted with one or more substituents as described herein. Each particular group substituent may be further optionally substituted with one to three of the following: halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, alicyclic, heteroalicyclic, heteroaryl, haloalkyl, and alkyl. For example, alkyl groups may be substituted with alkylsulfanils, and alkylsulfanils may be optionally substituted with one to three of the following: halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of (cycloalkyl)carbonylamino may be optionally substituted with one to three of the following: halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. Two alkoxy groups, When bonded to the same atom or adjacent atoms, these two alkoxy groups can form a ring together with the atom(s) to which they are bonded.

[0082]

[0094] As used herein, the term “substituted” generally refers to a situation in which a hydrogen atom in a given structure is replaced by a radical of a particular substituent, whether preceded by the term “optionally.” The particular substituents are described earlier in the definition and in the following descriptions of compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each of its substituted positions, such that more than one position in any given structure can be replaced by more than one substituent selected from a particular group; these substituents may be the same or different at each position. Ring substituents, such as heterocycloalkyls, can bond to another ring, such as a cycloalkyl, to form a spiro-dicyclic ring system, for example, where both rings share a common atom. Non-limiting examples of spiro-heterocycloalkyls include:

[0083] [ka] These are some examples.

[0084]

[0095] As those skilled in the art will recognize, the substituent combinations assumed in this description are combinations that result in the formation of stable or chemically feasible compounds.

[0085]

[0096] As used herein, the phrase “stable or chemically feasible” means a compound that remains substantially unchanged when subjected to conditions that enable the generation, detection, and recovery, purification, and use of the compound for one or more of the purposes disclosed herein. In some embodiments, a stable or chemically feasible compound is a compound that remains substantially unchanged when held at a temperature of 40°C or below for at least one week in the absence of moisture or other chemically reactive conditions.

[0086]

[0097] As used herein, “effective dose” is defined as the amount required to produce a therapeutic effect in the patient being treated, and is typically determined based on the patient’s age, surface area, weight, and condition. The interrelationship of doses for animals and humans (based on milligrams per square meter of body surface area) is described in Freireich et al., Cancer Chemother. Rep., 50:219 (1966). Body surface area can be roughly determined from the patient’s height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, “patient” refers to mammals, including humans.

[0087]

[0098] As used herein, the term "approximately" means within ±10% of the value. For example, a dose of approximately 100 mg / kg means a dose of 90 mg / kg to 110 mg / kg. This suggests that it may be done. As further examples, amounts of additional therapeutic agents ranging from approximately 50% to approximately 100% are presented, as are amounts of additional therapeutic agents ranging from 45-55% to 90-110%. Those skilled in the art will understand the scope and application of the term “approximately” when used to describe other values ​​disclosed herein.

[0088]

[0099] Unless otherwise specified, the structures illustrated herein also mean all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational)) of that structure, such as the (R) and (S) configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers for each chiral center. Thus, single stereochemical isomers of the compound, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) forms, are included in the scope of this specification. Alternatively, as used herein, “enantiomer excess (ee)” refers to a dimensionless molar ratio representing the purity of a chiral substance, for example, containing a single stereocenter. For example, an enantiomer excess of 0 would indicate a racemate (e.g., a 50:50 enantiomer mixture, or one enantiomer not being in excess of the other). As a further example, an enantiomer excess of 99 would indicate that the enantiomer is nearly sterically pure (i.e., one enantiomer is in large excess relative to the other). Enantiomer excess in percentage, %ee = ([(R)-compound]-[(S)-compound]) / ([(R)-compound]+[(S)-compound])×100, where (R)-compound > (S)-compound; or %ee = ([(S)-compound]-[(R)-compound]) / ([(S)-compound]+[(R)-compound])×100, where (S)-compound > (R)-compound). Furthermore, as used herein, “diastereomer excess (de)” refers to a dimensionless molar ratio representing the purity of a chiral substance containing one more stereocenter than 99. For example, a diastereomer excess of 0 would indicate an equimolar mixture of diastereoisomers. As a further example, a diastereomer excess of 99 would indicate that it is a nearly sterically pure diastereomer compound (i.e., one diastereomer is in a much larger excess than the other). The diastereomer excess can be calculated in a similar manner to that for ee. As those skilled in the art will understand, de is usually reported as percent de (%de). %de can be calculated in a similar manner to that for %ee. can.

[0089]

[0100] In certain embodiments, the compounds or inhibitors described herein are It has more than 0 ee, de, %ee, or %de. For example, in a particular embodiment, the compound or inhibitor described herein has 10 ee, de, %ee, or %de. In a particular embodiment, the compound or inhibitor described herein has 25 ee, de, %ee, or %de. In a particular embodiment, the compound or inhibitor described herein has 50 ee, de, %ee, or %de. In a particular embodiment, the compound or inhibitor described herein has 75 ee, de, %ee, or %de.

[0090]

[0101] In certain embodiments, the compounds or inhibitors described herein are Having a range of 90-100 ee, de, %ee, or %de. In certain embodiments, the compounds or inhibitors described herein have a range of 95-100 ee, de, %ee, or %de. In certain embodiments, the compounds or inhibitors described herein have a range of 97-100 ee, de, %ee, or %de. In certain embodiments, the compounds or inhibitors described herein have a range of 98-100 ee, de, %ee, or %de. In certain embodiments, the compounds or inhibitors described herein have a range of 99-100 ee, de, %ee, or %de.

[0091]

[0102] In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 1. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 2. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 3. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 4. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 5. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 6. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 7. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 8. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 9. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 10. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 11. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 12. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 13. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 14. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 15. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 16. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 17. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 18.In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 19. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 20. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 21. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 22. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 23. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 24. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 25. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 26. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 27. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 28. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 29. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 30. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 31. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 32. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 33. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 34. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 35. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, and also.In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 36. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 38. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 39. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 40. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 41. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 42. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 43. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 44. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 45. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 46. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 47. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 48. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 49. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 50. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 51. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 52. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 53.In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 54. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 55. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 56. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 57. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 58. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 59. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 60. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 61. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 62. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 63. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 64. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 65. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 66. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 67. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 68. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 69. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 70.In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 71. In this specification, ee, de, %ee, or %de is 72. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 73. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 74. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 75. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 76. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 77. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 78. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 79. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 80. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 81. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 82. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 83. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 84. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 85. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 86. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 87. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 88. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 89.In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 90. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 91. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 92. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 93. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 94. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 95. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 96. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 97. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 98. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 99. In one embodiment of the compounds or inhibitors described herein, ee, de, %ee, or %de is 100. In a particular embodiment, the compounds or inhibitors listed in Table 1 herein have ee, de, %ee, or %de as described in this paragraph. In a particular embodiment, the compounds or inhibitors 32, 34, 44, 57, 72, 121, 130, 149, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, as described in the Examples and / or Biological Examples, have ee, de, %ee, or %de as described in this paragraph. Unless otherwise specified, all tautomers of the compounds herein are within the scope of this specification.Furthermore, unless otherwise specified, the structures illustrated herein also mean that they include different compounds only in the presence of one or more isotopic enriched atoms. For example, the present invention. Compounds having the structure of hydrogen are replaced by deuterium or tritium or 13 C or 14 Except for carbon substitution with 14C-enriched carbon, these are within the scope of this specification. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0092]

[0103] As used herein, the term "&1" refers to a specific compound within that compound. The notation "&1" in a chemical element or atom (e.g., carbon) means that the compound was prepared as a mixture of two stereoisomers in the chemical element or atom mentioned (e.g., a diastereomer mixture having de or %de as described above).

[0093]

[0104] Chemical structures and nomenclature are based on ChemDraw, version 11.0.1 It originates from Cambridge, MA.

[0094]

[0105] The use of descriptors such as "first," "second," and "third" indicates that they are separate elements (for example) Note that this term is used to distinguish between elements (such as solvents, reaction steps, processes, and reagents) and may or may not refer to the relative order or relative time series of the elements being described.

[0095] Use of compounds and compositions

[0106] The bifunctional compounds described herein may be used in biological samples or patient odors. Therefore, it is useful for degrading BTK via the ubiquitin protein degradation pathway. Accordingly, one embodiment of the present disclosure provides a method for treating a BTK-mediated disease or disorder. As used herein, the term “BTK-mediated disease or disorder” means any disease, disorder, or other adverse condition in which BTK is known to play a role. In some cases, a BTK-mediated disease or disorder is a proliferative disorder or an autoimmune disorder. An example of a proliferative disorder is cancer.

[0096]

[0107] In one embodiment, what is provided herein is in the case where it is needed. This is a method for treating or preventing cancer. In certain embodiments, these methods include the step of orally administering a bifunctional compound to a subject in an amount capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, this amount is effective for treating or preventing cancer.

[0097]

[0108] In a particular embodiment, cancer is any of the following cancers. In this context, cancer includes solid tumors. In certain embodiments, cancer is a B-cell malignancy. In certain embodiments, cancer is chronic lymphocytic leukemia (CLL), small lymphocytic leukemia Parkinson's disease (SLL), transformed CLL or Richter transformation, small cell lymphoma, follicular lymphoma Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma, mantle The group consists of cellular lymphoma (MCL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), and central nervous system (CNS) lymphoma. Specific implementation Morphologically, the cancer is chronic lymphocytic leukemia. In certain embodiments, the cancer is small cell lymphoma. In certain embodiments, the cancer is follicular lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma. In certain embodiments, the cancer is non-Hodgkin lymphoma. In certain embodiments, the cancer is mantle cell lymphoma. In certain embodiments, the cancer is marginal zone lymphoma. In certain embodiments, the cancer is Waldenström macroglobulinemia. In certain embodiments, the cancer is small lymphocytic lymphoma (SLL). Specific embodiments In this context, the cancer is CNS lymphoma. In certain embodiments, the cancer is transformed CLL or Richter transformed.

[0098]

[0109] In certain embodiments, the subject has a mutant Bruton-type tyrosine kinase. In certain embodiments, the subject has a C481 mutant Bruton's tyrosine kinase. In certain embodiments, the subject has a C481S mutant Bruton's tyrosine kinase. In certain embodiments, the cancer is resistant to ibrutinib. Those skilled in the art will recognize that certain ibrutinib-resistant cancers express a C481 mutant Bruton's tyrosine kinase, for example, a C481S Bruton's tyrosine kinase. For example, in certain embodiments, the subject has a C481 mutant Bruton's tyrosine kinase, and the cancer is chronic lymphocytic leukemia (CLL).

[0099]

[0110] In another embodiment, what is provided herein is for those who require it. These are methods for degrading Bruton's tyrosine kinase. These methods involve orally administering a bifunctional compound to a subject in an amount capable of inducing proteolytic degradation of Bruton's tyrosine kinase. In certain embodiments, this amount is effective in degrading Bruton's tyrosine kinase in the subject. Bruton's tyrosine kinase may be expressed in any cells or tissues of the subject. In certain embodiments, Bruton's tyrosine kinase is expressed in splenocytes. In certain embodiments, Bruton's tyrosine kinase is expressed in peripheral blood mononuclear cells.

[0100]

[0111] In certain embodiments, the Bruton's tyrosine kinase is a mutant. In certain embodiments, the Bruton's tyrosine kinase contains a C481 mutation. In specific embodiments, the Bruton's tyrosine kinase contains a C481S mutation. In specific embodiments, the Bruton's tyrosine kinase is resistant to ibrutinib.

[0101]

[0112] In another embodiment, what is provided herein is for those who require it. These are methods for preventing B cell activation. These methods involve orally administering a bifunctional compound to a target in an amount capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, this amount is effective in preventing B cell activation. In certain embodiments, the B cells express CD69. In certain embodiments, the B cells express CD86. In certain embodiments, the B cells express both CD69 and CD86.

[0102]

[0113] In another embodiment, provided herein are mutant Bruton-type tyrosine These are methods for degrading the enzyme. These methods involve contacting cells expressing a mutant Bruton's tyrosine kinase with an amount of a bifunctional compound that can induce proteolysis of the Bruton's tyrosine kinase. In certain embodiments, this amount is effective in degrading the mutant Bruton's tyrosine kinase. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481 mutant. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481S mutant.

[0103]

[0114] In these methods, the bifunctional compound is capable of specifically binding BTK. The compound includes a portion capable of mobilizing ubiquitin ligase to degrade BTK, and further includes a portion capable of mobilizing ubiquitin ligase to degrade BTK. Specific compounds are described herein. These compounds can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions.

[0104]

[0115] The bifunctional compound is used in any dose deemed appropriate by the practitioner of the technology. It can be administered as follows: In certain embodiments, the dose is 0.1 to 1000 mg / kg. In certain embodiments, the dose is 0.1 to 900 mg / kg. In certain embodiments, the dose is 0.1 to 800 mg / kg. In certain embodiments, the dose is 0.1 to 700 mg / kg. In certain embodiments, the dose is 0.1 to 600 mg / kg. In certain embodiments, the dose is 0.1 to 500 mg / kg. g. In certain embodiments, the dose is 0.1 to 400 mg / kg. In certain embodiments, the dose is 0.1 to 300 mg / kg. In certain embodiments, the dose is 0.1 to 200 mg / kg. In certain embodiments, the dose is 0.1 to 100 mg / kg. In certain embodiments, the dose is selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg. In certain embodiments, the dose is about 25 mg / kg. In certain embodiments, the dose is about 50 mg / kg. In certain embodiments, the dose is about 75 mg / kg. In certain embodiments, the dose is about 100 mg / kg. In certain embodiments, the dose is about 150 mg / kg. In certain embodiments, the dose is about 200 mg / kg. In certain embodiments, the dose is approximately 250 mg / kg. In certain embodiments, the dose is approximately 300 mg / kg. In certain embodiments, the dose is approximately 400 mg / kg. In certain embodiments, the dose is approximately 450 mg / kg. In certain embodiments, the dose is approximately 500 mg / kg. In certain embodiments, the dose is approximately 600 mg / kg. In certain embodiments, the dose is approximately 700 mg / kg. In certain embodiments, the dose is approximately 750 mg / kg. In certain embodiments, the dose is approximately 800 mg / kg. In certain embodiments, the dose is approximately 900 mg / kg. In certain embodiments, the dose is approximately 1000 mg / kg.

[0105]

[0116] The dosage should be administered according to a schedule deemed appropriate by those skilled in the art. This is possible. In certain embodiments, the dose is administered once per day. In certain embodiments, the dose is administered twice per day. In certain embodiments, the dose is administered three times per day. In certain embodiments, the dose is administered four times per day. In certain embodiments, the dose is administered in divided doses. In certain embodiments, the dose is administered in doses divided into two doses per day. In certain embodiments, the dose is administered in doses divided into three doses per day. In certain embodiments, the dose is administered in doses divided into four doses per day.

[0106]

[0117] The medication is administered over any length of time that would be considered appropriate by those skilled in the art. It can be continued. In certain embodiments, the dose is administered daily over 14 days. In certain embodiments, the dose is administered daily over 13 days. In certain embodiments, the dose is administered daily over 12 days. In certain embodiments, the dose is administered daily over 11 days. In certain embodiments, the dose is administered daily over 10 days. In certain embodiments, the dose is administered daily over 9 days. In certain embodiments, the dose is administered daily over 8 days. In certain embodiments, the dose is administered daily over 7 days. In certain embodiments, the dose is administered daily over 6 days. In certain embodiments, the dose is administered daily over 5 days. In certain embodiments, the dose is administered daily over 4 days. In certain embodiments, the dose is administered daily over 3 days. In certain embodiments, the dose is administered daily over 2 days. In certain embodiments, the dose is administered daily over 1 day.

[0107]

[0118] In the medication schedule, the dosage is determined by the practitioner's judgment and administered daily. It can be administered cyclically. In certain embodiments, the dose is administered daily. In certain embodiments, the dose is administered with intervals between doses. In certain embodiments, the interval is 1 day. In certain embodiments, the interval is 2 days. In certain embodiments, the interval is 3 days. In certain embodiments, the interval is 4 days. In certain embodiments, the interval is 5 days. In certain embodiments, the interval is 6 days.

[0108]

[0119] In certain embodiments, the dose is administered weekly. The dosage is administered twice a week. In certain embodiments, the dosage is administered three times a week.

[0109]

[0120] In a particular embodiment, the dose(s) are divided into a first interval between dose(s). The doses are administered over a period of time with intervals in between, and then these doses(s) are re-administered over a period following a first interval between doses(s), where this dosing regimen can be repeated at the discretion of the practitioner of the art (i.e., cyclically or periodically, after, for example, second, third, etc., intervals between subsequent doses(s). For example, in one embodiment, the first dose is administered over a week, followed by a first interval of one week without administration of the first dose, then the second dose is re-administered over another week, followed by a second interval of one week without administration of the first or second dose, and so on, periodically. In this specification, other perturbations to the first, second, third, etc. doses(s), followed by perturbations to the first, second, third, etc. intervals(s), and combinations thereof are intended to be understood according to the needs of the practitioner of the art and the patient. For example, in one embodiment, a first dose is administered daily for one week, followed by a first interval of three weeks without the administration of the first daily dose, then a second dose is re-administered every other week for another week, followed by a second interval of four weeks without the administration of the first daily or second every-other-week dose, and so on, cyclically.

[0110]

[0121] The compound can be administered via any route deemed appropriate by the practitioner of the technology. It can be administered in this manner. In certain embodiments, the dose is administered orally. The formulation and technique for administration are described in detail below.

[0111]

[0122] In a particular embodiment, the term "cancer" includes, but is not limited to, the following cancers. It is not limited to these: Epidermoid oral cavity: squamous cell carcinoma (HNSCC) of the cheek cavity, lips, tongue, mouth, pharynx, and head and neck; heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma Myomas, fibromas, lipomas, and teratomas; Lungs: Bronchogenic carcinomas (squamous or epidermoid, anaplastic small cell, anaplastic large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrodic hamartoma, mesothelioma, non-small cell lung cancer (NSCLC); Gastrointestinal tract: Gastric cancer, esophageal (squamous cell) cancer Cancer (larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (small bowel or small intestines) (adenocarcinoma, lymphoma, carcinoid tumor) large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) Intestinal rectum, colon microsatellite-stable colorectal cancer (MSS CRC), rectum; urogenital tract: kidney ( Adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, fetal cancer, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), metastatic castration-resistant prostate cancer (mCRPC), muscle-invasive urothelial carcinoma; liver: hepatocellular carcinoma, bile duct Cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum sarcoma), multiple myeloma (MM), malignant giant cell chondroma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningosarcoma, glioma), brain ( Astrocytoma, medulloblastoma, glioma, ependymoma, germ blastoma (pineal glandoma), glioblastoma pleomorphonum, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma; Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (Squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), breast, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC); blood system: blood (myeloid leukemia (acute and chronic) (Sex), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), pilaris cell lymphoma; lymphoid disorders (e.g., mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevi, fat Tumors, hemangiomas, dermatofibromas, keloids, psoriasis; Thyroid: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; Adrenal gland: neuroblastoma; and metastatic melanoma.

[0112]

[0123] Examples of autoimmune disorders include urticaria, graft-versus-host disease (GVHD), and acute complications. Graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Barlow's disease, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polymyelitis (CRMO), Churg-Strauss syndrome (CSS), or Eosinophilic granuloma (EGPA), bullous pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia Evans syndrome, fibromyalgia, fibrous alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or bullous pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (opposite type) Acne, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immunothrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes mellitus), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus, Chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD) Mohren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNC B. Multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, squamous cellulitis (peripheral uveitis), personage-Turner syndrome, pemphigus, peripheral neuropathy, perivenosis-induced encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polymyelitis nodosa Pulsitis, polymyalgia syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's disease Tolosa syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity; Stiff Person Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Suzak Syndrome, Sympathetic Ophthalmitis (SO), Takayasu's Arteritis, Temporal Arteritis (Giant Cell Arteritis), Thrombocytopenic Purpura (TTP), Tolosa • Ramsay Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated junction Examples include histological diseases (UCTD), uveitis, vasculitis, leukoplakia, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0113]

[0124] In certain embodiments, the herein provides a mutant Breton-type Tyro This is a method for degrading synkinase. These methods involve contacting cells expressing a mutant Bruton's tyrosine kinase with a bifunctional compound in an amount capable of inducing proteolytic degradation of the Bruton's tyrosine kinase. In certain embodiments, the amount of the bifunctional compound capable of inducing proteolytic degradation of the Bruton's tyrosine kinase is an effective amount for degrading the mutant Bruton's tyrosine kinase. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481 mutant. In certain embodiments, the mutant Bruton's tyrosine kinase is the C481S mutant. The contact may be in vitro or in vivo. In certain embodiments, the contact may be in vitro. In certain embodiments, contact is in vivo. In certain embodiments, contact is in the object requiring it. Bifunctional compounds

[0114]

[0125] The method provided herein involves the administration of a bifunctional compound. This may be any compound described herein. In certain embodiments, the bifunctional compound comprises at least two parts. One part can specifically bind Bruton's tyrosine kinase (BTK). The other part degrades BTK. Ubiquitin ligase can be mobilized for this purpose. In certain embodiments, the ubiquitin ligase is E3 ligase. In certain embodiments, the ubiquitin ligase is cereblon (CRBN) or contains cereblon as a component.

[0115]

[0126] In these methods, the compound is given by formula (A1)

[0116] [ka] The compound may be a pharmaceutically acceptable salt thereof, where W is CH or N, D is a bond or linker, ring A is aryl or heteroaryl, ring B is aryl or heteroaryl, L is a bond or linker, and Y is a portion capable of binding ubiquitin ligase.

[0117]

[0127] In these methods, the compound is given by formula (A)

[0118] [ka] The compound may be a pharmaceutically acceptable salt thereof, where W is CH or N, D is a bond or -NH-, ring A is a phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or completely unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, where each monocyclic heterocycle and bicyclic heteroaryl of ring A has 1-3 heteroatoms independently selected from N, O, or S, and ring A may be a halo, -CN, -COOH, NH2, and optionally substituted C 1~6 Ring B is optionally and independently substituted with up to three substituents selected from alkyl groups, and ring B is a phenyl, a 5-6 membered heteroaryl, a 4-6 membered heterocycloalkyl, or an 8-10 membered (e.g., 8-9 membered or 9-10 membered) spirodicyclic heterocycle, and ring B is optionally substituted, and the heteroaryl and heterocycloalkyl of ring B has 1-3 heteroatoms independently selected from N, O, or S, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 These are bonds, -C(O)-N(R)-, -N(R)-C(O)-, and -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5A 7-12 member spiro or condensed bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic and bicyclic heterocycloalkyl groups are each optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~8 Alkyl-,

[0119] [ka] , 4-6 member cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p -, independently selected from N, O, or S It is a 4-6 member heterocycloalkyl having 1-2 heteroatoms, and the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m - A saturated, partially unsaturated, or fully unsaturated carbon ring with 5-6 members, or a saturated, partially unsaturated, or fully unsaturated heteroring with 1-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4 The elements are alkyl-, -N(R)-, -O-, -C(O)-, or -C(O)-N(R)-, where R is independently either -H or -C 1~3It is an alkyl group (e.g., methyl, ethyl, propyl, or isopropyl), where m, n, and p are each independently integers from 1 to 3 (e.g., 1, 2, or 3), and Y is

[0120] [ka] And in the formula, R 2 These are, independently, Halo, -CN, or -C. 1~4 It is alkyl, C 1~4 Each alkyl group is optionally and independently substituted with up to three examples of halo, -CN, -COOH, -COONH2, -NH2, or -CF3, where R'' and R''' are independently hydrogen (H or -H) or, together with the atom to which they are bonded, form a 5-6 member partially unsaturated or fully unsaturated benzo. It forms a condensed heterocycle, and Z is -C(R A )2- or -C(O)-, R A These are independently -H or -C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0121]

[0128] All linking groups L as defined in the compound of formula (A), excluding the R group. The part in parentheses is divalent unless otherwise specified. For example, any alkyl (e.g., n-propyl, n-butyl, n-hexyl), aryl (e.g., phenyl), cycloalkyl (e.g., cyclopropyl, cyclohexyl), heteroaryl, and heterocycloalkyl (e.g., piperidine, piperazine) present in L are divalent unless otherwise specified.

[0122]

[0129] In some embodiments, ring B is an optional ring having 1 to 2 nitrogen atoms. It is a 5-6 member heterocycloalkyl group substituted with a specific molecule. For example, ring B is piperidine-yl, piperizine-yl, or pyrrolidine-yl, and one of these is optionally substituted.

[0123]

[0130] In some embodiments, ring B is independently selected from N and S. It is a 5-6 member heteroaryl molecule with two or more heteroatoms, substituted by arbitrary choice. For example, ring B is pyridine-yl, pyrazine-yl, or pyrimidine, and one of these is substituted by arbitrary choice.

[0124]

[0131] In some embodiments, ring B is

[0125] [ka] And in the formula, R 10 is Halo, -H, -C 1~5 Alkyl (for example, -C) 1~3 Alkyl), 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH,

[0126] [ka] That is the case.

[0127]

[0132] In some embodiments, ring B is

[0128] [ka] And in the formula, R 10 teeth,

[0129] [ka] And in the formula, R 1 C 1~4 It is an alkyl group. For example, ring B is

[0130] [ka] And in the formula, R 10 teeth,

[0131] [ka] And in some cases, ring B is

[0132] [ka] In other cases, R 10 teeth,

[0133] [ka] That is the case.

[0134]

[0133] In some embodiments, ring A is

[0135] [ka] In this formula, ring A' together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic aryl or 9-10 membered bicyclic heteroaryl, and the bicyclic heteroaryl (i.e., a bicyclic heteroaryl containing ring A') has 1-3 heteroatoms independently selected from N, O, or S. For example, ring A is

[0136] [ka] That is the case.

[0137]

[0134] In some embodiments, X 1 , X 2 , and X 5 at least one of One of them is -N(R)-, -C(O)-N(R)-, or -CH2-.

[0138]

[0135] In some embodiments, X 1 It is -C(O)-N(R)-.

[0139]

[0136] In some embodiments, X 2 is -(O-CH2-CH2) n -,-( CH2-CH2-O) n -, or -C 1~5 It is alkyl-.

[0140]

[0137] In some embodiments, X 3 is to combine,

[0141] [ka] , -C 1~4 It is alkyl- or -N(R)-.

[0142]

[0138] In some embodiments, X 4 is a bond, -CH2-, or -N(R) - is

[0143]

[0139] In some embodiments, X 5 It is a combination.

[0144]

[0140] In some embodiments, X 1 ha-(O-CH2-CH2-CH2) m - And m is 1, X 2 It is -C(O)-N(R)-.

[0145]

[0141] In some embodiments, X 1 -CH2-, -C(O)-,

[0146] [ka] That is the case.

[0147]

[0142] In some embodiments, X 2 is a bond, -C(O)-, -C 1~5 Al kill-,

[0148] [ka] That is the case.

[0149]

[0143] In some embodiments, X 3 is a combination, -C 1~4 Alkyl-, 4~6 It is a cycloalkyl or -N(R)- group.

[0150]

[0144] In some embodiments, X 3 is a combination, -C 1~4 Alkyl-, -NH -,

[0151] [ka] That is the case.

[0152]

[0145] In some embodiments, X 4 is to combine,

[0153] [ka] , -C 1~4It is alkyl-, -CH2-CH2-N(R)-, or -N(R)-.

[0154]

[0146] In some embodiments, X 5 is a combination, -C 1~4 Alkyl-, -N( It is R)-, or -C(O)-N(R)-.

[0155]

[0147] In some embodiments, L is

[0156] [ka]

[0157] [ka]

[0158] [ka]

[0159] [ka] That is the case.

[0160]

[0148] In some embodiments, Y is

[0161] [ka] That is the case.

[0162]

[0149] In some embodiments, W is N.

[0163]

[0150] In some embodiments, D is a bond.

[0164]

[0151] This disclosure also relates to formula (B)

[0165] [ka] The compound or pharmaceutically acceptable salts thereof are also provided, where W is CH or N, D is a bond or -NH-, ring B1 is a 4-6 membered, fully saturated, partially unsaturated or fully unsaturated monocyclic heterocycle, or an 8-10 membered, fully saturated spirodicyclic heterocycle, ring B1 having 1-3 heteroatoms independently selected from N, O, or S, and optionally substituted with 1-3 groups selected from 5-membered heterocycloalkyls having 1-2 heteroatoms independently selected from N or O, and L is -X 1 -X 2 -X 3 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spiro or condensed bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic and bicyclic heterocycloalkyl groups are each optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-,

[0166] [ka] , 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p - is a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3, and R being independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0167] [ka] That is the case.

[0168]

[0152] In some embodiments, ring B1 is

[0169] [ka] Ring B1 consists of -CH3, -CH2OH, -CH2CH2OH, -C(O)OH, -CF3, -F,

[0170] [ka] These are 1 to 3 groups substituted by an arbitrary selection from the following. For example, ring B1 is

[0171] [ka] In other examples, ring B1 is

[0172] [ka] That is the case.

[0173]

[0153] In some embodiments, X 1 teeth,

[0174] [ka] That is the case.

[0175]

[0154] In some embodiments, X 2 is a combination, -C 1~5 Alkyl-, 4~6 A monocyclic cycloalkyl group with 4 to 6 members, or a monocyclic heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a combination, -C 1~3 Alkyl-, -C(O)-,

[0176] [ka] That is the case.

[0177]

[0155] In some embodiments, X 3 is a combination, -C 1~4 Alkyl-, -N( R)-,-(O-CH2-CH2) p -,-(CH2-CH2-O) p A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from -, or N, O, or S, where the heterocycloalkyl is optionally substituted with -CH3. For example, X 3 is to combine,

[0178] [ka] That is the case.

[0179]

[0156] In some embodiments, L is

[0180] [ka] That is the case.

[0181]

[0157] In some embodiments, W is N and D is a bond.

[0182]

[0158] This disclosure also relates to formula (C)

[0183] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where W is CH or N, ring C is a saturated, partially unsaturated or fully unsaturated 5-6 member monocyclic heterocycle having phenyl or 1-2 heteroatoms independently selected from N, O or S, the phenyl and heterocycle of ring C are each optionally substituted, and L is -X 1 -X 2 -X 3 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O-(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X 1 The bicyclic heterocycloalkyl and monocyclic heterocycloalkyl groups are each optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-,

[0184] [ka] , 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p - is a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3, and R being independently -H or -C 1~3 It is an alkyl group, and m, n, and p are each independent integers between 1 and 3.

[0185]

[0159] In some embodiments, W is N.

[0186]

[0160] In some embodiments, ring C is

[0187] [ka] For example, ring C is

[0188] [ka] In other examples, ring C is

[0189] [ka] That is the case.

[0190]

[0161] In some embodiments, X 1 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms. For example, X 1 teeth,

[0191] [ka] In some examples, X 1 teeth,

[0192] [ka] That is the case.

[0193]

[0162] In some embodiments, X 2 is a combination, -C 1~5 Alkyl-, 4~6 A monocyclic cycloalkyl group with 4 to 6 members, or a monocyclic heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a combination or -C 1~3 It is alkyl- (for example, -CH2-).

[0194]

[0163] In some embodiments, X 3 These are 4-6 member cycloalkyl groups, -N(R A 4-6 member heterocycloalkyl having 1- or 1-2 heteroatoms independently selected from N, O, or S, where the heterocycloalkyl is optionally substituted with -CH3. For example, X 3 teeth,

[0195] [ka] In other embodiments, X 3 teeth,

[0196] [ka] That is the case.

[0197]

[0164] In some embodiments, L is

[0198] [ka] For example, L is

[0199] [ka] That is the case.

[0200]

[0165] This disclosure also relates to formula (D)

[0201] [ka] The present invention also provides compounds of or pharmaceutically acceptable salts thereof, where W is CH or N, and ring A is

[0202] [ka] And L is -X 1 -X 2 -X 3 - and X 1 is -C 1~5 A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3, X 2 is a combination, -C 1~5 A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, and X1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3, X 3 is a combination, -C 1~4 A 4- to 6-membered monocyclic cycloalkyl group, or a 4- to 6-membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl group is optionally substituted with -CH3, and Y is

[0203] [ka] And R 10 is Halo, -H, -C 1~5 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH,

[0204] [ka] That is the case.

[0205]

[0166] In some embodiments, ring A is

[0206] [ka] That is the case.

[0207]

[0167] In some embodiments, X 1 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms, X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3. For example, X 1 teeth,

[0208] [ka] That is the case.

[0209]

[0168] In some embodiments, X 2 is a combination, -C 1~5 Alkyl-, 4~6 A monocyclic cycloalkyl group with 4 to 6 members, or a monocyclic heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a combination or -C 1~4 It is alkyl-.

[0210]

[0169] In some embodiments, X 3 This is a bond, a monocyclic cycloalkyl group with 4-6 members. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from or, N, O, or S. For example, X 3 teeth,

[0211] [ka] That is the case.

[0212]

[0170] In some embodiments, L is

[0213] [ka] That is the case.

[0214]

[0171] In some embodiments, R 10 is Halo, -H, -C 1~5 Alkyl ( For example, -C 1~3 These are alkyl groups, 3-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl groups, -CN, -OH, -CF3, -CH2OH, -C(O)OH, or -CH2CH2OH. For example, R 10 is Halo, -H, C 1~3It is alkyl, CF3, -CH2OH, -C(O)OH, or -CH2CH2OH. In other cases, R 10 teeth,

[0215] [ka] That is the case.

[0216]

[0172] In some embodiments, R 10 teeth,

[0217] [ka] That is the case.

[0218]

[0173] In some embodiments, R 10 teeth,

[0219] [ka] That is the case.

[0220]

[0174] In some embodiments, the compound of formula (D) is (D-1)

[0221] [ka] A compound of or a pharmaceutically acceptable salt thereof, where W is CH or N, and ring A is

[0222] [ka] And L is -X 1 -X 2 -X 3 - and X 1 is -C 1~5A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3, X 2 is a combination, -C 1~5 A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3, X 3 is a combination, -C 1~4 A 4- to 6-membered monocyclic cycloalkyl group, or a 4- to 6-membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl group is optionally substituted with -CH3, and Y is

[0223] [ka] And R 10 teeth,

[0224] [ka] That is the case.

[0225]

[0175] In some embodiments, ring A is

[0226] [ka] That is the case.

[0227]

[0176] In some embodiments, X 1 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms, X 1The monocyclic heterocycloalkyl group is optionally substituted with -CH3. For example, X 1 teeth,

[0228] [ka] That is the case.

[0229]

[0177] In some embodiments, X 2 is a combination, -C 1~5 Alkyl-, 4~6 A monocyclic cycloalkyl group with 4 to 6 members, or a monocyclic heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a combination or -C 1~4 It is alkyl-.

[0230]

[0178] In some embodiments, X 3 This is a bond, a monocyclic cycloalkyl group with 4-6 members. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from or, N, O, or S. For example, X 3 teeth,

[0231] [ka] That is the case.

[0232]

[0179] In some embodiments, L is

[0233] [ka] That is the case.

[0234]

[0180] In some embodiments, R 10 teeth,

[0235] [ka] That is the case.

[0236]

[0181] In some embodiments, R 10 teeth,

[0237] [ka] That is the case.

[0238]

[0182] In some embodiments, a compound of formula (D) or a compound of formula (D-1) is equation (D-2)

[0239] [ka] A compound of or a pharmaceutically acceptable salt thereof, comprising rings A, L, Y, and R 10 The term is defined as follows for the compound of formula (A), the compound of formula (D), and the compound of formula (D-1).

[0240]

[0183] In some embodiments, ring A is

[0241] [ka] That is the case.

[0242]

[0184] In some embodiments, X 1 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms, X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3. For example, X 1 teeth,

[0243] [ka] That is the case.

[0244]

[0185] In some embodiments, X 2 is a combination, -C 1~5 Alkyl-, 4~6 A monocyclic cycloalkyl group with 4 to 6 members, or a monocyclic heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a combination or -C 1~4 It is alkyl-.

[0245]

[0186] In some embodiments, X 3 This is a bond, a monocyclic cycloalkyl group with 4-6 members. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from or, N, O, or S. For example, X 3 teeth,

[0246] [ka] That is the case.

[0247]

[0187] In some embodiments, L is

[0248] [ka] That is the case.

[0249]

[0188] In some embodiments, R 10 teeth,

[0250] [ka] That is the case.

[0251]

[0189] In some embodiments, R 10 teeth,

[0252] [ka] That is the case.

[0253]

[0190] This disclosure also relates to formula (E)

[0254] [ka] The compound or pharmaceutically acceptable salts thereof are also provided, where D is a bond or -NH-, W is N or CH, ring A is a phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or completely unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, where each monocyclic heterocycle and bicyclic heteroaryl of ring A has 1-3 heteroatoms independently selected from N, O, or S, ring B is an optionally substituted 5-6 membered saturated, partially unsaturated, or completely unsaturated monocyclic heterocycle, or an optionally substituted 8-10 membered (e.g., 8-9 membered or 9-10 membered) spirodicyclic heterocycle, where ring B has 1-3 heteroatoms independently selected from N, O, or S, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 These are bonds, -C(O)-N(R)-, -N(R)-C(O)-, and -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X 1The monocyclic and bicyclic heterocycloalkyl groups are each optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-,

[0255] [ka] , 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m - A saturated, partially unsaturated, or fully unsaturated carbon ring with 5-6 members, or a saturated, partially unsaturated, or fully unsaturated heteroring with 1-3 heteroatoms independently selected from N, O, or S, X 5 R is a bond, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0256] [ka] X 1 , X 2 , X 3, X 4 , and X 5 At least one of them has a nitrogen atom, and Y is X 1 , X 2 , X 3 , X 4 , or X 5 It is directly bonded to L at the nitrogen atom.

[0257]

[0191] In some embodiments, ring B is

[0258] [ka] And in the formula, R 10 teeth,

[0259] [ka] And in the formula, R 1 C 1~4 It is an alkyl group. For example, ring B is

[0260] [ka] And in the formula, R 10 teeth,

[0261] [ka] In other examples, ring B is

[0262] [ka] That is the case.

[0263]

[0192] In some embodiments, R 10 teeth,

[0264] [ka] That is the case.

[0265]

[0193] In some embodiments, ring A is

[0266] [ka] That is the case.

[0267]

[0194] In some embodiments, X 5 is -N(R)-.

[0268]

[0195] In some embodiments, X 5 It is -C(O)-N(R)-.

[0269]

[0196] In some embodiments, X 5 It is a combination.

[0270]

[0197] In some embodiments, L is

[0271] [ka]

[0272] [ka]

[0273] [ka] That is the case.

[0274]

[0198] In some embodiments, Y is

[0275] [ka] That is the case.

[0276]

[0199] This disclosure also relates to formula (F)

[0277] [ka] The present invention also provides compounds of or pharmaceutically acceptable salts thereof, where W is CH or N and L is -X 1 -X 2 -X 3 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic and bicyclic heterocycloalkyl groups are each optionally substituted with -CH3, and X 2 is a combination, -C 1~5 Alkyl-,-(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-,

[0278] [ka] , 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p-,-(CH2-CH2-O) p - is a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3, and R being independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0279] [ka] That is the case.

[0280]

[0200] In some embodiments, W is N.

[0281]

[0201] In some embodiments, Y is

[0282] [ka] That is the case.

[0283]

[0202] In some embodiments, X 1 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms, X 1 Each of the monocyclic heterocycloalkyl groups is optionally substituted with -CH3. For example, X 1 teeth,

[0284] [ka] In some cases, X 1 teeth,

[0285] [ka] That is the case.

[0286]

[0203] In some embodiments, X 2 is a combination or -C 1~5 Alkyl- ru.

[0287]

[0204] In some embodiments, X 3 It is selected independently from N, O, or S. It is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms. For example, X 3 teeth,

[0288] [ka] In some cases, X 3 teeth,

[0289] [ka] That is the case.

[0290]

[0205] In some embodiments, L is

[0291] [ka] That is the case.

[0292]

[0206] In some embodiments, L is

[0293] [ka] That is the case.

[0294]

[0207] In some embodiments, W is N and L is

[0295] [ka] That is the case.

[0296]

[0208] This disclosure also relates to formula (G)

[0297] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, R 1 L and Y are as defined for the compound of formula (A).

[0298]

[0209] In some embodiments, R 1 It is methyl.

[0299]

[0210] In some embodiments, Y is

[0300] [ka] That is the case.

[0301]

[0211] In some embodiments, W is N.

[0302]

[0212] This disclosure also relates to formula (H)

[0303] [ka] The compound or pharmaceutically acceptable salts thereof are also provided, ring B, R 2 Z, W, D, and q are as defined in the compound of formula (A).

[0304]

[0213] In some embodiments, q is 0.

[0305]

[0214] This disclosure also relates to formula (J)

[0306] [ka] The compound or pharmaceutically acceptable salts thereof are also provided, with rings B, D, W, R 2 , q, and L are as defined in the compound of formula (A).

[0307]

[0215] This disclosure also relates to formula (K)

[0308] [ka] The present invention also provides compounds of or pharmaceutically acceptable salts thereof, wherein ring A is

[0309] [ka] Ring A is composed of halo, -CN, -carboxyl, -NH2, and optionally substituted -C 1~6 Alkyl (e.g., optionally substituted -C) 1~3 Up to three substituents selected from alkyl groups are optionally and independently substituted, V is a bond or -CH2-, and E and G are each independently 5- to 6-membered heterocycloalkyl groups, each heterocycloalkyl group containing at least one nitrogen atom. Rings B, W, R 2 q, R'', R''', and ring A' are as defined in the compound of formula (A). In some embodiments, ring A' together with the phenyl ring to which ring A' is fused forms a 9-10 membered bicyclic aryl or 9-10 membered bicyclic heteroaryl, the bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S.

[0310]

[0216] In some embodiments, D is a bond and W is nitrogen.

[0311]

[0217] This disclosure also relates to formula (M)

[0312] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, R 10A is -H,

[0313] [ka] And in the formula, R 1 C 1~4 It is alkyl, X 1 is -C 1~5 It is alkyl-, and ring C-1 is a 5-6 member heterocycloalkyl having one nitrogen atom, and Y is,

[0314] [ka] That is the case.

[0315]

[0218] In some embodiments, R 10A is -H or

[0316] [ka] That is the case.

[0317]

[0219] In some embodiments, R 10A teeth,

[0318] [ka] And R 1 These are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or isobutyl. For example, R 1 It is methyl.

[0319]

[0220] In some embodiments, X 1 Methylene (-CH2-), ethylene ( It is -CH2CH2-) or propylene (-CH2CH2CH2-). For example, X 1 It is methylene (-CH2-).

[0320]

[0221] In some embodiments, ring C-1 is

[0321] [ka] For example, ring C-1 is

[0322] [ka] That is the case.

[0323]

[0222] This disclosure relates to formula (X)

[0324] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 C 1~3 It is an alkyl group, where ring A is a phenyl group, a 5-6 member partially or completely unsaturated monocyclic heterocycle, a 9-10 member bicyclic aryl group, or a 9-10 member bicyclic heteroaryl group, where the heterocycle and bicyclic heteroaryl of ring A each independently have 1-3 heteroatoms independently selected from N, O, or S, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2)m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, and X 1 The bicyclic heterocycloalkyl group is optionally substituted with a 4-6 member monocyclic heterocycloalkyl group having -CH3 or 1-2 heteroatoms independently selected from N, O, or S, and X 1 The monocyclic heterocycloalkyl group is optionally substituted with -CH3, X 2 is, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-,

[0325] [ka] , 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated or fully unsaturated carbon ring having 0-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4The elements are alkyl-, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, and m, n, and p are each independent integers between 1 and 3. Y is

[0326] [ka] And in the formula, R 2 Each is independently a halo or C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A Each of these is independently -H or C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0327]

[0223] In some cases, the compound of formula (X) is of formula (I)

[0328] [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 C 1~3 It is an alkyl group, where ring A is a phenyl group, a 9-10 membered bicyclic aryl group, or a 9-10 membered bicyclic heteroaryl group having 1-3 heteroatoms independently selected from N, O, or S, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-, 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated or fully unsaturated heteroring having 1-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4 The elements are alkyl-, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3 (e.g., 1, 2, or 3). Y is

[0329] [ka] And in the formula, R 2 Each is independently a halo or C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A Each of these is independently -H or C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0330]

[0224] In some embodiments, q is 0. In other embodiments, q is 1 And R 2 is -F.

[0331]

[0225] In some embodiments, Z is -CH2- or -C(O)-.

[0332]

[0226] In some embodiments, Y is

[0333] [ka] That is the case.

[0334]

[0227] In other embodiments, Y is

[0335] [ka] That is the case.

[0336]

[0228] In some embodiments, R 1 is -C 1~3 It is alkyl. For example, R 1 is methyl, ethyl, propyl, or isopropyl. In other embodiments, R 1 It is methyl.

[0337]

[0229] In some embodiments, R is independently -H or -CH3 Yes, there is. For example, each R is -H.

[0338]

[0230] In some embodiments, X 1 -C(O)-N(R)-, -N(R) -C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. In some embodiments, X 1 is -C(O)-N(R)-. For example, X 1 is -C(O)-N(H)-, -C(O)-N(CH3)-, or -C(O)-N(CH2CH3)-. In other embodiments, X 1 X is a 5-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and the heterocycloalkyl is optionally substituted with -CH3. For example, X 1 teeth,

[0339] [ka] In other examples, X 1 X is a 7-10 membered spironicyclic heterocycloalkyl ring having 1-3 heteroatoms (e.g., N) independently selected from N, O, or S. 1 teeth,

[0340] [ka] In other embodiments, X 1 is -(O-CH2-CH2)m -or-(O-CH2-CH2-CH2) m - and in the formula, m is 1, 2, 3. For example, X 1 is -(O-CH2-CH2) m -or-(O-CH2-CH2-CH2) m - and m is 1. In another example, X 1 is -(O-CH2-CH2) m -or-(O-CH2-CH2-CH2) m - and m is 2. In some embodiments, X 1 is -C 1~5 It is alkyl-. For example, X 1 These include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). In some embodiments, X 1 -CH2-, -C(O)-,

[0341] [ka] That is the case.

[0342]

[0231] In some embodiments, X 2 This is a bond, -(O-CH2-CH2) n - ,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 The alkyl-, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. In some embodiments, X 2 X is a bond. In some embodiments, X 2 is -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, or -C 1~5 It is alkyl-, where n is 1, 2, or 3. For example, X 1is -C(O)-N(R)-, and X 2 is -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, or -C 1~5 It is alkyl-. In some examples, X 2 is -(O-CH2-CH2) n -or-(CH2-CH2-O) n - and in the formula, n is either 1 or 2. In other examples, X 2 is -C 1~5 It is alkyl-. For example, X 2 These include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). In other examples, X 2 X is a bond, -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some examples, X 2 X is a cycloalkyl group with 4 to 6 members. For example, X 2 teeth,

[0343] [ka] In other examples, X 2 X is a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 2 teeth,

[0344] [ka] That is the case.

[0345]

[0232] In some embodiments, X 3 is a combination, -C 1~4 Alkyl-, 4~6 Member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p-, a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3. In some embodiments, X 3 X is a bond. In some embodiments, X 3 These include methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, X 3 X is cyclopentyl or cyclohexyl. In some embodiments, X 3 is -N(H)-. In other embodiments, X 3 is -(O-CH2-CH2) p -or-(CH2-CH2-O) p - and in the formula, p is either 1 or 2.

[0346]

[0233] In some embodiments, X 4 The bond is -CH2-CH2-N(R)- , -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated, or fully unsaturated heteroring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, X 4 is to combine,

[0347] [ka] , -C 1~4 It is alkyl-, -CH2-CH2-N(R)-, or -N(R)-. For example, X 4 is -CH2-CH2-N(H)- or -N(H)-. In other examples, X 4 These include methyl, ethyl, propyl, isopropyl, butyl, and sec-butyl.

[0348]

[0234] In some embodiments, X 5 is a combination, -C 1~4Alkyl-, -N( In some embodiments, X 5 X is a bond. In some embodiments, X 5 These include methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, X 5 is -N(H)- or - It is C(O)-N(H)-.

[0349]

[0235] In some embodiments, L is

[0350] [ka]

[0351] [ka]

[0352] [ka]

[0353] [ka] Selected from.

[0354]

[0236] This disclosure also includes formula (IA):

[0355] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 C 1~3 It is alkyl, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, - (O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-, 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p -, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated or fully unsaturated heteroring having 1-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4 The elements are alkyl-, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0356] [ka] And in the formula, R 2 Each of these independently controls the Halo or -C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A These are independently -H or -C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0357]

[0237] In other embodiments, the variables of formula (IA) are each, formula (X) or (I The compounds of ) are defined herein.

[0358]

[0238] This disclosure also relates to formula (IB)

[0359] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 C 1~3 It is alkyl, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl ring having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and the heterocycloalkyl is optionally substituted with -CH3, X2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-, 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p -, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated or fully unsaturated heteroring having 1-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4 The elements are alkyl-, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0360] [ka] And in the formula, R 2 Each is independently a halo or C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A Each of these is independently -H or C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0361]

[0239] In other embodiments, the variables of formula (IB) are each, formula (X) or (I The compounds of ) are defined herein.

[0362]

[0240] This disclosure also relates to formula (II)

[0363] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 , R 2 L, Z, and Z are defined herein for compounds of formula (X), (I), (IA), or (IB), respectively.

[0364]

[0241] In some embodiments, the compound of formula (II) is formula (II-A) or (II-B)

[0365] [ka] A compound of or a pharmaceutically acceptable salt thereof, where X 2 , X 3 , X 4 , and X 5 These are defined herein for compounds of formula (X), (I), (IA), (IB), or (II), respectively.

[0366]

[0242] This disclosure also relates to formula (III)

[0367] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 C 1~3 It is alkyl, and L is -X 1 -X 2 -X 3- and X 1 is a 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, the heterocycloalkyl is optionally substituted with -CH3, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl is optionally substituted with -CH3, and X 2 is a combination or -C 1~5 Alkyl- and X 3 is a combination, -C 1~4 A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, and Y is

[0368] [ka] And in the formula, R 2 Each is independently a halo or C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A Each of these is independently -H, and q is 0, 1, or 2.

[0369]

[0243] This disclosure also relates to formula (IV)

[0370] [ka] We also provide compounds of or pharmaceutically acceptable salts thereof, where R 1 C 1~3 It is alkyl, and L is -X 1 -X 2 -X 3 -X 4 -X 5 - and X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m-, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, and X 2 This is a bond, -(O-CH2-CH2) n -,-(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 Alkyl-, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X 3 is a combination, -C 1~4 Alkyl-, 4-6 member cycloalkyl, -N(R)-, -(O-CH2-CH2) p -,-(CH2-CH2-O) p -, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3, X 4 The bond is -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-,-(O-CH2-CH2-CH2) m -, or a 5-6 member saturated, partially unsaturated or fully unsaturated heteroring having 1-3 heteroatoms independently selected from N, O, or S, X 5 is a combination, -C 1~4 The elements are alkyl-, -N(R)-, or -C(O)-N(R)-, where R is independently -H or -C 1~3 It is an alkyl group, where m, n, and p are each independently integers between 1 and 3, and Y is,

[0371] [ka] And in the formula, R 2 Each of these independently controls the Halo or -C 1~4 It is alkyl, and Z is -C(R A )2- or -C(O)-, R A These are independently -H or -C 1~4 It is an alkyl group, and q is 0, 1, or 2.

[0372]

[0244] General synthesis scheme

[0245] The compound is prepared according to any technique deemed appropriate by those skilled in the art. It can be synthesized. In certain embodiments, the compound is prepared according to International Application No. PCT / US2019 / 56112, filed on 14 October 2019, which is incorporated herein by reference in whole. An exemplary synthesis scheme is described below.

[0373]

[0246] General Procedure 1: Amide Coupling

[0247] Amine (0.03 mmol), Acid (0.03 mmol), HATU (0.04 A mixture of (R)-3-( Xasamide was reacted as described above to provide 3-((4-(9-(3-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)propoxy)propanoyl)-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide (compound 57).

[0374]

[0248] Scheme 1: Synthesis of compound 57 via amide formation

[0375] [ka]

[0376]

[0249] Other amide-containing compounds in this specification synthesized using general procedure 1 are chemically compounded The combined values ​​were 2-9, 10-14, 19, 20, 22-28, 61, 62, 63, and 67.

[0377]

[0250] General Procedure 2: Reductive Amination

[0251] Amine TFA salt (0.07 mmol), aldehyde (0.1 mmol), tori A mixture of ethylamine (0.28 mmol) and DCE was stirred at room temperature for 10 minutes. NaBH(OAc)3 (0.14 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite, washed with CH2Cl2, concentrated, and purified by HPLC (H2O / MeCN containing 0.1% TFA) to obtain the amine product. In Scheme 2, an exemplary reductive amination is provided, where (R)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-carboxamide is converted as above, (3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-3 - Treatment with carvalenthide yielded 3-((4-(1-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide (compound 32).

[0378]

[0252] Scheme 2: Synthesis of compound 32 via reductive amination

[0379] [ka]

[0380]

[0253] Other amine-containing compounds in this specification synthesized using general procedure 2 are chemically compounded The combined values ​​were 33, 46, 56, 15-18, 21, 31, 48-52, 54, 59, 60, 35, 36, and 38-45.

[0381]

[0254] Scheme 3: Synthesis of the Compounds of the Disclosure

[0382] [ka]

[0383]

[0255] An intermediate that can be produced by deesterifying intermediate (1-6) Compound (3-1) is treated with an amine, Y-NH2, under coupling conditions to produce compound (3-2) of the present disclosure, where the terminal linking group of L is an amide.

[0384]

[0256] General Procedure 3: Aryl Fluoride Replacement

[0257] Amine (0.22 mmol), Aryl fluoride (0.22 mmol), DIP A mixture of EA (0.88 mmol) and DMF (1 mL) was stirred at 90°C for 16 hours. The mixture was purified by HPLC (H2O / MeCN containing 0.1% TFA) to obtain the desired product. In Scheme 3, an exemplary aryl fluoride substitution is provided, where (R)-3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidine-1 (-yl)piperidine-1-yl)pyrazine-2-carboxamide is treated with 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione as described above to provide 3-((4-(6-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide (compound 34).

[0385]

[0258] Scheme 3: Synthesis of compound 34 via aryl fluoride substitution

[0386] [ka] Other arylamine-containing compounds in this specification synthesized using general procedure 3 are compounds 55, 29, 47, 53, 58, 64-66, 37, and 30.

[0387]

[0259] The compounds shown in Table 1 were synthesized using the synthesis scheme described above.

[0388]

[0260] [Table 1-1]

[0389] [Table 1-2]

[0390] [Table 1-3]

[0391] [Table 1-4]

[0392] [Table 1-5]

[0393] [Table 1-6]

[0394] [Table 1-7]

[0395] [Table 1-8]

[0396] [Table 1-9]

[0397] Table 1-10

[0398] Table 1-11

[0399] Table 1-12

[0400] Table 1-13

[0401] Table 1-14

[0402] Table 1-15

[0403] Table 1-16

[0404] Table 1-17

[0405] Table 1-18

[0406] Table 1-19

[0407] Table 1-20

[0408] Table 1-21

[0409] Table 1-22

[0410] Table 1-23

[0411] Table 1-24

[0412] Table 1-25

[0413] Table 1-26

[0414] Table 1-27

[0415] Table 1-28

[0416] Table 1-29

[0417] Table 1-30

[0418] Table 1-31

[0419] Table 1-32

[0420] Table 1-33

[0421] Table 1-34

[0422] Table 1-35

[0423] Table 1-36

[0424] Table 1-37

[0425] Table 1-38

[0426] Table 1-39

[0427] [Table 1-40]

[0428] [Table 1-41]

[0429] [Table 1-42]

[0430] [Table 1-43]

[0431] Formulation and administration

[0261] Pharmaceutical composition

[0262] The compounds described herein are pharmaceutically acceptable carriers, diluents, and argons. The compounds can be formulated into pharmaceutical compositions further comprising a carrier or vehicle. In one embodiment, the Disclosure provides a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the Disclosure is a pharmaceutical composition comprising an effective amount of the Compound of the Disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Examples of pharmaceutically acceptable carriers include pharmaceutical diluents, excipients, or carriers that are appropriately selected with respect to the intended dosage form and in accordance with conventional pharmaceutical practice.

[0432]

[0263] According to another embodiment, this specification relates to the compounds herein or their pharmaceutically permitted The present specification provides compositions comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The pharmaceutical compositions of this specification comprise a therapeutically effective amount of a compound of formula (A1), (A), (B), (C), (D), (D-1), (D-2), (E), (F), (G), (H), (J), (K), (M), (I), (IA), (IB), (II), (II-A), (II-B), (III), (IV), and / or (X), where “therapeutically effective amount” means (a) an amount effective to measurably degrade (or reduce the amount of BTK) BTK in a biological sample or patient; or (b) an amount effective to treat and / or improve a disease or disorder mediated by BTK.

[0433]

[0264] The term “patient” as used herein refers to an animal, or a mammal, "i" means human.

[0434]

[0265] The specific compounds of this disclosure are available in their free form for treatment, or as appropriate. It may also be understood that it may exist as a pharmaceutically acceptable derivative (e.g., a salt) of the compound. According to this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts / free bodies or derivatives that can directly or indirectly provide the compound or its metabolites or residues as otherwise described herein when administered to a patient in need.

[0435]

[0266] As used herein, the term “pharmaceutically acceptable salt” means a sound salt. This refers to salts that are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, within the bounds of medical judgment.

[0436]

[0267] Medicinally acceptable salts are well known in the art. For example, SMBer ge et al. describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences 1977, 66, 1-19, which is incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of this specification include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfate, formate, fumarate, glucoheptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate Examples include palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and ballate salts. Suitable salts derived from alkali metals, alkaline earth metals, ammonium, and N + (C 1~4Examples include alkyl) tetrasalts. This specification also envisions the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0437]

[0268] A pharmaceutically acceptable carrier is an inactivating agent that does not excessively inhibit the biological activity of the compound. It may contain sexually active ingredients. A pharmaceutically acceptable carrier should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or free from other undesirable reactions or side effects upon administration to the subject. Standard formulation techniques can be used.

[0438]

[0269] A pharmaceutically acceptable carrier, adjuvant, or as used herein Examples of vehicles include any solvent, diluent, or other liquid vehicle suitable for the desired specific dosage form, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds described herein, for example, by producing any undesirable biological effect or by interacting adversely with any other component(s) of the otherwise pharmaceutically acceptable composition, the use of such conventional carrier medium is intended to be within the scope of this specification. As used herein, the phrase “adverse effect” encompasses any unwanted and unfavorable effect of a treatment (e.g., a prophylactic or therapeutic agent). Adverse effects are not always unwanted, but unwanted effects are not necessarily unfavorable. Side effects from treatment (preventive or therapeutic drugs) may be harmful, unpleasant, or dangerous. Side effects include, but are not limited to, fever, chills, malaise, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, nephrotoxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), myelotoxicity (including leukopenia, myelosuppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, somnolence, pain (including muscle pain, bone pain, and headache), alopecia, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0439]

[0270] Some examples of materials that can serve as pharmaceutically acceptable carriers include io Calcium exchanger, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering agents (such as tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), partial glyceride mixtures, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, methylcellulose, hydroxypropyl methylcellulose, lanolin fat, sugars, e.g., lactose, glucose, and sucrose; starch, e.g., corn starch and Potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol or polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffers; as well as other non-toxic, compatible lubricants, e.g., sodium lauryl sulfate and magnesium stearate; and colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances. Preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0440]

[0271] As used herein, the term “measurably disassembled” means this specification This means (a) BTK activity, or (b) a measurable decrease in the concentration of BTK in a sample over time, between a sample containing the compound and BTK and an equivalent sample containing BTK in the absence of the compound.

[0441] Administration

[0272] The compositions of this disclosure are administered orally. Pharmacologically acceptable compositions of this specification It can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Typically, lubricants such as magnesium stearate are also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners, flavorings, or colorings may also be added as needed.

[0442]

[0273] For oral administration, the liquid dosage form is a pharmaceutically acceptable emulsion or micro Examples of active compounds include, but are not limited to, emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds herein, liquid formulations may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and fragrance agents.

[0443]

[0274] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Granules are an example. In such solid dosage forms, the active compound herein is at least one inert pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, e.g., paraffin; f) quaternary a Absorption enhancers such as monium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, which are mixed with the substance. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0444]

[0275] Similar types of solid compositions also include lactose or milk sugar, as well as high molecular weight It can be used as a filler in flexible and rigid gelatin capsules using excipients such as polyethylene glycol. Solid dosage forms of tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. The solid dosage forms may optionally contain opacifiers. These solid dosage forms may also be solid dosage forms of compositions that optionally release the active ingredient(s) in a delayed manner, for example, only in specific parts of the intestinal tract. Examples of usable embedding compositions include polymers and waxes. Similar types of solid compositions may also be used as fillers in flexible and rigid gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0445]

[0276] The active compounds herein may also be one or more excipients as previously mentioned. The active compound may also be in a microencapsulated form. Solid dosage forms of tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also, as is common practice, include further substances other than the inert diluent, such as tableting lubricants, and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. These dosage forms may optionally include an opacifier, and may also be compositional dosage forms that optionally release the active ingredient(s) in a delayed manner, for example, only in a specific part of the intestinal tract. Examples of usable embedding compositions include polymeric substances and waxes.

[0446]

[0277] The compounds described herein are intended to facilitate administration and to ensure uniformity of the dosage. They are formulated in dose unit form. As used herein, the phrase “dose unit form” refers to a physically distinct unit of the drug appropriate for the patient being treated. However, it will be understood that the total daily dose of the compounds and compositions of this disclosure will be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular patient or organism will vary depending on a variety of factors, including the disorder being treated and its severity; the activity of the particular compound used; the particular composition used; the patient’s age, weight, general health, sex, and diet; the time of administration, route of administration, and elimination rate of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in medical technology.

[0447]

[0278] Compounds of the present disclosure which can be combined with a carrier material to produce a single-dosage-form composition The amount of substance will vary depending on the host being treated, the specific administration method, and other factors. These compositions should be formulated so that a dose of 0.01 to 100 mg / kg body weight / day of the compound or inhibitor can be administered to the patient receiving these compositions.

[0448]

[0279] Depending on the specific condition or disease that should be treated or prevented, the condition should be treated. Further therapeutic agents that are typically administered to treat or prevent a particular disease or condition may also be present in the compositions of this disclosure. Any additional medications administered are known to be "appropriate for the disease or condition being treated."

[0449]

[0280] For example, combining a chemotherapeutic agent or other antiproliferative agent with the compound of the present disclosure increases It can treat reproductive diseases and cancer. Examples of known chemotherapeutic agents include PI3K inhibitors (e.g., idelalisib and copanlisib), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib and acalabrutinib), etoposide, CD20 antibodies (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ubrituximab), and Retuzumab, bendamustine, cladribine, doxorubicin, chlorambucil, prednisone, midostaurin, lenalidomide, pomalidomide, checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembolizumab, atezolizumab, avelumab, durvalumab), artificial cell therapy (e.g., CAR-T therapy - Kymriah) Examples include, but are not limited to, (Registered Trademark), Yescarta (Registered Trademark), Gleevec (Trademark), Adriamycin, Dexamethasone, Vincristine, Cyclophosphamide, Fluorouracil, Topotecan, Taxol, Interferon, and platinum derivatives.

[0450]

[0281] In some cases, radiotherapy may involve the compounds of this disclosure (or their compounds). A pharmaceutically acceptable salt is administered to the patient in need during the course of treatment.

[0451]

[0282] Other examples of drugs that can be combined with the compounds or inhibitors of this disclosure This includes drugs for the treatment of Alzheimer's disease, e.g., Aricept® and Excelon®; drugs for the treatment of Parkinson's disease, e.g., L-DOPA / carbidopa, entacapone, ropinol, pramipexole, bromocriptine, pergolide, trihexefendyl, and amantadine; drugs for the treatment of multiple sclerosis (MS), e.g., beta-interferon (e.g., Avonex® and Rebif®); Co Paxone® and mitoxantrone; treatments for asthma, e.g., albuterol and Singulair®; drugs for treating schizophrenia, e.g., Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, e.g., corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressant agents, e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinson's disease agents; agents for treating cardiovascular diseases, e.g., beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases, e.g., corticosteroids, cholestyramine, interferon, and antiviral agents; agents for treating hematological disorders, e.g., corticosteroids, antileukemia agents, and growth factors; and agents for treating immunodeficiency disorders, e.g., gamma globulin, but not limited to these.

[0452]

[0283] The amount of further therapeutic agents present in the composition of this disclosure is such that the therapeutic agent is the only active agent. The amount of the agent in a composition will not exceed the amount that would normally be administered. The amount of further therapeutic agents in the compositions disclosed herein is in the range of about 50% to 100% of the amount that would normally be present in a composition containing that agent as the sole therapeutically active agent. [Examples]

[0453]

[0284] Additional embodiments are disclosed in more detail in the following embodiments, but claims It is never intended to limit the scope of this.

[0454] Example 1

[0455] [ka]

[0456]

[0285] Methyl 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl Synthesis of picolinate: A mixture of methyl 5-fluoropyridine-2-carboxylate (1020 mg, 6.58 mmol), 4-(1,3-dioxolan-2-yl)piperidine (1033 mg, 6.58 mmol), N,N-diisopropylethylamine (2.29 mL, 13.15 mmol), and DMSO (6.5 mL) was stirred overnight at 100°C. The mixture was cooled to room temperature. H2O (8.1 mL) was added, and the mixture was filtered. The solid was collected and dried to obtain methyl 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]pyridine-2-carboxylate (1.90 g, 98.8%). LCMS:C 15 H 20 Calculated value for N2O4: 292, Measured value: m / z = 293 [M + H] + .

[0457]

[0286] 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl) pico Synthesis of phosphoric acid: A mixture of methyl 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]pyridine-2-carboxylate (1.90 g, 6.50 mmol), sodium hydroxide (324.95 mg, 8.12 mmol), THF (8.4 mL), and water (8.4 mL) was stirred at room temperature for 2 hours. Volatile substances were removed. MeCN (11.8 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The mixture was filtered, and the solid was collected to obtain 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]pyridine-2-carboxylic acid (1.68 g, 92.9%). LCMS:C 14 H 18 Calculated value for N2O4: 278, measured value: m / z = 279 [M + H] + .

[0458] Example 2

[0459] [ka]

[0460]

[0287] (R)-5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl Synthesis of (3R)-N-(2,6-dioxopiperidine-3-yl)picolinamide: 5-[4-(1,3-dioxolann-2-yl)piperidine-1-yl]pyridine-2-carboxylic acid (196 mg, 0.70 mmol), (3R)-3-aminopiperidine-2,6-dione A mixture of hydrochloride (115 mg, 0.70 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium, hexafluoro-lambda 5-phosphanoid (535 mg, 1.41 mmol), N,N-diisopropylethylamine (0.31 mL, 1.76 mmol), and DMF (2 mL) was stirred at room temperature for 30 minutes. 0.1 M HCl (1 mL) in water was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered and washed with cold water H2O. The solid was collected to obtain 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]-N-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-carboxamide (0.272 g, 99.4%). LCMS:C 19 H 24 Calculated value of N4O5: 388, measured value: m / z = 389 [M+H] + .

[0461]

[0288] (R)-N-(2,6-dioxopiperidine-3-yl)-5-(4-hormi Synthesis of (R)-N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)picolinamide: A mixture of 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]-N-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-carboxamide (259 mg, 0.67 mmol), THF (3 mL), and 2 M HCl (3 mL) was stirred at 50°C for 1 hour. Saturated aqueous NaHCO3 was added until the pH was approximately 7-8. CHCl3 / iPrOH was added, and the organic layer was dried over MgSO4, filtered, and concentrated. MeCN was added, and the mixture was sonicated for approximately 10 minutes. The mixture was filtered, and the solid was collected to obtain (R)-N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)picolinamide (0.155 g, 68%). LCMS:C 17 H 20 Calculated value for N4O4: 344, Measured value: m / z = 345 [M+H] + .

[0462] Example 3

[0463] [ka]

[0464]

[0289] (S)-5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl Synthesis of (L)-N-(2,6-dioxopiperidine-3-yl)picolinamide: (3S)-3-aminopiperidine-2,6-dione hydrochloride (118.28 mg, 0.72 mmol), 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]pyridine-2-carboxylic acid (200 mg, 0.72 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium, hexafluoro-lambda 5-phosphanoid (546 mg, 1.44 mmol), N,N-diisopropylethylamine (0.32 mL, 1.80 mmol), and DMF (2 mL) were stirred at room temperature for 30 minutes. 1 M aqueous HCl was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the solid 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]-N-[(3S)-2,6-dioxopiperidine-3-yl]pyridine-2-carboxamide (0.2750 g, 99%) was collected. LCMS:C 19 H 24 Calculated value of N4O5: 388, measured value: m / z = 389 [M+H] + .

[0465]

[0290] (S)-N-(2,6-dioxopiperidine-3-yl)-5-(4-hormi Synthesis of Lupiperidine-1-yl) Picolinamide: A mixture of 5-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]-N-[(3S)-2,6-dioxopiperidine-3-yl]pyridine-2-carboxamide (332 mg, 0.85 mmol), THF (3 mL), and 2 M HCl (3 mL) was stirred at 50°C for 1 hour. Saturated aqueous NaHCO3 was added until the pH was approximately 7-8. CHCl3 / iPrOH was added, and the organic layer was dried over MgSO4, filtered, and concentrated. MeCN was added, and the mixture was sonicated for approximately 10 minutes. The mixture was filtered, and the solid was collected to obtain (S)-N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)picolinamide (175 mg, 60%). LCMS:C 17 H 20 Calculated value for N4O4: 344, Measured value: m / z = 345 [M+H]+ .

[0466] Example 4 Synthesis of 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{[4-(piperazine-1-yl)phenyl]amino}pyrazine-2-carboxamide:

[0467]

[0291] tert-butyl(3R)-3-{[(2-chloroethyl)carbamoyl] Minopiperidine-1-carboxylate

[0468] [ka]

[0469]

[0292] tert-butyl(3R)-3-aminopiperidine in DCM (250mL) To a mixture of 1-1-carboxylate (25.0 g, 125 mmol) and triethylamine (34.8 mL, 25.3 g, 250 mmol), 1-chloro-2-isocyanatoethane (12.8 mL, 15.8 mL, 150 mmol) was added over 25 minutes. Mild exothermic reaction was observed. After 4 hours, 100 mL of water was added. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The mixture was dissolved in ethyl acetate, eluted with ethyl acetate, and filtered through 1000 cc of silica gel in a 2000 mL Buchner funnel. The resulting solution was concentrated under vacuum to obtain tert-butyl(3R)-3-{[(2-chloroethyl)carbamoyl]amino}piperidine-1-carboxylate (40.6 g, 106%), which was used without further purification. LCMS:C 13 H 24 Calculated value for ClN3O3: 305, measured value: m / z = 306 [M + H] + .

[0470]

[0293] tert-butyl(3R)-3-(2-oxoimidazolidine-1-yl)pi Peridine-1-carboxylate

[0471] [ka]

[0472]

[0294] tert-butyl(3R)-3-{[ To a mixture of (2-chloroethyl)carbamoyl]amino}piperidine-1-carboxylate (40.3 g, 132 mmol), 60% sodium hydride (10.6 g, 264 mmol) was gradually added. The mixture was melted in a condenser and stirred overnight at room temperature. A further amount of 60% sodium hydride (5.65 g, 141 mmol) was added. The mixture foamed. After 10 minutes, mild exothermic reaction was observed. After 2 hours, 75 mL of water was added to quench the reaction. The layers were separated. The aqueous layer was extracted with two 50 mL doses of DCM. The combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum. The resulting material was divided between acetonitrile and hexane. The acetonitrile layer was concentrated under vacuum to obtain tert-butyl(3R)-3-(2-oxoimidazolidine-1-yl)piperidine-1-carboxylate (33.9 g, 95.4%). LCMS:C 13 H 23 Calculated value of N3O3: 269, measured value: m / z = 270 [M+H] + .

[0473]

[0295] tert-butyl(3R)-3-(3-methyl-2-oxoimidazolidine- 1-yl)piperidine-1-carboxylate

[0474] [ka]

[0475]

[0296] tert-butyl(3R)-3-(2) in ice-cooled THF (300mL) A mixture of oxoimidazolidine-1-yl)piperidine-1-carboxylate (33.8 g, 126 mmol) was gradually mixed with 60% sodium hydride (10.1 g, 251 mmol). After 5 minutes, the condenser was removed. The mixture was allowed to foam for 1 hour. The mixture was cooled in an ice bath. Methyl iodide (11.7 mL, 26.7 g, 188 mmol) was added over 5 minutes. The mixture was allowed to foam. The condenser was warmed to room temperature. After stirring at room temperature for 16 hours, the mixture was quenched with water (75 mL). The layers were separated. The organic layer was washed with brine. The combined aqueous layer was extracted twice with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting substance was divided between acetonitrile and hexane. The acetonitrile layer was filtered and concentrated under vacuum to obtain tert-butyl(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-carboxylate (38.4 g, 108%), which was used as a crude product without further purification. LCMS:C 14 H 25 Calculated value of N3O3: 283, measured value: m / z = 306 [M + Na] + .

[0476]

[0297] 1-Methyl-3-[(3R)-piperidine-3-yl]imidazolidin-2- On hydrochloride

[0477] [ka]

[0478]

[0298] tert-butyl(3R)-3-(3-methyl-2-oxoimidazolidine- 1-yl)piperidine-1-carboxylate (35.1 g, 124 mmol) was stirred for 2 hours in a 4 M solution of hydrogen chloride in dioxane (310 mL, 1.24 mol). The mixture was concentrated under vacuum to obtain 1-methyl-3-[(3R)-piperidine-3-yl]imidazolidined-2-one hydrochloride (35.0 g, 128%), which was used as a crude product without further purification. LCMS:C9H 17Calculated value of N3O: 183, measured value: m / z = 184 [M + H] + .

[0479]

[0299] 3-Chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidine) -1-yl)piperidine-1-yl]pyrazine-2-carbonilicate

[0480] [ka]

[0481]

[0300] 3,5-Dichloropyrazine-2-Carbonitrile (21.6g, 124mmo) l) was added to a mixture of 1-methyl-3-[(3R)-piperidine-3-yl]imidazolidine-2-one hydrochloride (27.2 g, 124 mmol) and N,N-diisopropylethylamine (86.3 mL, 495 mmol) in ice-cooled DMF (300 mL). After 15 minutes, the condenser was removed. After stirring for 16 hours, the mixture was diluted with 800 mL of water. The mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude residue was purified by flash chromatography using a 0-3% MeOH / DCM gradient on a 330g silica gel column to obtain 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-carbonitrile (22.1g, 55.6%). LCMS:C 14 H 17 Calculated value for ClN6O: 320, measured value: m / z = 320 [M + H] + .

[0482]

[0301] tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl Tyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate

[0483] [ka]

[0484]

[0302] 3-Chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidine) A mixture of (-1-yl)piperidine-1-yl]pyrazine-2-carbonitride (244 mg, 0.76 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (211 mg, 0.76 mmol), Pd(OAc)2 (56.4 mg, 0.25 mmol), BINAP (156.3 mg, 0.25 mmol), and Cs2CO3 (7434 mg, 2.28 mmol) was degassed and backfilled five times with N2. The mixture was stirred at 100°C for 90 minutes. The mixture was washed with MeOH / siRNA, filtered through Celite, concentrated, and purified by MPLC (0-100% siRNA in CH2Cl2) to obtain tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate (259 mg, 60.7%). LCMS:C 30 H 40 Calculated value for N8O3: 560, Measured value: m / z = 561 [M+H] + .

[0485]

[0303] tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-( 3-Methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate

[0486] [ka]

[0487]

[0304] H2O2 (30% in water, 2.50 mL, 0.24 mmol) is prepared using tert-br The mixture was added to a mixture of 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate (259 mg, 0.46 mmol), Cs2CO3 (150.5 mg, 0.46 mmol), MeOH (9 mL), and DMSO (0.5 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated. Ether was added, and the organic phase was washed with H2O and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-10% MeOH in CH2Cl2) to obtain tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate (252 mg, 94%). LCMS:C 30 H 42 Calculated value for N8O4: 578, Measured value: m / z = 579 [M+H] + .

[0488]

[0305] 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl) [Piperidin-1-yl]-3-{[4-(piperazine-1-yl)phenyl]amino}pyrazine-2-carboxamide

[0489] [ka]

[0490]

[0306] tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-( A mixture of 3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]piperidine-1-carboxylate (252 mg, 0.44 mmol), hydrogen chloride (4 M in dioxane, 2.72 mL, 10.89 mmol), and THF (2 mL) was stirred at room temperature for 2 hours. After removing volatile substances, 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{[4-(piperidine-4-yl)phenyl]amino}pyrazine-2-carboxamide (209 mg, quantified) was obtained.

[0491] Example 5

[0492] [ka]

[0493]

[0307] (R)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl) Synthesis of peridine-1-yl)-3-((6-(piperidine-4-yl)pyridine-3-yl)amino)pyrazine-2-carboxamide: It was prepared in the same manner as the preparation of 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{[4-(piperidine-4-yl)phenyl]amino}pyrazine-2-carboxamide, using tert-butyl 4-(5-aminopyridine-2-yl)piperidine-1-carboxylate instead of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate.

[0494] Example 6

[0495] [ka]

[0496]

[0308] (R)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl) Synthesis of peridine-1-yl)-3-((2-(piperidine-4-yl)pyrimidine-5-yl)amino)pyrazine-2-carboxamide: It was prepared in the same manner as the preparation of 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{[4-(piperidine-4-yl)phenyl]amino}pyrazine-2-carboxamide, using tert-butyl 4-(5-aminopyrimidine-2-yl)piperidine-1-carboxylate instead of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate.

[0497] Example 7

[0498] [ka]

[0499]

[0309] (R)-3-((1-(azetidine-3-yl)-1H-pyrazole-4-yl Synthesis of (3R)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide: Prepared in the same manner as the preparation of 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{[4-(piperidine-4-yl)phenyl]amino}pyrazine-2-carboxamide, using tert-butyl 3-(4-amino-1H-pyrazole-1-yl)azetidine-1-carboxylate instead of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate.

[0500] Example 8

[0501]

[0310] (R)-3-((4-(3,9-diazaspiro[5.5]undecane-3-i Synthesis of (Phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide:

[0502] [ka]

[0503]

[0311] tert-butyl9-(4-nitrophenyl)-3,9-diazaspiro[5. 5] Synthesis of undecane-3-carboxylate:

[0312] 4-Fluoronitrobenzene (554.7 mg, 3.93 mmol), DMF A mixture of (20 mL), ethylbis(propan-2-yl)amine (2.74 mL, 15.7 mmol), and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1000 mg, 3.93 mmol) was stirred overnight at 90°C. ÂTED and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-50% ÂTED in hexane) to obtain tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1287.00 mg, 87.2%). 20 H 29 Calculated value for N3O4: 375, measured value: m / z = 376 [M+H] + .

[0504]

[0313] tert-butyl9-(4-aminophenyl)-3,9-diazaspiro[5. 5] Synthesis of undecane-3-carboxylate:

[0314] tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5. 5) The mixture of undecane-3-carboxylate (1.29 g, 3.43 mmol), Pd / C (36 mg, 0.34 mmol), and EtOH (30 mL) was degassed and backfilled five times with H2. The mixture was stirred at room temperature for 2 hours.

[0505]

[0315] The mixture is filtered through Celite while being washed with toluene / MeOH, and then concentrated. This yielded tert-butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (871 mg, 73.5%). LCMS:C 20 H 31 Calculated value of N3O2: 345, measured value: m / z = 346 [M + H] + .

[0506]

[0316] tert-butyl(R)-9-(4-((3-cyano-6-(3-(3-meth Synthesis of ru-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate:

[0317] tert-butyl9-(4-aminophenyl)-3,9-diazaspiro[5. 5] Undecane-3-carboxylate (162.6 mg, 0.47 mmol), 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl) pipette A mixture of lysine-1-yl]pyrazine-2-carbonitrile (151 mg, 0.47 mmol), Pd(OAc)2 (34.9 mg, 0.16 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalene]-2-yl]diphenylphosphan (96.7 mg, 0.16 mmol), and cesium carbonate (460 mg, 1.41 mmol) was degassed and backfilled five times with N2. The mixture was stirred at 100°C for 90 minutes. The mixture was washed with MeOH / Âti and filtered through Celite, concentrated, and purified by MPLC (0-100% Âti in CH2Cl2) to obtain tert-butyl 9-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl)]-3,9-diazaspiro[5.5]undecane-3-carboxylate (204 mg, 68.8%). LCMS:C 34 H 47 Calculated value of N9O3: 629, measured value: m / z = 630 [M + H] + .

[0507]

[0318] tert-butyl(R)-9-(4-((3-carbamoyl-6-(3-(3 Synthesis of -methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate:

[0319] H2O2 (30% in H2O, 0.55 mL, 0.05 mmol), tert Butyl 9-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl)]-3,9-diazaspiro[5.5]undecane-3-carboxylate (204 mg, 0.32 mmol), cesium carbonate (106 mg, 0.32 mmol), MeOH (6 mL), and DMSO (0.3 mL) were added. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated. Ether was added, and the organic phase was washed with H2O and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-10% MeOH in CH2Cl2) to obtain tert-butyl 9-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (95.00 mg, 45%). LCMS:C 34 H 49 Calculated value for N9O4: 647, Measured value: m / z = 648 [M+H] + .

[0508]

[0320] (R)-3-((4-(3,9-diazaspiro[5.5]undecane-3-i Synthesis of (Phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide:

[0321] tert-butyl9-[4-({3-carbamoyl-6-[(3R)-3-( A mixture of 3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (25 mg, 0.04 mmol), CH2Cl2 (1 mL), and TFA (0.2 mL) was stirred at room temperature for 1 hour. After removing volatile substances, 3-[(4-{3,9-diazaspiro[5.5]undecane-3-yl}phenyl)amino]-5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyrazine-2-carboxamide (21.00 mg, 99.4%) was obtained. LCMS:C 29 H 41 Calculated value of N9O2: 547, measured value: m / z = 548 [M + H] + .

[0509] Example 9 General Procedure B

[0510] [ka]

[0511]

[0322] Step 1: 2-(2,6-dioxopiperidine-3-yl)-5-fluoroiso Synthesis of indoline-1,3-zion:

[0323] 5-fluoro-1,3-dihydro-2-benzoflavin in HOAc (50 mL) A mixture of 1,3-dione (5.0 g, 30.10 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.9 g, 42.14 mmol), and NaOAc (4.2 g, 51.17 mmol) was stirred at 120°C for 5 hours and then concentrated under vacuum. The residue was washed with water, and the solid was collected by filtration. The crude product was washed twice with water, then twice with ethyl acetate, and dried in an oven to obtain a light brown solid, 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione (7.7 g, 92%). 1H NMR(300MHz,DMSO-d6)δ11.16(s,1H), 8.03~8.00(m,1H), 7.87~7.85(m,1H), 7.75~7.7 0(m,1H), 5.19~5.15(m,1H), 2.94~2.86(m,1H), 2.63~2.48(m,2H), 2.12~2.06(m,1H). 19 F NMR(300MHz,DMSO-d6)δ-102.078.

[0512]

[0324] Step 2: Amine substitution of aryl fluoride

[0325] 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-di In a solution of hydro-1H-isoindole-1,3-dione (1.0 g, 3.62 mmol) in N-methylpyrrolidone (10 mL), R x R y NH (3.60 mmol) and DIEA (1.4 g, 10.83 mmol) were added. The resulting solution was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase flash chromatography to obtain the corresponding final product. x R y This corresponds to any amine R group as defined elsewhere in this specification.

[0513]

[0326] Step 3: Alcohol Oxidation

[0327] Des Martin Periodinane (1.54 mmol) is mixed with alkyl alcohol (0.77 mmol) was added to a mixture of CH2Cl2 (10 mL). The mixture was stirred at room temperature for 1 hour. CH2Cl2 and aqueous Na2SO3 were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (20-100% siRNA in hexane) to obtain the aldehyde.

[0514] Example 10

[0328] 2-(2,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl Synthesis of (Cyl)piperidine-1-yl)isoindoline-1,3-dione:

[0515] [ka]

[0516]

[0329] Using general procedure B, piperidine-4-ylmethanol yielded two yellow solids. -(2,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl)piperidine-1-yl)isoindoline-1,3-dione (938.7 mg, 70%) was obtained. 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H), 7.65(d,J=8.4Hz,1H), 7.30(d,J=2.4H) z,1H), 7.23(dd,J=8.4,2.4Hz,1H), 5.07(dd,J=12.6,5.4Hz,1H), 4.51(t,J= 5.1Hz,1H), 4.07(d,J=13.2Hz,2H), 3.27(t,J=5.7Hz,2H), 2.99~2.80(m,3H) , 2.62~2.55(m,2H), 2.17~1.95(m,1H), 1.76~1.67(m,3H), 1.24~1.12(m,2H). MS(ESI)(C 19 H 21 N3O5)[M+H] + Calculated value: 372.1; measured value: 372.2.

[0517] Example 11

[0330] 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoi Synthesis of soindolin-5-yl)piperidine-4-carbaldehyde:

[0518] [ka]

[0519]

[0331] 2-(2,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl Using general procedure B, 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbaldehyde was obtained from (C)piperidine-1-yl)isoindorin-1,3-dioxoisoindorin-5-yl). MS(ESI)(C 19 H 19 N3O5)[M+H] + The calculated value is 370, and the measured value is 370.

[0520] Example 12

[0332] 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl Synthesis of (Cyl)azetidine-1-yl)isoindoline-1,3-dione:

[0521] [ka]

[0522]

[0333] Using general procedure B, azetidine-3-ylmethanol hydrochloride was prepared to produce a yellow solid. The substance 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl)azetidine-1-yl)isoindoline-1,3-dione (1.85 g, 68%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H), 7.63(d,J=8.4Hz,1H), 6.76(d,J=2.0Hz,1H), 6.62(dd,J=8.4,2.0Hz,1H), 5.06(dd,J=12.4,5.2Hz,1H), 4.86( t,J=5.2Hz,1H), 4.05(t,J=8.4Hz,2H), 3.77(dd,J=8.4,5.2Hz,2H), 3.60( t,J=5.2Hz,2H), 3.00~2.81(m,2H), 2.65~2.53(m,2H), 2.06~1.96(m,1H). MS(ESI)(C 17 H 17 N3O5)[M+H] + Calculated value: 344.1; measured value: 344.4.

[0523]

[0334] Example 13

[0335] 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoi Synthesis of soindolin-5-yl)azetidine-3-carbaldehyde:

[0524] [ka]

[0525]

[0336] 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl Using general procedure B, 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-carbaldehyde was obtained from (C)azetidine-1-yl)isoindoline-1,3-dione. MS(ESI)(C 17 H 15 N3O5)[M+H] + The calculated value is 342, and the measured value is 342.

[0526] Example 14

[0337] 2-(2,6-dioxopiperidine-3-yl)-5-((S)-3-(Hyd Synthesis of roxymethyl)pyrrolinidine-1-yl)isoindoline-1,3-dione:

[0527] [ka]

[0528]

[0338] Using general procedure B, (S)-pyrrolidine-3-ylmethanol turns yellow solid The compound 2-(2,6-dioxopiperidine-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione (643.1 mg, 33%) was obtained. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H), 7.64(d,J=8.4Hz,1H), 6.89(d,J=2.1Hz,1H), 6.80(dd,J=8.4,2.1Hz,1H), 5.06(dd,J=12.9,5.4Hz,1H) ), 4.78(t,J=5.4Hz,1H), 3.59~3.41(m,5H), 3.22~3.17(m,1H), 2.95~2.83(m,1H), 2.67~2.44(m,3H), 2.12~1.88(m,2H), 1.87~1.76(m,1H). MS(ESI)(C 18 H 19 N3O5)[M+H] + Calculated value: 358.1; measured value: 358.1.

[0529] Example 15

[0339] (3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3- Synthesis of dioxoisoindoline-5-yl)pyrrolidine-3-carbaldehyde:

[0530] [ka]

[0531]

[0340] (2,6-Dioxopiperidine-3-yl)-5-((S)-3-(hydrox Using methyl)pyrrolidine-1-yl)isoindoline-1,3-dione, general procedure B is applied. Then, (3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-carbaldehyde was obtained. MS(ESI) (C 18 H 17 N3O5)[M+H] + The calculated value is 356, and the measured value is 356.

[0532] Example 16

[0341] N-(4-(piperidine-4-yl)phenyl)-6-(thiazole-2-yl) Synthesis of imidazo[1,2-a]pyrazine-8-amine:

[0533] [ka]

[0534]

[0342] tert-butyl4-(4-((6-bromoimidazo[1,2-a]pyrazine Synthesis of 6-8-yl)amino)phenyl)piperidine-1-carboxylate: A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (1 g), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.1 g), DIEA (1.3 mL), and iPrOH (10 mL) was stirred overnight at 80°C. The mixture was poured into water and filtered. After washing with water and Et2O, tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazine-8-yl)amino)phenyl)piperidine-1-carboxylate (0.70 g, 41%) was obtained. LCMS:C 22 H 26 Calculated value for BrN5O2: 471, measured value: m / z = 472 [M + H] + .

[0535]

[0343] tert-butyl4-(4-((6-(thiazole-2-yl)imidazo[1 Synthesis of [2-a]pyrazine-8-yl)amino)phenyl]piperidine-1-carboxylate:

[0344] tert-butyl4-[4-({6-bromoimidazo[1,2-a]pyrazine A mixture of 50 mg of 8-ylamino)phenyl piperidine-1-carboxylate, 25 mg of tetrakis(triphenylphosphine)palladium, 23 mg of sodium carbonate, 40 mg of 2-(tributylstannyl)-1,3-thiazole, and 1 mL of 1,4-dioxane was stirred overnight at 50°C. Ether and H2O were added, the organic layer was dried over MgSO4, filtered, concentrated, and analyzed by HPLC (5-95°C in H2O). Purified by MeCN, tert-butyl 4-(4-((6-(thiazole-2-yl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl]piperidine-1-carboxylate (24 mg, 48%) was obtained.

[0536]

[0345] N-(4-(piperidine-4-yl)phenyl)-6-(thiazole-2-yl) Synthesis of N-(4-(piperidine-4-yl)phenyl)-6-(thiazole-2-yl)imidazo[1,2-a]pyrazine-8-amine: A mixture of tert-butyl 4-(4-((6-(thiazole-2-yl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl]piperidine-1-carboxylate (24 mg), TFA (0.5 mL), and CH2Cl2 (0.5 mL) was stirred at room temperature for 1 hour. After removing volatile substances, N-(4-(piperidine-4-yl)phenyl)-6-(thiazole-2-yl)imidazo[1,2-a]pyrazine-8-amine was obtained.

[0537] Example 17

[0538] [ka]

[0539]

[0346] [1-(5-bromopyridine-2-yl)piperidine-4-yl]methanol

[0347] 5-bromo-2-fluoropyridine (559 mg) in DMF (7.00 mL) To a mixture of [1-(5-bromopyridine-2-yl)piperidine-4-yl]methanol (366 mg, 3.18 mmol) and potassium carbonate (0.88 g, 6.35 mmol), piperidine-4-yl methanol was added. The mixture was stirred overnight at 90°C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous Na2SO4, and concentrated under vacuum. The crude residue was purified by flash chromatography using 0-10% MeOH / DCM on a 40 g column to obtain [1-(5-bromopyridine-2-yl)piperidine-4-yl]methanol (0.841 g, 97.6%). LCMS:C 11 H 15Calculated value for BrN2O: 270, measured value: m / z = 271 [M + H] + .

[0540] Example 18

[0541] [ka]

[0542]

[0348] {1-[2',6'-bis(benzyloxy)-[3,3'-bipyridine]- 6-yl]piperidine-4-yl}methanol

[0349] [1-(5-bromopyridine-2-yl)piperidine-4-yl]methanol (93.0 mg, 0.34 mmol), 2,6-bis(benzyloxy)pyridine-3-ylboronic acid (172 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium (0) (39.6 mg, 0.03 mmol), and potassium carbonate (94.8 mg, 0.69 mmol) were precipitated in THF (3.00 mL) and water (1.00 mL) in a microwave vial. The mixture was microwaved at 120°C for 40 minutes. The organic layer was directly placed on a silica gel cartridge, and the mixture was purified by flash chromatography using a 24 g column and eluted with 0-10% MeOH / DCM. The resulting substance was re-purified by flash chromatography using 0-50% ethyl acetate / DCM on a 24g column to obtain {1-[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]piperidine-4-yl}methanol (0.097g, 58.7%). LCMS:C 30 H 31 Calculated value of N3O3: 481, measured value: m / z = 482 [M + H] + .

[0543] Example 19

[0544] [ka]

[0545]

[0350] 3-{6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3 -ylpiperidine-2,6-dione

[0351] {1-[2',6'-bis(benzyloxy)} in ethanol (3.00 mL) A mixture of )-[3,3'-bipyridine]-6-yl]piperidine-4-yl}methanol (97.0 mg, 0.20 mmol) was mixed with 10% palladium carbon (97.0 mg). The mixture was stirred under an H2 atmosphere for 3 hours. The mixture was filtered through a Celite pad washed with 50 mL of DCM. The resulting solution was concentrated and then purified by flash chromatography on a 24 g column with elution at 0-20% MeOH / DCM to obtain 3-{6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl}piperidine-2,6-dione (0.0214 g, 34.3%). LCMS:C 16 H 21 Measured value of N3O3: 303, Measured value of m / z: 304 [M+H] + .

[0546] Example 20

[0547] [ka]

[0548]

[0352] 3-bromo-5-[(3R)-3-(3-methyl-2-oxoimidazolidine) -1-yl)piperidine-1-yl]pyridine-2-carbonilicate

[0353] 1-Methyl-3-[(3R)-piperidine-3-yl]imidazolidin-2- Ontrifluoroacetate (1.40 g, 4.72 mmol), 3-bromo-5-fluoropyridine-2-carbonitrile (948 mg, 4.72 mmol), and N,N-diisopropylethylamine (2.46 mL, 1.83 g, 14.2 mmol) were stirred in DMF (12.00 mL) at 90°C for 2 hours. The mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by flash chromatography using 0-10% MeOH / DCM on a 40 g column to obtain 3-bromo-5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyridine-2-carbonitrile (828 mg, 48.2%). LCMS:C 15 H 18 Calculated value for BrN5O: 363, Measured value: m / z = 364 [M + H] + .

[0549] Example 21

[0550] [ka]

[0551]

[0354] 3-bromo-5-[(3R)-3-(3-methyl-2-oxoimidazolidine) -1-yl)piperidine-1-yl]pyridine-2-carbonilicate

[0355] 3-bromo-5-[(3R)-3-(3-methyl-2-oxoimidazolidine) [1-yl]piperidine-1-yl]pyridine-2-carbonitrile (283 mg, 0.78 mmol), tert-butyl2-amino4H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (185 mg, 0.78 mmol), and cesium carbonate (1.01 g, 3.11 mmol) were suspended in dioxane (6.00 mL). Vacuum was applied to the vial until the contents foamed, and the headspace was backfilled with argon for 5 cycles. (Acetyloxy)palladio acetate (34.89 mg, 0.16 mmol) and BINAP (96.8 mg, 0 0.16 mmol) was added. Vacuum was applied to the vial until the contents foamed, and the headspace was backfilled with argon for 5 cycles. The mixture was heated overnight at 90°C. The mixture was cooled, diluted with DCM, and filtered. The resulting solution was concentrated under vacuum and then purified by flash chromatography on a 40 g column with elution at 0-10% MeOH / DCM to obtain tert-butyl 2-({2-cyano-5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyridine-3-yl}amino)-4H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (253 mg, 62.4%). LCMS:C 26 H 35 Calculated value for N9O3: 521, Measured value: m / z = 522 [M + H] + .

[0552] Example 22

[0553] [ka]

[0554]

[0356] 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl) [Piperidin-1-yl]-3-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-ylamino}pyridine-2-carboxamide trifluoroacetate

[0357] tert-butyl 2-({2-carbamoyl-5} in DCM (1.00 mL) -[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]pyridine-3-yl}amino)-4H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (20.00 mg, 0.04 mmol) and hydrogen chloride (4 M in dioxane, 1.00 mL, 0.15 g, 4.00 mmol) were stirred for 1 hour. The mixture was concentrated to obtain 5-[(3R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl]-3-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-ylamino}pyridine-2-carboxamide trifluoroacetate (0.021 g, 100%). LCMS:C 21 H 29 Calculated value of N9O2: 439, measured value: m / z = 440 [M + H] + .

[0555] Example 23

[0556] [ka]

[0557]

[0358] A: 3,5-Dichloropyrazine-2-Carbonitrile (1.5g, 8.62mg) A mixture of t-butyl N-piperidinyl carbamate (2.07 g, 10.4 mmol) and i-Pr2NEt (3 mL, 17.2 mmol) was dissolved in DMF (10 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with  (20 mL), washed with H2O (2 × 30 mL), and then concentrated to obtain a yellow oil. Flash chromatography (SiO2, 10 → 15% CH2Cl2 / Â) yielded a white solid tert-butyl(R)-(1-(6-chloro-5-cyanopyrazine-2-yl)piperidine-3-yl)carbamate (2.5 g, 86%). LCMS:C 15 H 20Calculated value for ClN5O2: 338, Measured value: m / z = 339 [M + H] + .

[0558]

[0359] B:tert-butyl(R)-(1-(6-chloro-5-cyanopyrazine-2 A mixture of (-yl)piperidine-3-yl)carbamate (800 mg, 2.37 mmol), 4-methylsulfonylaniline (405 mg, 2.37 mmol), (acetyloxy)paragioacetate (106 mg, 0.47 mmol), BINAP (295 mg, 0.47 mmol), and Cs2CO3 (3.09 g, 9.47 mmol) was suspended in DCE (35 mL), and the mixture was degassed under a stream of N2 for 5 minutes. The reaction mixture was heated at 110 °C for 2.5 hours, then cooled, diluted with RINKAN (50 mL), filtered on Celite, and concentrated. Purification (SiO2, 10 → 65% siRNA / CH2Cl2) yielded tert-butyl(R)-(1-(5-cyano-6-((4-(methylsulfonyl)phenyl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (760 mg, 68%). LCMS:C 22 H 28 Calculated value of N6O4S: 472, measured value: m / z = 473 [M + H] + .

[0559]

[0360] C:tert-butylN-[(3R)-1-{5-cyano-6-[(4-meth [Isulfonylphenyl)amino]pyrazine-2-yl]piperidine-3-yl]carbamate (760 mg, 1.61 mmol) was dissolved in MeOH (5 mL), and NaOH (100 mg) and H2O2 (33%, water-soluble, 1 mL) were added. The reaction mixture was stirred for 20 minutes, then diluted with ACN (2 mL), and stirred for another 10 minutes. Exothermic reaction was observed upon addition of ACN. After concentrating the mixture, it was diluted with 50 mL of ethyl acetate, and the organic phase was washed with H2O (2 × 15 mL). The combined organic extract was dried (MgSO4) and filtered. The solution was concentrated to obtain tert-butyl(R)-(1-(5-carbamoyl-6-((4-(methylsulfonyl)phenyl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate, which was then purified (SiO2, 0 → 10% MeOH / CH2Cl2). LCMS:C 22 H 30 Calculated value for N6O5S: 490, Measured value: m / z = 491 [M + H] + .

[0560]

[0361] D:tert-butylN-[(3R)-1-{5-carbamoyl-6-[(4 [-methanesulfonylphenyl)amino]pyrazine-2-yl}piperidine-3-yl]carbamate was dissolved in CH2Cl2 (5 mL), and TFA (2 mL) was added at room temperature. After 1 hour, the reaction mixture was concentrated in a high-viscosity oil, subsequently dissolved in ACN / H2O, and lyophilized to obtain (R)-5-(3-aminopiperidine-1-yl)-3-((4-(methylsulfonyl)phenyl)amino)pyrazine-2-carboxamide (402 mg, 44%, 3 steps) as the TFA salt. LCMS:C 17 H 22 Calculated value of N6O3S: 390, Measured value: m / z = 391 [M + H] + .

[0561] Example 24

[0562] [ka]

[0563]

[0362] By procedure B, tert-butyl(R)-(1-(5-cyano-6-((3- Methylisothiazole-5-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (5.6g, 89%) was obtained. LCMS:C 19 H 25 Calculated value of N7O2S: 415, Calculated value: m / z = 416 [M + H] + .

[0564]

[0363] Procedure C tert-butyl(R)-(1-(5-carbamoyl-6-( (3-methylisothiazol-5-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (850 mg, 82%) was obtained. LCMS:C 19 H 27 Calculated value for N7O3S: 433, Measured value: m / z = 434 [M + H] + .

[0565]

[0364] By procedure D, (R)-5-(3-aminopiperidine-1-yl)-3-(( 3-Methylisothiazole-5-yl)amino)pyrazine-2-carboxamide (600 mg, 74%) was obtained. LCMS:C 14 H 19 N7OS calculated value: 333, measured value: m / z = 334 [M+H] + .

[0566] Example 25

[0567] [ka]

[0568]

[0365] By procedure B, tert-butyl(R)-(1-(5-cyano-6-((1- Methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (941 mg, 80%) was obtained. LCMS:C 19 H 26 Calculated value of N8O2: 398, measured value: m / z = 399 [M + H] + .

[0569]

[0366] By procedure C, tert-butyl(R)-(1-(5-carbamoyl-6-( (1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (297 mg, 95%) was obtained. LCMS:C 19 H 28Calculated value for N8O3: 416, Measured value: m / z = 417 [M+H] + .

[0570]

[0367] By procedure D, (R)-5-(3-aminopiperidine-1-yl)-3-(( 1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-carboxamide was obtained. LCMS:C 14 H 20 Calculated value for N8O: 316, measured value: m / z = 317 [M + H] + .

[0571]

[0368] By procedure D, (R)-5-(3-aminopiperidine-1-yl)-3-(( 1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-carboxamide was obtained. LCMS:C 14 H 20 Calculated value for N8O: 4 = 316, measured value: m / z = 317 [M + H] + .

[0572] Example 26

[0573] [ka]

[0574]

[0369] E:2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoin Dol-1,3-dione (500 mg, 1.81 mmol) and 4-piperidinone hydrochloride (245 mg, 1.81 mmol) were dissolved in NMP (3 mL), and i-Pr2NEt (703 mg, 5.43 mmol) was added. The mixture was heated at 90°C for 16 hours and then diluted with ethyl acetate. The organic phase was washed (2 × H2O, saturated NaCl aqueous solution), dried (Na2SO4), concentrated, and purified (SiO2, 10 → 100% ethyl acetate / hexane) to obtain 2-(2,6-dioxopiperidine-3-yl)-5-(4-oxopiperidine-1- I obtained (131 mg, 20%) isoiindole-1,3-dione. LCMS:C18 H 17 Calculated value of N3O5: 355, measured value: m / z = 356 [M + H] + .

[0575] Example 27

[0576] [ka]

[0577]

[0370] Using procedure E with piperidine-4-ylmethanol, the yellow solid 2-(2 ,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl)piperidine-1-yl)isoindoline-1,3-dione (939 mg, 70%) was obtained. 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H), 7.65(d,J=8.4Hz,1H), 7.30(d,J=2.4H) z,1H), 7.23(dd,J=8.4,2.4Hz,1H), 5.07(dd,J=12.6,5.4Hz,1H), 4.51(t,J= 5.1Hz,1H), 4.07(d,J=13.2Hz,2H), 3.27(t,J=5.7Hz,2H), 2.99~2.80(m,3H) , 2.62~2.55(m,2H), 2.17~1.95(m,1H), 1.76~1.67(m,3H), 1.24~1.12(m,2H). LCMS:C 19 H 21 Calculated value for N3O5: 371, measured value: m / z = 372 [M + H] + .

[0578]

[0371] F:2-(2,6-dioxopiperidine-3-yl)-5-[4-(hydrox [Cimethyl)piperidine-1-yl]isoindole-1,3-dione (1.50 g, 4.04 mmol) was dissolved in CH2Cl2 (15 mL), and 1,1-bis(acetyloxy)-3-oxo-1-lambda5,2-benzoiodoxol-1-yl acetate (1.88 g, 4.44 mmol) was added all at once at room temperature. After 5 hours, the reaction mixture was diluted with NaHCO3 (2 mL, saturated aqueous solution), Na2S2O3 (saturated aqueous solution) was added, and the mixture was stirred for 30 minutes. The organic phase was removed. The aqueous layer was extracted (CH2Cl2 2 × 20 mL), the combined organic phase was dried (Na2SO4), filtered, and concentrated. Purification (2 → 6% MeOH in SiO2, CH2Cl2) yielded 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl]piperidine-4-carbaldehyde (1.20 g, 80%). LCMS:C 19 H 19 Calculated value of N3O5: 369, measured value: m / z = 370 [M+H] + .

[0579] Example 28

[0580] [ka]

[0581]

[0372] (R)-3-amino-1-N-Cbz-piperidine (253mg, 1.08mg) 126 mg, 1.19 mmol) of tert-butyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (200 mg, 1.08 mmol) and LiClO4 were sequentially added to a 10 mL ACN solution. After stirring at 80°C for 16 hours, the reaction mixture was concentrated under reduced pressure. Purification (SiO2, 0 → 5% MeOH / CH2Cl2) yielded the desired product (441 mg, 97%). LCMS:C 22 H 33 Calculated value of N3O5: 419, measured value: m / z = 420 [M+H] + .

[0582]

[0373] CDI (255 mg, 1.57 mmol) and DBU (392 μL, 2.6 2 mmol) benzyl(3R)-3-({[1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-yl]methyl}amino)piperidine-1-carboxy The phosphate (440 mg, 1.05 mmol) was sequentially added to a 2.6 mL solution of ACN. After stirring at 80°C for 30 minutes, the reaction mixture was concentrated under reduced pressure. Purification (SiO2, 0 → 5% MeOH / CH2Cl2) yielded the desired product (363 mg, 78%). LC-MS:C 23 H 31 Calculated value for N3O6: 445, measured value: m / z = 446 [M + H] + .

[0583]

[0374] tert-butyl7-[(3R)-1-[(benzyloxy)carbonyl] A solution of peridine-3-yl]-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate (363 mg, 0.81 mmol, 1 equivalent) in MeOH (8.1 mL) was stirred with Pd / C (36.3 mg, 10 wt%) under an H2 balloon. After stirring for 2 hours, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain tert-butyl(R)-6-oxo-7-(piperidine-3-yl)-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate. LCMS:C 15 H 25 Calculated value for N3O4: 311, Measured value: m / z = 312 [M + H] + .

[0584]

[0375] Procedure A tert-butyl 7-[(3R)-1-(6-chloro-5-sil Anopyrazine-2-yl)piperidine-3-yl]-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate (364 mg, 95%, 2 steps) was obtained. LCMS:C 20 H 25 Calculated value for ClN6O4: 448, Measured value: m / z = 449 [M + H] +.

[0585]

[0376] By procedure B, tert-butyl(R)-7-(1-(5-cyano-6-(( 1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-carboxylate (131 mg, 56%) was obtained. LCMS:C 24 H 31 Calculated value for N9O4: 509, measured value: m / z = 510 [M+H] + .

[0586]

[0377] Procedure C tert-butyl(R)-7-(1-(5-carbamoyl-6 -((1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-carboxylate (121 mg, 89%) was obtained. LCMS:C 24 H 33 Calculated value for N9O5: 527, measured value: m / z = 528 [M+H] + .

[0587]

[0378] Compound 211: An unpurified amine is obtained by procedure D, and then procedure Q is applied to it to obtain 5- [(3R)-3-[2-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}methyl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl]piperidine-1-yl]-3-[(1-methylpyrazole-4-yl)amino]pyrazine-2-carboxamide (13.8 mg, 49%, 2 steps) was obtained. 1H NMR (500MHz, Atomori-d3) δ10.74(s,1H), 8.94(s,1H), 7.87(s,1H) , 7.65(d,J=8.6Hz,1H), 7.50(s,1H), 7.47(d,J=0.8Hz,1H), 7.37(s, 1H), 7.31(d,J=2.4Hz,1H), 7.17(dd,J=8.7,2.4Hz,1H), 5.79(s,1H), 5.07~4.88(m,1H), 4.50(d,J=12.8Hz,1H), 4.19(d,J=13.6Hz,1H), 4.00(d,J=13.1Hz,2H), 3.84(s,3H), 3.78(dd,J=19.2,10.2Hz,2H), 3.45(d,J=8.1Hz,1H), 3.39(d,J=8.1Hz,1H), 3.34(d,J=8.1Hz,1H) , 3.31~3.25(m,1H), 3.17(dd,J=12.9,10.4Hz,1H), 3.14~3.07(m,1H), 2.97(td,J=12.8,2.7Hz,2H), 2.87~2.63(m,3H), 2.39(d,J=6.9Hz ,2H), 2.31~2.26(m,1H), 2.15~2.08(m,1H), 1.91(dt,J=13.3,3.5Hz,1H), 1.88~1.84(m,1H), 1.81(dd,J=12.1, 3.6Hz,3H), 1.70(tt,J=11.1,3.9Hz,1H), 1.61(dtd,J=11.6,7.4,4.0Hz,1H), 0.90(dq,J=7.8,6.0,5.5Hz,3H). LCMS:C 38 H 44 N 12 Calculated value of O7: 780, measured value: m / z=781[M+H] + .

[0588] Example 29

[0589]

[0379] Compound 212

[0590]

change

[0591]

[0380] Unpurified amine is obtained by procedure D, and then procedure Q is applied to it to obtain 5-[(3R)-3 -(2-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl]piperidine-1-yl]-3-[(1-methylpyrazole-4-yl)amino]pyrazine-2-carboxamide (9.5 mg, 34%, 2 steps) was obtained. 1 ¹H NMR (500MHz, acetonitrile-d3) δ 10.71 (s, 1H), 8.90 (s, 1H), 7.84 (s, 1H), 7.63 (d, J=8.5Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.28 (d, J=2.4Hz, 1H), 7.15 (dd ,J=8.6,2.4Hz,1H), 5.75(s,1H), 4.93(dd,J=12.3,5.4Hz,1H), 4.50(dd,J=13.1 ,4.1Hz,1H), 4.18(d,J=13.6Hz,1H), 3.81(s,3H), 3.81~3.66(m,3H), 3.44(d,J=8 .0Hz,1H), 3.40(d,J=8.0Hz,1H), 3.34(d,J=7.9Hz,1H), 3.31(d,J=7.8Hz,1H), 3 .17~3.00(m,4H), 2.83~2.60(m,3H), 2.36(tt,J=8.3,3.7Hz,1H), 2.12~2.05(m,2 H), 1.96(s,1H), 1.87(dq,J=13.4,3.3Hz,1H), 1.79(ddd,J=16.5,10.2,4.2Hz,3 H), 1.70~1.59(m,1H), 1.33(qd,J=9.6,5.0Hz,1H), 0.87(dt,J=11.1,5.7Hz,2H). LCMS:C 37 H 42 N 12 Calculated value for O7: 766, Measured value: m / z = 767 [M + H] + .

[0592] Example 30

[0593] [ka]

[0594]

[0381] Q: 4-(2-oxoethyl)-piperidine-1,4-dicarboxylic acid 1-te A mixture of rt-butyl ester 4-ethyl ester (23.7 mg, 79 μmol) and (R)-5-(3-aminopiperidine-1-yl)-3-((3-methylisothiazol-5-yl)amino)pyrazine-2-carboxamide (41 mg, 103 μmol, TFA salt) was dissolved in DCE (1 mL) and stirred at room temperature for 5 minutes, after which NaBH(OAc)3 (33 mg, 160 μmol) was added all at once. After 16 hours, the mixture was diluted with CH2Cl2 and NaHCO3 (saturated aqueous solution), and the aqueous phase was extracted (CH2Cl23 × 5 mL). The combined organic extract was dried (Na2SO4), filtered, and concentrated. The crude residue was purified (RP-HPLC) to obtain tert-butyl 2-[(3R)-1-{5-carbamoyl-6- [(3-methyl-1,2-thiazole-5-yl)amino]pyrazine-2-yl}piperidine-3-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (40 mg, 68%) was obtained. LCMS:C 27 H 38 Calculated value for N8O4S: 570, measured value: m / z = 571

[0595]

[0382] Compound 205: An unpurified amine is obtained by procedure D, and then procedure Q is applied to it to obtain 5- [(3R)-3-[8-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}methyl)-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]piperidine-1-yl]-3-[(3-methyl-1,2-thiazole-5-yl)amino]pyrazine-2-carboxamide (29.7 mg, 49%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.29(s,1H), 11.08(s,1H), 7.92(s,1H), 7.84(s,1H), 7.66(d,J= 8.5Hz,1H), 7.58(s,1H), 7.32(d,J=2.3Hz,1H), 7.24(dd,J=8.8,2.3Hz,1H), 6.86(s,1H), 5.07(dd,J=12.8,5.4Hz,1H), 4.46(s,2H), 4.05(d,J=13.0Hz,2H), 3.83(d,J=10.9Hz,1H) , 3.12(t,J=12.6Hz,1H), 2.98(t,J=12.4Hz,2H), 2.89(t,J=12.9Hz,1H), 2.76(d,J=9.1Hz ,2H), 2.71~2.55(m,3H), 2.30(s,3H), 2.15(d,J=6.9Hz,2H), 2.09~1.94(m,3H), 1.94~1.69(m,9 H), 1.62(d,J=13.1Hz,1H), 1.36(dd,J=25.7,12.6Hz,2H), 1.25(s,1H), 1.15(d,J=12.5Hz,2H). LCMS:C 41 H 49 N 11 Calculated value of O6S: 823, measured value: m / z=824.

[0596] Example 31

[0597]

change

[0598]

[0383] R: 1-(tert-ブトキシカルボニル)ピペリジン-4-カルボン acid (2 A mixture of 2.35 mg, 100 μmol) of (1,2,3-benzotriazole-1-yloxy)tris(dimethylamino)phosphanium, hexafluoro-lambda-5-phosphanoid (50 mg, 110 μmol), and i-Pr2NEt (65 μL, 370 μmol) were added at room temperature. After 5 minutes, 5-[(3R)-3-aminopiperidine-1-yl]-3-[(3-methyl-1,2-thiazole-5-yl)amino]pyrazine-2-carboxamide (25.00 mg, 70 μmol) was added, and the mixture was stirred for 20 minutes. The reaction mixture was diluted with H2O and extracted (CH2Cl23 × 5 mL). The combined organic extract was dried (Na2SO4), filtered, and concentrated. The crude residue was purified (SiO2, 0 → 10% MeOH / CH2Cl2) to obtain tert-butyl 4-{[(3R)-1-{5-carbamoyl-6-[(3-methyl-1,2-thiazole-5-yl)amino]pyrazine-2-yl}piperidine-3-yl]carbamoyl}piperidine-1-carboxylate (25 mg, 61%). The product was dissolved in a mixture of CH2Cl2 (1 mL) and TFA (1 mL), stirred for 30 minutes, then concentrated and dried. LCMS:C 25 H 36 Calculated value for N8O4S: 544, measured value: m / z = 546

[0599] Example 32

[0600]

[0384] Compound 217

[0601] [ka]

[0602]

[0385] Procedure Q 5-[(3R)-3-[1-({1-[2-(2,6-Gioq Sopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-amide]piperidine-1-yl]3-[(3-methyl-1,2-thiazole-5-yl)amino]pyrazine-2-carboxamide (18 mg, 19%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.27(d,J=32.4Hz,1H), 11.06(s,1H), 8.01(s,1H), 7.84(d,J=18.1Hz,1H), 7.63(d,J=8.4Hz,1H), 7. 58~7.43(m,2H), 7.28(s,1H), 7.20(d,J=9.1Hz,1H), 6.85(d,J=22.5Hz,1H), 5.05(dd,J=12.9,5.4Hz,1H), 4.17(s,1H), 4.00( d,J=14.4Hz,2H), 3.74(d,J=14.2Hz,1H), 3.57(s,1H), 3.48~3.35(m,3H), 3.09~2.77(m,3H), 2.72~2.54(m,2H), 2.28(s,3H), 2.22~2.05(m,2H), 2.05~1.90(m,3H), 1.80(s,3H), 1.70(d,J=11.6Hz,3H), 1.64~1.28(m,5H), 1.23(s,1H), 1.20~0.96(m,3H). LCMS:C 38 H 46 N 12 O6S calculated value: 798, measured value: m / z = 799 [M+H] + .

[0603] Example 33

[0604]

[0386] Compound 215

[0605] [ka]

[0606]

[0387] Procedure Q 5-((3R)-3-(1-((1-(2-(2,6-Gioq Sopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-carboxamide)piperidine-1-yl)3-((1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-carboxamide (9.7 mg, 33%) was obtained. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H), 10.87(s,1H), 7.98(s,1H), 7.81(d,J=6.9Hz,1H), 7.66(s,1H), 7.64(d,J=8.5Hz,1H ), 7.55(s,1H), 7.48(s,1H), 7.30(d,J=2.1Hz,1H), 7.28~7.19(m,2H), 5.06(dd,J=12.8,5.4Hz,1H), 4.29(s,1H), 4.04(d,J =13.0Hz,2H), 3.94(d,J=13.0Hz,1H), 3.86(s,3H), 3.70(s,1H), 3.08(t,J=10.9Hz,1H), 3.01~2.92(m,2H), 2.90~2.78(m,3 H), 2.09(h,J=6.3Hz,3H), 2.00(dd,J=11.8,6.0Hz,1H), 1.92~1.71(m,8H), 1.59(d,J=24.4Hz,7H), 1.12(d,J=12.5Hz,3H). LCMS:C 39 H 48 N 12 Calculated value of O6: 780, measured value: m / z=781[M+H] + .

[0607] Example 34

[0608]

[0388] Compound 218

[0609]

change

[0610]

[0389] 2-(2, in the mixture of CH2Cl2(1mL) and NMP(0.1mL) A solution of 6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl)piperidine-1-yl)isoindoline-1,3-dione (37.1 mg, 100 μM) and Et3N (18.1 μL, 13 mg, 130 μmol) was cooled to 0°C, and then a 10 μL solution of 4-nitrophenyl chloroformate (20.2 mg, 0.10 mmol) was added. After 10 minutes, the ice bath was removed, the reaction mixture was stirred for 1 hour, diluted with H2O (1 mL), and extracted (CH2Cl22 × 3 mL). The combined organic extract was dried (Na2SO4), filtered, and concentrated. Unpurified nitrophenyl carbonate and 5-[(3R)-3-aminocyclohexyl]-3-[(4-methanesulfonylphenyl)amino]pyrazine-2-carboxate Mid (19.5 mg, 50 μmol) was dissolved in DMF (0.5 mL), and Et3N (18.1 μL, 13.1 mg, 130 μmol) was added. The mixture was stirred at room temperature for 1 hour, then filtered and purified (RP-HPLC) to obtain (1-(2-(2,6-dioxopiperidine-3). We obtained (-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl((R)-1-(5-carbamoyl-6-((4-(methylsulfonyl)phenyl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (17 mg, 39%). 1 ¹H NMR (500MHz, chloroform-d): δ 11.60 (s, 1H), 7.99 (d, J=13.7Hz, 1H), 7.94~7.75 (m, 4H), 7.55 (s, 0H), 5.30 (s, 2H), 4.96 (dd, J=12.2, 5.8Hz, 1H), 4.39~3.12 (m, 13H), 2.89 (t, J=19.6Hz, 1H), 2.84~2.65 (m, 1H), 2.20~2.10 (m, 1H), 2.10~1.98 (m, 1H), 1.59 (s, 15H). LCMS: C 37 H 41 Calculated value of N9O9S: 787, measured value: m / z = 788 [M + H] + .

[0611] Example 35

[0612] [ka]

[0613]

[0390] (R)-3-amino-1-N-Cbz-piperidine (253mg, 1.08mg) 126 mg, 1.19 mmol) of tert-butyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (200 mg, 1.08 mmol) and LiClO4 were sequentially added to a 10 mL ACN solution. After stirring at 80°C for 16 hours, the reaction mixture was concentrated under reduced pressure. Purification (SiO2, 0 → 5% MeOH / CH2Cl2) yielded the desired product (441 mg, 97%). LCMS:C 22 H 33 Calculated value of N3O5: 419, measured value: m / z = 420 [M+H] + .

[0614]

[0391] CDI (255 mg, 1.57 mmol) and DBU (392 μL, 2.6 2 mmol) benzyl(3R)-3-({[1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-yl]methyl}amino)piperidine-1-carboxy The phosphate (440 mg, 1.05 mmol) was sequentially added to a 2.6 mL solution of ACN. After stirring at 80°C for 30 minutes, the reaction mixture was concentrated under reduced pressure. Purification (SiO2, 0 → 5% MeOH / CH2Cl2) yielded the desired product (363 mg, 78%). LC-MS:C 23 H 31 Calculated value for N3O6: 445, measured value: m / z = 446 [M + H] + .

[0615]

[0392] tert-butyl7-[(3R)-1-[(benzyloxy)carbonyl] A solution of peridine-3-yl]-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate (363 mg, 0.81 mmol, 1 equivalent) in MeOH (8.1 mL) was stirred with Pd / C (36.3 mg, 10 wt%) under an H2 balloon. After stirring for 2 hours, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain tert-butyl(R)-6-oxo-7-(piperidine-3-yl)-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate. LCMS:C 15 H 25 Calculated value for N3O4: 311, Measured value: m / z = 312 [M + H] + .

[0616]

[0393] Procedure A tert-butyl 7-[(3R)-1-(6-chloro-5-sil Anopyrazine-2-yl)piperidine-3-yl]-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate (364 mg, 95%, 2 steps) was obtained. LCMS:C 20 H 25 Calculated value for ClN6O4: 448, Measured value: m / z = 449 [M + H] + .

[0617]

[0394] By procedure B, tert-butyl(R)-7-(1-(5-cyano-6-(( 1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-carboxylate (131 mg, 56%) was obtained. LCMS:C 24 H 31 Calculated value for N9O4: 509, measured value: m / z = 510 [M+H] + .

[0618]

[0395] Procedure C tert-butyl(R)-7-(1-(5-carbamoyl-6 -((1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-carboxylate (121 mg, 89%) was obtained. LCMS:C 24 H 33 Calculated value for N9O5: 527, measured value: m / z = 528 [M+H] + .

[0619]

[0396] Compound 213: An unpurified amine is obtained by procedure D, and then procedure Q is applied to it to obtain 5- ((3R)-3-(2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)methyl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)piperidine-1-yl)-3-((1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-carboxamide (8.4 mg, 30%, 2 steps) was obtained. 1 ¹H NMR (500MHz, acetonitrile-d3) δ 10.72 (s, 1H), 8.91~8.84 (m, 1H), 7.84 (s, 1H), 7.60 (d, J=8.3Hz, 1H), 7.46 (d, J=17.7Hz, 2H), 7.34 (s, 1H), 6.76 (s, 1H), 6.59 (d, J=8.5Hz, 1H), 5.75 (s, 1H), 4.92 (dd, J=12.2, 5.3Hz, 1H), 4.49 (dd, J=12. 6,4.2Hz,1H), 4.18(d,J=13.7Hz,1H), 4.08(t,J=7.7Hz,2H), 3.83~3.66(m,6H), 3.47~3.33(m,4H), 3.16~3.03(m,2) H), 2.81~2.62(m,5H), 2.08(d,J=17.1Hz,2H), 2.01~1.96(m,1H), 1.92~1.75(m,1H), 1.66(qt,J=11.5,4.0Hz,1H). LCMS:C 36 H 40 N 12 Calculated value for O7: 752, Measured value: m / z = 753 [M + H] + .

[0620] Example 36

[0621] [ka]

[0622]

[0397] By procedure B, tert-butyl(R)-(1-(5-cyano-6-((1- Methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (941 mg, 80%) was obtained. LCMS:C 19 H 26 Calculated value of N8O2: 398, measured value: m / z = 399 [M + H] + .

[0623]

[0398] Procedure C tert-butyl(R)-(1-(5-carbamoyl-6-( (1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-yl)piperidine-3-yl)carbamate (297 mg, 95%) was obtained. LCMS:C 19 H 28 Calculated value for N8O3: 416, Measured value: m / z = 417 [M+H] + .

[0624]

[0399] By procedure D, (R)-5-(3-aminopiperidine-1-yl)-3-(( 1-methyl-1H-pyrazole-4-yl)amino)pyrazine-2-carboxamide was obtained. LCMS:C 14 H 20 Calculated value for N8O: 4 = 316, measured value: m / z = 317 [M + H] + .

[0625] Example 37

[0400] Compound 216

[0626] [ka]

[0627]

[0401] By procedure R, (R)-3-((1-methyl-1H-pyrazole-4-yl) Amino)-5-(3-(piperidine-4-carboxamide)piperidine-1-yl)pyra Zin-2-carboxamide (199 mg, 75%) was obtained. LCMS:C 20 H 29 Calculated value of N9O2: 427, measured value: m / z = 428 [M + H] + .

[0628]

[0402] According to procedure Q, 5-[(3R)-3-[1-({1-[2-(2,6-Gioq Sopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]azetidine-3-yl}methyl)piperidine-4-amide]piperidine-1-yl]-3-[(1-methylpyrazole-4-yl)amino]pyrazine-2-carboxamide (8.4 mg, 10%) was obtained. 1 H NMR (500MHz, acetonitrile-d3) δ10.74(s,1H), 8.87(s,1H), 7.92(s,1H), 7.59(d ,J=8.3Hz,1H), 7.45(d,J=7.4Hz,2H), 7.38~7.22(m,1H), 6.76(d,J=2.1Hz,1 H), 6.59(dd,J=8.3,2.2Hz,1H), 6.34(d,J=7.2Hz,1H), 5.72(s,1H), 4.92(d d,J=12.3,5.3Hz,1H), 4.24~4.16(m,1H), 4.11(t,J=8.1Hz,2H), 3.87(s,3H) , 3.85~3.78(m,2H), 3.68(dd,J=8.2,5.4Hz,2H), 3.45(td,J=9.0,8.5,4.4H z,1H), 3.35(dd,J=13.1,7.8Hz,1H), 3.28(s,1H), 2.97(ddt,J=10.1,7.8,4. 2Hz,1H), 2.90~2.79(m,2H), 2.70(dddt,J=21.8,13.4,7.8,4.3Hz,3H), 2.5 7(d,J=7.4Hz,2H), 2.11~2.01(m,3H), 1.87~1.77(m,2H), 1.71~1.49(m,6H). LCMS:C 37 H 44 N 12Calculated value for O6: 752, measured value: m / z = 753

[0629] Example 38

[0403] General Procedure 1: Amide Coupling

[0404] Amine (0.03 mmol), Acid (0.03 mmol), HATU (0.04 A mixture of mmol) , DIPEA (0.15 mmol), and DMF was stirred at room temperature for 30 minutes. The mixture was purified by HPLC (H2O / MeCN, using 0.1% TFA). An amide product was obtained.

[0630]

[0405] General Procedure 2: Reductive Amination

[0406] Amine TFA salt (0.07 mmol), aldehyde (0.1 mmol), tori A mixture of ethylamine (0.28 mmol) and DCE was stirred at room temperature for 10 minutes. NaBH(OAc)3 (0.14 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite, washed with CH2Cl2, concentrated, and purified by HPLC (H2O / MeCN, using 0.1% TFA) to obtain the amine product.

[0631]

[0407] General Procedure 3: Aryl Fluoride Replacement

[0408] Amine (0.22 mmol), Aryl fluoride (0.22 mmol), DIP A mixture of EA (0.88 mmol) and DMF (1 mL) was stirred at 90°C for 16 hours. The mixture was purified by HPLC (H2O / MeCN, using 0.1% TFA) to obtain the desired result. We obtained the product.

[0632] Example 39

[0409] Preparation according to general procedure 2

[0410] Compound 195

[0633] [ka]

[0634]

[0411] 1 H NMR (500MHz, DMSO-d6) δ11.19(s,1H), 10.85(s,1H), 8.71(d,J=8.2Hz,1H), 8.32(d,J=2.9Hz,1H), 7.85(d,J=8.8Hz,1H), 7.76(s,1H ), 7.67(s,1H), 7.51(d,J=8.1Hz,2H), 7.42(dd,J=8.9,2.9Hz,1H), 7.34(s,1H), 7.18(d,J=8.2Hz,2H), 4.75(ddd,J=13.2,8.2,5.4H z,1H), 4.34(dd,J=39.7,12.8Hz,2H), 3.96(d,J=12.5Hz,2H), 3.62(d,J=11.0Hz,1H), 3.28(dd,J=14.4,7.4Hz,5H), 3.11~2.76(m,8 H), 2.73(s,3H), 2.19(dd,J=10.7,5.3Hz,3H), 2.08~1.93(m,3H), 1.89~1.71(m,8H), 1.59(d,J=29.1Hz,4H), 1.23(d,J=14.3Hz,5H). LCMS:C 42 H 54 N 12 Calculated value of O5: 806, measured value: m / z=807[M+H] + .

[0635]

[0412] Compound 194

[0636]

change

[0637]

[0413] 1H NMR (500MHz, DMSO-d6) δ11.30(s,1H), 10.86(s,1H), 8.71(d,J=8.1Hz,1H), 8.36(s,1H), 7.88(d,J=8.7Hz,1H), 7.79( s,1H), 7.69(s,1H), 7.58(d,J=7.9Hz,2H), 7.46(d,J=8.8Hz,1H), 7.36(s,1H), 7.19(d,J=8.2Hz,2H), 4.75(ddd,J=13. 1,8.2,5.4Hz,1H), 4.42~4.25(m,2H), 4.01(d,J=12.9Hz,2H), 3.65(dd,J=13.8,7.9Hz,3H), 3.27(t,J=8.3Hz,3H), 3. 17~2.87(m,6H), 2.86~2.70(m,5H), 2.27~2.10(m,2H), 2.11~1.69(m,12H), 1.68~1.47(m,2H), 1.30(d,J=52.1Hz,3H). LCMS:C 42 H 54 N 12 Calculated value of O5: 806, measured value: m / z=807[M+H] + .

[0638]

[0414] Compound 201

[0639]

change

[0640]

[0415] 1H NMR(500MHz,アセトニトリル-d3)δ11.13(s,1H),8.92(s,1H),7.67~7.55(m,5H),7.43(s,1H),7.21(d,J=8 .0Hz,2H), 7.11(d,J=7.4Hz,1H), 6.99(d,J=8.5Hz,1H), 6.37(s,1H), 5.81(s,1H), 5.01~4.92(m,1H ), 4.43(d,J=12.4Hz,1H), 4.31(d,J=13.2Hz,1H), 4.11(d,J=8.5Hz,1H), 3.71(s,1H), 3.63~3.54(m ,2H), 3.45~3.23(m,5H), 3.19(s,2H), 3.14~2.92(m,4H), 2.76(d,J=14.2Hz,9H), 1.93~1.63(m,5H). LCMS:C 43 H 51 N 11 Calculated value of O6: 817, measured value: m / z=818[M+H] + .

[0641]

[0416] Compound 202

[0642]

change

[0643]

[0417] 1H NMR(500MHz,アセトニトリル-d3)δ11.13(s,1H),8.93(s,1H),8.65(s,1H),7.60(dd,J=17.5,6.7Hz,5H),7.43(s,1H),7 .21(d,J=8.0Hz,2H), 7.12(d,J=7.0Hz,1H), 6.89(d,J=8.3Hz,1H), 6.46(s,1H), 5.83(s,1H), 4.98(dd,J=12.5,5 .2Hz,1H), 4.51~4.16(m,4H), 3.72(s,1H), 3.60(d,J=12.4Hz,2H), 3.46~3.26(m,7H), 3.03(tt,J=30.3,14.5Hz, 6H), 2.89~2.63(m,8H), 2.42(d,J=8.7Hz,2H), 2.31(d,J=12.7Hz,2H), 2.05(d,J=17.6Hz,3H), 1.94~1.59(m,4H). LCMS:C 43 H 51 N 11 Calculated value of O6: 817, measured value: m / z=818[M+H] + .

[0644]

[0418] Compound 204

[0645]

change

[0646]

[0419] 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H), 10.72(s,1H), 8.57(s,2H), 7.75(s,1H), 7.66(d,J=8 .8Hz,2H), 7.34(s,1H), 6.92(d,J=2.1Hz,1H), 6.84(dd,J=8.4,2.1Hz,1H), 5.06(dd,J=12. 9,5.4Hz,1H), 4.22(dd,J=37.3,13.0Hz,2H), 3.79~3.40(m,9H), 3.28~3.05(m,16H), 2.97~2.8 2(m,2H), 2.67(s,4H), 2.24~1.95(m,2H), 1.78(q,J=5.6,5.1Hz,5H), 1.52(s,2H), 1.25(s,4H). LCMS:C 40 H 48 N 14 Calculated value of O6: 820, measured value: m / z=821[M+H] + .

[0647]

[0420] Compound 207

[0648]

change

[0649]

[0421] 1 H NMR (500MHz, DMSO-d6) δ11.27(s,1H), 11.07(s,1H), 8.55(d,J=2.4Hz,1H), 8.13~8.05(m,1H), 7.84~7. 78(m,1H), 7.73(s,1H), 7.65(d,J=8.4Hz,1H), 7.40(d,J=2.5Hz,1H), 7.22(d,J=8.6Hz,1H), 6.92(d,J= 2.2Hz,1H), 6.83(dd,J=8.7,2.2Hz,1H), 5.06(dd,J=12.9,5.4Hz,1H), 4.31(s,2H), 3.67~3.38(m,4H), 3.30~2.81(m,8H), 2.72(s,3H), 2.69~2.55(m,1H), 2.43~2.33(m,2H), 2.23~1.46(m,11H), 1.25(s,3H). LCMS:C 42 H 50 N 12 Calculated value of O6: 818, measured value: m / z=819[M+H] + .

[0650]

[0422] Compound 208

[0651]

change

[0652]

[0423] 1 H NMR (500MHz, DMSO-d6) δ11.28(s,1H), 11.08(s,1H), 8.55(d,J=2.6Hz,1H), 8.10(d,J=8.4Hz,1H), 7.81(s,1H), 7.7 3(s,1H), 7.65(d,J=8.2Hz,1H), 7.40(d,J=2.6Hz,1H), 7.21(d,J=8.6Hz,1H), 6.79(d,J=2.1Hz,1H), 6.66(dd,J=8. 4,2.1Hz,1H), 5.06(dd,J=12.8,5.4Hz,1H), 4.31(d,J=12.8Hz,2H), 4.16(t,J=8.2Hz,2H), 3.77~3.55(m,4H), 3.27 (dd,J=11.3,4.9Hz,2H), 3.16~2.81(m,6H), 2.74~2.55(m,7H), 2.16~1.97(m,3H), 1.91~1.42(m,9H), 1.25(s,5H). LCMS:C 41 H 48 N 12 Calculated value of O6: 818, measured value: m / z=819[M+H] + .

[0653]

[0424] Compound 209

[0654]

change

[0655]

[0425] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H), 10.89(s,1H), 8.10(s,1H), 7.71(d,J=2.8Hz,1H ), 7.66(d,J=8.5Hz,1H), 7.61(d,J=4.5Hz,2H), 7.31(dd,J=7.8,2.5Hz,2H), 7.24(dd,J=8.8,2.3Hz,1H), 5.12~4.94(m,2H), 4.43(d,J=12.5Hz,1H), 4.30(d,J=13.2Hz,1H), 4.05(d,J=12.9Hz,2H), 3.75~3.56(m, 3H), 3.28(t,J=8.2Hz,2H), 3.10~2.83(m,5H), 2.73(s,3H), 2.67~2.53(m,2H), 2.40(d,J=6.8Hz,2H), 2.0 2(ddd,J=12.9,5.7,3.2Hz,1H), 1.90~1.69(m,6H), 1.68~1.48(m,2H), 1.20(qd,J=14.1,12.4,4.3Hz,2H). LCMS:C 39 H 47 N 13 Calculated value of O6: 793, measured value: m / z=794[M+H] + .

[0656]

[0426] Compound 210

[0657]

change

[0658]

[0427] 1 H NMR (500MHz, DMSO-d6) δ11.15(s,2H), 11.03(s,1H), 9.46(d,J=28.8Hz,1H), 7.87(d,J=7.8Hz, 1H), 7.75(d,J=9.7Hz,2H), 7.65(d,J=7.3Hz,2H), 7.53(s,2H), 7.33(s,1H), 7.09(s,2H), 5.16 (dd,J=13.2,5.2Hz,1H), 4.41(dtd,J=57.1,31.0,29.6,15.4Hz,7H), 3.62(tt,J=9.7,4.2Hz,1 H), 3.43~2.85(m,16H), 2.71(s,3H), 2.67~2.58(m,1H), 2.09~1.70(m,9H), 1.66~1.42(m,6H). LCMS:C 43 H 53 N11 Calculated value of O5: 793, measured value: m / z=794[M+H] + .

[0659]

[0428] Compound 196

[0660]

change

[0661]

[0429] 1 H NMR(500MHz,アセトニトリル-d3)δ11.17(s,1H),8.91(s,1H),7.65(d,J=8.2Hz,2H),7.58(s,1H),7.41(s,1H),7.24(d,J=8.2H z,2H), 6.84(d,J=8.6Hz,1H), 6.41(s,1H), 6.33(d,J=8.7Hz,1H), 5.79(s,1H), 5.14(dd,J=12.9,5.3Hz,1H), 3.81~3.65( m,5H), 3.61(t,J=8.3Hz,1H), 3.49~3.39(m,2H), 3.38~3.31(m,4H), 3.27~3.20(m,2H), 3.20~3.12(m,1H), 3.10~2.96(m ,2H), 2.95~2.80(m,3H), 2.80~2.67(m,2H), 2.54~2.01(m,6H), 1.92~1.80(m,1H), 1.78~1.70(m,2H), 1.70~1.65(m,4H). LCMS:C 39 H 48 N 10 O4's calculated value is 720, measured value: m / z=721[M+H] + .

[0662]

[0430] Compound 197

[0663]

change

[0664]

[0431] 1H NMR(500MHz,アセトニトリル-d3)δ11.18(s,1H),9.77(s,1H),8.91(s,1H),7.65(d,J=8.2Hz,2H),7.58(s,1H),7.41(s,1H),7.24( d,J=8.2Hz,2H), 6.85(d,J=8.5Hz,1H), 6.41(s,1H), 6.33(d,J=8.5Hz,1H), 5.80(s,1H), 5.15(dd,J=12.8,5.4Hz,1H), 3.78 ~3.70(m,5H), 3.61(t,J=8.5Hz,1H), 3.49~3.39(m,2H), 3.38~3.31(m,4H), 3.28~3.20(m,2H), 3.20~3.13(m,1H), 3.12~2.9 6(m,2H), 2.92~2.84(m,3H), 2.80~2.71(m,2H), 2.57~2.03(m,6H), 1.92~1.79(m,1H), 1.80~1.71(m,2H), 1.71~1.65(m,4H). LCMS:C 39 H 48 N 10 O4's calculated value is 720, measured value: m / z=721[M+H] + .

[0665]

[0432] Compound 198

[0666]

change

[0667]

[0433] 1H NMR (500MHz, アセトニトリル-d3) δ11.14(s,1H), 8.99(s,1H), 8.93(s,1H), 7.66~7.56(m,3H), 7.43(s,1H), 7.23(d, J=8.2Hz,2H), 6.86(d,J=8.4Hz,1H), 6.45(s,1H), 6.37(s,1H), 5.84(s,1H), 5.15(dd,J=12.8,5.4Hz,1H), 4. 42(d,J=12.8Hz,1H), 4.31(d,J=13.7Hz,1H), 3.77~3.67(m,3H), 3.63~3.59(m,1H), 3.50~3.13(m,10H), 3.13 ~2.96(m,4H), 2.95~2.41(m,7H), 2.36~2.32(m,1H), 2.17~2.08(m,6H), 1.94~1.77(m,6H), 1.68~1.64(m,1H). LCMS:C 43 H 54 N 12 O5's calculated value is 818, measured value: m / z=819[M+H] + .

[0668]

[0434] Compound 199

[0669]

change

[0670]

[0435] 1H NMR (500MHz, アセトニトリル-d3) δ11.14(s,1H), 9.07(s,1H), 8.92(s,1H), 7.66~7.56(m,3H), 7.43(s,1H), 7.23(d, J=8.3Hz,2H), 6.85(d,J=8.4Hz,1H), 6.44(s,1H), 6.36(s,1H), 5.83(s,1H), 5.15(dd,J=12.8,5.2Hz,1H), 4. 42(d,J=12.4Hz,1H), 4.31(d,J=13.5Hz,1H), 3.77~3.67(m,3H), 3.62~3.56(m,1H), 3.50~3.12(m,8H), 3.13~ 2.96(m,4H), 2.95~2.68(m,6H), 2.69~2.19(m,6H), 2.18~2.09(m,5H), 1.97~1.85(m,5H), 1.70~1.64(m,1H). LCMS:C 43 H 54 N 12 O5's calculated value is 818, measured value: m / z=819[M+H] + .

[0671]

[0436] Compound 200

[0672]

change

[0673]

[0437] 1H NMR (500MHz, DMSO-d6) δ11.30(s,1H), 10.82(s,1H), 7.97(d,J=2.5Hz,1H), 7.79(d,J=2.7Hz,1H), 7.69(s ,1H), 7.57(d,J=8.2Hz,2H), 7.43~7.34(m,2H), 7.22~7.14(m,2H), 6.86(d,J=8.8Hz,1H), 4.31(d,J=14.0 Hz,4H), 3.75(dd,J=12.2,4.9Hz,1H), 3.65~3.56(m,3H), 3.40~3.21(m,3H), 3.13~2.94(m,6H), 2.90~2.6 2(m,6H), 2.27~2.10(m,3H), 2.10~1.94(m,5H), 1.88~1.76(m,6H), 1.61~1.55(m,1H), 1.35~1.14(m,3H). LCMS:C 41 H 53 N 11 O4's calculated value is 763, measured value: m / z=764[M+H] + .

[0674]

[0438] Compound 206

[0675]

change

[0676]

[0439] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H), 10.93(s,1H), 7.89~7.84(m,2H), 7.75(d,J=2.6Hz,1H), 7.66(d,J=8.5Hz,1H), 7.3 5~7.18(m,3H), 5.83(s,1H), 5.77(s,1H), 5.06(dd,J=13.0,5.4Hz,1H), 4.12~3.95(m,5H), 3.83(d,J=13.2Hz,1H), 3.74( t,J=12.2Hz,1H), 3.70~3.55(m,3H), 3.28~3.21(m,2H), 3.04~2.95(m,3H), 2.93~2.82(m,4H), 2.67(s,3H), 2.62~2.35(m ,3H), 2.05~1.98(m,1H), 1.94~1.90(m,1H), 1.87~1.76(m,5H), 1.75~1.66(m,1H), 1.63~1.53(m,1H), 1.26~1.15(m,3H). LCMS:C 40 H 48 N 12 O6's calculated value is 792, measured value: m / z=793[M+H] + .

[0677]

[0440] Compound 214

[0678]

change

[0679]

[0441] 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H), 10.93(s,1H), 7.89~7.82(m,2H), 7.75(d,J=2.6Hz,1H), 7.64(d,J=8.4Hz,1H), 7.32(d,J =3.2Hz,1H), 6.93(d,J=2.2Hz,1H), 6.84(dd,J=8.7,2.2Hz,1H), 5.83(s,1H), 5.05(dd,J=13.3,5.3Hz,1H), 4.02(t,J=5.7Hz,2 H), 3.83(d,J=13.2Hz,1H), 3.78~3.58(m,4H), 3.56~3.38(m,2H), 3.27~3.16(m,3H), 3.05~2.82(m,4H), 2.71(q,J=7.4Hz,1H), 2.66(s,3H), 2.62~2.40(m,6H), 2.22~2.14(m,1H), 2.02~1.98(m,1H), 1.86~1.66(m,4H), 1.62~1.53(m,1H), 1.36~1.08(m,2H). LCMS:C 39 H 46 N 12 O6's calculated value is 778, measured value: m / z=779[M+H] + .

[0680]

[0442] Compound 216

[0681]

change

[0682]

[0443] 1H NMR (500MHz, Atomori-d3) δ10.74(s,1H), 8.87(s,1H), 7.92(s,1H), 7.59(d ,J=8.3Hz,1H), 7.45(d,J=7.4Hz,2H), 7.38~7.22(m,1H), 6.76(d,J=2.1Hz,1 H), 6.59(dd,J=8.3,2.2Hz,1H), 6.34(d,J=7.2Hz,1H), 5.72(s,1H), 4.92(d d,J=12.3,5.3Hz,1H), 4.24~4.16(m,1H), 4.11(t,J=8.1Hz,2H), 3.87(s,3H) , 3.85~3.78(m,2H), 3.68(dd,J=8.2,5.4Hz,2H), 3.45(td,J=9.0,8.5,4.4H z,1H), 3.35(dd,J=13.1,7.8Hz,1H), 3.28(s,1H), 2.97(ddt,J=10.1,7.8,4. 2Hz,1H), 2.90~2.79(m,2H), 2.70(dddt,J=21.8,13.4,7.8,4.3Hz,3H), 2.5 7(d,J=7.4Hz,2H), 2.11~2.01(m,3H), 1.87~1.77(m,2H), 1.71~1.49(m,6H). LCMS:C 37 H 44 N 12 Calculated value of O6: 753, measured value: m / z=754.

[0683]

[0444] Compound 213

[0684]

change

[0685]

[0445] 1H NMR (500MHz, Atomori-d3) δ10.75(s,1H), 8.90(s,1H), 7.87(s,1 H), 7.63(d,J=8.2Hz,1H), 7.50(s,1H), 7.47(s,1H), 7.37(s,1H), 6.79(d,J=2.1Hz,1H), 6.62(dd,J=8.3,2.1Hz,1H), 5.78(s,1H), 4.95(dd,J=12.3,5.4Hz,1H), 4.52(d,J=13.0Hz,1H), 4.21(d,J=13 .6Hz,1H), 4.11(t,J=7.7Hz,2H), 3.85(s,3H), 3.80(q,J=9.1Hz,2H), 3.73(ddd,J=12.7,8.2,4.7Hz,3H), 3.48(d,J=8.0Hz,1H), 3. 45~3.35(m,3H), 3.20~3.05(m,2H), 2.86~2.63(m,6H), 2.05~1.99(m,1H), 1.93~1.78(m,2H), 1.76~1.59(m,1H), 0.97~0.81(m,1H). LCMS:C 36 H 40 N 12 O7's calculated value: 753, measured value: m / z=754.

[0686]

[0446] Compound 205

[0687]

change

[0688]

[0447] 1H NMR (500MHz, DMSO-d6) δ12.29(s,1H), 11.08(s,1H), 7.92(s,1H), 7.84(s,1H), 7.66(d,J=8.5Hz,1H), 7.58(s,1H), 7.32(d,J=2.3Hz,1H), 7.24(dd,J=8.8,2.3Hz,1H), 6.86(s,1H), 5.07(dd,J=12.8,5.4Hz,1H), 4.46(s,2H), 4.05(d,J=13.0Hz,2H), 3.83(d,J=10.9Hz,1H), 3.12 (t,J=12.6Hz,1H), 2.98(t,J=12.4Hz,2H), 2.89(t,J=12.9Hz,1H), 2.76(d,J=9.1Hz,2H), 2.71~2.55(m,3H), 2.30(s,3H), 2.15(d,J=6.9H z,2H), 2.09~1.94(m,3H), 1.94~1.69(m,9H), 1.62(d,J=13.1Hz,1H), 1.36(dd,J=25.7,12.6Hz,2H), 1.25(s,1H), 1.15(d,J=12.5Hz,2H). LCMS:C 41 H 49 N 11 Calculated value of O6S: 823, measured value: m / z=824.

[0689]

[0448] Compound 211

[0690]

change

[0691]

[0449] 1H NMR (500MHz, アセトニトリル-d3) δ10.74(s,1H), 8.94(s,1H), 7.87(s,1H), 7.65(d,J=8.6Hz,1H), 7.50 (s,1H), 7.47(d,J=0.8Hz,1H), 7.37(s,1H), 7.31(d,J=2.4Hz,1H), 7.17(dd,J=8.7,2.4Hz,1H), 5.79(s,1H), 5.07~4.88(m,1H), 4.50(d,J=12.8Hz,1H), 4.19(d,J=13.6Hz,1H), 4.00(d,J=13.1 Hz,2H), 3.84(s,3H), 3.78(dd,J=19.2,10.2Hz,2H), 3.45(d,J=8.1Hz,1H), 3.39(d,J=8.1Hz,1H ), 3.34(d,J=8.1Hz,1H), 3.31~3.25(m,1H), 3.17(dd,J=12.9,10.4Hz,1H), 3.14~3.07(m,1H), 2 .97(td,J=12.8,2.7Hz,2H), 2.87~2.63(m,3H), 2.39(d,J=6.9Hz,2H), 2.31~2.26(m,1H), 2.15~ 2.08(m,1H), 1.91(dt,J=13.3,3.5Hz,1H), 1.88~1.84(m,1H), 1.81(dd,J=12.1,3.6Hz,3H), 1.7 0(tt,J=11.1,3.9Hz,1H), 1.61(dtd,J=11.6,7.4,4.0Hz,1H), 0.90(dq,J=7.8,6.0,5.5Hz,3H). LCMS:C 38 H 44 N 12 O7's calculated value: 780, measured value: m / z=781.

[0692]

[0450] Compound 212

[0693]

change

[0694]

[0451] 1H NMR(500MHz,アセトニトリル-d3)δ10.71(s,1H),8.90(s,1H),7.84(s,1H),7.63(d,J=8 .5Hz,1H), 7.47(s,1H), 7.44(s,1H), 7.34(s,1H), 7.28(d,J=2.4Hz,1H), 7.15(dd ,J=8.6,2.4Hz,1H), 5.75(s,1H), 4.93(dd,J=12.3,5.4Hz,1H), 4.50(dd,J=13.1 ,4.1Hz,1H), 4.18(d,J=13.6Hz,1H), 3.81(s,3H), 3.81~3.66(m,3H), 3.44(d,J=8 .0Hz,1H), 3.40(d,J=8.0Hz,1H), 3.34(d,J=7.9Hz,1H), 3.31(d,J=7.8Hz,1H), 3 .17~3.00(m,4H), 2.83~2.60(m,3H), 2.36(tt,J=8.3,3.7Hz,1H), 2.12~2.05(m,2 H), 1.96(s,1H), 1.87(dq,J=13.4,3.3Hz,1H), 1.79(ddd,J=16.5,10.2,4.2Hz,3 H), 1.70~1.59(m,1H), 1.33(qd,J=9.6,5.0Hz,1H), 0.87(dt,J=11.1,5.7Hz,2H). LCMS:C 37 H 42 N 12 O7's calculated value: 766, measured value: m / z=767.

[0695]

[0452] Compound 215

[0696]

change

[0697]

[0453] 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H), 10.87(s,1H), 7.98(s,1H), 7.81(d,J=6.9Hz,1H), 7.66(s,1H), 7.64(d,J=8.5Hz,1H ), 7.55(s,1H), 7.48(s,1H), 7.30(d,J=2.1Hz,1H), 7.28~7.19(m,2H), 5.06(dd,J=12.8,5.4Hz,1H), 4.29(s,1H), 4.04(d,J =13.0Hz,2H), 3.94(d,J=13.0Hz,1H), 3.86(s,3H), 3.70(s,1H), 3.08(t,J=10.9Hz,1H), 3.01~2.92(m,2H), 2.90~2.78(m,3 H), 2.09(h,J=6.3Hz,3H), 2.00(dd,J=11.8,6.0Hz,1H), 1.92~1.71(m,8H), 1.59(d,J=24.4Hz,7H), 1.12(d,J=12.5Hz,3H). LCMS:C 39 H 48 N 12 Calculated value of O6: 780, measured value: m / z=781.

[0698]

[0454] Compound 217

[0699]

change

[0700]

[0455] 1H NMR (500MHz, DMSO-d6) δ12.27(d,J=32.4Hz,1H), 11.06(s,1H), 8.01(s,1H), 7.84(d,J=18.1Hz,1H), 7.63(d,J=8.4Hz,1H), 7. 58~7.43(m,2H), 7.28(s,1H), 7.20(d,J=9.1Hz,1H), 6.85(d,J=22.5Hz,1H), 5.05(dd,J=12.9,5.4Hz,1H), 4.17(s,1H), 4.00( d,J=14.4Hz,2H), 3.74(d,J=14.2Hz,1H), 3.57(s,1H), 3.48~3.35(m,3H), 3.09~2.77(m,3H), 2.72~2.54(m,2H), 2.28(s,3H), 2.22~2.05(m,2H), 2.05~1.90(m,3H), 1.80(s,3H), 1.70(d,J=11.6Hz,3H), 1.64~1.28(m,5H), 1.23(s,1H), 1.20~0.96(m,3H). LCMS:C 38 H 46 N 12 Calculated value of O6S: 798, measured value: m / z=799.

[0701]

[0456] Compound 218

[0702]

change

[0703]

[0457] 1 H NMR(500MHz,クロロホルム-d)δ11.60(s,1H)、7.99(d,J=13.7Hz,1H)、7.94~7.75(m,4H)、7.55(s,1H)、5.30(s,2H)、4.96(dd,J=12.2, 5.8Hz,1H), 4.39~3.12(m,13H), 2.89(t,J=19.6Hz,1H), 2.84~2.65(m,1H), 2.20~2.10(m,1H), 2.10~1.98(m,1H), 1.59(s,15H). LCMS:C 37 H 41 Calculated value of N9O9S: 787, measured value: m / z=788.

[0704]

[0458] Compound 203

[0705] [ka]

[0706]

[0459] LCMS:C 38 H 37 Calculated value of N9O4S: 715, measured value: m / z=71 6.

[0707]

[0460] Biological example 1

[0461] Cell culture

[0462] Ramos cells (CRL-1596) American Type Obtained from Culture Collection. TMD8 cells obtained from Tokyo Medical and Dental University. Ramos cells were heated and inactivated by 10% FBS (Fisher, MT35015CV RPMI-1640 medium (ATCC, 30) supplemented with Corning Premium fetal bovine serum (manufactured by Corning Premium). TMD8 cells were grown in MEM alpha medium (Fisher, 12571063) supplemented with 10% heat-inactivated FBS (Corning Premium fetal bovine serum, Fisher, MT35015CV). All cells were cultured at 37°C under 5% CO2.

[0708]

[0463] Human peripheral blood mononuclear cells (PBMCs) are obtained from 1) the buffy coat of a healthy human donor. Ficoll-Paque (trademark) (GE Healthcare) is used to isolate peripheral blood hematopoietic cells. PBMCs were obtained either by using (1) or directly from LeukoPak donations. PBMCs were grown at 37°C under 5% CO2 in RPMI supplemented with 10% heat-inactivated FBS (Corning Premium fetal bovine serum from Fisher, MT35015CV), 1X penicillin / streptomycin, and 2 mM glutamine.

[0709]

[0464] BTK C481S Development of knock-in cell lines

[0465] BTK C481S In order to generate cell lines that express a specific gRNA, Cas9 RNPs were introduced into cells by electroporation. Gene editing was evaluated in a polyclonal cell population by sequencing. Monoclonal cell lines were prepared by diluting single cells in single wells, and mutations were confirmed by sequencing.

[0710]

[0466] Western blot time-course assay

[0467] Determination of the dynamics of CTM-induced BTK degradation

[0468] Plate the cells in a 6-well plate, and the final DMSO concentration is greater than 0.2%. Cells were treated with DMSO or CTM. After treatment, cells were collected at the time shown in the figure, washed once with PBS, and lysed. Western blot analysis was performed using a BTK-specific antibody (Cell Signaling, 8547).

[0711]

[0469] Biological example 2

[0470] Cellular BTK degradation assay

[0471] DC after 4 hours of incubation 50 The effectiveness is determined by measuring the value. In vitro cell screening for

[0472] Add BTK CTM to cells in a round-bottom 96-well plate and finalize with DMSO The concentration was increased to over 0.2%, and incubated at 37°C under 5% CO2 for 4 hours. BTK levels were determined using the Cisbio Total-BTK HTRF (homologous time-resolved fluorescence) kit (63ADK064PEG) according to the manufacturer's protocol. Briefly, cells were incubated in 1X complementary lysis buffer for 30 minutes. Cell lysates were combined with two different specific BTK antibodies in a milky white low-volume 96-well plate (Cisbio, 66PL96005), one of which was Eu 3+ - One was conjugated with a cryptotate FRET donor, and the other with a d2FRET acceptor. The assay control was Eu 3+ - The system includes wells containing cell lysates with only cryptotate FRET donor antibodies, and wells containing both lysis buffers without HTRF antibodies and control lysates supplied from cells or Cisbio. The HTRF ratio is calculated as (acceptor signal at 665 nm / donor signal at 620 nm) × 10⁻¹⁶ 4 The calculation was performed as follows. Background HTRF levels were determined from a control well containing donor cells but no acceptor or antibody cells. Background HTRF levels were subtracted from all samples. The readings were recorded as HTRF levels relative to the HTRF levels of cells treated with DMSO. DC50 values ​​were obtained by performing a 4-parameter nonlinear regression using GraphPad Prism 7.02.

[0712]

[0473] As shown in Figure 1, multiple cell lines in the presence of the compounds provided herein Robust, time-dependent degradation of BTK was observed in primary human B cells. As shown in Figure 2, several compounds provided herein induced degradation of BTK or ibrutinib-resistant C481S mutant BTK in Ramos cells expressing wild-type BTK.

[0713]

[0474] Biological example 3

[0475] Proteomics

[0476] Determining the global effects of BTK CTM treatment on the proteome

[0477] TMD8 cells were triple-treated with DMSO or CTM 50nM. After 6 hours, Cells were collected, washed twice with PBS, and stored as a frozen cell pellet. Proteomic analysis included sample preparation, tandem mass tag (TMT) labeling, fraction analysis, mass spectrometry, and This included data processing, which was performed by MS Bioworks.

[0714]

[0478] As shown in Figure 3, the compounds provided herein are used in BT cells in TMD8 cells. K was selectively decomposed.

[0715]

[0479] Biological example 4

[0480] Cell survival assay

[0481] Evaluation of the effect of BTK degradation in BTK-dependent cell lines

[0482] Quantifying the amount of ATP present as a substitute for the number of viable cells in a culture, Ce llTiter-Glo 2.0 bioluminescent cell survival assay (Promega, G9242) Cell viability was determined using the following method. Cells were plated at a density of 2000–4000 cells per well in a 96-well plate. Serial dilutions of BTK CTM or a comparator compound were added to achieve a final DMSO concentration of over 0.3%, and the plates were incubated at 37°C under 5% CO2 for 72 hours. CellTiter-Glo reagent was added to the cells at a 1:20 dilution, and the plates were incubated at room temperature for 10 minutes. The luminescence signal was then read using an EnVision plate reader. Controls included wells containing DMSO-treated cells and wells containing only the medium without cells. The background luminescence signal was determined using the control wells containing only the medium without cells and then subtracted from all sample wells. The luminescence values ​​were then normalized to the DMSO-treated wells and recorded as the percentage of viable cells.

[0716]

[0483] As shown in Figure 4, wild-type BTK cells are treated with the compounds provided herein. The mutant C4813 BTK cells were sensitive to ibrutinib. While they retained sensitivity to the compounds provided herein, they showed reduced sensitivity to ibrutinib.

[0717]

[0484] Biological example 5

[0485] B-cell activation assay

[0486] Evaluation of the effect of BTK degradation on B cell receptor signaling

[0487] Thaw frozen human peripheral blood mononuclear cells (PBMCs) and treat with DMSO or a compound for 4 hours. The cells were left undisturbed and then stimulated with 10 μg / mL anti-IgM (Jackson Immunoresearch 109-006-129) for 18 hours, while additional DMSO-treated samples were left unstimulated. The compound remained present throughout the stimulation period. Cells were stained with a viable / dead dye (Fisher L34976), followed by CD20 (Biolegend 302330) and CD3 (BD ​​Pharmingen). The cells were stained with fluorophore conjugate antibodies against CD86 (Biolegend 305416) and CD69 (Biolegend 310906). The stained cells were fixed in PFA and scanned with an Attune NxT Acoustic Focusing Flow Cytometer (Thermo-Fisher A29004), and FlowJo( Data was analyzed using v10.5.3) and GraphPad Prism (v7.00) software. Single viable lymphocytes were classified as B cells (CD20+CD3-) and T cells. Gated to cells (CD3+CD20-), with geometric mean fluorescence intensity of CD86 and CD69 The degree of activation (MFI) was calculated for each group. The MFI of unstimulated samples was used to quantify baseline activation. It was used for chemical purposes.

[0718]

[0488] As shown in Figure 5, compound-mediated degradation of BTK is activated in B cells. This prevented anti-IgM-induced upregulation of Kerr CD69 and CD86.

[0719]

[0489] Biological example 6

[0490] Cellular Aiolos Degradation Assay

[0491] In vitro cell screening to determine IMiD activity

[0492] Thaw frozen human peripheral blood mononuclear cells (PBMCs) and treat with DMSO or a compound for 24 hours. The procedure is performed, followed by the Foxp3 / transcription factor fixation / permeabilization kit (eBioscience, 00-552 3) The cells were fixed and permeabilized using CD20 (Biolegend 302330). The mice were stained with fluorophore conjugate antibodies against CD3 (BD ​​Pharmingen 552127) and Aiolos (Biolegend 371106). Additional DMSO-treated PBMC sets were stained with CD20, CD3, and AlexaFluor647 conjugate mouse IgG1 isotype control antibodies (Biolegend 400136). The colored cells were scanned with an Attune NxT Acoustic Focusing Flow Cytometer (Thermo-Fisher A29004), and FlowJo(v10) was used to scan them. Data were analyzed using GraphPad Prism (v7.00) software. Single lymphocytes were gated to B cells (CD20+CD3-) and T cells (CD3+CD20-), and the geometric mean fluorescence intensity (MFI) of Aiolos was calculated for each population. The MFI of the isotype control was calculated for each population and used to quantify background staining. The Aiolos degradation rate was determined using the following formula: % degradation = 100 * (sample MFI - isotype MFI) / (DMSO MFI - isotype MFI) for each compound. The calculation was performed on the sample.

[0720]

[0493] Exemplary results are shown in Figure 9.

[0721]

[0494] Biological example 7

[0495] Mouse PD assay

[0496] Determination of whether CTM catalyzes BTK degradation in vivo

[0497] Method for determining the pharmacological profile of BTK degrader, CD-1 or This was performed by administering CTM to either BALB / c mice. CTM was prepared in a suitable formulation and administered via forced oral administration (PO) at suitable dose levels and frequencies reported from prior pharmacokinetic and tolerability studies. Following CTM administration, BTK levels in blood or splenocytes were measured using flow cytometry or HTRF. When assessing BTK levels via flow cytometry, either whole blood or splenocytes were first treated with ACK RBC lysis buffer to promote erythrocyte lysis. The remaining cells were then stained with fluorophore conjugate antibodies against CD45, TCR beta, and CD45R(B220). The cell pellet was washed with 1×PBS and fixed and permeabilized for 24 hours using a Foxp3 / transcription factor fixation / permeabilization kit. The cells were then intracellularly stained with non-conjugate BTK antibody and detected with fluorophore conjugate secondary antibody. Stained cells were scanned on an Attune NxT Acoustic Focusing Flow Cytometer (Thermo-Fisher A29004), and Fl Data were analyzed using owJo (v10.5.3) and GraphPad Prism (v7.00) software. Lymphocytes were gated to B cells defined as CD45+ TCR beta-B220+ and T cells defined as CD45+ TCR beta+ B220-. BTK geometric mean fluorescence intensity (MFI) was used to identify B and T cells. The calculation was performed for each cell. The BTK degradation rate of samples treated with each compound was calculated using the following formula: % degradation = 100 * (treated sample B cell BTK MFI - treated sample T cell BTK MFI) / vehicle B cell BTK MFI - vehicle T cell BTK MFI).

[0722]

[0498] As shown in Figure 6, after 6 hours of treatment, dose-proportional BTK levels were observed in splenic cells. A decrease in BTK levels was observed and was associated with exposure to the compound in plasma. As shown in Figure 7, dose- and dimt-dependent decreases in BTK levels were observed in circulating mouse B cells after a single oral administration.

[0723]

[0499] Biological example 8

[0500] TMD8 xenotransplant efficacy study

[0501] Evaluation of the antitumor effect of BTK degradation in vivo

[0502] TMD8 or TMD8 BTK C481S CBs that have any of the tumor cells. 17. The antitumor activity of CTM and ibrutinib was evaluated in female SCID mice. Mice were given either TMD8 or TMD8 BTK. C481S One of the cells was subcutaneously inoculated, and once the tumor reached a predetermined size, participants were randomized to receive either a treatment group, vehicle control, CTM (30 mg / kg), or ibrutinib (30 mg / kg). Mice with tumors were administered CTM or ibrutinib orally once daily (QD) or twice daily (BID).

[0724]

[0503] Tumors and body weight were measured three times a week over a 21-day period. On the final day, the tumor growth inhibition rate (%TGI) was calculated using the formula [1-(T-T0 / C-T0)]×100. In the formula, T and C represent the mean tumor sizes in the treatment (T) group and the control (C) group, respectively, and T0 refers to the tumor size at randomization.

[0725]

[0504] As shown in Figure 8, treatment with the compounds described herein is performed on wild-type BTK xenotransplants. It caused tumor growth inhibition in models and ibrutinib-resistant C481S xenograft models.

[0726]

[0505] Biological example 9

[0506] Cellular BTK degradation assay

[0507] Cellular BTK degradation rate was measured using two diastereomers of compound 130 in TMD8 cells. Measurements were taken within the cell for 4 hours as described above. DC 50 Value and EC 50 The value represents the concentration where the response lies between the upper and lower approximate nonlinear regression curves.

[0727] [Table 2]

[0728]

[0508] Biological example 10

[0509] BTK degradation rate (total BTK HTRF) in TMD8 cells over 24 hours

[0510] This example evaluates whether the effectiveness of BTK CTM shifts to a longer time point. D C 50 The value is typically calculated at the 4-hour mark. Most CTMs tested were slightly stronger at 24 hours than at 4 hours.

[0729] [Table 3]

[0730]

[0511] Biological example 11

[0512] BTK degradation in 4 hours in TMD8 cells expressing BTK-C481S Rate (total BTK HTRF)

[0513] This example evaluates the effectiveness of CTM in the disassembly of BTK-C481S. CT The BTK binding site utilized in M ​​binds to the BTK active site. This example evaluates whether the active site mutation C481S affects CTM-induced BTK degradation. CTM is effective against Bruton's tyrosine kinase C481S, but generally has 2-3 times higher potency against WT BTK compared to BTK-C481S.

[0731] [Table 4-1]

[0732] [Table 4-2]

[0733]

[0514] Biological example 12

[0515] BTK degradation rate in Mino cells after 4 hours (total BTK HTRF)

[0516] This example evaluates the efficacy of CTM in a model of mantle cell lymphoma (MCL). To evaluate effective therapeutic indicators, similar to the TMD8 cell (ABC-DLBCL) model described above, BTK CTM was assayed in a model of corn cell lymphoma. The tested CTM showed efficacy against BTK degradation in MCL cell lines (Mino and Rec-1) and TMD8 cells. It had the effect of [something].

[0734] [Table 5]

[0735]

[0517] Biological example 13

[0518] BTK degradation rate in human PBMCs (BTK flow cytometry)

[0519] This example is not of a transformed or immortalized cancer cell line, but of primary human B cells. This study evaluates the efficacy of CTM. Primary cells are considered a physiologically appropriate model. Therefore, this example, in addition to cell line models, demonstrates the efficacy, dynamics, and levels of BTK degradation within these cells. Furthermore, this assay is established as capable of monitoring BTK degradation within primary human B cells, which may serve as a clinical biomarker.

[0736] [Table 6]

[0737]

[0520] Biological example 14

[0521] Ikaros and Aiolos degradation in mantle cell lymphoma lines (Ikaros and Aiolos flow cytometry)

[0522] This example evaluates the IMiD activity of CTM in a cell model of mantle cell lymphoma (MCL). Currently approved MCL treatments include ibrutinib and lenalidomide, and both targeted BTKs and associated CRBNs suggest that these are viable therapies in this metric. These assays determine the efficacy of CTM in degrading IMiD neosubstrates in the MCL cell model and enable efficacy studies in MCL xenografting. This is to generate data for reporting. These data demonstrate the IMiD activity of some compounds (e.g., compound 149) but not others (e.g., compound 130), showing that IMiD neosubstrates are more strongly degraded in Rec-1 cells than in Mino cells, supporting Rec-1 cells in subsequent in vitro and in vivo studies.

[0738] [Table 7]

[0739]

[0523] As shown in Figures 10A and 10B, compound 44 is used in TMD8 cells and / Alternatively, it has several effects on neosubstrate and ITK levels in MOLT4 cells after 24 hours.

[0740]

[0524] As shown in Figures 10A and 10B, compound 72 produced CRBN in 24 hours. It does not affect the neosubstrate, but it does affect the ITK level.

[0741]

[0525] As shown in Figures 10A and 10B, compound 121 showed CRB in 24 hours. There is minimal impact on N-neo substrates and ITK.

[0742]

[0526] As shown in Figures 11A and 11B, compounds 44 and 149 are present in cells There is some impact on CRBN neosubstrate and ITK levels.

[0743]

[0527] As shown in Figure 12, other CTMs tested, including compounds 72 and 130, It had a slight effect on ITK levels, but did not exhibit IMiD activity. Biological example 15

[0528] TEC kinase degradation

[0529] This example shows that CTM treatment affects the levels of the non-target protein TEC kinase. Evaluate whether it is.

[0744]

[0530] BTK and TEC kinases are two members of the TEC kinase family. It has been shown that BTK inhibitors such as ibrutinib affect TEC activity. This non-targeted effect of ibrutinib on TEC kinase was involved in the bleeding clinically observed with ibrutinib treatment. To determine the effect of BTK CTM on intracellular TEC levels, K562 cells were treated with CTM at concentrations of 0.026–2000 nM for 4 hours. TEC levels in cell lysates were evaluated by Western blotting.

[0745]

[0531] The tested CTM was found in K562 cells, as shown in Figures 13A to 13D. It has a mild to moderate effect on EC kinase levels, but the degradation of BTK is more potent than that of TEC. CTM includes compounds 44, 72, 149, and 130.

[0746]

[0532] Biological example 16

[0533] B-cell activation assay (flow cytometry)

[0534] This example evaluates whether CTM treatment affects B cell receptor (BCR) signaling. BTK is downstream of B cell receptor activation and leads to the upregulation of activation markers CD86 and CD69 on the surface of B cells. These data illustrate that degradation of BTK, as well as inhibition of BTK by ibrutinib, can block this signaling pathway.

[0747] [Table 8]

[0748]

[0535] Biological example 17

[0536] T-cell activation assay (ELISA and flow cytometry)

[0537] This example evaluates whether CTMs with IMiD activity affect T cell activation. T cell activation is thought to be one way in which IMiDs such as lenalidomide and pomalidomide can modulate the immune system. These assays were performed to evaluate whether BTK CTM, with or without IMiD activity, affects the activation of primary human T cells after stimulating T cell receptors with anti-CD3 / anti-CD28 stimulation. T cell activation was measured using IL-2 secretion (ELISA assay) and the activation marker CD25 on the surface of T cells. CD69 was measured by upregulation (flow cytometry). The data are presented as a magnification change in response to baseline (stimulation with anti-CD3 / anti-CD28 stimulation in the absence of the compound).

[0749]

[0538] Lenalidomide and pomalidomide induce IL-2 secretion, baseline It increases CD25 and CD69 expression beyond Bell's (anti-CD3 / anti-CD28 stimulation alone).

[0750]

[0539] Ibrutinib treatment increased IL-2 secretion and CD25 compared to baseline. This leads to a decrease in CD69 expression. Since BTK is not present in T cells, this may be due to the non-targeting effect of ibrutinib on other kinases such as ITK.

[0751]

[0540] CTMs with IMiD activity (compounds 44, 149, 30, and 25, etc.) These treatments increased IL-2 secretion, but not to the levels observed in IMiD. These CTM treatments either did not alter or decreased CD25 and CD69 levels due to the non-IMiD effects of the CTM, which potentially affect ITK.

[0752]

[0541] These data relate to the IMiD neosubstrate degradation activity and IL-2 secretion of specific CTMs. This suggests a correlation between its expressive effect on T cell activation in that respect.

[0753] [Table 9]

[0754]

[0542] Biological example 18

[0543] Cell viability assay (CellTiter-Glo)

[0544] This example evaluates the effect of CTM-mediated degradation on cell viability. Specific B The adverse effects on cells have been shown to be dependent on BCR signaling, i.e., BTK for survival. Here, we evaluated the ability of CTM to influence survival in BTK-dependent cell lines. Mino and Rec-1 are mantle cell lymphomas sensitive to IMiD. This is a model. In these MCL cell lines, BTK CTM affected degradation, and CTMs with IMiD activity (compounds 44 and 149) were potenter than CTMs with minimal IMiD activity (compound 130).

[0755] [Table 10]

[0756]

[0545] Biological example 19

[0546] This example evaluates the effect of CTM-mediated degradation on cell viability. Specific B Adverse effects on cells have been shown to depend on BCR signaling, i.e., BTK for survival. Here, we evaluated the ability of CTM to affect viability in BTK-dependent cell lines. The ABC-DLBCL cell line TMD8 was highly sensitive to BTK degradation or inhibition, while TMD8 cell lines expressing the ibrutinib-resistant mutant BTK-C481S maintained sensitivity to BTK degradation (approximately 2–5 times lower sensitivity than the wild type) but were not sensitive to BTK inhibition.

[0757] [Table 11-1]

[0758] [Table 11-2]

[0759] [Table 11-3]

[0760]

[0547] Biological example 20

[0548] In vivo degradation of BTK in mouse PD experiments using oral administration.

[0549] This example shows the inclusion of BTK CTM via direct mouse PD measurement after oral administration. We will evaluate the vivo activity.

[0761]

[0550] Various BTK CTMs exhibit robust in vivo BTK degradation activity. The study demonstrated that the effects varied from inactive compounds to compounds that maintained BTK degradation even 24 hours after single oral administration. This data helped to understand the in vivo BTK degradation / resynthesis rate. Screening was completed at 90 mg / kg over 6 hours, and then, after potent BTK degradation was observed with the initial set of compounds, the dose was changed to a lower dose / longer time. This assay was useful in selecting compounds for in vivo efficacy experiments. The assay showed a good correlation between mouse PD results and in vivo efficacy in a mouse tumor model.

[0762] [Table 12-1]

[0763] [Table 12-2]

[0764] [Table 12-3]

[0765] [Table 12-4]

[0766] [Table 12-5]

[0767]

[0551] Biological example 21

[0552] PD data from rats, dogs, and cynos.

[0553] In this example, the compound was profiled for its effects in non-mouse species. These data were used to evaluate the potential for BTK degradation in humans and to estimate effective human doses.

[0768]

[0554] Multiple BTK CTMs are potent BTK components in rats, dogs, and cynos. The therapeutic effect was demonstrated. Based on this data, the predicted human dose suggests an effective dose of less than 500 mg / day.

[0769] [Table 13-1]

[0770] [Table 13-2]

[0771] [Table 13-3]

[0772]

[0555] Biological example 22

[0556] Non-human primate (cyno) DRF PD data

[0557] This example shows the efficacy and tolerability of BTK CTM after several consecutive days of administration. We will evaluate this and investigate the efficacy of the compounds against BTK and Aiolos degradation.

[0773]

[0558] The compounds were generally very well tolerated, even at high doses. All compounds were The compound demonstrated potent BTK degradation. Compound 149 demonstrated Aiolos degradation 14 days after administration, while other tested CTM compounds did not demonstrate Aiolos degradation.

[0774]

[0559] The data in the table below is from a study in which animals were administered the specified oral dose daily. The results were obtained. BTK and Aiolos levels were analyzed 24 hours after the previous dose.

[0775] [Table 14]

[0776]

[0560] Biological example 23

[0561] Mouse DRF PD Data

[0562] This example shows the efficacy and tolerability of BTK CTM after several consecutive days of administration. We will evaluate this and assess the efficacy of the compound against BTK degradation.

[0777]

[0563] The compounds were generally very well tolerated even at high doses. All tested compounds The compound demonstrated strong BTK degradation.

[0778]

[0564] The data in the table below is from a study in which animals were administered the specified oral dose daily. This is what was obtained. BTK level analysis was performed 24 hours after the previous dose.

[0779] [Table 15]

[0780]

[0565] Biological example 24

[0566] Exposure of compounds in plasma in cyno DRF studies

[0567] This example shows in vivo BTK and / or Aiol in cyno. Evaluate the plasma concentration of compounds that cause OS degradation.

[0781]

[0568] Determine the plasma concentration, and this data will determine the dose and effective compound concentration in humans. This indicates.

[0782]

[0569] The data in the table below is from a study in which animals were administered the specified oral dose daily. The results were obtained. Analysis of the compound concentration in plasma was performed 24 hours after the initial administration.

[0783] [Table 16-1]

[0784] [Table 16-2]

[0785]

[0570] Biological example 25

[0571] Efficacy in mouse xenograft models

[0572] This example shows B-cell malignancy with / without inhibitor-driven BTK mutations in C481. We will investigate the effects of various BTK CTMs in related disease models, including tumor-modeled WT and C481S TMD8 models.

[0786]

[0573] BTK CTM showed significant efficacy in both WT and C481S tumor models. To demonstrate its effectiveness.

[0787] [Table 17-1]

[0788] [Table 17-2]

[0789] [Table 17-3]

[0790] [Table 17-4]

[0791]

[0574] %TGI is defined as (1 - (average volume of treated tumor) / (average volume of control tumor)) × 100%.

[0792]

[0575] Biological example 26

[0576] BTK CTM PK Data

[0577] This example establishes the relationship between PK-PD effectiveness and estimates human exposure using BTK Evaluate the in vivo plasma concentration of CTM.

[0793]

[0578] The in vivo PK properties of BTK CTM differed among the various compounds tested. It was varied. Molecules with moderate to low in vivo clearance were identified. Suitable exposures enabling vigorous BTK degradation were demonstrated for multiple compounds, allowing for the estimation of human doses and human PKs.

[0794] [Table 18-1]

[0795] [Table 18-2]

[0796]

[0579] %F=(AUCinf PO*IV dose) / (AUCinf IV*PO dose)*100

[0797] Other Embodiments

[0580] The above description is for illustrative purposes only and is not applicable to the attached claims. It should be understood that this does not limit the scope of the disclosure as defined herein. Other aspects, advantages, and modifications are provided in the following claims. There was a slight effect on ITK levels, but no effect on IMiD activity.

Claims

1. A method for treating or preventing an autoimmune disease or cancer in a subject requiring such treatment, comprising the step of orally administering a certain amount of a bifunctional compound to the subject, wherein the bifunctional compound can induce proteolysis of Bruton's tyrosine kinase, and the amount is effective in treating or preventing an autoimmune disease or cancer.

2. The method according to claim 1, wherein the cancer includes a solid tumor.

3. The method according to claim 1, wherein the cancer is a B-cell malignant tumor.

4. The aforementioned cancers are comprised of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter transformed, small cell lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), central nervous system (CNS) lymphoma, metastatic melanoma, squamous cell carcinoma of the head and neck (HNSCC), non-small cell lung cancer (NSCLC), platinum-resistant epithelial ovarian cancer (EOC), gastric cancer, metastatic castration-resistant prostate cancer (mCRPC), triple-negative breast cancer (TNBC), muscle-invasive urothelial carcinoma, mesothelioma, cervical cancer, microsatellite-stable colorectal cancer (MSS-CRC), and multiple myeloma (MM). The method according to claim 1, selected from the above.

5. The method according to claim 1, wherein the autoimmune disease is selected from the group consisting of graft-versus-host disease (GVHD), acute graft-versus-host disease, and immune thrombocytopenic purpura (ITP).

6. The method according to any one of claims 1 to 5, wherein the subject has a C481 mutant Bruton-type tyrosine kinase.

7. The method according to any one of claims 1 to 6, wherein the cancer is ibrutinib resistant.

8. The method according to any one of claims 1 to 7, wherein the subject has a C481 mutant Bruton tyrosine kinase and the cancer is chronic lymphocytic leukemia (CLL).

9. A method for degrading splenocyte Bruton's tyrosine kinase in a subject requiring such degradation, comprising the step of orally administering a certain amount of a bifunctional compound to the subject, wherein the bifunctional compound can induce proteolysis of Bruton's tyrosine kinase, and the amount is effective in degrading splenocyte Bruton's tyrosine kinase in the subject.

10. The method according to claim 9, wherein the Bruton's tyrosine kinase is a C481 mutant Bruton's tyrosine kinase.

11. A method for preventing B cell activation in a subject requiring such activation, comprising the step of orally administering a certain amount of a bifunctional compound to the subject, wherein the bifunctional compound can induce proteolysis of Bruton's tyrosine kinase, and the amount is effective in preventing B cell activation.

12. The method according to claim 11, wherein the B cells express CD69 and / or CD86.

13. The method according to any one of claims 1 to 12, wherein the difunctional compound is administered to the subject at a dose of 0.1 to 500 mg / kg.

14. The method according to any one of claims 1 to 13, wherein the difunctional compound is administered to the subject at a dose selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg.

15. The method according to any one of claims 1 to 14, wherein the difunctional compound is administered once, twice, three times, or four times per day.

16. The method according to any one of claims 1 to 15, wherein the difunctional compound is administered daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

17. The method according to any one of claims 1 to 16, wherein the bifunctional compound is administered periodically.

18. A method for degrading C481S Bruton's tyrosine kinase, comprising the step of contacting a cell expressing the C481S Bruton's tyrosine kinase with a bifunctional compound in an amount effective for degrading the C481S Bruton's tyrosine kinase.

19. The method according to claim 18, wherein the method is in vitro.

20. The method according to claim 18, wherein the method is in vivo.

21. The method according to claim 18, wherein the contact of cells expressing the C481S Bruton-type tyrosine kinase with a bifunctional compound in an amount effective for degrading the C481S Bruton-type tyrosine kinase is performed in the object requiring such contact.

22. The aforementioned bifunctional compound is of formula (A) 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, D is a bond or -NH-, Ring A is a phenyl molecule, a 9-10 membered bicyclic aryl molecule, a 5-6 membered partially or completely unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl molecule, wherein the monocyclic heterocycle and bicyclic heteroaryl molecule of ring A are independently selected from N, O, or S. It has one to three selected heteroatoms, and ring A is halo, -CN, -COOH, NH ２ , and C replaced by optional selection １～６ Up to three substituents selected from alkyl groups are optionally and independently substituted. Ring B is a phenyl molecule, a 5-6 membered heteroaryl molecule, a 4-6 membered heterocycloalkyl molecule, or an 8-10 membered spirodicyclic heterocycle, and ring B is optionally substituted, and the heteroaryl and heterocycloalkyl molecules of ring B have 1-3 heteroatoms independently selected from N, O, or S. L is -X １ -X ２ -X ３ -X ４ -X ５ - and X １ is a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ), ｍ -, -O(C ６ H ４ )-, -(O-CH ２ -CH ２ -CH ２ ), ｍ -, -C １～５ alkyl-, N, O or S; or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O or S, and the monocyclic and bicyclic heterocycloalkyl of X １ are each optionally substituted with -CH ３ . X ２ However, the bond, -(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X ３ However, bond, -C １～８ Alkyl-, 【Chemistry 2】 , 4-6 member cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, X ４ However, the bond, -CH ２ -CH ２ -N(R)-, -N(R)-, -C １～４ Alkyl-,-(O-CH ２ -CH ２ -CH ２ ) ｍ - A saturated, partially unsaturated, or fully unsaturated carbon ring with 5 to 6 members, or a saturated, partially unsaturated, or fully unsaturated heteroring with 1 to 3 heteroatoms independently selected from N, O, or S, X ５ However, bond, -C １～４ Alkyl-, -N(R)-, -O-, -C(O)-, or -C(O)-N(R)-, Each R is independently either hydrogen or -C １～３ It is alkyl, m, n, and p are each independent integers between 1 and 3. Y, 【Chemistry 3-1】 【Chemistry 3-2】 And in the formula, R ２ Each of these independently produces a halo, -CN, or C １～４ It is alkyl, C １～４ The alkyl groups are Halo, -CN, -COOH, and -COONH, respectively. ２ , -NH ２ , or -CF ３ In up to three examples, substitutions are made by arbitrary selection and independently. R'' and R''' are either independently hydrogen atoms, or together with the atoms to which they are bonded, they form a 5-6 member partially unsaturated or fully unsaturated benzo-condensed heterocycle. Z is -C(R Ａ ) ２ - or -C(O)-, R Ａ Each of these independently produces hydrogen or -C １～４ It is alkyl, q is 0, 1, or 2. The method according to any one of claims 1 to 21.

23. The method according to claim 22, wherein ring B is a 5-6 member heterocycloalkyl group optionally substituted with 1-2 nitrogen atoms.

24. The method according to claim 22, wherein ring B is an optionally substituted 5-6 member heteroaryl having 1-2 heteroatoms independently selected from N and S.

25. Ring B is 【Chemistry 4】 And in the formula, R １０ but, 【Transformation 5】 And in the formula, R １ C １～４ It is an alkyl group. The method according to claim 22.

26. Ring B is 【Transformation 6】 And in the formula, R １０ but, 【Transformation 7】 That is, The method according to claim 22 or 25.

27. Ring B is 【Transformation 8】 The method according to claim 25 or 26.

28. R １０ but, 【Chemistry 9】 The method according to any one of claims 25 to 27.

29. Ring A is 【Chemistry 10】 The method according to any one of claims 22 to 28, wherein, in the formula, ring A' together with the phenyl ring to which ring A' is fused, forms a 9-10 membered bicyclic aryl or 9-10 membered bicyclic heteroaryl, and the bicyclic heteroaryl has 1 to 3 heteroatoms independently selected from N, O, or S.

30. Ring A is 【Chemistry 11】 The method according to any one of claims 22 to 29.

31. X １ , X ２ , and X ５ At least one of them is -N(R)-, -C(O)-N(R)-, or -CH ２ - The method according to any one of claims 22 to 30 or a pharmaceutically acceptable salt thereof.

32. X １ The method according to any one of claims 22 to 31, wherein is -C(O)-N(R)-.

33. X ２ However, -(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, or -C １～５ A pharmaceutically acceptable salt thereof according to any one of claims 22 to 32, wherein the salt is alkyl-.

34. X ３ However, 【Chemistry 12】 , -C １～４ The method according to any one of claims 22 to 33, wherein the member is alkyl- or -N(R)-.

35. X ４ However, the bond, -CH ２ The method according to any one of claims 22 to 34, wherein - or -N(R)-.

36. X ５ A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein the bond is a compound.

37. X １ ga-(O-CH ２ -CH ２ -CH ２ ) ｍ - and m is 1, X ２ The method according to any one of claims 22 to 31, wherein is -C(O)-N(R)-.

38. X １ However, -CH ２ -, -C(O)-, 【Chemistry 13】 The method according to any one of claims 22 to 31.

39. X ２ is a bond, -C(O)-, -C １～５ alkyl-, 【Chemistry 14】 The method according to any one of claims 22 to 31, 37, or 38.

40. X ３ However, bond, -C １～４ The method according to any one of claims 22 to 31 or 37 to 39, wherein the member is alkyl-, 4 to 6-membered cycloalkyl, or -N(R)-.

41. X ３ However, bond, -C １～４ Alkyl-, -NH-, 【Chemistry 15】 The method according to any one of claims 22 to 31 or 37 to 40.

42. X ４ However, 【Chemistry 16】 , -C １～４ alkyl-, -CH ２ -CH ２ -N(R)-, or -N(R)-, the method according to any one of claims 22 to 31 or 37 to 41.

43. X ５ However, bond, -C １～４ The method according to any one of claims 22 to 31 or 37 to 42, wherein the member is alkyl-, -N(R)-, or -C(O)-N(R)-.

44. L, 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 【Chemistry 17-4】 The method according to any one of claims 22 to 30.

45. Y, [Chemistry 18] The method according to any one of claims 22 to 44.

46. The method according to any one of claims 22 to 45, wherein W is N.

47. The method according to any one of claims 22 to 46, wherein D is a bond.

48. The compound of formula (A) is of formula (B) 【Chemistry 19】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, D is a bond or -NH-, Ring B1 is a 4-6 membered, fully saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle, or an 8-10 membered, fully saturated spirodicyclic heterocycle, and ring B1 has 1-3 heteroatoms independently selected from N, O, or S, and halo, -CH ３ , -CF ３ , -C(O)OH, -CH ２ It is optionally substituted with 1 to 3 groups selected from a 5-membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N or O, which are optionally substituted with OH or oxo. L is -X １ -X ２ -X ３ - and X １ is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ) ｍ -, -O(C) ６ H ４ )-,-(O-CH ２ -CH ２ -CH ２ ) ｍ -, -C １～５ A 7-12 member spiro or condensed bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ The aforementioned monocyclic and bicyclic heterocycloalkyls are, respectively, -CH ３ It is replaced by optional selection, X ２ However, the bond, -(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X ３ However, bond, -C １～４ Alkyl-, 【Chemistry 20】 , 4-6 member cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, Each R is independently either hydrogen or -C １～３ It is alkyl, m, n, and p are each independent integers between 1 and 3. Y, 【Chemistry 21】 The method according to claim 22.

49. Ring B1 is 【Chemistry 22】 And ring B1 is -CH ３ ien-CH ２ OH, -C(O)OH, -CF ３ fluorine, 【Chemistry 23】 One to three bases that are replaced by an arbitrary selection from, The method according to claim 48.

50. Ring B1 is 【Chemistry 24】 The method according to claim 48 or 49.

51. Ring B1 is 【Chemistry 25】 The method according to any one of claims 48 to 50.

52. X １ but, 【Chemistry 26】 The method according to any one of claims 48 to 51.

53. X ２ However, bond, -C １～５ Alkyl-, 4-6 member monocyclic cycloalkyl, or 4-6 member monocyclic hematophor having 1-2 heteroatoms independently selected from N, O, or S The method according to any one of claims 48 to 52, wherein the material is telocycloalkyl.

54. X ２ However, bond, -C １～３ Alkyl-, -C(O)-, 【Chemistry 27】 The method according to any one of claims 48 to 53.

55. X ３ However, bond, -C １～４ Alkyl-, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - A 4-6 member heterocycloalkyl having one or two heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ The method according to any one of claims 48 to 54, wherein the substitution is by optional choice.

56. X ３ However, 【Chemistry 28】 The method according to any one of claims 48 to 55.

57. L, 【Chemistry 29】 The method according to any one of claims 48 to 56.

58. The method according to any one of claims 48 to 57, wherein W is N and D is a bond.

59. The compound of formula (A) is of formula (C) 【Transformation 30】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, Ring C is a saturated, partially unsaturated, or fully unsaturated 5-6 member monocyclic heterocycle having phenyl or 1-2 heteroatoms independently selected from N, O, or S, and the phenyl and heterocycle of ring C are each optionally substituted. L is -X １ -X ２ -X ３ - and X １ is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ) ｍ -, -O-(C ６ H ４ )-,-(O-CH ２ -CH ２ -CH ２ ) ｍ -, -C １～５ A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ The bicyclic heterocycloalkyl and monocyclic heterocycloalkyl are, respectively, -CH ３ It is replaced by optional selection, X ２ However, the bond, -(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X ３ However, bond, -C １～４ Alkyl-, 【Chemistry 31】 , 4-6 member cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, Each R is independently either hydrogen or -C １～３ It is alkyl, m, n, and p are each independent integers between 1 and 3. The method according to claim 22.

60. Ring C is 【Chemistry 32】 The method according to claim 59.

61. Ring C is 【Transformation 33】 The method according to claim 59 or 60.

62. X １ The method according to any one of claims 59 to 61, wherein the heteroatom is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S.

63. X １ but, 【Transformation 34】 The method according to any one of claims 59 to 62.

64. X ２ However, bond, -C １～５ The method according to any one of claims 59 to 63, wherein the molecule is an alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having one or two heteroatoms independently selected from N, O, or S.

65. X ２ However, bond or -C １～３ A compound or pharmaceutically acceptable salt according to any one of claims 41 to 46, wherein the compound is alkyl-.

66. X ３ However, it is a 4-6 member heterocycloalkyl having a 4-6 member cycloalkyl, -N(R)-, or 1-2 heteroatoms independently selected from N, O, or S, The aforementioned heterocycloalkyl is -CH ３ The method according to any one of claims 59 to 65, wherein the substitution is made by optional choice.

67. X ３ but, 【Chemistry 35】 The method according to any one of claims 59 to 66.

68. L, 【Transformation 36】 The method according to any one of claims 59 to 67.

69. The compound of formula (A) is of formula (D) 【Chemistry 37】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, Ring A is 【Transformation 38】 And, L is -X １ -X ２ -X ３ - and X １ However, -C １～５ A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, X １ The aforementioned monocyclic heterocycloalkyl is -CH ３ It is replaced by optional selection, X ２ However, bond, -C １～５ A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, X １ The aforementioned monocyclic heterocycloalkyl is -CH ３ It is replaced by optional selection, X ３ However, bond, -C １～４ An alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, Y, 【Chemistry 39】 And, R １０ But, hello, -C １～５ Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, -CN, -OH, -CF ３ , -C(O)OH, -CH ２ OH, -CH ２ CH ２ OH, 【Chemistry 40】 That is, The method according to claim 22.

70. The compound of formula (D) is formula (D-1) 【Chemistry 41】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, Ring A is 【Chemistry 42】 And, L is -X １ -X ２ -X ３ - and X １ However, -C １～５ A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, X １ The aforementioned unit A cyclic heterocycloalkyl group is -CH ３ It is replaced by optional selection, X ２ However, bond, -C １～５ A 4-6 member monocyclic heterocycloalkyl having alkyl- or 1-2 heteroatoms independently selected from N, O, or S, X １ The aforementioned monocyclic heterocycloalkyl is -CH ３ It is replaced by optional selection, X ３ However, bond, -C １～４ An alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, Y, 【Chemistry 43】 And, R １０ but, 【Chemistry 44】 That is, The method according to claim 69.

71. The compound of formula (D) is of formula (D-2) 【Chemistry 45】 The method according to claim 69, wherein the compound is or a pharmaceutically acceptable salt thereof.

72. Ring A is 【Chemistry 46】 The method according to any one of claims 69 to 71.

73. X １ However, it is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ The aforementioned monocyclic heterocycloalkyl is -CH ３ The method according to any one of claims 69 to 72, wherein the substitution is by optional choice.

74. X １ but, 【Chemistry 47】 The method according to any one of claims 69 to 73.

75. X ２ However, bond, -C １～５ Alkyl-, 4-6 member monocyclic cycloalkyl, or 4-6 member monocyclic hematophor having 1-2 heteroatoms independently selected from N, O, or S The method according to any one of claims 69 to 74, wherein the material is telocycloalkyl.

76. X ２ However, bond or -C １～４ The method according to any one of claims 69 to 75, wherein the alkyl group is alkyl.

77. X ３ The method according to any one of claims 69 to 76, wherein the bond is a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S.

78. X ３ but, 【Chemistry 48】 The method according to any one of claims 69 to 77.

79. L, 【Chemistry 49】 The method according to any one of claims 69 to 78.

80. R １０ but, [Transformation 50] The method according to any one of claims 69 to 79.

81. R １０ but, 【Chemistry 51】 The method according to any one of claims 69 to 79.

82. The compound of formula (A) is of formula (E) 【Chemistry 52】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, D is a bond or -NH-, W is N or CH, Ring A is a phenyl molecule, a 9-10 membered bicyclic aryl molecule, a 5-6 membered partially or completely unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl molecule, wherein the monocyclic heterocycle and bicyclic heteroaryl molecules of ring A each have 1-3 heteroatoms independently selected from N, O, or S. Ring B is a 5-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle, or an 8-10 member spirodicyclic heterocycle, which is substituted by arbitrary selection. Ring B has 1 to 3 heteroatoms independently selected from N, O, or S. L is -X １ -X ２ -X ３ -X ４ -X ５ - and X １ However, the bonds are -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ) ｍ -, -O(C) ６ H ４ )-,-(O-CH ２ -CH ２ -CH ２ ) ｍ -, -C １～５ A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ The aforementioned monocyclic and bicyclic heterocycloalkyls are, respectively, -CH ３ It is replaced by optional selection, X ２ However, the bond, -(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X ３ However, bond, -C １～４ Alkyl-, 【Chemistry 53】 , 4-6 member cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - A 4-6 member heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, X ４ However, the bond, -CH ２ -CH ２ -N(R)-, -N(R)-, -C １～４ Alkyl-,-(O-CH ２ -CH ２ -CH ２ ) ｍ - A saturated, partially unsaturated, or fully unsaturated carbon ring with 5 to 6 members, or a saturated, partially unsaturated, or fully unsaturated heteroring with 1 to 3 heteroatoms independently selected from N, O, or S, X ５ However, the bond is -N(R)- or -C(O)-N(R)-, Each R is independently either hydrogen or -C １～３ It is alkyl, m, n, and p are each independent integers between 1 and 3. Y, 【Chemistry 54】 X １ , X ２ , X ３ , X ４ , and X ５ At least one of them has a nitrogen atom, and Y is X １ , X ２ , X ３ , X ４ , or X ５ It is directly bonded to L at the nitrogen atom. 、 The method according to claim 22.

83. Ring B is 【Transformation 55】 And in the formula, R １０ but, 【Transformation 56】 And in the formula, R １ C １～４ It is an alkyl group. The method according to claim 82.

84. Ring B is 【Chemistry 57】 And in the formula, R １０ but, 【Transformation 58】 That is, The method according to claim 82 or 83.

85. Ring B is 【Chemistry 59】 The method according to any one of claims 82 to 84.

86. R １０ but, 【Transformation 60】 The method according to any one of claims 82 to 85.

87. Ring A is 【Chemistry 61】 The method according to any one of claims 82 to 86.

88. X ５ The method according to any one of claims 82 to 87, wherein is -N(R)-.

89. X ５ The method according to any one of claims 82 to 87, wherein is -C(O)-N(R)-.

90. X ５ The method according to any one of claims 82 to 87, wherein the combination is a bond.

91. L, 【Chemistry 62-1】 【Chemistry 62-2】 【Chemistry 62-3】 The method according to any one of claims 82 to 87.

92. Y, 【Transformation 63】 The method according to any one of claims 82 to 91.

93. The compound of formula (A) is of formula (F) 【Chemistry 64】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, W is CH or N, L is -X １ -X ２ -X ３ - and X １ is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH ２ -CH ２ ) ｍ -, -O(C) ６ H ４ )-,-(O-CH ２ -CH ２ -CH ２ ) ｍ -, -C １～５ A 7-12 member spirodicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ The aforementioned monocyclic and bicyclic heterocycloalkyls are, respectively, -CH ３ It is replaced by optional selection, X ２ However, bond, -C １～５ Alkyl-,-(O-CH ２ -CH ２ ) ｎ -, - (CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ Alkyl-, a 4-6 member monocyclic cycloalkyl, or a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, X ３ However, bond, -C １～４ Alkyl-, 【Transformation 65】 , 4-6 member cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, - (CH ２ -CH ２ -O) ｐ - One or two heteroatoms independently selected from N, O, or S It is a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is -CH ３ It is replaced by optional selection, Each R is independently either hydrogen or -C １～３ It is alkyl, m, n, and p are each independent integers between 1 and 3. Y, 【Chemical 66】 The method according to claim 22.

94. The method according to claim 93, wherein W is N.

95. Y, 【Transformation 67】 The method according to claim 93 or 94.

96. X １ However, it is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, and X １ Each of the aforementioned monocyclic heterocycloalkyl groups is -CH ３ The method according to any one of claims 93 to 95, wherein the substitution is by optional choice.

97. X １ but, 【Transformation 68】 The method according to any one of claims 93 to 96.

98. X １ but, 【Transformation 69】 The method according to any one of claims 93 to 97.

99. X ２ However, bond or -C １～５ The method according to any one of claims 93 to 98, wherein the alkyl group is alkyl.

100. X ３ The method according to any one of claims 93 to 99, wherein the heteroatom is a 4-6 member monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S.

101. X ３ but, 【Transformation 70】 The method according to any one of claims 93 to 100.

102. X ３ but, 【Chemistry 71】 The method according to any one of claims 93 to 100.

103. L, 【Chemistry 72】 The method according to any one of claims 93 to 102.

104. The compound of formula (A) is of formula (G) 【Transformation 73】 The method according to claim 22, wherein the compound is or a pharmaceutically acceptable salt thereof.

105. R １ The method according to claim 104, wherein is methyl.

106. Y, 【Chemistry 74】 The method according to claim 104 or 105.

107. The method according to any one of claims 104 to 106, wherein W is N.

108. The compound of formula (A) is of formula (H) 【Chemistry 75】 The method according to claim 22, wherein the compound is or a pharmaceutically acceptable salt thereof.

109. The method according to claim 108, wherein q is 0.

110. The compound of formula (A) is of formula (J) 【Transformation 76】 The method according to claim 22, wherein the compound is or a pharmaceutically acceptable salt thereof.

111. The compound of formula (A) is of formula (K) 【Chemical 77】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring A is 【Transformation 78】 Ring A consists of halo, CN, carboxyl, and NH. ２ , and C replaced by optional selection １～６ Up to three substituents selected from alkyl groups are optionally and independently substituted. V is bonded or -CH ２ - and E and G are each independently 5-6 member heterocycloalkyl groups, and each heterocycloalkyl group contains at least one nitrogen atom. The method according to claim 22.

112. The method according to claim 111, wherein D is a bond and W is a nitrogen atom.

113. The compound of formula (A) is of formula (M) 【Chemistry 79】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １０Ａ However, hydrogen, 【Chemistry 80】 And in the formula, R １ However, C １～４ It is alkyl, X １ However, -C １～５ It is alkyl-, Ring C-1 is a 5-6 member heterocycloalkyl group having one nitrogen atom. Y, 【Chemistry 81】 The method according to claim 22.

114. R １０Ａ However, hydrogen or 【Chemistry 82】 The method according to claim 113.

115. R １０Ａ but, 【Chemistry 83】 And R １ The method according to claim 113 or 114, wherein is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or isobutyl.

116. R １ The method according to any one of claims 113 to 115, wherein is methyl.

117. X １ However, -CH ２ -ien-CH ２ CH ２ -, or -CH ２ CH ２ CH ２ - The method according to any one of claims 113 to 116.

118. X １ ga-CH ２ - The method according to any one of claims 113 to 117.

119. Ring C-1 is, 【Chemical 84】 The method according to any one of claims 113 to 118.

120. Ring C-1 is, 【Chemical 85】 The method according to any one of claims 113 to 119.

121. The method according to claim 1, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

122. The method according to any one of claims 1 to 121, wherein the compound is administered in the form of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle, or adjuvant.

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