Bifunctional compounds for degrading BTK with enhanced IMiD activity

Abstract

The present disclosure relates to compounds useful for degrading BTK via the ubiquitin proteolytic pathway with enhanced IMiD activity. The disclosure also provides pharma- ceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various diseases, conditions, or disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 225,401, filed July 23, 2021, the contents of which are incorporated by reference in their entirety into this specification.

[0002] Field

[0002] The present disclosure provides novel bifunctional compounds for targeted proteolysis of Bruton's tyrosine kinase (BTK) and methods of treating diseases regulated by BTK. In certain embodiments, the compounds can degrade Bruton's tyrosine kinase with enhanced IMiD activity. In certain embodiments, the compounds are useful in methods of treating diseases susceptible to the combination of BTK and IMiD modulation. [Background technology]

[0003] background

[0003] BTK is a member of the TEC family of kinases and is a crucial signaling hub in the B cell antigen receptor (BCR) pathway. Mutations in BTK result in X-linked agammaglobulinemia (XLA), in which B cell maturation is impaired and leads to reduced immunoglobulin production. Hendriks, et al., 2011, Expert Opin Ther Targets 15: 1002-1021, 2011. The central role of BTK in B cell signaling and function makes it an attractive therapeutic target for B cell malignancies and autoimmune and inflammatory diseases. Ibrutinib, a covalent inhibitor of BTK, has been approved to treat chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and other B cell malignancies, as well as graft-versus-host disease (GvHD). Miklos, et al., 2017, Blood, 120 (21): 2243-2250. Currently, ibrutinib and second generation BTK inhibitors are being investigated for oncology and immune-related indications, such as rheumatoid arthritis. Akinleye, et al., 2013, J of Hematolo Oncol. 6:59;Liu, et al., 2011, J Pharm and Exper Ther. 338 (1): 154-163;Di Paolo, et al., 2011, Nat Chem Biol. 7 (1): 41-50.

[0004]

[0004] As an alternative to stoichiometric inhibition, proteolysis of BTK can have dramatic consequences on B cell function by effectively blocking BCR signaling. Removal of BTK protein abolishes BTK kinase activity and protein interactions or scaffolding functions of BTK. Specific degradation of BTK can be achieved using heterobifunctional small molecules that recruit BTK to ubiquitin ligase, thus promoting ubiquitination and proteasomal degradation of BTK. 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 can present a mechanism of action for preventing BTK activity and BCR signaling that is distinct from that of stoichiometric BTK inhibition. Furthermore, this degradative approach can effectively target the C481S mutant form of BTK, a mutation that has been observed clinically and confers resistance to inhibition by ibrutinib. Woyach, et al., 2012, Blood, 120 (6): 1175-1184, 2012.

[0005]

[0005] Using degrading compounds that destroy target proteins by CRBN has already yielded candidate anti-cancer drugs. Okumura et al., 2020, Pharmaceuticals 13: 95. These drugs not only target cancer cells but also trigger a strong immune response, in part by degrading, for example, Ikaros and Aiolos and increasing IL-2 secretion. The immunomodulatory imide drug (IMiD) portion of these compounds is thought to be responsible for the strong immune effects. Together, these degrading compounds impede tumor growth directly and via the immune system. Quach et al., 2010, Leukemia 24: 22-32.

[0006]

[0006] It has been discovered that certain of these compounds have activities in addition to degrading BTK. In particular, certain BTK compounds have activity similar to immunomodulatory imide (IMiD) drugs, such as pomalidomide and lenalidomide. Upon binding to CRBN, IMiDs alter the substrate repertoire of the CRBN ubiquitin ligase complex, in part by leading to the degradation of non-physiological or neo-substrates. As with other IMiDs, these compounds can promote the formation of a ternary complex with CRBN, leading to the ubiquitination and degradation of two transcription factors, Aiolos and Ikaros. Gandhi et al., 2014, Brit. J. Haematol. 164(6):8111-821;Kronke et al., 2014, Science 343:301-305;Lu et al., 2013, Science 343:305-309. Clinically, the IMiD lenalidomide has been approved by the FDA for the treatment of multiple myeloma (MM), myelodysplastic syndrome with 5q deletion (MDS), mantle cell lymphoma (MCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL). The optimized IMiD drug pomalidomide is more potent than lenalidomide and has shown efficacy in relapsed MM patients, including those resistant to both lenalidomide and bortezomib. This purposeful dual activity of degrading Ikaros and Aiolos, together with the well-defined oncogenic target BTK, makes the compound useful for the treatment or prevention of diseases and disorders susceptible to BTK and IMiD modulation. Summary of the Invention [Means for solving the problem]

[0007] overview

[0007] Provided herein is a method for treating or preventing a disease, disorder, or condition in a subject in need thereof by administering a compound capable of degrading Bruton's tyrosine kinase with enhanced IMiD activity. In the examples provided herein, the compounds are shown to recruit CRBN and degrade BTK with enhanced IMiD activity. Specifically, in certain embodiments, the exemplary compounds promote the degradation of Aiolos or Ikaros while degrading BTK. In certain embodiments, the compounds also induce IL-2, another marker of IMiD activity. By degrading BTK with significant IMiD activity, the compounds are useful for treating or preventing diseases and disorders susceptible to BTK regulation and IMiD regulation.

[0008]

[0008] In one aspect, provided herein are methods of treating or preventing a disease, disorder, or condition in a subject in need thereof. These methods include administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase with enhanced IMiD activity. In certain embodiments, the amount is effective to treat or prevent the disease, disorder, or condition. In certain embodiments, the method is for treating or preventing cancer, such as B-cell malignancies.

[0009] In one aspect, provided herein are methods of treating or preventing a B cell malignancy, disorder, or condition in a subject in need thereof. These methods include administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase with increased IMiD activity. In certain embodiments, the amount is effective to treat or prevent the B cell malignancy.

[0010]

[0010] In another aspect, provided herein are methods for degrading Bruton's tyrosine kinase in a subject in need thereof. These methods include administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase with increased IMiD activity. In certain embodiments, the amount is effective to degrade Bruton's tyrosine kinase in the subject.

[0011]

[0011] In another aspect, provided herein are methods of preventing B cell activation in a subject in need thereof. These methods include administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase with enhanced IMiD activity. In certain embodiments, the amount is effective to prevent B cell activation.

[0012]

[0012] In another aspect, provided herein are methods for degrading mutant Bruton's tyrosine kinase. These methods include contacting a cell expressing mutant Bruton's tyrosine kinase with an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase with enhanced IMiD activity. In certain embodiments, the amount is effective to degrade mutant Bruton's tyrosine kinase. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481 mutation. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481S mutation.

[0013]

[0013] In these methods, the bifunctional compound comprises a moiety capable of specifically binding BTK with enhanced IMiD activity. Certain compounds are described herein. The compounds can be administered in any form, including pharma- ceutically acceptable salts and pharmaceutical compositions. In certain embodiments, the compounds are administered orally.

[0014] The methods provided herein are useful for treating or preventing diseases, conditions and disorders mediated by Bruton's tyrosine kinase, including, for example, cancers, including B-cell malignancies. [Brief description of the drawings]

[0015] Brief explanation of the figure [Figure 1]

[0015] Provides the effect of Compound 5 on the REC-1 human mantle cell line compared to control compounds as well as ibrutinib, acalabrutinib, pomalidomide and lenalidomide. [Diagram 2]

[0016] 1 shows that compound 5 degrades both BTK and the immunomodulatory cereblon neosubstrate Aiolos. [Diagram 3]

[0017] Compound 5 is shown to be active against ibrutinib-resistant tumor cell lines [Figure 4]

[0018] We show that 80% BTK degradation drives potent antitumor activity in preclinical models. Ikaros and Aiolos degradation achieve target coverage even at therapeutic doses. [Diagram 5]

[0019] 1 shows robust BTK degradation observed with compound 5 across all dose levels and malignancies. [Figure 6]

[0020] 1 shows rapid and sustained degradation of BTK in patients with CLL by compound 5. [Figure 7]

[0021] Figure 3 shows that compound 5 exhibits greater Ikaros degradation, consistent with cereblon immunomodulatory effects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description

[0022] Provided herein are methods of using bifunctional compounds to induce proteolysis of Bruton's tyrosine kinase (BTK) via the ubiquitin proteolytic pathway.

[0017]

[0023] As used herein, the following definitions shall apply unless otherwise indicated.

[0018] definition

[0024] For purposes herein, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0019]

[0025] As described herein, "IMiD" activity refers to immunomodulatory imidrug activity. In certain embodiments, the IMiD activity is for an IMiD compound. In certain embodiments, the IMiD compound is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, ivedomide, and apremilast. In certain embodiments, the IMiD activity is measured by downregulation of an IMiD target. In certain embodiments, the target is Aiolos. In certain embodiments, the target is Ikaros. In certain embodiments, "enhanced IMiD activity" refers to a maximum degradation of Aiolos of more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, or more than 90% under physiological conditions. In certain embodiments, "low IMiD activity" refers to maximal degradation of Ikaros of greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, or greater than 90% under physiological conditions. An exemplary assay for Ikaros degradation is provided in the Examples herein.

[0020]

[0026] As used herein, a "protecting group" refers to a moiety or functional group that is introduced into a molecule by chemical modification of the functional group to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Wuts and Greene: "Greene's Protective Groups in Organic Synthesis," 4th Ed, Wuts, PGM and Greene, TW, Wiley-Interscience, New York: 2006.

[0021]

[0027] As described herein, the compounds herein can be optionally substituted with one or more substituents, such as, for example, those exemplified generally herein or by the specific classes, subclasses and species described herein.

[0022]

[0028] As used herein, the terms "hydroxyl" or "hydroxy" refer to an --OH moiety.

[0023]

[0029] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as described below.

[0024]

[0030] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. The alkyl group can be straight-chained 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. An alkyl group can have one or more substituents, such as halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), heteroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aryl, heteroaryl, acyl (e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, It may be substituted (i.e., optionally substituted) with no, alkylaminocarbonyl, 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, sulfamido, oxo, carboxy, carbamoyl, alicyclicoxy, heteroalicyclicoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Without being limited thereto, some examples of substituted alkyl include carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (e.g., (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (alicyclic)alkyl or haloalkyl.

[0025]

[0031] As used herein, an "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 an alkyl group, an alkenyl group can 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 substituted with one or more substituents such as halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), heteroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (alicyclic)carbonyl or (heteroalicyclic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, aryl ... and the like. The aryl group may be optionally substituted with aryl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, heteroalicyclic amino, or aliphatic sulfonylamino), sulfonyl (e.g., alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heteroalicyclicoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without being limited thereto, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (e.g., (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl, (alicyclic)alkenyl, or haloalkenyl.

[0026]

[0032] As used herein, an "alkynyl" 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 having at least one triple bond. Alkynyl groups can be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group can be substituted with one or more substituents, such as aroyl, heteroaroyl, 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-), amido (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, aryloxy ... and the like. The heteroarylcarbonyl group can be optionally substituted with arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl), urea, thiourea, sulfamoyl, sulfamido, 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.

[0027]

[0033] As used herein, "amide" encompasses both "aminocarbonyl" and "carbonylamino." These terms, when used alone or in conjunction with another group, refer to an amide group, such as -N(R X )-C(O)-RY or -C(O)-N(R X )2 (when used at the terminal end) and -C(O)-N(R X )-or-N(R X )-C(O)- (when used internally), where R X and R Y can be aliphatic, alicyclic, aryl, araliphatic, heteroalicyclic, heteroaryl or heteroaraliphatic. Examples of amide groups include alkylamide (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heteroalicyclic)amide, (heteroaralkyl)amide, (heteroaryl)amide, (heterocycloalkyl)alkylamide, arylamide, aralkylamide, (cycloalkyl)alkylamide or cycloalkylamide.

[0028]

[0034] As used herein, an "amino" group is -NR X R Y In the formula, R X and R Y Each of is independently hydrogen (H or -H), aliphatic, alicyclic, (alicyclic)aliphatic, aryl, araliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is defined herein and optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is understood to mean -NR X -, where R X has the same meaning as defined above.

[0029]

[0035] As used herein, an "aryl" group used alone or as part of a larger moiety, such as in "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 of the rings in the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2-3 membered carbocyclic rings. For example, benzo-fused groups include 2 or more C 4~8 Aryl includes phenyl fused to a carbocyclic moiety. Aryl includes aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl (e.g., (aliphatic)carbonyl; (alicyclic)carbonyl). Optionally substituted with one or more substituents including: ((alicyclic)aliphatic)carbonyl; (araliphatic)carbonyl; (heteroalicyclic)carbonyl; ((heteroalicyclic)aliphatic)carbonyl; or (heteroaraliphatic)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; sulfamido; or carbamoyl. Alternatively, aryl can be unsubstituted.

[0030]

[0036] Non-limiting examples of substituted aryls include haloaryls (e.g., mono-, di-(e.g., p,m-dihaloaryls) and (trihalo)aryls); (carboxy)aryls (e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls and (alkoxycarbonyl)aryls); (amido)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 (e.g., (aminosulfonyl)amino)aryls or ((dialkyl)amino)aryls). (alkylsulfonyl)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; ((heteroalicyclic)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.

[0031]

[0037] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group substituted with an aryl group (e.g., C 1~4 "Aliphatic", "alkyl" and "aryl" are defined herein. An example of an araliphatic, e.g., aralkyl, group is benzyl.

[0032]

[0038] As used herein, an “aralkyl” group refers to an alkyl group substituted with an aryl group (e.g., C 1~4 "Aryl" refers to an aralkyl group (an alkyl group). Both "alkyl" and "aryl" are defined above. An example of an aralkyl group is benzyl. An aralkyl can be one or more substituents such as an aliphatic (e.g., alkyl, alkenyl or alkynyl, including carboxyalkyl, hydroxyalkyl or haloalkyl, such as trifluoromethyl), alicyclic (e.g., cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, aroyl, aryloxy ... and optionally substituted with alkylcarbonyloxy, amido (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, sulfamido, oxo or carbamoyl.

[0033]

[0039] As used herein, a "bicyclic ring system" includes 6-12 (e.g., 8-12 or 9, 10, or 11) membered structures forming two rings, the two rings having at least one atom in common (e.g., two atoms in common). Bicyclic ring systems include bialicyclic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0034]

[0040] As used herein, "alicyclic" groups encompass "cycloalkyl" and "cycloalkenyl" groups, each of which is optionally substituted as described below.

[0035]

[0041] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0036]

[0042] A "cycloalkenyl" group, as used herein, 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-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0037]

[0043] The cycloalkyl or cycloalkenyl group may have one or more substituents such as phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl) carbonylamino or (heteroaraliphatic)carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl or (heteroaraliphatic)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, sulfamido, oxo or carbamoyl.

[0038]

[0044] As used herein, the term "heteroalicyclic" encompasses heterocycloalkyl and heterocycloalkenyl groups, each of which is optionally substituted as described below.

[0039]

[0045] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused, bridged, or spiro) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., nitrogen (N), oxygen (O), sulfur (S), or a combination thereof). Non-limiting examples of heterocycloalkyl groups include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octa ... Benzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[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. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form a structure such as tetrahydroisoquinoline, which is classified as a heteroaryl.

[0040]

[0046] A "heterocycloalkenyl" group, as used herein, refers to a monocyclic or bicyclic (e.g., a 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds and in which one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heteroalicyclics are numbered according to standard chemical nomenclature.

[0041]

[0047] The heterocycloalkyl or heterocycloalkenyl group may have one or more substituents, such as phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, and optionally substituted with aryloxy, arylamino or (heteroaraliphatic)carbonylamino, nitro, carboxy (e.g., HOOC-, alkoxycarbonyl or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl or (heteroaraliphatic)carbonyl), nitro, cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0042]

[0048] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, where one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and the monocyclic ring system is aromatic, or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having 2 to 3 rings. For example, benzo-fused groups include benzo (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl) fused to one or two 4-8 membered heteroalicyclic moieties. Some examples of heteroaryl 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, pryl, cinnolyl, quinolyl, quinazolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl. Other examples of heteroaryl include 1,2,3,4-tetrahydroisoquinoline and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0043]

[0049] 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-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0044]

[0050] Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0045]

[0051] Heteroaryl may be one or more substituents, such as aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl (e.g., an aliphatic carbocyclic ring, Heteroaryl is optionally substituted with aryl, (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)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, sulfamido, or carbamoyl. Alternatively, heteroaryl can be unsubstituted.

[0046]

[0052] 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); (amido)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)heteroaryls. and (alkyl)heteroaryl; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl)heteroaryl; (heteroalicyclic)heteroaryl; (alicyclic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl (e.g., (alkylcarbonyl)heteroaryl); (alkyl)heteroaryl; or (haloalkyl)heteroaryl (e.g., trihaloalkylheteroaryl).

[0047]

[0053] As used herein, a "heteroaromatic aliphatic" (e.g., heteroaralkyl group) refers to an aliphatic group (e.g., C 1~4 "Aliphatic", "alkyl" and "heteroaryl" are defined above.

[0048]

[0054] As used herein, a "heteroaralkyl" group refers to an alkyl group substituted with a heteroaryl group (e.g., C 1~4 Both "alkyl" and "heteroaryl" are defined above. Heteroaralkyl refers to a heteroaryl group which may be substituted with one or more substituents such as 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, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkyl ... and optionally substituted with aryloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0049]

[0055] As used herein, "cyclic moiety" and "cyclic group" refer to monocyclic, bicyclic and tricyclic ring systems, including alicyclic, heteroalicyclic, aryl or heteroaryl, each of which are defined previously.

[0050]

[0056] As used herein, "bridged bicyclic ring system" refers to a bicyclic heteroalicyclic ring system or a bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, 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]octyl. 3,7 Bridged bicyclic ring systems include one or more substituents such as 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, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxy ... and optionally substituted with oxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0051]

[0057] As used herein, an "acyl" group refers to a formyl group or R X —C(O)— (e.g., alkyl-C(O)—, also referred to as “alkylcarbonyl”), where R X and "alkyl" is as previously defined. Acetyl and pivaloyl are examples of acyl groups.

[0052]

[0058] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of the aroyl or heteroaroyl are optionally substituted as previously defined herein.

[0053]

[0059] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" is as previously defined herein.

[0054]

[0060] As used herein, a "carbamoyl" group has the structure -O-CO-NR X R Y or -NR X -CO-OR Z In the formula, R X and R Y is defined above, and R Z may be aliphatic, aryl, araliphatic, heteroalicyclic, heteroaryl, or heteroaraliphatic.

[0055]

[0061] As used herein, a "carboxy" group refers to -COOH (when used as a terminal group); or -OC(O)- or -C(O)O- (when used as an internal group).

[0056]

[0062] As used herein, an ester is an ester of -COOR X (when used as an end group); or -COOR X - (when used as an internal group), where R X is defined above.

[0057]

[0063] As used herein, formate refers to -OC(O)H.

[0058]

[0064] As used herein, acetate is defined as -OC(O)R X In the formula, R X is defined above.

[0059]

[0065] As used herein, a "haloaliphatic" group refers to an aliphatic group that is substituted with one to three halogens. For example, the term haloalkyl includes the group -CF3.

[0060]

[0066] As used herein, a "mercapto" or a "sulfhydryl" group refers to --SH.

[0061]

[0067] As used herein, a "sulfo" group refers to -SO3H or -SO3R X (when used terminally) or -S(O)3- (when used internally).

[0062]

[0068] As used herein, a "sulfamide" group has the structure -NR X -S(O)2-NR Y R Z (when used at the terminal end) and -NR X -S(O)2-NR Y - (when used internally), where R X , R Y and R Z is defined above.

[0063]

[0069] As used herein, a "sulfamoyl" group has the structure -OS(O)-NR Y R Z In the formula, R Y and R Z is defined above.

[0064]

[0070] As used herein, a "sulfonamide" group has the structure -S(O)-NR X R Y or -NR X -S(O)2-R Z (when used terminally); or -S(O)2-NR X -or-NR X -S(O)- (when used internally), where R X , RY and R Z is defined above.

[0065]

[0071] As used herein, a "sulfanyl" group is -SR X (when used terminally) and -S- (when used internally), where R X is defined above. Examples of sulfanyl include aliphatic-S-, alicyclic-S-, aryl-S-, and the like.

[0066]

[0072] As used herein, a "sulfinyl" group is -S(O)-R X (when used terminally) and -S(O)- (when used internally), where R X is defined above. Examples of sulfinyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, and / or the like.

[0067]

[0073] As used herein, a "sulfonyl" group is -S(O)-R X (when used terminally) and -S(O)- (when used internally), where R X is defined above. Examples of sulfonyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic(aliphatic))-S(O)-, cycloaliphatic-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, (alicyclic(amido(aliphatic)))-S(O)-, and / or the like.

[0068]

[0074] As used herein, a "sulfoxy" group is -OS(O)-R X Or -S(O)-OR X (when used terminally) and -OS(O)- or -S(O)-O- (when used internally), wherein R X is defined above.

[0069]

[0075] As used herein, a "halogen" or "halo" group refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0070]

[0076] As used herein, "alkoxycarbonyl," encompassed by the term carboxy, used alone or in conjunction with another group, refers to groups such as alkyl-OC(O)-.

[0071]

[0077] As used herein, "alkoxyalkyl" refers to an alkyl group, such as alkyl-O-alkyl-, where alkyl is defined above.

[0072]

[0078] As used herein, "carbonyl" refers to --C(O)--.

[0073]

[0079] As used herein, "oxo" refers to =O.

[0074]

[0080] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(R P )2, wherein R P is aliphatic, alkoxy, aryloxy, heteroaryloxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryl, heteroaryl, alicyclic or amino.

[0075]

[0081] As used herein, an “aminoalkyl” refers to a group having the structure (R X )2N-alkyl-.

[0076]

[0082] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0077]

[0083] As used herein, a "urea" group has the structure -NR X -CO-NR Y R Z A "thiourea" group has the structure -NRX -CS-NR Y R Z (when each is used at the terminal) and -NR X -CO-NR Y -OR-NR X -CS-NR Y - (when each is used internally), where R X , R Y and R Z is defined above.

[0078]

[0084] As used herein, a "guanidine" group has the structure -N=C(N(R X R Y ))N(R X R Y ) or -NR X -C(=NR X )NR X R Y In the formula, R X and R Y is defined above.

[0079]

[0085] As used herein, the term "amidino" group refers to a group having the structure -C=(NR X )N(R X R Y ), where R X and R Y is defined above.

[0080]

[0086] As used herein, the term "vicinal" generally refers to the arrangement of substituents on a group containing two or more carbon atoms, where the substituents are attached to adjacent carbon atoms.

[0081]

[0087] As used herein, the term "geminal" generally refers to the arrangement of substituents on a group that includes two or more carbon atoms, where the substituents are attached to the same carbon atom.

[0082]

[0088] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when it is at the end of a substituent that is not further attached to the remainder of the chemical structure. Carboxyalkyl (i.e., R X An example of a carboxy group used terminally is alkyl-C(O)O- or alkyl-OC(O)-. An example of a carboxy group used terminally is alkyl-C(O)O- or alkyl-OC(O)-. An example of a carboxy group used internally is alkyl-C(O)O- or alkyl-OC(O)-. An example of a carboxy group used internally is alkyl-C(O)O- or alkyl-O(CO)-aryl-.

[0083]

[0089] As used herein, "aliphatic chain" refers to a branched or linear aliphatic group (e.g., an alkyl, alkenyl, or alkynyl group). A linear aliphatic chain has the structure -[CH] v - (wherein v is 1 to 12). A branched aliphatic chain is a linear 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. However, Q should be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains, where alkyl, alkenyl and alkynyl are defined above.

[0084]

[0090] The phrase "optionally substituted" is used interchangeably herein with the phrase "substituted or unsubstituted." As described herein, the compounds herein can be optionally substituted with one or more substituents, as generally exemplified above or as exemplified by the specific classes, subclasses and species described herein. As described herein, the variables R, R 1 , R 2 The variables R, L, Y, and Z, as well as other variables contained in formulae A-X or I-IV described herein, include specific groups, such as alkyl and aryl. 10 , RA , R 1 , R 2 , L, L 1 Each of the specific groups for A, D, W, E, V, G, Y, and Z, as well as the other variables contained therein, can be optionally substituted with one or more of the substituents described herein. Each of the substituents of the specific groups is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, alicyclic, heteroalicyclic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group can be substituted with an alkylsulfanyl, which can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are attached to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atoms to which they are attached.

[0085]

[0091] As used herein, the term "substituted", whether preceded by the term "optionally" or not, generally refers to the replacement of a hydrogen atom in a given structure with a specified substituent group. Specific substituents are described in the definition above and in the compound description and examples below. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when multiple positions in any given structure can be substituted with multiple substituents selected from a specified group, the substituents can be the same or different at all positions. A ring substituent, such as a heterocycloalkyl, can be bonded to another ring, such as a cycloalkyl, to form a spiro bicyclic ring system, e.g., both rings share one common atom. Non-limiting examples of spiro heterocycloalkyl are: [ka] Includes.

[0086]

[0092] As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this description are those combinations that result in the formation of stable or chemically feasible compounds.

[0087]

[0093] As used herein, the phrase "stable or chemically feasible" refers to compounds that do not change substantially when subjected to conditions that permit their production, detection, and their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not change substantially when kept at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0088]

[0094] As used herein, "effective amount" is defined as the amount required to provide a therapeutic effect to the treated patient, and is typically determined based on the age, surface area, weight and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area can be roughly determined from the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0089]

[0095] As used herein, the term "about" means within ±10% of a value. For example, a dose of about 100 mg / kg would realize that the dose could be 90 mg / kg to 110 mg / kg. As a further example, an amount of additional therapeutic agent in the range of about 50% to about 100% would realize that the amount of additional therapeutic agent ranges from 45-55% to 90-110%. When used to describe other values ​​described herein, one of skill in the art would recognize the range and application of the term "about."

[0090]

[0096] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, (R)- and (S)-configurations, (Z)- and (E)-double bond isomers, and (Z)- and (E)-conformer isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of this description. Alternatively, as used herein, "enantiomeric excess (ee)" refers to a dimensionless molar ratio that describes the purity of, for example, a chiral material containing a single asymmetric center. For example, an enantiomeric excess of 0 indicates a racemic (e.g., a 50:50 mixture of enantiomers or no excess of one enantiomer over the other). As a further example, an enantiomeric excess of 99 indicates a nearly stereochemically pure enantiomeric compound (i.e., a large excess of one enantiomer over the other). Enantiomeric excess, 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, "diastereomeric excess (de)" refers to a dimensionless molar ratio that describes the purity of a chiral substance that contains multiple asymmetric centers. For example, a diastereomeric excess of 0 indicates an equimolar mixture of diastereoisomers. As a further example, a diastereomeric excess of 99 indicates a nearly stereochemically pure diastereomeric compound (i.e., a large excess of one diastereomer over the other). Diastereomeric excess may be calculated in a similar manner as ee. As one of ordinary skill in the art will recognize, de is usually reported as de percent (de%). de% may be calculated in a similar manner as ee%.

[0091]

[0097] In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% of greater than 0. For example, in certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% of 10. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% of 25. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% of 50. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% of 75.

[0092]

[0098] In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% range of 90-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% range of 95-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% range of 97-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% range of 98-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, ee% or de% range of 99-100.

[0093]

[0099] 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, the 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% or de% is 36. In one embodiment of the compounds or inhibitors described herein, ee, de, ee% or de% is 37. 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, the ee, de, ee% or de% is 39. In one embodiment of the compounds or inhibitors described herein, the 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 a compound or inhibitor described herein, ee, de, ee% or de% is 50. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 51. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 52. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 53. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 54. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 55. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 56. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 57. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 58. In one embodiment of the compounds or inhibitors described herein, the ee, de, ee% or de% is 59. In one embodiment of the compounds or inhibitors described herein, the 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 one embodiment of the compounds or inhibitors described herein, 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, the ee, de, ee% or de% is 79. In one embodiment of the compounds or inhibitors described herein, the ee, de, ee% or de% is 80.In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 81. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 82. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 83. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 84. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 85. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 86. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 87. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 88. In one embodiment of a compound or inhibitor 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, the ee, de, ee% or de% is 99. In one embodiment of the compounds or inhibitors described herein, the ee, de, ee% or de% is 100.In certain embodiments, the compounds or inhibitors described in Table 1 herein have ee, de, ee% or de% as described in this paragraph. In certain embodiments, any of compounds 1-22 as described in the Examples and / or Biological Examples have ee, de, ee% or de% as described in this paragraph. Unless otherwise stated, all tautomeric forms of the compounds described herein are within the scope of this description. Additionally, unless otherwise stated, structures depicted herein may contain one or more isotopic variations. The term also means to include compounds which differ only in the presence of an atom enriched in the 13 C- or 14 Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this description. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0094]

[0100] As used herein, the term "&1" means that a compound containing the "&1" designation at a particular chemical element or atom (e.g., carbon) within the compound was prepared as a mixture of two stereoisomers at the noted chemical element or atom (e.g., a diastereomeric mixture having de or de % as described above).

[0095]

[0101] Chemical structures and nomenclature are obtained from ChemDraw, version 11.0.1, Cambridge, MA.

[0096]

[0102] It should be noted that the use of the descriptors "first," "second," "third," etc. is used to distinguish separate elements (e.g., solvents, reaction steps, processes, reagents, etc.) and may or may not refer to the relative order or relative chronological order of the described elements.

[0097] Uses of the Compounds and Compositions

[0103] Bifunctional compounds that degrade BTK have been previously described, for example, in PCT / US2019 / 56112, filed October 14, 2019, published as WO 2020 / 081450 (April 23, 2020), and PCT / US2020 / 063176, filed December 3, 2020, published as WO 2021 / 113557 (June 10, 2021), each of which is incorporated by reference in its entirety. Many of these BTK degraders have been found to have little or mixed IMiD activity. In contrast, in some embodiments, the bifunctional compounds described herein are useful for degrading BTK in biological samples or patients with enhanced IMiD activity. Thus, one embodiment of the present disclosure provides a method of treating a BTK-mediated disease or disorder. As used herein, the term "BTK-mediated disease or disorder" refers to any disease, disorder, or other deleterious condition in which BTK is known to play a role. Optionally, the BTK-mediated disease or disorder is a proliferative disorder. Examples of proliferative disorders include cancer, such as B-cell malignancies.

[0098]

[0104] The IMiD activity of a compound can be measured by any technique deemed appropriate by the skilled artisan. In certain embodiments, the IMiD activity is measured as Aiolos degradation. In certain embodiments, the IMiD activity is measured as Ikaros degradation. In certain embodiments, the IMiD activity is measured as IL2 activation. In certain embodiments, the IMiD activity is measured as any combination thereof. In certain embodiments, the IMiD activity is measured in vivo. In certain embodiments, the IMiD activity is measured in vitro, for example in a cell-based assay.

[0099]

[0105] In certain embodiments, the IMiD activity of the compound is at least 50% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 60% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 70% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 75% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 80% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 90% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is at least 100% of the IMiD activity of the reference compound. In certain embodiments, the reference compound is thalidomide, lenalidomide, or pomalidomide. In certain embodiments, the activity is measured by IC 50 , or EC 50 , or DC 50 In certain embodiments, activity is measured as D max In certain embodiments, activity is measured by Western blot.

[0100]

[0106] In certain embodiments, the maximum degradation of Aiolos under physiological conditions is greater than 50%, 60%, 70%, 75%, 80%, 85% or 90%. In certain embodiments, the maximum degradation of Ikaros under physiological conditions is greater than 50%, 60%, 70%, 75%, 80%, 85% or 90%.

[0101]

[0107] In these methods, the compound comprises a moiety capable of specifically binding BTK and further comprises a moiety capable of recruiting ubiquitin ligase to degrade BTK. Certain compounds are described herein. The compounds can be administered in any form, including pharma- ceutically acceptable salts and pharmaceutical compositions.

[0102]

[0108] The enhanced IMiD activity may result in the compounds described herein having increased immunomodulatory activity compared to other BTK degrading compounds, which may result in enhanced treatment or prevention of certain cancers, such as B-cell malignancies.

[0103]

[0109] In certain embodiments, the compound is administered for up to 14 days. In certain embodiments, the compound is administered for at least 15 days, at least 20 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or longer.

[0104]

[0110] In the dosing schedule, the doses can be administered on consecutive days or periodically, as determined by one of skill in the art. In certain embodiments, the doses are administered on consecutive days. In certain embodiments, the doses are administered with an interval between the 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.

[0105]

[0111] In certain embodiments, the frequency of chronic administration is daily. In certain embodiments, the frequency of chronic administration is twice a day. In certain embodiments, the frequency of chronic administration is three times a day. In certain embodiments, the frequency of chronic administration is four times a day. In certain embodiments, the frequency of chronic administration is once a week. In certain embodiments, the frequency of chronic administration is twice a week.

[0106]

[0112] In certain embodiments, the doses are administered for a period of time with a first interval between doses, and then the doses are re-administered for a period of time following the first interval between doses, and this dosing regimen can be repeated (i.e., periodically or cyclically, e.g., after a second, third, etc. interval between administration of subsequent doses) as determined by the skilled artisan. For example, in one embodiment, the first dose is administered for one week, followed by a first interval of one week without administration of the first dose; then the second dose is re-administered for another week, followed by a second interval of one week without administration of the first or second dose, and so on (cyclically). Other variations in the first, second, third, etc. doses, followed by variations in the first, second, third, etc. intervals, and combinations thereof, are contemplated herein as recognized by the skilled artisan and the needs of 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 first daily dose administration; then a second dose is re-administered twice weekly for another week, followed by a second interval of four weeks without the first daily dose administration or the second twice weekly dose administration, etc. (cyclical).

[0107]

[0113] The compound may be administered at any dose deemed appropriate by one of skill in the art. In certain embodiments, the dose is 0.1-1000 mg / kg. In certain embodiments, the dose is 0.1-900 mg / kg. In certain embodiments, the dose is 0.1-800 mg / kg. In certain embodiments, the dose is 0.1-700 mg / kg. In certain embodiments, the dose is 0.1-600 mg / kg. In certain embodiments, the dose is 0.1-500 mg / kg. In certain embodiments, the dose is 0.1-400 mg / kg. In certain embodiments, the dose is 0.1-300 mg / kg. In certain embodiments, the dose is 0.1-200 mg / kg. In certain embodiments, the dose is 0.1-100 mg / kg.

[0108]

[0114] In certain embodiments, the dose is 100-600 mg / kg. In certain embodiments, the dose is 200-600 mg / kg. In certain embodiments, the dose is 250-600 mg / kg. In certain embodiments, the dose is 300-600 mg / kg. In certain embodiments, the dose is selected from the group consisting of 50 mg / kg, 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 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 about 250 mg / kg. In certain embodiments, the dose is about 300 mg / kg. In certain embodiments, the dose is about 400 mg / kg. In certain embodiments, the dose is about 450 mg / kg. In certain embodiments, the dose is about 500 mg / kg. In certain embodiments, the dose is about 600 mg / kg. In certain embodiments, the dose is about 700 mg / kg. In certain embodiments, the dose is about 750 mg / kg. In certain embodiments, the dose is about 800 mg / kg. In certain embodiments, the dose is about 900 mg / kg. In certain embodiments, the dose is about 1000 mg / kg.

[0109]

[0115] In certain embodiments, the dose is selected from 100 mg, 200 mg, and 300 mg. In certain embodiments, the dose is 100 mg. In certain embodiments, the dose is 200 mg. In certain embodiments, the dose is 300 mg.

[0110]

[0116] The compounds can be administered by any route of administration deemed appropriate by one of skill in the art. In certain embodiments, the dose is administered orally. Formulations and techniques for administration are described in detail below.

[0111]

[0117] In one aspect, provided herein is a method of treating or preventing cancer in a subject in need thereof. In certain embodiments, the method comprises orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, the amount is effective to treat or prevent cancer.

[0112]

[0118] In certain embodiments, the cancer is any cancer described below. In certain embodiments, the cancer comprises a solid tumor. In certain embodiments, the cancer is a B-cell malignancy. In certain embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter's transformation, small cell lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM) and central nervous system (CNS) lymphoma. In certain embodiments, 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's 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 Waldenstrom's macroglobulinemia. In certain embodiments, the cancer is small lymphocytic lymphoma (SLL). In certain embodiments, the cancer is CNS lymphoma. In certain embodiments, the cancer is transformed CLL or Richter's transformation.

[0113]

[0119] In certain embodiments, the subject has a mutated Bruton's tyrosine kinase. In certain embodiments, the subject has a C481 mutated Bruton's tyrosine kinase. In certain embodiments, the subject has a C481S mutated 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 C481 mutated Bruton's tyrosine kinase, for example C481S Bruton's tyrosine kinase. For example, in certain embodiments, the subject has a C481 mutated Bruton's tyrosine kinase and the cancer is chronic lymphocytic leukemia (CLL).

[0114]

[0120] In certain embodiments, the compounds described herein can treat patients with ibrutinib-resistant cancer. In certain embodiments, the subject has a C481S, L528W, M437R or V416L mutant Bruton's tyrosine kinase. In certain embodiments, the subject has a C481S mutant Bruton's tyrosine kinase. In certain embodiments, the subject has a L528W mutant Bruton's tyrosine kinase. In certain embodiments, the subject has a M437R mutant Bruton's tyrosine kinase. In certain embodiments, the subject has a V416L mutant Bruton's tyrosine kinase.

[0115]

[0121] In certain embodiments, the compounds described herein can treat patients having a disease selected from the group consisting of Waldenstrom's macroglobulinemia, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), DLBCL, follicular lymphoma, and chronic lymphocytic leukemia. In certain embodiments, the disease is Waldenstrom's macroglobulinemia. In certain embodiments, the disease is marginal zone lymphoma (MZL). In certain embodiments, the disease is mantle cell lymphoma (MCL). In certain embodiments, the disease is DLBCL. In certain embodiments, the disease is follicular lymphoma. In certain embodiments, the disease is chronic lymphocytic leukemia.

[0116]

[0122] In certain embodiments, the compounds described herein can treat patients with a disease or disorder selected from the group consisting of chronic lymphocytic leukemia (CLL) with BTK C481 mutation; CLL without BTK C481 mutation; mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM); follicular lymphoma (FL); and diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the disease or disorder is chronic lymphocytic leukemia (CLL) with BTK C481 mutation. In certain embodiments, the disease or disorder is CLL without BTK C481 mutation. In certain embodiments, the disease or disorder is mantle cell lymphoma (MCL). In certain embodiments, the disease or disorder is marginal zone lymphoma (MZL). In certain embodiments, the disease or disorder is Waldenstrom's macroglobulinemia (WM). In certain embodiments, the disease or disorder is follicular lymphoma (FL). In certain embodiments, the disease or disorder is diffuse large B-cell lymphoma (DLBCL).

[0117]

[0123] In another aspect, provided herein are methods of degrading Bruton's tyrosine kinase in a subject in need thereof. These methods include orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, the amount is effective to degrade Bruton's tyrosine kinase in the subject. Bruton's tyrosine kinase can be expressed in any cell or tissue 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.

[0118]

[0124] In certain embodiments, the Bruton's tyrosine kinase is mutated. In certain embodiments, the Bruton's tyrosine kinase comprises a C481 mutation. In certain embodiments, the Bruton's tyrosine kinase comprises a C481S mutation. In certain embodiments, the Bruton's tyrosine kinase is resistant to ibrutinib.

[0119]

[0125] In another aspect, provided herein are methods of preventing B cell activation in a subject in need thereof. These methods include orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, the amount is effective to prevent 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 CD69 and CD86.

[0120]

[0126] In another aspect, provided herein are methods for degrading mutant Bruton's tyrosine kinase. These methods include contacting a cell expressing mutant Bruton's tyrosine kinase with an amount of a bifunctional compound capable of inducing proteolysis of Bruton's tyrosine kinase. In certain embodiments, the amount is effective to degrade mutant Bruton's tyrosine kinase. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481 mutation. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481S mutation.

[0121]

[0127] In certain embodiments, the term "cancer" includes, but is not limited to, the following cancers: oral epidermoid: oral cavity, lip, tongue, mouth, pharynx, head and neck squamous cell carcinoma (HNSCC); cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), bronchioloalveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, non-small cell lung carcinoma (NSCLC); Gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectum, microsatellite stable colorectal cancer (MSS CRC), rectum; genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), metastatic castration-resistant prostate cancer (mCRPC), muscle-invasive urothelial carcinoma; liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocyte tumors, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma (MM), malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, cervical adenocarcinoma, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), Breast, Triple-negative breast cancer (TNBC), Platinum-resistant epithelial ovarian cancer (EOC); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple bone marrow tumors, Myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell; lymphatic system disorders (e.g., mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dendritic nevus, lipoma, hemangioma, dermatofibroma, keloid, 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.

[0122]

[0128] In certain embodiments, the cancer is a B cell malignancy. In certain embodiments, the B cell malignancy is diffuse large B cell lymphoma (DLBCL). In certain embodiments, the B cell malignancy is mediastinal B cell lymphoma. In certain embodiments, the B cell malignancy is follicular lymphoma. In certain embodiments, the B cell malignancy is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). In certain embodiments, the B cell malignancy is mantle cell lymphoma (MCL). In certain embodiments, the B cell malignancy is marginal zone lymphoma. In certain embodiments, the B cell malignancy is extranodal marginal zone B cell lymphoma. In certain embodiments, the B cell malignancy is nodal marginal zone B cell lymphoma. In certain embodiments, the B cell malignancy is Burkitt's lymphoma. In certain embodiments, the B cell malignancy is lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia). In certain embodiments, the B cell malignancy is hairy cell leukemia. In certain embodiments, the B cell malignancy is primary central nervous system (CNS) lymphoma. In certain embodiments, the B cell malignancy is primary intraocular lymphoma.

[0123]

[0129] In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is myelodysplastic syndrome. In certain embodiments, the cancer is Kaposi's sarcoma.

[0124]

[0130] In certain embodiments, the disease or disorder is graft-versus-host disease (GVHD).

[0125]

[0131] In certain embodiments, provided herein are methods of degrading mutant Bruton's tyrosine kinase. These methods include contacting a cell expressing a mutant Bruton's tyrosine kinase with an amount of a bifunctional compound capable of inducing proteolysis of the Bruton's tyrosine kinase. In certain embodiments, the amount of the bifunctional compound capable of inducing proteolysis of the Bruton's tyrosine kinase is an amount effective to degrade the mutant Bruton's tyrosine kinase. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481 mutation. In certain embodiments, the mutant Bruton's tyrosine kinase is a C481S mutation. The contacting can be in vitro or in vivo. In certain embodiments, the contacting is in vitro. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in a subject in need thereof.

[0126] compound

[0132] The methods provided herein include administration of a compound. The compound can be any compound described herein. In certain embodiments, the compound includes at least two moieties. One moiety can specifically bind Bruton's tyrosine kinase (BTK). The other moiety can recruit a ubiquitin ligase and degrade BTK. In certain embodiments, the ubiquitin ligase is an E3 ligase. In certain embodiments, the ubiquitin ligase is cereblon (CRBN) or includes cereblon as a component.

[0127]

[0133] In these methods, the compound is of formula (A1) [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; D is a bond or a linker; ring A is aryl or heteroaryl; ring B is aryl or heteroaryl; L is a bond or a linker; and Y is a moiety capable of binding a ubiquitin ligase.

[0128]

[0134] In these methods, the compound is of formula (A) [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; D is a bond or -NH-; Ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of Ring A each have 1-3 heteroatoms independently selected from N, O or S, and Ring A is selected from halo, -CN, -COOH, NH2 and optionally substituted C 1~6 Ring B is optionally substituted with up to 3 substituents selected from alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, Ring B is optionally substituted, and the heteroaryl and heterocycloalkyl 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 -X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, 7-12 membered spiro or fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 Each of the monocyclic and bicyclic heterocycloalkyls is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n-, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~8 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p X is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O or S; 5 is a bond, -C 1~4 alkyl-, -N(R)-, -O-, -C(O)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl (e.g., methyl, ethyl, propyl, or iso-propyl); and each of m, n, and p is independently an integer from 1 to 3 (e.g., 1, 2, or 3); and Y is [ka] wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl, or NH2.

[0129]

[0135] All moieties of the linking group L as defined for compounds of formula (A), except for the moieties of the group R, are divalent moieties unless otherwise specified. For example, any alkyl (e.g., n-propyl, n-butyl, n-hexyl, etc.), aryl (e.g., phenyl), cycloalkyl (e.g., cyclopropyl, cyclohexyl, etc.), heteroaryl, heterocycloalkyl (e.g., piperidine, piperazine, etc.) present in L are divalent unless otherwise specified.

[0130]

[0136] In some embodiments, Ring B is an optionally substituted 5-6 membered heterocycloalkyl having 1-2 nitrogen atoms, e.g., Ring B is piperidin-yl, piperidin-yl, or pyrrolidin-yl, any of which is optionally substituted.

[0131]

[0137] In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from N and S. For example, Ring B is pyridin-yl, pyrazin-yl, or pyrimidine, any of which is optionally substituted.

[0132]

[0138] In some embodiments, Ring B is [ka] and R 10 is halo, -H, -C 1~5 Alkyl (e.g., -C 1~3 alkyl), 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH, [ka] It is.

[0133]

[0139] In some embodiments, Ring B is [ka] and R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is [ka] and R 10 teeth, [ka] Optionally, ring B is [ka] In other cases, R 10 teeth, [ka] It is.

[0134]

[0140] In some embodiments, ring A is [ka] and ring A' together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic aryl or a 9-10 membered bicyclic heteroaryl, the bicyclic heteroaryl (i.e. the bicyclic heteroaryl containing ring A') having 1-3 heteroatoms independently selected from N, O or S. For example, ring A can be [ka] It is.

[0135]

[0141] In some embodiments, X 1 , X 2 and X 5 At least one of is -N(R)-, -C(O)-N(R)-, or -CH2-.

[0136]

[0142] In some embodiments, X 1 is -C(O)-N(R)-.

[0137]

[0143] In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n -or-C 1~5 It is alkyl-.

[0138]

[0144] In some embodiments, X 3 is a bond, [ka] , -C 1~4 It is alkyl- or -N(R)-.

[0139]

[0145] In some embodiments, X 4 is a bond, -CH2- or -N(R)-.

[0140]

[0146] In some embodiments, X 5 is a bond.

[0141]

[0147] In some embodiments, X 1 is -(O-CH2-CH2-CH2) m m is 1 and X 2 is -C(O)-N(R)-.

[0142]

[0148] In some embodiments, X 1 -CH2-, -C(O)-, [ka] It is.

[0143]

[0149] In some embodiments, X 2 is a bond, -C(O)-, -C 1~5 Alkyl-, [ka] It is.

[0144]

[0150] In some embodiments, X 3 is a bond, -C 1~4 It is alkyl-, 4- to 6-membered cycloalkyl or -N(R)-.

[0145]

[0151] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -NH-, [ka] It is.

[0146]

[0152] In some embodiments, X 4 is a bond, [ka] , -C 1~4 Alkyl-, -CH2-CH2-N(R)- or -N(R)-.

[0147]

[0153] In some embodiments, X 5 is a bond, -C 1~4 Alkyl-, -N(R)- or -C(O)-N(R)-.

[0148]

[0154] In some embodiments, L is [ka] [ka] [ka] [ka] It is.

[0149]

[0155] In some embodiments, Y is [ka] wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl, or NH2.

[0150]

[0156] In some embodiments, Y is [ka] wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl, or NH2.

[0151]

[0157] The present disclosure relates to a compound of formula (B): [ka] or a pharma- ceutically acceptable salt thereof, wherein 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 spiro bicyclic heterocycle, Ring B1 having 1-3 heteroatoms independently selected from N, O or S and optionally substituted with halo, -CH3, -CF3, -C(O)OH, -CH2OH or oxo, and optionally substituted with 1-3 groups selected from 5 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N or O; L is -X 1 -X 2 -X 3 -X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5alkyl-, 7-12 membered spiro or fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 Each of the monocyclic and bicyclic heterocycloalkyls is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p and R is independently -H or -C. 1~3 alkyl; each of m, n, and p is independently an integer from 1 to 3; and Y is as defined above.

[0152]

[0158] In some embodiments, ring B1 is [ka] and ring B1 is -CH3, -CH2OH, -CH2CH2OH, -C(O)OH, -CF3, -F, [ka] For example, ring B1 is optionally substituted with 1 to 3 groups selected from [ka] In another example, ring B1 is [ka] It is.

[0153]

[0159] In some embodiments, X 1 teeth, [ka] It is.

[0154]

[0160] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond, -C 1~3 Alkyl-, -C(O)-, [ka] It is.

[0155]

[0161] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3. For example, X 3 is a bond, [ka] It is.

[0156]

[0162] In some embodiments, L is [ka] It is.

[0157]

[0163] In some embodiments, W is N and D is a bond.

[0158]

[0164] The present disclosure relates to a compound of formula (C) [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; ring C is phenyl or a saturated, partially unsaturated or fully unsaturated 5-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O or S, each of the phenyl and heterocycle of ring C being optionally substituted; and L is -X 1 -X 2 -X 3 -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 alkyl-, 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 Each of the bicyclic heterocycloalkyl and monocyclic heterocycloalkyl is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p and R is independently -H or -C. 1~3 alkyl; and each of m, n, and p is independently an integer from 1 to 3.

[0159]

[0165] In some embodiments, W is N.

[0160]

[0166] In some embodiments, Ring C is [ka] For example, ring C is [ka] In another example, ring C is [ka] It is.

[0161]

[0167] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 1 teeth, [ka] In some cases, X 1 teeth, [ka] It is.

[0162]

[0168] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~3 Alkyl- (e.g., -CH2-).

[0163]

[0169] In some embodiments, X 3 is a 4- to 6-membered cycloalkyl, -N(R)-, or a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, the heterocycloalkyl being optionally substituted with -CH3. For example, X 3 teeth, [ka] In another embodiment, X 3 teeth, [ka] It is.

[0164]

[0170] In some embodiments, L is [ka] For example, L is [ka] It is.

[0165]

[0171] The present disclosure relates to a compound of formula (D) [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; ring A is [ka] and L is -X1 -X 2 -X 3 -X 1 -C 1~5 alkyl- or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; X 1 is optionally substituted with -CH; 2 is a bond, -C 1~5 alkyl- or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; X 1 is optionally substituted with -CH; 3 is a bond, -C 1~4 alkyl-, 4-6 membered monocyclic cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; Y is as described herein; R 10 is halo, -H, -C 1~5 Alkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH, [ka] It is.

[0166]

[0172] In some embodiments, ring A is [ka] It is.

[0167]

[0173] In some embodiments, X 1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; 1 The monocyclic heterocycloalkyl of the formula: is optionally substituted with -CH3. For example, X 1 teeth, [ka] It is.

[0168]

[0174] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0169]

[0175] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] It is.

[0170]

[0176] In some embodiments, L is [ka] It is.

[0171]

[0177] In some embodiments, R 10 is halo, -H, -C 1~5 Alkyl (e.g., -C 1~3 alkyl), 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, -CN, -OH, -CF, -CHOH, -C(O)OH, or -CHCHOH. For example, R 10 is halo, -H, C 1~3 alkyl, CF, -CHOH, -C(O)OH or -CHCHOH. In other cases, R 10 teeth, [ka] It is.

[0172]

[0178] In some embodiments, R 10 teeth, [ka] It is.

[0173]

[0179] In some embodiments, R 10 teeth, [ka] It is.

[0174]

[0180] In some embodiments, the compound of formula (D) is (D-1): [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; ring A is [ka] and L is -X 1 -X 2 -X 3 -X 1 -C 1~5 alkyl- or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; X 1 is optionally substituted with -CH; 2 is a bond, -C 1~5 alkyl- or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; X 1 is optionally substituted with -CH; 3 is a bond, -C 1~4alkyl-, 4-6 membered monocyclic cycloalkyl, or 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; Y is as described herein; R 10 teeth, [ka] It is.

[0175]

[0181] In some embodiments, ring A is [ka] It is.

[0176]

[0182] In some embodiments, X 1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; 1 The monocyclic heterocycloalkyl of is optionally substituted with -CH3. For example, X 1 teeth, [ka] It is.

[0177]

[0183] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0178]

[0184] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] It is.

[0179]

[0185] In some embodiments, L is [ka] It is.

[0180]

[0186] In some embodiments, R 10 teeth, [ka] It is.

[0181]

[0187] In some embodiments, R 10 teeth, [ka] It is.

[0182]

[0188] In some embodiments, the compound of formula (D) or the compound of formula (D-1) has the formula (D-2): [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, L, Y and R 10 The term is as defined for compounds of formula (A), compounds of formula (D) and compounds of formula (D-1).

[0183]

[0189] In some embodiments, ring A is [ka] It is.

[0184]

[0190] In some embodiments, X 1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; 1The monocyclic heterocycloalkyl of the formula: is optionally substituted with -CH3. For example, X 1 teeth, [ka] It is.

[0185]

[0191] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0186]

[0192] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] It is.

[0187]

[0193] In some embodiments, L is [ka] It is.

[0188]

[0194] In some embodiments, R 10 teeth, [ka] It is.

[0189]

[0195] In some embodiments, R 10 teeth, [ka] It is.

[0190]

[0196] The present disclosure relates to a compound of formula (E) [ka] or a pharma- ceutically acceptable salt thereof, wherein D is a bond or -NH-; W is N or CH; ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O, or S; ring B is an optionally substituted 5-6 membered saturated, partially or fully unsaturated monocyclic heterocycle or an optionally substituted 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, wherein ring B has 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 Each of the monocyclic and bicyclic heterocycloalkyls is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p X is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O or S; 5 is a bond, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 each of m, n, and p is independently an integer from 1 to 3; Y is as described herein, and X 1 , X 2 , X 3 , X 4 and X 5 At least one of X has a nitrogen atom, and Y is 1 , X 2 , X 3 , X 4 Or X 5 is bonded directly to L at the nitrogen atom of

[0191]

[0197] In some embodiments, Ring B is [ka] and R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is [ka] and R 10 teeth, [ka] In another example, ring B is [ka] It is.

[0192]

[0198] In some embodiments, R 10 teeth, [ka] It is.

[0193]

[0199] In some embodiments, ring A is [ka] It is.

[0194]

[0200] In some embodiments, X 5 is -N(R)-.

[0195]

[0201] In some embodiments, X 5 is -C(O)-N(R)-.

[0196]

[0202] In some embodiments, X 5 is a bond.

[0197]

[0203] In some embodiments, L is [ka] [ka] [ka] It is.

[0198]

[0204] The present disclosure relates to a compound of formula (F) [ka] or a pharma- ceutically acceptable salt thereof, wherein W is CH or N; L is -X 1 -X 2 -X 3 -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 alkyl-, 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 Each of the monocyclic and bicyclic heterocycloalkyls is optionally substituted with -CH3; 2 is a bond, -C 1~5 Alkyl-, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p-, -(CH2-CH2-O) p and R is independently -H or -C. 1~3 is alkyl; each of m, n, and p is independently an integer from 1 to 3; and Y is as described herein.

[0199]

[0205] In some embodiments, W is N.

[0200]

[0206] In some embodiments, X 1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; 1 Each of the monocyclic heterocycloalkyls is optionally substituted with -CH3. For example, X 1 teeth, [ka] In some cases, X 1 teeth, [ka] It is.

[0201]

[0207] In some embodiments, X 2 is a bond or -C 1~5 It is alkyl-.

[0202]

[0208] In some embodiments, X 3 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] In some cases, X 3 teeth, [ka] It is.

[0203]

[0209] In some embodiments, L is [ka] It is.

[0204]

[0210] In some embodiments, L is [ka] It is.

[0205]

[0211] In some embodiments, W is N; L is [ka] It is.

[0206]

[0212] The present disclosure relates to a compound of formula (G) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , L and Y are as defined for compounds of formula (A).

[0207]

[0213] In some embodiments, R 1 is methyl.

[0208]

[0214] In some embodiments, W is N.

[0209]

[0215] The present disclosure relates to a compound of formula (M) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 10A is -H, [ka] and R 1 is C 1~4 is alkyl; X 1 -C 1~5 alkyl-; Ring C-1 is a 5-6 membered heterocycloalkyl having one nitrogen atom; and Y is as described herein.

[0210]

[0216] In some embodiments, R 10A is -H, or [ka] It is.

[0211]

[0217] In some embodiments, R 10A teeth, [ka] and R 1 is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl or iso-butyl. For example, R 1 is methyl.

[0212]

[0218] In some embodiments, X 1 is methylene (-CH2-), ethylene (-CH2CH2-) or propylene (-CH2CH2CH2-). For example, X 1 is methylene (-CH2-).

[0213]

[0219] In some embodiments, ring C-1 is [ka] For example, ring C-1 is [ka] It is.

[0214]

[0220] The present disclosure relates to a compound of formula (X) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 ring A is phenyl, a 5- to 6-membered partially or fully unsaturated monocyclic heterocycle, a 9- to 10-membered bicyclic aryl, or a 9- to 10-membered bicyclic heteroaryl, each of which independently has 1 to 3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -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 is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O or S; 1 is optionally substituted with -CH3 or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S; 1 is optionally substituted with -CH; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered monocyclic cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, [ka] , 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) pX is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5-6 membered saturated, partially unsaturated or fully unsaturated carbocyclic ring having 0 to 3 heteroatoms independently selected from N, O or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; each of m, n, and p is independently an integer from 1 to 3; Y is as described herein, and each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 alkyl; and q is 0, 1 or 2.

[0215]

[0221] Optionally, the compound of formula (X) is a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; ring A is phenyl, a 9-10 membered bicyclic aryl, or a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -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 X is a 7-12 membered spiro bicyclic 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 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p X is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 each of m, n, and p is independently an integer from 1 to 3 (e.g., 1, 2, or 3); Y is as described herein, and each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C1~4 alkyl; and q is 0, 1 or 2.

[0216]

[0222] In some embodiments, q is 0. In other embodiments, q is 1 and R 2 is -F.

[0217]

[0223] In some embodiments, Z is -CH2- or -C(O)-.

[0218]

[0224] In some embodiments, R 1 -C 1~3 For example, R 1 is methyl, ethyl, propyl, or iso-propyl. 1 is methyl.

[0219]

[0225] In some embodiments, each R is independently -H or -CH. For example, each R is -H.

[0220]

[0226] In some embodiments, 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 In some embodiments, X is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. 1 is -C(O)-N(R)-. For example, X 1 is -C(O)-N(H)-, -C(O)-N(CH)-, or -C(O)-N(CHCH)-. In other embodiments, X 1is a 5-6 membered 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, [ka] In another example, X 1 is a 7-10 membered spiro bicyclic heterocycloalkyl ring having 1-3 heteroatoms (e.g., N) independently selected from N, O, or S. For example, X 1 teeth, [ka] In another embodiment, X 1 is -(O-CH2-CH2) m -or-(O-CH2-CH2-CH2) m - (wherein m is 1, 2, or 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 -C 1~5 For example, X 1 is methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), etc. In some embodiments, X 1 -CH2-, -C(O)-, [ka] It is.

[0221]

[0227] In some embodiments, X 2 is the bond, -(O-CH2-CH2) n-, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. In some embodiments, X 2 is a bond. In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n -or-C 1~5 alkyl- (wherein n is 1, 2 or 3). For example, X 1 is -C(O)-N(R)-, and X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n -or-C 1~5 In some instances, X is an alkyl group. 2 is -(O-CH2-CH2) n -or-(CH2-CH2-O) n - (wherein n is 1 or 2). In another example, X 2 -C 1~5 For example, X 2 is methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc. 2 is a bond, -CH-, -CHCH-, or -CHCHCH-. In some examples, X 2 is a 4- to 6-membered cycloalkyl. For example, X 2 teeth, [ka] In another example, X 2 is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 2 teeth, [ka] It is.

[0222]

[0228] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p In some embodiments, X is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, and the heterocycloalkyl is optionally substituted with -CH. 3 is a bond. In some embodiments, X 3 is methyl, ethyl, propyl, iso-propyl, butyl, etc. In some embodiments, X 3 is cyclopentyl or cyclohexyl. 3 In another embodiment, X is -N(H)-. 3 is -(O-CH2-CH2) p -or-(CH2-CH2-O) p - (wherein p is 1 or 2).

[0223]

[0229] In some embodiments, X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5-6 membered saturated, partially unsaturated or fully unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O or S. In some embodiments, X 4 is a bond, [ka] , -C 1~4 Alkyl-, -CH2-CH2-N(R)- or -N(R)-. For example, X 4 is -CH2-CH2-N(H)- or -N(H)-. 4 is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, and the like.

[0224]

[0230] In some embodiments, X 5 is a bond, -C 1~4 In some embodiments, X is alkyl-, -N(R)-, or -C(O)-N(R)-. 5 is a bond. In some embodiments, X 5 is methyl, ethyl, propyl, iso-propyl, butyl, etc. In some embodiments, X 5 is -N(H)- or -C(O)-N(H)-.

[0225]

[0231] In some embodiments, L is [ka] [ka] [ka] [ka] is selected from.

[0226]

[0232] The present disclosure provides a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5X is a 7-12 membered spiro bicyclic 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 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O or S, the heterocycloalkyl being optionally substituted with -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 each of m, n, and p is independently an integer from 1 to 3; Y is as described herein, and each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 alkyl; and q is 0, 1 or 2.

[0227]

[0233] In other embodiments, each of the variables in formula (IA) is as defined herein for compounds of formula (X) or (I).

[0228]

[0234] The present disclosure relates to a compound of formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -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 membered spiro bicyclic 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 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p- or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O or S, the heterocycloalkyl being optionally substituted with -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 each of m, n, and p is independently an integer from 1 to 3; Y is as described herein, and each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 alkyl; and q is 0, 1 or 2.

[0229]

[0235] In other embodiments, each of the variables in formula (IB) is as defined herein for compounds of formula (X) or (I).

[0230]

[0236] The present disclosure relates to a compound represented by formula (III) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 1is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3 or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; X 2 is a bond or -C 1~5 Alkyl-; X 3 is a bond, -C 1~4 is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH; Y is as described herein, and each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A is independently -H; and q is 0, 1 or 2.

[0231]

[0237] The present disclosure relates to a compound of formula (IV) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5X is a 7-12 membered spiro bicyclic 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 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O or S, the heterocycloalkyl being optionally substituted with -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 each of m, n, and p is independently an integer from 1 to 3; Y is as described herein, and each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 alkyl; and q is 0, 1 or 2.

[0232]

[0238] In certain embodiments of any of Formulas AX or I-IV, Y is [ka] wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl, or NH2.

[0233]

[0239] In certain embodiments of any of Formulas AX or I-IV, Y is, in some embodiments, [ka] wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl, or NH2.

[0234]

[0240] In certain embodiments of any of Formulas AX or I-IV, Y is, in some embodiments, [ka] [ka] Either:

[0235] General synthesis scheme

[0241] The compounds can be prepared or synthesized by any technique deemed appropriate by a person skilled in the art. In certain embodiments, the compounds are prepared according to International Application PCT / US2019 / 56112, filed October 14, 2019, which is incorporated herein by reference in its entirety. An exemplary synthesis scheme is described below.

[0236]

[0242] General Procedure 1: Amide Coupling [ka]

[0243] Intermediate (3-1), which can be generated by deesterifying intermediate (1-6), is treated with an amine, Y-NH, under coupling conditions to generate compound (3-2) of the present disclosure, in which the terminal linking group of L is an amide.

[0237]

[0244] General Procedure 2: Reductive amination. [ka]

[0245] Intermediate (3-1), which can be generated by deesterifying intermediate (1-6), is treated with an amine, Y-NH, under coupling conditions to generate compounds of the invention (3-2), in which the terminal linking group of L is an amide.

[0238]

[0246] General Procedure 3: Aryl Fluoride Substitution. [ka]

[0247] Intermediate (3-1), which can be generated by deesterifying intermediate (1-6), is treated with any aryl fluoride, YF, under coupling conditions to generate compounds of the invention (3-2), in which the terminal linking group of L is NH.

[0239]

[0248] The compounds in Table 1 can be synthesized using the synthetic scheme described above.

[0240] [Table 1]

[0241] [Table 2]

[0242] [Table 3]

[0243] [Table 4]

[0244] [Table 5]

[0245] Formulation and Administration

[0250] Pharmaceutical Compositions

[0251] The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharma- ceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present disclosure provides a pharmaceutical composition comprising the above-mentioned compound and a pharma- ceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present disclosure is a pharmaceutical composition comprising an effective amount of the compound of the present disclosure or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers that are appropriately selected for the intended administration form and are consistent with normal pharmaceutical practice.

[0246]

[0252] According to another embodiment, the present description provides compositions comprising a compound herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The present description provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulae A-X or I-IV, where a "therapeutically effective amount" is an amount that is effective (a) to measurably degrade BTK (or reduce the amount of BTK) in a biological sample or in a patient; or (b) to treat and / or ameliorate a disease or disorder mediated by BTK.

[0247]

[0253] The term "patient", as used herein, means an animal, alternatively a mammal, and alternatively a human.

[0248]

[0254] It is also recognized that certain compounds of the present disclosure may be present in free form for treatment or, where appropriate, as a pharma- ceutically acceptable derivative thereof (e.g., salt). According to the present disclosure, a pharma- ceutically acceptable derivative includes, but is not limited to, a pharma- ceutically acceptable prodrug, salt, ester, salt of such an ester, or any other adduct / extract or derivative that, upon administration to a patient in need thereof, can directly or indirectly provide a compound as otherwise described herein, or a metabolite or residue thereof.

[0249]

[0255] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

[0250]

[0256] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharma-ceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharma-ceutically acceptable non-toxic acid addition salts include the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid; or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-type salts. + (C 1~4The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0251]

[0257] Pharmaceutically acceptable carriers may contain inactive ingredients that do not excessively inhibit the biological activity of the compound. Pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or devoid of other undesired reactions or side effects upon administration to a subject. Standard pharmaceutical formulation techniques can be used.

[0252]

[0258] Pharmaceutically acceptable carriers, adjuvants or vehicles, as used herein, include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharma-ceutically acceptable compositions and known techniques for their preparation. Use of any conventional carrier medium is intended to be within the scope of this description, except insofar as such medium is incompatible with the compounds described herein, for example, by causing undesired biological effects or interacting with any other component of the pharma-ceutically acceptable composition in an otherwise deleterious manner. As used herein, the phrase "side effects" encompasses undesired and deleterious effects of a treatment (e.g., a prophylactic or therapeutic agent). Side effects are always undesirable, but unwanted effects are not necessarily untoward. Adverse effects from a treatment (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, kidney toxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metal tingling, prolonged gestation, weakness, somnolence, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0253]

[0259] Some examples of materials that can serve as pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid or potassium sorbate), saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solution, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and perfumes. Preservatives and antioxidants may also be present in the composition, at the discretion of the formulator.

[0254]

[0260] As used herein, the term "measurably degrade" refers to (a) a difference in BTK activity between a sample containing a compound described herein and BTK and a comparable sample containing BTK in the absence of the compound; or (b) a measurable reduction in the concentration of BTK in a sample over time.

[0255] Administration

[0261] The composition of the present disclosure is administered orally. The pharmaceutically acceptable composition of the present description can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Diluents useful for oral administration in capsule form include lactose and dried corn starch. When aqueous suspension is required for oral use, active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavors or colorants can also be added.

[0256]

[0262] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compounds herein, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, 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 and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfumes.

[0257]

[0263] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compounds herein are mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0258]

[0264] Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. Solid dosage forms may optionally contain opacifying agents. These solid dosage forms may also be of a composition such that they optionally release the active ingredient only in a certain part of the intestinal tract, for example, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0259]

[0265] The active compounds herein may also be in microencapsulated form with one or more excipients as mentioned above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compounds may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, 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 forms may also contain buffering agents. They may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient only, optionally in a delayed manner, for example, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0260]

[0266] The compounds described herein are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase "dosage unit form" refers to a physically discrete unit of drug that is appropriate for the patient being treated. However, it is understood that the total daily usage of the compounds and compositions of the present disclosure is determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the age, weight, overall health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound being used; the duration of treatment; the drugs used in combination or concurrently with the specific compound being used, and similar factors well known in the medical arts.

[0261]

[0267] The amount of the compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. The compositions should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of compound or inhibitor can be administered to a patient receiving these compositions.

[0262]

[0268] Depending on the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of the present disclosure. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0263]

[0269] For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of the present disclosure to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, 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 ublituximab), aretuzumab, bendamustine, cladribine, doxorubicin, chlorambucil, prednisolone, and cyclosporine. These include, but are not limited to, rifabutin, midostaurin, lenalidomide, pomalidomide, checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembolizumab, atezolizumab, avelumab, durvalumab), engineered cell therapy (e.g., CAR-T therapy - Kymriah®, Yescarta®), Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon, and platinum derivatives.

[0264]

[0270] Optionally, radiation therapy is administered during the course of treatment and a compound of the present disclosure (or a pharma- ceutically acceptable salt thereof) is administered to a patient in need thereof.

[0265]

[0271] Other examples of agents with which the compounds or inhibitors of the present disclosure may be combined include, but are not limited to, treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; agents for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; agents for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, and cyclosporine. immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's agents; agents for treating cardiovascular disease such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons and antivirals; agents for treating blood disorders such as corticosteroids, anti-leukemia agents and growth factors; and agents for treating immune deficiency disorders such as gamma globulin.

[0266]

[0272] The amount of additional therapeutic agent present in the compositions of the present disclosure is no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions ranges from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent. EXAMPLES

[0267] Working Example

[0273] Further embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0268] Example 1

[0274] General Procedure 1: Amide Coupling

[0275] A mixture of amine (0.03 mmol), acid (0.03 mmol), HATU (0.04 mmol), DIPEA (0.15 mmol) and DMF was stirred at room temperature for 30 min. The mixture was purified by HPLC (HO / MeCN with 0.1% TFA) to give the amide product. Compound 21 was prepared by procedure 1.

[0269]

[0276] General Procedure 2: Reductive Amination

[0277] A mixture of amine TFA salt (0.07 mmol), aldehyde (0.1 mmol), triethylamine (0.28 mmol) and DCE was stirred at room temperature for 10 min. NaBH(OAc)3 (0.14 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was filtered through celite, washed with CHCl2, concentrated and purified by HPLC (H0 / MeCN with 0.1% TFA) to give the amine product. Compounds 6, 7 and 199 were prepared by procedure 2.

[0270]

[0278] General Procedure 3: Aryl Fluoride Substitution

[0279] A mixture of amine (0.22 mmol), aryl fluoride (0.22 mmol), DIPEA (0.88 mmol) and DMF (1 mL) was stirred at 90° C. for 16 h. The mixture was purified by HPLC (HO / MeCN with 0.1% TFA) to give the desired product. Compound 20 was prepared by procedure 3.

[0271]

[0280] Compounds 3-19 are prepared according to PCT / US2019 / 56112, filed October 14, 2019, which is incorporated herein by reference in its entirety.

[0272]

[0281] Example 1 - Compound 1. [ka]

[0282] A mixture of 3,5-dichloropyrazine-2-carbonitrile (850 mg, 4.89 mmol), piperidine (0.48 mL, 4.89 mmol), ethyl bis(propan-2-yl)amine (1.70 mL, 9.77 mmol) and DMF (20 mL) was stirred at room temperature for 2 h. EtOAc and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated and purified by MPLC (0-100% EtOAc in hexanes) to give 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile (1079.6 mg, 99.2%). LCMS: C 10 H 11 Required value for ClN4: 222, Measured value: m / z=223 [M+H] + .

[0273]

[0283] A mixture of tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (1398 mg, 5.63 mmol), 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile (1254 mg, 5.63 mmol), palladium acetate (253 mg, 1.13 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane (701 mg, 1.13 mmol) and cesium carbonate (5504 mg, 16.89 mmol) was degassed and filled with N2 five times. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through celite, washed with MeOH / EtOAc, concentrated and purified by MPLC (0-100% EtOAc in CH2Cl2) to give tert-butyl 6-((3-cyano-6-(piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.830 g, 74.8%). LCMS: C 24 H 30 N6O2 required value: 434, measured value: m / z=435 [M+H] + .

[0274]

[0284] A 30% aqueous solution of H2O2 (7.11 mL) was added to a mixture of cesium carbonate (1372 mg, 4.21 mmol), DMSO (2.5 mL), MeOH (50 mL) and tert-butyl 6-((3-cyano-6-(piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1830 mg, 4.21 mmol). The mixture was stirred at room temperature for 30 min. The mixture was concentrated. EtOAc 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 give tert-butyl 6-((3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.6470 g, 86.4%). LCMS: C 24 H 32 N6O3 required value: 452, measured value: m / z=453 [M+H] + .

[0275]

[0285] A mixture of tert-butyl 6-((3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1647 mg, 3.64 mmol), CHCl (30 mL) and TFA (6 mL) was stirred at room temperature for 2 h. Volatiles were removed. The mixture was filtered through a NaHCO cartridge, concentrated and purified by reverse phase MPLC (5-90% MeCN in H0) to give 5-(piperidin-1-yl)-3-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrazine-2-carboxamide (1.2800 g, 99.8%). LCMS: C 19 H 24 NO required value: 352, measured value: m / z=353 [M+H] + .

[0276] Example 2—Compound 2. [ka]

[0286] Sodium triacetoxyborohydride (372 mg, 1.75 mmol) was added to a mixture of AcOH (1 drop), benzyl 3-oxoazetidine-1-carboxylate (120 mg, 0.58 mmol), 5-(piperidin-1-yl)-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazine-2-carboxamide (206 mg, 0.58 mmol) and DCE (5 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, aqueous NaHCO3 was added and the organic layer was dried over MgSO4, filtered, concentrated and carried on to the next step without further purification. LCMS: C 30 H 35 Required value for N7O3: 541, Measured value: m / z=542 [M+H] +

[0277]

[0287] A mixture of benzyl 3-(6-{[3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl]amino}-3,4-dihydro-1H-isoquinolin-2-yl)azetidine-1-carboxylate (315 mg, 0.58 mmol), Pd / C (62 mg, 0.58 mmol) and EtOH (10 mL) was evacuated and backfilled with H2 five times. The mixture was stirred at room temperature overnight. The mixture was filtered, washed with MeOH / EtOAc, concentrated and carried on to the next step. LCMS: C 22 H 29 Required value for NO: 407, Measured value: m / z=408 [M+H] + .

[0278]

[0288] A mixture of rac-2-[(3R)-2,6-dioxopiperidin-3-yl]-5-fluoroisoindole-1,3-dione (24.40 mg, 0.09 mmol), 3-{[2-(azetidin-3-yl)-3,4-dihydro-1H-isoquinolin-6-yl]amino}-5-(piperidin-1-yl)pyrazine-2-carboxamide (30 mg, 0.07 mmol), N,N-diisopropylethylamine (0.04 mL, 0.22 mmol) and DMSO (1 mL) was stirred at 90° C. for 4 hours. The mixture was purified by HPLC (5-95% MeCN in HO with 0.1% TFA) to give rac-3-{[2-(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}azetidin-3-yl)-3,4-dihydro-1H-isoquinolin-6-yl]amino}-5-(piperidin-1-yl)pyrazine-2-carboxamide (0.0096 g, 19.6%). 11H NMR (500 MHz, acetonitrile-d3) δ 11.22 (s, 1H), 8.89 (s, 1H), 7.72 - 7.65 (m, 2H), 7.59 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.78 - 6.70 (m, 1H), 5.81 (s, 1H), 4.97 (dd, J = 12.3, 5.5 Hz, 1H), 4.51 - 4.35 (m, 3H), 4.20 (s, 2H), 3.73 (t, J = 5.4 Hz, 4H), 3.15 (s, 2H), 2.74 (td, J = 20.0, 19.1, 11.0 Hz, 3H), 1.71 (d, J = 35.4 Hz, 8H). LCMS: C 35 H 37 Required value for N9O5: 663, measured value: m / z = 664 [M + H]+.

[0279]

Table 6

[0280]

Table 7

[0281]

Table 8

[0282]

Table 9

[0283]

Table 10

[0284]

Table 11

[0285]

Table 12

[0286] [Table 13]

[0287]

[0289] Biological Example 1

[0290] Compounds 1-19 were assayed for IMiD activity.

[0288]

[0291] Frozen human peripheral blood mononuclear cells (PBMCs) were thawed and treated with DMSO or compounds for 24 hours, then fixed and permeabilized using the Foxp3 / Transcription Factor Fixation / Permeabilization Kit (eBioscience, 00-5523). Cells were stained with fluorophore-conjugated antibodies against CD20 (Biolegend 302330), CD3 (BD ​​Pharmingen 552127) and Aiolos (Biolegend 371106). An additional set of DMSO-treated PBMCs was stained for CD20, CD3 and an AlexaFluor647-conjugated mouse IgG1 isotype control antibody (Biolegend 400136). Stained cells were run on an Attune NxT Acoustic Focusing flow cytometer (Thermo-Fisher A29004) and data were analyzed using FlowJo (v10.5.3) and GraphPad Prism (v7.00) software. Single lymphocytes were gated for B cells (CD20+CD3-) and T cells (CD3+CD20-) and Aiolos geometric mean fluorescence intensity (MFI) was calculated for each population. The MFI of the isotype control was calculated for each population and used to quantify background staining. Percent Aiolos degradation was calculated for each compound treated sample using the following formula: % decomposition=100 * (Sample MFI-Isotype MFI) / (DMSO MFI-Isotype MFI) Each compound demonstrated enhanced and measurable IMiD activity, as shown in Table 2 below. DC50 is the compound concentration that degrades 50% of Aiolos. Dmax is the maximum percent Aiolos degradation in the assay.

[0289] [Table 14]

[0290]

[0292] Biological Example 2

[0293] Compound 5 induced loss of viability in lymphoma cell lines.

[0291]

[0294] The data presented in FIG. 1 show that in the REC-1 human mantle cell line, which is only partially dependent on BTK for its survival, treatment with compound 5 results in a robust loss of viability in a concentration-dependent manner.

[0292]

[0295] The effect of compound 5 is significantly more pronounced when compared to one of the control compounds, a BTK degrader with no IMiD activity, as well as to the covalent BTK inhibitors ibrutinib and acalabrutinib. The control compound was prepared as described in International Application PCT / US2020 / 063176, filed December 3, 2020, published as International Publication WO 2021 / 113557 (June 10, 2021), which is incorporated by reference in its entirety. Compound 5 is more pronounced when compared to the IMiD molecules pomalidomide and lenalidomide, which efficiently degrade not only BTK, but also Aiolos and Ikaros. These data suggest that the combination of BTK degrading and IMiD activity may be more effective in treating B cell malignancies than either activity alone.

[0293]

[0296] In Figure 1, A) daily oral treatment with Compound 5 at 30 mg / kg resulted in lower mean arthritis scores than Ibrutinib at 30 mg / kg. The effect of Compound 5 achieved similar clinical benefits to dexamethasone with minimal weight loss (B) compared to dexamethasone and vehicle. The significance of clinical arthritis scores (A) was determined from the area under the curve (AUC) of the mean paw scores calculated for individual mice. (C) Serum levels of anti-type II collagen IgG. Statistical significance was determined between vehicle control and treatment groups by one-way Kruskal-Wallis ANOVA and Dunn's multiple comparison test.

[0294]

[0297] The data presented in Figure 2, 2A show that compound 5 potently degrades BTK in TMD8 cells (human DLBCL cell line). Figure 2B shows that compound 5 degrades Aiolos in human T cells with similar potency as lenalidomide and pomalidomide. Compound 5 is active against ibrutinib-resistant tumor cell lines (see Figure 3). BTK-C481 mutations are the most common resistance mutations to ibrutinib and other covalent BTK inhibitors. Thus, the activity of compound 5 against BTK-C481 provides a therapeutic option for patients with resistance to BTK inhibitors.

[0295]

[0298] Preclinical Models

[0299] 80%+ BTK degradation drives the potent antitumor activity achieved with compound 5 in preclinical models (see FIG. 4). Ikaros and Aiolos degradation achieve the target range even at therapeutic doses.

[0296]

[0300] Biological Example 3

[0301] Clinical trial design for oral administration of compound 5

[0302] The clinical trial was conducted at 12 institutions, including Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, City of Hope (Duarte, California), National Institutes of Health Clinical Center, Sarah Cannon Research Institute, Colorado Blood Cancer Institute, Florida Cancer Specialists, Tennessee Oncology, University of California (San Francisco), University of California (Irvine), OSU Wexner Medical Center and Swedish Cancer Institute (Seattle).

[0297]

[0303] Patients were treated with four different dose levels of Compound 5: dose level 1 (100 mg), dose level 2 (200 mg), dose level 3 (300 mg) and dose level 4 (400 mg). The objectives of this study were to evaluate safety and tolerability, identify the maximum tolerated dose and evaluate PK / PD.

[0298]

[0304] The patients evaluated in this study were treated for a disease or disorder selected from the group consisting of chronic lymphocytic leukemia (CLL) with BTK C481 mutation (n, approximately 20); CLL without BTK C481 mutation (n, approximately 20); mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM) (n, approximately 20); follicular lymphoma (FL) (n, approximately 20); and diffuse large B-cell lymphoma (DLBCL) (n, approximately 20). Tables 3 and 4 below summarize the patient characteristics. This is a heavily pretreated patient population, including dual-resistant CLL patients.

[0299] [Table 15]

[0300] [Table 16]

[0301]

[0305] Figure 5 shows the robust BTK degradation observed with Compound 5 across all dose levels and malignancies. Rapid and sustained degradation of BTK by Compound 5 in patients with CLL was achieved by day 15 as shown in Figure 6. Treatment with Compound 5 at 100 mg resulted in greater Ikaros degradation in patients (confirmed by Western blot, see Figure 7), which is consistent with published reports of cereblon immunomodulatory effects.

[0302]

[0306] Compound 5 demonstrated degradation of the cereblon neo-substrate Ikaros

[0307] Frozen patient PBMCs collected at baseline and on day 8 of cycle 1 were processed into protein lysates and degradation of the cereblon neo-substrate Ikaros was determined using Western blot on a Jess™ Simple Western automated system. After 1 week of treatment with Compound 5, Ikaros degradation (Figure 7) was detected in all patients. Similar degrees of Ikaros degradation (ranging from 26.1 to 60.5% degradation) were observed between patients receiving 100 mg or 200 mg. Ikaros degradation of 75.2 to 95.7% was detected in patients receiving 300 mg of Compound 5.

[0303]

[0308] Frozen PBMC from patients were prepared and Ikaros protein levels were assessed using Western blot with a Jess™ Simple Western automated system.

[0304]

[0309] Figure 7A, Western blot analysis showed a reduction in the Ikaros protein band in one CLL patient receiving 100 mg of compound on day 8 of cycle 1. PBMCs from a healthy donor treated ex vivo for 4 hours with 1 μM compound 5 were used as a positive control.

[0305]

[0310] FIG. 7A, Densitometric analysis of Ikaros degradation in all patients was obtained after normalization to β-actin and % Ikaros degradation was calculated relative to baseline values ​​from each patient.

[0306]

[0311] A list of materials used for flow cytometry is provided in Table 5 below.

[0307] [Table 17]

[0308]

[0312] Biological Example 4

[0313] Western blot assay for Ikaros degradation

[0314] For Ikaros degradation assessment, patient PBMCs were lysed in lysis buffer RIPA buffer (Fisher, PI89901), complete mini EDTA-free protease inhibitor (Sigma, 11836170001), protease inhibitor cocktail (Sigma, P2714) and phosphatase inhibitor cocktails 2 and 3 (Sigma, P5726 and P0044) and stored overnight at -80°C. Cells were then thawed, centrifuged at 8000×g for 5 min and lysate supernatants were transferred to fresh tubes. Protein levels were determined by BCA assay performed according to the manufacturer's protocol (EMD Millipore, Cat. No. 71285-3). A total of 3 μg protein was loaded and a 1:50 dilution of primary anti-Ikaros (Cell Signaling Technology, Cat. No. 14859) and 1:50 anti-β-actin (Cell Signaling Technology, Cat. No. 8457) were used. Ikaros analysis was performed using the Jess™ Simple Western automated system (Protein Simple, San Jose, Calif.) according to the manufacturer's instructions.

[0309] Other embodiments

[0315] It should be understood that the above description is intended to be illustrative, and not limiting, of the scope of the present disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A pharmaceutical composition for treating or preventing a disease, the pharmaceutical composition comprising a bifunctional compound, the bifunctional compound being capable of inducing proteolysis of Bruton's tyrosine kinase, the bifunctional compound having enhanced IMiD activity, the bifunctional compound is administered for at least 15 days, the bifunctional compound has the formula (A) 【Chemical 1】 (wherein, W is CH or N; D is a bond or -NH-; Ring A is phenyl, 9-10 membered bicyclic aryl, 5-6 membered partially or fully unsaturated monocyclic heterocyclic or 9-10 membered bicyclic heteroaryl, the monocyclic heterocyclic and bicyclic heteroaryl of Ring A each having 1-3 heteroatoms independently selected from N, O and S, Ring A is unsubstituted or independently substituted with up to 3 substituents selected from halo, -CN, -COOH, NH₂ and unsubstituted or substituted C₁₋₆ alkyl; Ring B is phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 8-10 membered spirobicyclic heterocyclic, Ring B is unsubstituted or substituted, the heteroaryl and heterocycloalkyl of Ring B having 1-3 heteroatoms independently selected from N, O and S; L is -X₁-X₂-X₃-X₄-X₅-; X₁ is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH₂-CH₂)m-, -O(C₆H₄)-, -(O-CH₂-CH₂-CH₂)m-, -C₁₋₅ alkyl-, 7-12 membered spiro or fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O and S or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, each of the monocyclic and bicyclic heterocycloalkyl of X₁ being unsubstituted or substituted with -CH₃; X₂ is a bond, -(O-CH₂-CH₂)n-, -(CH₂-CH₂-O)n-, -N(R)-C(O)-, -N(R)-, -C(O)-, -C₁₋₅ alkyl-, 4-6 membered monocyclic cycloalkyl or 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S; X3 is a bond, -C1-8 alkyl-, [Chemical 2] , a 4- to 6-membered cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2)p-, -(CH2-CH2-O)p-, a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl being unsubstituted or substituted with -CH3; X4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C1-4 alkyl-, -(O-CH2-CH2-CH2)m-, a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O and S; X5 is a bond, -C1-4 alkyl-, -N(R)-, -O-, -C(O)- or -C(O)-N(R)-; each R is independently hydrogen or -C1-3 alkyl; and each of m, n and p is independently an integer from 1 to 3; and Y is 【Chemical 3】 wherein each T is independently CH or N; and each Z is independently -CH2- or -C(O)-; and each R' is hydrogen, methyl or NH2) a compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition.

2. The bifunctional compound is formulated for one or more of the following purposes: chronic administration (wherein the frequency of chronic administration is optionally once a week, twice a week, once a day, twice a day, three times a day or four times a day), administration for more than 1 month or administration for more than 1 year, and administration at 100 - 600 mg / kg body weight / day, 200 - 600 mg / kg body weight / day or 300 - 600 mg / kg body weight / day. The pharmaceutical composition according to claim 1.

3. The disease is cancer, the pharmaceutical composition according to claim 1.

4. The disease is B-cell malignancy, the pharmaceutical composition according to claim 1. **Claim 5**: The pharmaceutical composition according to claim 1, wherein the disease is cancer selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter transformation, 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, head and neck squamous cell carcinoma (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). **Claim 6** The pharmaceutical composition according to claim 1, wherein the disease is selected from the group consisting of Waldenström macroglobulinemia, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), DLBCL, follicular lymphoma, and chronic lymphocytic leukemia. **Claim 7** The pharmaceutical composition according to claim 1, wherein the disease is multiple myeloma, myelodysplastic syndrome, Kaposi sarcoma, or post-transplant lymphoproliferative disorder. **Claim 8** The pharmaceutical composition according to claim 1, wherein the disease is graft-versus-host disease. **Claim 9** The pharmaceutical composition according to claim 1, wherein the Bruton's tyrosine kinase is C481 mutant Bruton's tyrosine kinase. **Claim 10** The pharmaceutical composition according to claim 1, wherein the Bruton's tyrosine kinase is C481S, L528W, M437R, or V416L mutant Bruton's tyrosine kinase. **Claim 11**: The pharmaceutical composition according to claim 1, wherein the disease is a disease selected from the group consisting of chronic lymphocytic leukemia (CLL) with BTK C481 mutation; CLL without BTK C481 mutation; mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM); follicular lymphoma (FL); and diffuse large B-cell lymphoma (DLBCL). **Claim 12**: The pharmaceutical composition according to claim 1, wherein the disease is cancer, and the cancer is ibrutinib-resistant. **Claim 13** The pharmaceutical composition according to claim 1, wherein ring B is an unsubstituted or substituted 5- to 6-membered heterocycloalkyl having 1 to 2 nitrogen atoms.

14. The pharmaceutical composition according to claim 1, wherein ring B is an unsubstituted or substituted 5- to 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N and S.

15. Ring B is 【Chemical Formula 4】 selected from, R １０ is [Chemical Formula 5] and R １ is C １～４ an alkyl group and / or Ring B is 【Chemical Formula 6】 selected from, and R10 is 【Chemical Formula 7】 is and / or Ring B is [Chemical 8] is and / or R10 is 【Chemical Formula 9】 is the pharmaceutical composition according to claim 1.

16. Ring A is 【Chemical Formula 10】 and ring A' together with the phenyl ring to which ring A' is fused forms a 9- to 10-membered bicyclic aryl or 9- to 10-membered bicyclic heteroaryl, and the bicyclic heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S. and / or Ring A is 【Chemical Formula 11】 is the pharmaceutical composition according to claim 1.

17. X １ , X ２ and X ５ at least one of which is —N(R)—, —C(O)—N(R)— or —CH ２ —. and / or X1 is -C(O)-N(R)-. and / or X2 is -(O-CH2-CH2)n-, -(CH2-CH2-O)n- or -C1-5 alkyl-. and / or X3 is a bond, 【Chemical 12】 , -C1-4 alkyl- or -N(R)-. and / or X4 is a bond, -CH2- or -N(R)-. and / or X5 is a bond. and / or X1 is -(O-CH2-CH2-CH2)m-, m is 1, and X2 is -C(O)-N(R)-. and / or X1 is -CH2-, -C(O)-, 【Chemical 13】 is and / or X2 is a bond, -C(O)-, -C1-5 alkyl-, 【Chemical 14】 is and / or X3 is a bond, -C1-4 alkyl-, 4- to 6-membered cycloalkyl or -N(R)-. and / or X3 is a bond, -C1-4 alkyl-, -NH-, 【Chemical Formula 15】 is and / or X4 is a bond, 【Chemical 16】 , -C1-4 alkyl-, -CH2-CH2-N(R)- or -N(R)-. and / or X5 is a bond, -C1-4 alkyl-, -N(R)- or -C(O)-N(R)- is the pharmaceutical composition according to claim 1.

18. L is 【Chemical 17】 【Chemical 18】 【Chemical 19】 【Chemical 20】 is the pharmaceutical composition according to claim 1.

19. Y is 【Chemical 21】 is the pharmaceutical composition according to claim 1.

20. The pharmaceutical composition according to claim 19, wherein Z is CH or -C(O)-.

21. The compound of formula (A) is a compound of formula (B) 【Chemical 22】 wherein W is CH or N; D is a bond or -NH-; Ring B1 is a 4- to 6-membered fully saturated, partially unsaturated or fully unsaturated monocyclic heterocyclic ring or an 8- to 10-membered fully saturated spirobicyclic heterocyclic ring, ring B1 has 1 to 3 heteroatoms independently selected from N, O and S, and is unsubstituted or substituted with 1 to 3 groups selected from halo, -CH ３ , -CF ３ , -C(O)OH, -CH ２ OH or is unsubstituted or substituted with oxo and is substituted with 1 to 3 groups selected from 5-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O; L is -X １ -X ２ -X ３ -; 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 alkyl-, a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and each of the monocyclic and bicyclic heterocycloalkyls of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a 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, 4- to 6-membered monocyclic cycloalkyl or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S; X ３ is a bond, -C １～４ alkyl-, 【Chemical 23】 , 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ), ｐ -, -(CH ２ -CH ２ -O), ｐ -, 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is unsubstituted or substituted with -CH ３ ; Each R is independently hydrogen or -C １～３ alkyl; and each of m, n and p is independently an integer from 1 to 3) or a pharmaceutically acceptable salt thereof, and / or ring B1 is 【Chemical 24】 and ring B1 is unsubstituted or substituted with 1 to 3 groups selected from -CH3, -CH2OH, -C(O)OH, -CF3, fluorine, 【Chemical Formula 25】 and / or ring B1 is and / or 【Chemical 26】 ring B1 is and / or ring B1 is 【Chemical 27】 and / or X1 is and / or 【Chemical Formula 28】 X2 is a bond, -C1-5alkyl-, a 4-6 membered monocyclic cycloalkyl or a 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S. and / or X2 is a bond, -C1-3alkyl-, -C(O)-, and / or X3 is a bond, -C1-4alkyl-, -N(R)-, -(O-CH2-CH2)p-, -(CH2-CH2-O)p- or a 4-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl being unsubstituted or substituted with -CH3. 【Chemical 29】 and / or X3 is a bond, and / or L is and / or 【Chemical 30】 W is N and D is a bond, the pharmaceutical composition according to claim 1.

22. The compound of formula (A) is a compound of formula (C) 【Chemical Formula 31】 wherein W is CH or N; ring C is phenyl or a saturated, partially unsaturated or fully unsaturated 5-6 membered monocyclic heterocycle having 1 to 2 heteroatoms independently selected from N, O and S, each of said phenyl and heterocycle of ring C being unsubstituted or substituted; each of m, n and p is independently an integer from 1 to 3) or a pharmaceutically acceptable salt thereof, 【Chemical 32】 and / or ring C is and / or L is -X １ -X ２ -X ３ -; X １ is 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, a 7- to 12-membered spiro bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and each of the bicyclic heterocycloalkyl and the monocyclic heterocycloalkyl of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a 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, 4- to 6-membered monocyclic cycloalkyl or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S; X ３ is a bond, -C １～４ alkyl-, 【Chemical 33】 , 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ), ｐ -, -(CH ２ -CH ２ -O) ｐ -, 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, wherein said heterocycloalkyl is unsubstituted or substituted with -CH ３ ; Each R is independently hydrogen or -C １～３ alkyl; and ring C is and / or X1 is a 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S. and / or 【Chemical 34】 X1 is and / or X1 is 【Chemical 35】 and / or X1 is and / or X1 is and / or 【Chemical 36】 X1 is and / or X2 is a bond, -C1-5 alkyl-, a 4-6 membered monocyclic cycloalkyl or a 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and / or X2 is a bond or -C1-3 alkyl-, and / or X3 is a 4-6 membered cycloalkyl, -N(R)- or a 4-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and the heterocycloalkyl is unsubstituted or substituted with -CH3, and / or X3 is 【Chemical 37】 as follows, and / or L is 【Chemical 38】 as follows, the pharmaceutical composition according to claim 1.

23. The compound of formula (A) is a compound of formula (D) 【Chemical Formula 39】 wherein, W is CH or N; Ring A is 【Chemical 40】 as follows, L is -X １ -X ２ -X ３ -; X １ is -C １～５ alkyl or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and the monocyclic heterocycloalkyl of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from bond, -C １～５ alkyl - or N, O and S, and the monocyclic heterocycloalkyl of X １ is unsubstituted or substituted with -CH ３ ; X ３ is a bond, -C １～４ alkyl, 4- to 6-membered monocyclic cycloalkyl or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl being unsubstituted or substituted with -CH ３ ; and R １０ is halo, -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, 【Chemical 41】 as follows) or a pharmaceutically acceptable salt thereof, or, The compound of formula (D) is a compound of formula (D-1) 【Chemical 42】 wherein, W is CH or N; Ring A is 【Chemical 43】 as follows, L is -X1-X2-X3-; X1 is -C1-5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and the monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3; X2 is a bond, -C1-5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and the monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3; X3 is a bond, -C1-4 alkyl-, a 4-6 membered monocyclic cycloalkyl or a 4-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and the heterocycloalkyl is unsubstituted or substituted with -CH3; and R10 is 【Chemical 44】 as follows) or a pharmaceutically acceptable salt thereof, or, The compound of formula (D) is a compound of formula (D-2) 【Chemical 45】 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 1.

24. Ring A is 【Chemical 46】 as follows, and / or X1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and the monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3. and / or X1 is 【Chemical 47】 as follows. and / or X2 is a bond, -C1-5alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S. and / or X2 is a bond or -C1-4alkyl-. and / or X3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S. and / or X3 is 【Chemical 48】 as follows. and / or L is 【Chemical 49】 as follows. and / or R10 is 【Chemical 50】 as follows. and / or R10 is 【Chemical Formula 51】 as follows. The pharmaceutical composition according to claim 23.

25. The compound of formula (A) is of formula (E) 【Chemical Formula 52】 wherein D is a bond or -NH-; W is N or CH; Ring A is phenyl, a 9- to 10-membered bicyclic aryl, a 5- to 6-membered partially or fully unsaturated monocyclic heterocyclic ring, or a 9- to 10-membered bicyclic heteroaryl, and the monocyclic heterocyclic ring and bicyclic heteroaryl of Ring A each have 1 to 3 heteroatoms independently selected from N, O, and S; Ring B is an unsubstituted or substituted 5- to 6-membered saturated, partially unsaturated or fully unsaturated monocyclic heterocyclic ring, or an unsubstituted or substituted 8- to 10-membered spirobicyclic heterocyclic ring, and Ring B has 1 to 3 heteroatoms independently selected from N, O, and S; L is -X １ -X ２ -X ３ -X ４ -X ５ -; X １ is a 7- to 12-membered spiro bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from C, -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 and S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and each of the monocyclic and bicyclic heterocycloalkyls of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a 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, 4- to 6-membered monocyclic cycloalkyl or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S; X ３ is a bond, -C １～４ alkyl-, 【Chemical Formula 53】 , 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ), ｐ -, -(CH ２ -CH ２ -O), ｐ -, and is a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and the heterocycloalkyl is unsubstituted or substituted with -CH ３ ; X ４ is a bond, -CH ２ -CH ２ -N(R)-, -N(R)-, -C １～４ alkyl-, -(O-CH ２ -CH ２ -CH ２ ) ｍ -, a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O and S; X ５ is a bond, -N(R)- or -C(O)-N(R)-; Each R is independently hydrogen or -C １～３ alkyl; Each of m, n, and p is independently an integer from 1 to 3; X １ , X ２ , X ３ , X ４ and X ５ at least one of which has a nitrogen atom, and Y is directly bonded to L at the nitrogen atom of X １ , X ２ , X ３ , X ４ or X ５ (directly bonded to L at the nitrogen atom thereof) or a pharmaceutically acceptable salt thereof. and / or Ring B is 【Chemical 54】 as follows, and R10 is 【Chemical Formula 55】 as follows, and R1 is a C1-4 alkyl group. and / or Ring B is 【Chemical 56】 as follows, and R10 is 【Chemical 57】 as follows. and / or Ring B is 【Chemical Formula 58】 as follows. and / or R10 is 【Chemical Formula 59】 as follows. and / or Ring A is 【Chemical Formula 60】 as follows. and / or X5 is -N(R)-. and / or X5 is -C(O)-N(R)-. and / or X5 is a bond. and / or L is 【Chemical Formula 61】 【Chemical Formula 62】 【Chemical Formula 63】 as follows. and / or Y is 【Chemical Formula 64】 as follows. The pharmaceutical composition according to claim 1.

26. The compound of formula (A) is of formula (F) 【Chemical Formula 65】 wherein W is CH or N; L is -X １ -X ２ -X ３ -; X １ is 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, 7- to 12-membered spiro bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O and S, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and each of the monocyclic and bicyclic heterocycloalkyls of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a bond, -C １～５ alkyl-, -(O-CH ２ -CH ２ ), ｎ -(CH ２ -CH ２ -O), ｎ -(NR)-C(O)-, -(NR)-, -C(O)-, -C １～５ alkyl-, a 4- to 6-membered monocyclic cycloalkyl or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S; X ３ is a bond, -C １～４ alkyl-, 【Chemical Formula 66】 , 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ), ｐ -, -(CH ２ -CH ２ -O), ｐ -, 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is unsubstituted or substituted with -CH ３ ; Each R is independently hydrogen or -C １～３ alkyl; and each of m, n, and p is independently an integer from 1 to 3) a compound of or a pharmaceutically acceptable salt thereof, and / or W is N, and / or Y is 【Chemical 67】 wherein each T is independently CH or N; and each Z is independently -CH₂- or -C(O)-; and each R' is hydrogen, methyl, or NH₂, and / or X₁ is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and each of said monocyclic heterocycloalkyl of X₁ is unsubstituted or substituted with -CH₃, and / or X₁ is 【Chemical Formula 68】 wherein and / or X₁ is 【Chemical Formula 69】 wherein and / or X₂ is a bond or -C₁₋₅alkyl-, and / or X₃ is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and / or X₃ is 【Chemical Formula 70】 wherein and / or X₃ is 【Chemical 71】 wherein and / or L is 【Chemical Formula 72】 wherein, the pharmaceutical composition according to claim 1.

27. The compound of formula (A) is a compound of formula (G) 【Chemical 73】 or a pharmaceutically acceptable salt thereof, and / or R １ is methyl, and / or Y is 【Chemical Formula 74】 and each T is independently CH or N; and each Z is independently -CH ２ - or -C(O)-; and each R' is hydrogen, methyl or NH ２ is and / or W is N, the pharmaceutical composition according to claim 1.

28. The bifunctional compound is selected from Table 1 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 1. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】

29. A compound selected from the following or a pharmaceutically acceptable salt thereof. 【Table 6】

30. The bifunctional compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, and one or more selected from the group consisting of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle, the pharmaceutical composition according to any one of claims 1 to 28.

31. A bifunctional compound or a pharmaceutically acceptable salt thereof according to claim 29, and one or more selected from the group consisting of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle, a pharmaceutical composition.

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