Bifunctional compounds for degrading BTK with reduced IMiD activity

Abstract

The present disclosure relates to compounds useful for degrading BTK via the ubiquitin proteolytic pathway with little or no 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 / 221,905, filed July 14, 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 for treating diseases regulated by BTK. In certain embodiments, the compounds can degrade Bruton's tyrosine kinase with little or no IMiD activity. In certain embodiments, the compounds are useful for methods of treating diseases with longer duration of administration, higher doses, or both. [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 resulted in 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 hinder tumor growth directly and via the immune system. Quach et al., 2010, Leukemia 24: 22-32. However, outside the context of cancer therapy, strong IMiD activity can result in unwanted side effects. These side effects may limit the use of CRBN binding degrading compounds for cancer and similar malignancies, with few therapeutic options. Compounds with reduced or eliminated IMiD activity are useful for treating for longer duration and / or at higher doses, thereby providing new therapies, including for indications other than cancer. Summary of the Invention [Means for solving the problem]

[0006] overview

[0006] 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 little or no IMiD activity. In the examples provided herein, the compounds are shown to recruit CRBN and degrade BTK with little or no IMiD activity. Specifically, in certain embodiments, the exemplary compounds degrade BTK while not promoting the degradation of Aiolos or Ikaros. In certain embodiments, the compounds also do not induce IL-2, another marker of IMiD activity. By degrading BTK without significant IMiD activity, the compounds can be tolerated at higher doses with fewer side effects than other degrading compounds that regulate CRBN.

[0007]

[0007] 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 little or no 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, an autoimmune disease, or an inflammatory disease.

[0008]

[0008] In one aspect, provided herein are methods of treating or preventing a brain 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 little or no IMiD activity. In certain embodiments, the amount is effective to treat or prevent the brain disease, disorder, or condition. In certain embodiments, the method is for treating or preventing a brain tumor.

[0009]

[0009] 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 little or no IMiD activity. In certain embodiments, the amount is effective to degrade Bruton's tyrosine kinase in the subject.

[0010]

[0010] 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 little or no IMiD activity. In certain embodiments, the amount is effective to prevent B cell activation.

[0011]

[0011] In another aspect, 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 with little or no IMiD activity. In certain embodiments, the amount is 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.

[0012]

[0012] In these methods, the bifunctional compound comprises a moiety capable of specifically binding BTK with little or no 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.

[0013]

[0013] The methods provided herein are useful for treating or preventing diseases, conditions and disorders mediated by Bruton's tyrosine kinase, including, for example, cancer, autoimmune conditions and inflammatory conditions. [Brief description of the drawings]

[0014] Brief explanation of the figure [Figure 1A]

[0014] The effect of Compound 1 on a collagen-induced arthritis model is provided, including clinical arthritis scores (Figure 1A). [Figure 1B]

[0014] The effect of Compound 1 on collagen-induced arthritis model, including body weight (Figure 1B), is provided. [Figure 1C]

[0014] The effect of Compound 1 on a collagen-induced arthritis model, including serum collagen IgG (Figure 1C), is provided. [Diagram 2]

[0015] 1 provides the effect of Compound 1 on experimental autoimmune encephalomyelitis. [Figure 3A]

[0016] 3 provides the effect of Compound 1 on a systemic lupus erythematosus model, including urine protein scores (FIG. 3A). [Figure 3B]

[0016] The effect of Compound 1 on a systemic lupus erythematosus model, including DNA titers (Figure 3B), is provided. [Figure 3C]

[0016] The effects of Compound 1 on a systemic lupus erythematosus model, including glomerular diameter and histological score (Figure 3C), are provided. [Figure 4A]

[0017] The effect of Compound 1 dosing on the B cell compartment, including BTK degradation (FIG. 4A), is provided. [Figure 4B]

[0017] The effect of Compound 1 dosing on the B cell compartment, including B cell percentage (Figure 4B), is provided. [Figure 4C]

[0017] The effect of Compound 1 dosing on the B cell compartment, including bone marrow plasma cell depletion (Figure 4C), is provided. [Figure 5A]

[0018] The effect of Compound 1 on plasma cell production by immunization is provided, including treatment groups (FIG. 5A). [Figure 5B]

[0018] The effect of Compound 1 on plasma cell production by immunization, including Bruton's tyrosine kinase degradation (Figure 5B), is provided. [Figure 5C]

[0018] The effect of Compound 1 on plasma cell production by immunization, including B cell effects (Figure 5C), is provided. [Figure 5D]

[0018] The effect of Compound 1 on plasma cell production by immunization, including the plasma cell effect (Figure 5D), is provided. [Figure 6A]

[0019] Clinical arthritis scores for Compound 1, the control compound and the control antibody (FIG. 6A) are provided. [Figure 6B]

[0019] The plasma cell counts in the spleen for Compound 1, the control compound and the control antibody (Figure 6B) are provided. [Figure 6C]

[0019] The plasma cell counts in bone marrow for Compound 1, the control compound and the control antibody (Figure 6C) are provided. [Figure 7]

[0020] Compound 1 exposure in mouse cerebrospinal fluid over time following a single dose is provided. [Figure 8A]

[0021] Tumor burden in a mouse brain tumor model (Figure 8A) is provided. [Figure 8B]

[0021] BTK degradation in a mouse brain tumor model (Figure 8B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] 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.

[0016]

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

[0017] 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.

[0018]

[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, iverdimide, 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, "low IMiD activity" refers to a maximum degradation of Aiolos of less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, or less than 10% under physiological conditions. In certain embodiments, "low IMiD activity" refers to a maximum degradation of Ikaros of less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, or less than 10% under physiological conditions. An exemplary assay for Aiolos degradation is provided in the Examples herein.

[0019]

[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.

[0020]

[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.

[0021]

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

[0022]

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

[0023]

[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.

[0024]

[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.

[0025]

[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.

[0026]

[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.

[0027]

[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.

[0028]

[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.

[0029]

[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.

[0030]

[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.

[0031]

[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.

[0032]

[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.

[0033]

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

[0034]

[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.

[0035]

[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.

[0036]

[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.

[0037]

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

[0038]

[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.

[0039]

[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.

[0040]

[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.

[0041]

[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.

[0042]

[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.

[0043]

[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.

[0044]

[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.

[0045]

[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).

[0046]

[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.

[0047]

[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.

[0048]

[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.

[0049]

[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.

[0050]

[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.

[0051]

[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.

[0052]

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

[0053]

[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.

[0054]

[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).

[0055]

[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.

[0056]

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

[0057]

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

[0058]

[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.

[0059]

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

[0060]

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

[0061]

[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.

[0062]

[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.

[0063]

[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.

[0064]

[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.

[0065]

[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.

[0066]

[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.

[0067]

[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.

[0068]

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

[0069]

[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)-.

[0070]

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

[0071]

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

[0072]

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

[0073]

[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.

[0074]

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

[0075]

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

[0076]

[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.

[0077]

[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.

[0078]

[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.

[0079]

[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.

[0080]

[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.

[0081]

[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 an alkyl-C(O)O- or alkyl-OC(O)-. An alkylcarboxy group is an example of a carboxy group used terminally. A group is internal when it is present in the middle or at the end of a substituent of a chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0082]

[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.

[0083]

[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 , R A , R 1 , R 2 , L, L 1 Each of the specific groups for 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.

[0084]

[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 above in the definitions 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.

[0085]

[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.

[0086]

[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.

[0087]

[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.

[0088]

[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, those of skill in the art will recognize the range and application of the term "about."

[0089]

[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%.

[0090]

[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.

[0091]

[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.

[0092]

[0099] In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 1. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 2. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 3. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 4. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 5. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 6. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 7. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 8. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 9. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 10. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 11. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 12. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 13. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 14. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 15. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 16. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 17. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 18. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 19.In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 20. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 21. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 22. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 23. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 24. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 25. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 26. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 27. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 28. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 29. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 30. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 31. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 32. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 33. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 34. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 35. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 36. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 37. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 38.In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 39. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 40. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 41. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 42. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 43. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 44. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 45. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 46. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 47. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 48. In one embodiment of a compound or inhibitor 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 a compound or inhibitor described herein, ee, de, ee% or de% is 59. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 60. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 61. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 62. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 63. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 64. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 65. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 66. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 67. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 68. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 69. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 70. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 71. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 72. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 73. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 74. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 75. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 76.In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 77. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 78. In one embodiment of a compound or inhibitor described herein, ee, de, ee% or de% is 79. In one embodiment of a compound or inhibitor described herein, 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, the ee, de, ee% or de% is 87. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 88. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 89. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 90. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 91. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 92. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 93. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 94. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 95.In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 96. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 97. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 98. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 99. In one embodiment of a compound or inhibitor described herein, the ee, de, ee% or de% is 100. In certain embodiments, the compound or inhibitor described herein in Table 1 is The compounds or inhibitors described 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 are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 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.

[0093]

[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).

[0094]

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

[0095]

[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.

[0096] 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. Because many of these BTK degraders also have IMiD activity, these compounds have increased toxicity from the IMiD activity, which limits their potential use, and the IMiD activity is not expected to provide additional therapeutic benefit. In contrast, in some embodiments, the bifunctional compounds described herein are useful for degrading BTK in biological samples or patients with little or no IMiD activity. Thus, one embodiment of the present disclosure provides a method for treating a BTK-mediated disease or disorder. As used herein, the term "BTK-mediated disease or disorder" 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 or an autoimmune disorder or an inflammatory disorder. Examples of proliferative disorders include cancer.

[0097]

[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.

[0098]

[0105] In certain embodiments, the IMiD activity of the compound is less than 30% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is less than 25% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is less than 20% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is less than 15% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is less than 10% of the IMiD activity of the reference compound. In certain embodiments, the IMiD activity of the compound is less than 5% 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.

[0099]

[0106] 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. Particular compounds are described herein. The compound can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions.

[0100]

[0107] Due to the low IMiD activity, the compounds described herein may result in lower toxicity compared to other BTK degrading compounds, which may allow for higher doses of the compounds, longer duration of treatment, more frequent treatments, or any combination thereof.

[0101]

[0108] In certain embodiments, the compound is administered chronically. "Chronic administration" and "chronically" refer to administration that continues on a schedule for 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.

[0102]

[0109] 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.

[0103]

[0110] 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.

[0104]

[0111] 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).

[0105]

[0112] 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.

[0106]

[0113] In certain embodiments, the dose is selected from the group consisting of 10-100 mg / kg, 20-30 mg / kg, and 45-55 mg / kg. In certain embodiments, the dose is 10-100 mg / kg. In certain embodiments, the dose is 20-30 mg / kg. In certain embodiments, the dose is 45-55 mg / kg. In certain embodiments, the dose is about 10 mg / kg. In certain embodiments, the dose is about 100 mg / kg. In certain embodiments, the dose is about 20 mg / kg. In certain embodiments, the dose is about 30 mg / kg. In certain embodiments, the dose is about 45 mg / kg. In certain embodiments, the dose is about 55 mg / kg. In certain embodiments, the dose is 10 mg / kg. In certain embodiments, the dose is 100 mg / kg. In certain embodiments, the dose is 20 mg / kg. In certain embodiments, the dose is 30 mg / kg. In certain embodiments, the dose is 45 mg / kg. In certain embodiments, the dose is 55 mg / kg.

[0107]

[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.

[0108]

[0115] 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.

[0109]

[0116] In certain embodiments, the method is for the treatment or prevention of cancer, an autoimmune condition, or an inflammatory condition.

[0110]

[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.

[0111]

[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.

[0112]

[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).

[0113]

[0120] In another aspect, provided herein are methods for 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.

[0114]

[0121] 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.

[0115]

[0122] 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.

[0116]

[0123] 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.

[0117]

[0124] 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.

[0118]

[0125] In certain embodiments, the cancer is a brain tumor. In certain embodiments, the cancer is an acoustic neuroma. In certain embodiments, the cancer is an astrocytoma. In certain embodiments, the cancer is a pilocytic astrocytoma. In certain embodiments, the cancer is a juvenile pilocytic astrocytoma. In certain embodiments, the cancer is a low-grade astrocytoma. In certain embodiments, the cancer is an anaplastic astrocytoma. In certain embodiments, the cancer is a glioblastoma. In certain embodiments, the cancer is a chordoma. In certain embodiments, the cancer is a CNS lymphoma. In certain embodiments, the cancer is a craniopharyngioma. In certain embodiments, the cancer is a glioma. In certain embodiments, the cancer is a brain stem glioma. In certain embodiments, the cancer is an ependymoma. In certain embodiments, the cancer is a mixed glioma. In certain embodiments, the cancer is an optic glioma. In certain embodiments, the cancer is a subependymoma. In certain embodiments, the cancer is a medulloblastoma. In certain embodiments, the cancer is a meningioma. In certain embodiments, the cancer is a metastatic brain tumor. In certain embodiments, the cancer is an oligodendroglioma. In certain embodiments, the cancer is a pituitary tumor. In certain embodiments, the cancer is a primitive neuroectodermal (PNET). In certain embodiments, the cancer is a rhabdoid tumor. In certain embodiments, the cancer is a schwannoma.

[0119]

[0126] In certain embodiments, the disease is selected from the group consisting of Waldenstrom's macroglobulinemia, marginal zone lymphoma, mantle cell lymphoma, primary central nervous system lymphoma, and chronic lymphocytic leukemia. In certain embodiments, the disease is Waldenstrom's macroglobulinemia. In certain embodiments, the disease is marginal zone lymphoma. In certain embodiments, the disease is mantle cell lymphoma. In certain embodiments, the disease is primary central nervous system lymphoma. In certain embodiments, the disease is chronic lymphocytic leukemia.

[0120]

[0127] Examples of autoimmune disorders include urticaria, graft-versus-host disease (GVHD), acute graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Baro's disease, Behcet's disease, and rheumatoid arthritis (RH). -Cett's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophil fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myocarditis IBM, Interstitial Cystitis (IC), Juvenile Arthritis, Juvenile Diabetes Mellitus (Type 1 Diabetes), Juvenile Myositis (JM), Kawasaki Disease, Lambert-Eaton Syndrome, Leukocytoclastic Vasculitis, Lichen Planus, Lichen Sclerosus, Lignin Conjunctivitis, Linear IgA Disease (LAD), Lupus, Chronic Lyme Disease, Meniere's Disease, Microscopic Polyangiitis (MPA), Mixed Connective Tissue Disease (MCTD), Mooren's Ulcer, Mucca-Habermann Disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple Sclerosis, Myasthenia Gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis Optica, Neutropenia,Ocular cicatricial pemphigoid, Optic neuritis, Relapsing rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsplanitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndrome type I, II, III, Polymyalgia rheumatica, Polymyositis, Post-myocardial infarction syndrome, Post-pericardiotomy syndrome, Biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy These include: relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)). In certain embodiments, the autoimmune disorder is warm autoimmune hemolytic anemia (wAIHA). In certain embodiments, the autoimmune disorder is systemic sclerosis. In certain embodiments, the autoimmune disorder is systemic sclerosis, membranous nephropathy.

[0121]

[0128] Examples of inflammatory disorders include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, and rhinitis. , pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland / parotitis, cheilitis, pulpitis, subglossitis, esophagitis, gastritis, gastroenteritis, enteritis, colitis, small intestine colitis, duodenitis, ileitis, appendicitis, proctitis, hepatitis, ascending biliary These include: ductitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, soft tissue, myositis, synovitis / tendinitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendonitis, panniculitis, osteochondritis: osteitis / osteomyelitis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis and lymphadenitis.

[0122]

[0129] 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.

[0123] compound

[0130] 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 is capable of specifically binding Bruton's tyrosine kinase (BTK). The other moiety is capable of recruiting a ubiquitin ligase and degrading 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.

[0124]

[0131] 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.

[0125]

[0132] 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 1~6Ring 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-, -C≡C-, 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; 4is 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); each of m, n, and p is independently an integer from 1 to 3 (e.g., 1, 2, or 3); Y is [ka] each J is independently aryl or heteroaryl; each K is independently absent, -CH-, -NH-, -NMe-, or -O-; 1~4 The alkyl is optionally and independently substituted with up to three halo, -CN, -COOH, -COONH2, -NH2, or -CF3.

[0126]

[0133] All moieties of the linking group L as defined in the 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.

[0127]

[0134] 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.

[0128]

[0135] 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.

[0129]

[0136] 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.

[0130]

[0137] 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.

[0131]

[0138] 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.

[0132]

[0139] In some embodiments, X 1 , X 2 and X 5 At least one of is -N(R)-, -C(O)-N(R)-, or -CH2-.

[0133]

[0140] In some embodiments, X 1 is -C(O)-N(R)-.

[0134]

[0141] In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n -or-C 1~5 It is alkyl-.

[0135]

[0142] In some embodiments, X 3 is a bond, -C≡C-, -C 1~4 It is alkyl- or -N(R)-.

[0136]

[0143] In some embodiments, X 4is a bond, -CH2- or -N(R)-.

[0137]

[0144] In some embodiments, X 5 is a bond.

[0138]

[0145] In some embodiments, X 1 is -(O-CH2-CH2-CH2) m m is 1 and X 2 is -C(O)-N(R)-.

[0139]

[0146] In some embodiments, X 1 -CH2-, -C(O)-, [ka] It is.

[0140]

[0147] In some embodiments, X 2 is a bond, -C(O)-, -C 1~5 Alkyl-, [ka] It is.

[0141]

[0148] In some embodiments, X 3 is a bond, -C 1~4 It is alkyl-, 4- to 6-membered cycloalkyl or -N(R)-.

[0142]

[0149] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -NH-, [ka] It is.

[0143]

[0150] In some embodiments, X 4 is a join, [ka] , -C 1~4 Alkyl-, -CH2-CH2-N(R)- or -N(R)-.

[0144]

[0151] In some embodiments, X 5 is a bond, -C 1~4 Alkyl-, -N(R)- or -C(O)-N(R)-.

[0145]

[0152] In some embodiments, L is [ka] [ka] [ka] [ka] [ka] In some embodiments, Y is [ka] wherein each J is independently aryl or heteroaryl and each K is independently absent, -CH2-, -NH-, -NMe-, or -O-.

[0146]

[0153] In some embodiments, Y is [ka] wherein each J is independently aryl or heteroaryl and each K is independently absent, -CH2-, -NH-, -NMe-, or -O-.

[0147]

[0154] 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 1~5 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 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) pand 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.

[0148]

[0155] 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 other examples, ring B1 is [ka] It is.

[0149]

[0156] In some embodiments, X 1 teeth, [ka] It is.

[0150]

[0157] 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.

[0151]

[0158] 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.

[0152]

[0159] In some embodiments, L is [ka] It is.

[0153]

[0160] In some embodiments, W is N and D is a bond.

[0154]

[0161] 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 -, -C1~5 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-, -C≡C-, 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.

[0155]

[0162] In some embodiments, W is N.

[0156]

[0163] In some embodiments, Ring C is [ka] For example, ring C is [ka] In other examples, ring C is [ka] It is.

[0157]

[0164] 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 examples, X 1 teeth, [ka] It is.

[0158]

[0165] 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-).

[0159]

[0166] 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.

[0160]

[0167] In some embodiments, L is [ka] For example, L is [ka] It is.

[0161]

[0168] 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 -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 1~4 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.

[0162]

[0169] In some embodiments, ring A is [ka] It is.

[0163]

[0170] 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.

[0164]

[0171] 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-.

[0165]

[0172] 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.

[0166]

[0173] In some embodiments, L is [ka] It is.

[0167]

[0174] 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.

[0168]

[0175] In some embodiments, R 10 teeth, [ka] It is.

[0169]

[0176] In some embodiments, R 10 teeth, [ka] It is.

[0170]

[0177] 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 -C1~5 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 teeth, [ka] It is.

[0171]

[0178] In some embodiments, ring A is [ka] It is.

[0172]

[0179] 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.

[0173]

[0180] In some embodiments, X 2 is a bond, -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. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0174]

[0181] 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.

[0175]

[0182] In some embodiments, L is [ka] It is.

[0176]

[0183] In some embodiments, R 10 teeth, [ka] It is.

[0177]

[0184] In some embodiments, R 10 teeth, [ka] It is.

[0178]

[0185] 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 10The term is as defined in the compounds of formula (A), (D) and (D-1).

[0179]

[0186] In some embodiments, ring A is [ka] It is.

[0180]

[0187] 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.

[0181]

[0188] 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-.

[0182]

[0189] 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.

[0183]

[0190] In some embodiments, L is [ka] It is.

[0184]

[0191] In some embodiments, R 10 teeth, [ka] It is.

[0185]

[0192] In some embodiments, R 10 teeth, [ka] It is.

[0186]

[0193] 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 1~5alkyl-, 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 1~5 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-, -C≡C-, 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 , X3 , X 4 Or X 5 is bonded directly to L at the nitrogen atom of

[0187]

[0194] 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 other examples, ring B is [ka] It is.

[0188]

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

[0189]

[0196] In some embodiments, ring A is [ka] It is.

[0190]

[0197] In some embodiments, X 5 is -N(R)-.

[0191]

[0198] In some embodiments, X 5is -C(O)-N(R)-.

[0192]

[0199] In some embodiments, X 5 is a bond.

[0193]

[0200] In some embodiments, L is [ka] [ka] [ka] It is.

[0194]

[0201] 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 1~5alkyl-, 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-, -C≡C-, 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.

[0195]

[0202] In some embodiments, W is N.

[0196]

[0203] 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.

[0197]

[0204] In some embodiments, X 2 is a bond or -C 1~5 It is alkyl-.

[0198]

[0205] In some embodiments, X 3is 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.

[0199]

[0206] In some embodiments, L is [ka] It is.

[0200]

[0207] In some embodiments, L is [ka] It is.

[0201]

[0208] In some embodiments, W is N; L is [ka] It is.

[0202]

[0209] 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).

[0203]

[0210] In some embodiments, R 1 is methyl.

[0204]

[0211] In some embodiments, W is N.

[0205]

[0212] 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.

[0206]

[0213] In some embodiments, R 10A is -H, or [ka] It is.

[0207]

[0214] 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.

[0208]

[0215] In some embodiments, X 1 is methylene (-CH2-), ethylene (-CH2CH2-) or propylene (-CH2CH2CH2-). For example, X 1 is methylene (-CH2-).

[0209]

[0216] In some embodiments, ring C-1 is [ka] For example, ring C-1 is [ka] It is.

[0210]

[0217] 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 1~5alkyl-, 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-, -C≡C-, 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 5-6 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.

[0211]

[0218] 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 1~3alkyl; ring A is phenyl, 9-10 membered bicyclic aryl, or 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; X5 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 -C 1~4 alkyl; and q is 0, 1 or 2.

[0212]

[0219] In some embodiments, q is 0. In other embodiments, q is 1 and R 2 is -F.

[0213]

[0220] In some embodiments, Z is -CH2- or -C(O)-.

[0214]

[0221] In some embodiments, R 1 -C 1~3 For example, R 1 is methyl, ethyl, propyl, or iso-propyl. 1 is methyl.

[0215]

[0222] In some embodiments, each R is independently -H or -CH. For example, each R is -H.

[0216]

[0223] 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 1~5In 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 1 is 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 1is methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), etc. In some embodiments, X 1 -CH2-, -C(O)-, [ka] It is.

[0217]

[0224] 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 examples, X is alkyl. 2 is -(O-CH2-CH2) n -or-(CH2-CH2-O) n - (wherein n is 1 or 2). In other examples, X 2 -C 1~5 For example, X 2 is methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), etc. 2is 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.

[0218]

[0225] 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).

[0219]

[0226] 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 join, [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.

[0220]

[0227] 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)-.

[0221]

[0228] In some embodiments, L is [ka] [ka] [ka] [ka] is selected from.

[0222]

[0229] 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 1~5 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 - 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, -C1~4 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.

[0223]

[0230] In other embodiments, each of the variables in formula (IA) is as defined herein for compounds of formula (X) or (I).

[0224]

[0231] 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.

[0225]

[0232] In other embodiments, each of the variables in formula (IB) is as defined herein for compounds of formula (X) or (I).

[0226]

[0233] 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 1 is 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.

[0227]

[0234] 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 1~5 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 - 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 1~4alkyl; and q is 0, 1 or 2.

[0228]

[0235] In certain embodiments of any of Formulas AX or I-IV, Y is [ka] wherein each J is independently aryl or heteroaryl; and each K is independently absent, -CH2-, -NH-, -NMe-, or -O-.

[0229]

[0236] In certain embodiments of any of Formulas AX or I-IV, Y is [ka] wherein each J is independently aryl or heteroaryl; and each K is independently absent, -CH2-, -NH-, -NMe-, or -O-.

[0230]

[0237] In certain embodiments of any of Formulas AX or I-IV, Y is [ka] Either:

[0231]

[0238] In certain embodiments of any of Formulas AX or I-IV, Y is [ka] Either:

[0232] General synthesis scheme

[0239] 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.

[0233]

[0240] General Procedure 1: Amide Coupling [ka]

[0241] Intermediate (3-1), which can be generated by deesterifying intermediate (1-6), is treated with an amine, Y-NH2, under coupling conditions to generate compound (3-2) of the present disclosure, in which the terminal linking group of L is an amide.

[0234]

[0242] General Procedure 2: Reductive amination. [ka]

[0243] Intermediate (3-1), which can be generated by deesterifying intermediate (1-6), is treated with an amine, Y-NH2, under coupling conditions to generate compounds of the invention (3-2), in which the terminal linking group of L is an amide.

[0235]

[0244] General Procedure 3: Aryl Fluoride Substitution. [ka]

[0245] 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.

[0236]

[0246] The compounds in Table 1 can be synthesized using the synthetic scheme described above.

[0237] [Table 1]

[0238] [Table 2]

[0239] [Table 3]

[0240] [Table 4]

[0241] [Table 5]

[0242] [Table 6]

[0243] [Table 7]

[0244] Formulation and Administration

[0248] Pharmaceutical Compositions

[0249] 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.

[0245]

[0250] 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.

[0246]

[0251] The term "patient", as used herein, means an animal, alternatively a mammal, and alternatively a human.

[0247]

[0252] 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 provide, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0248]

[0253] 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.

[0249]

[0254] 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.

[0250]

[0255] 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.

[0251]

[0256] 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.

[0252]

[0257] 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.

[0253]

[0258] 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.

[0254] Administration

[0259] The composition of the present disclosure is administered orally. The pharma-ceutically acceptable composition described herein 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. For oral administration in capsule form, useful diluents 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.

[0255]

[0260] 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.

[0256]

[0261] 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.

[0257]

[0262] 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 may 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.

[0258]

[0263] 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.

[0259]

[0264] 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.

[0260]

[0265] 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.

[0261]

[0266] 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."

[0262]

[0267] 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.

[0263]

[0268] 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.

[0264]

[0269] 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.

[0265]

[0270] 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

[0266] Working Example

[0271] 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.

[0267] Example 1

[0272] General Procedure 1: Amide Coupling

[0273] 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.

[0268]

[0274] General Procedure 2: Reductive Amination

[0275] 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.

[0269]

[0276] General Procedure 3: Aryl Fluoride Substitution

[0277] 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.

[0270]

[0278] Compounds 10-22 are prepared according to PCT / US2019 / 56112, filed October 14, 2019, which is incorporated by reference in its entirety.

[0271] Example 2

[0279] Prepared according to general procedure 2:

[0280] compound 1 [ka]

[0281] 1 H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),10.85(s,1H),8.71(d,J=8.2Hz,1H),8.32(d,J=2.9Hz,1H),7.85(d,J=8.8Hz,1H),7.76(s,1H),7.67(s,1H),7.5 1(d,J=8.1Hz,2H),7.42(dd,J=8.9,2.9Hz,1H),7.34(s,1H),7.18(d,J=8.2Hz,2H),4.75(ddd,J=13.2,8.2,5.4Hz,1H),4.34(dd ,J=39.7,12.8Hz,2H),3.96(d,J=12.5Hz,2H),3.62(d,J=11.0Hz,1H),3.28(dd,J=14.4,7.4Hz,5H),3.11-2.76(m,8H),2.73(s, 3H),2.19(dd,J=10.7,5.3Hz,3H),2.08-1.93(m,3H),1.89-1.71(m,8H),1.59(d,J=29.1Hz,4H),1.23(d,J=14.3Hz,5H).LCMS:C 42 H 54 N 12 O5 theoretical value: 806, measured value: m / z=807 [M+H] + .

[0272]

[0282] compound 2 [ka]

[0283] 1H NMR(500MHz,DMSO-d6)δ 11.30(s,1H),10.86(s,1H),8.71(d,J=8.1Hz,1H),8.36(s,1H),7.88(d,J=8.7Hz,1H),7.79(s,1H),7.69(s,1H), 7.58(d,J=7.9Hz,2H),7.46(d,J=8.8Hz,1H),7.36(s,1H),7.19(d,J=8.2Hz,2H),4.75(ddd,J=13.1,8.2,5.4Hz,1 H),4.42-4.25(m,2H),4.01(d,J=12.9Hz,2H),3.65(dd,J=13.8,7.9Hz,3H),3.27(t,J=8.3Hz,3H),3.17-2.87(m, 6H),2.86-2.70(m,5H),2.27-2.10(m,2H),2.11-1.69(m,12H),1.68-1.47(m,2H),1.30(d,J=52.1Hz,3H).LCMS:C 42 H 54 N 12 O5 theoretical value: 806, measured value: m / z=807 [M+H] + .

[0273]

[0284] compound 3 [ka]

[0285] Prepared by a procedure similar to 3-((4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide but starting from methyl 5-bromopyrimidine-2-carboxylate. Obtained 5-(4-((4-(4-((3-carbamoyl-6-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-N-((RS)-2,6-dioxopiperidin-3-yl)pyrimidine-2-carboxamide (33 mg). 11H NMR (500 MHz, DMSO-d6) δ 11.35 - 11.26 (m, 1H), 10.88 (s, 1H), 8.91 (s, 1H), 8.84 (d, J = 8.2 Hz, 1H), 8.61 (s, 2H), 7.80 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.36 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 4.76 (ddd, J = 13.0, 8.3, 5.3 Hz, 1H), 4.38 - 4.27 (m, 2H), 4.09 (d, J = 12.8 Hz, 2H), 3.68 - 3.61 (m, 3H), 3.35 (dt, J = 14.2, 7.7 Hz, 2H), 3.27 (t, J = 8.0 Hz, 2H), 3.14 - 2.92 (m, 8H), 2.87 - 2.75 (m, 2H), 2.73 (s, 3H), 2.60 - 2.44 (m, 1H), 2.26 - 2.13 (m, 2H), 2.10 - 1.72 (m, 10H), 1.62 - 1.53 (m, 1H), 1.34 (q, J = 11.4 Hz, 2H). LCMS: C 41 H 53 N 13 Theoretical value of O5 is 807, measured value: m / z = 808 [M + H] + 。

[0274]

[0286] Compound 4

Chem.

[0287] 1H NMR (500MHz, acetonitrile-d3) δ 11.26(s,1H), 9.59(s,1H), 8.78(s,1H), 8.35-8.26(m,2H), 7.95(d,J=8.8Hz,1H), 7.70(s,1H), 7.61(s,1H), 7.52(d,J=8.5Hz,1H), 7.43(s,1H), 7.37(dd,J=8.9,2.8Hz,1H), 7.15(d,J=8.4Hz,1H), 5.84(s,1H), 4.81-4.70(m,1H), 4.59(d,J=15 .2Hz,1H),4.18(d,J=15.1Hz,1H),3.98(d,J=13.1Hz,2H),3.73(t,J=5.4Hz,5H),3.44-3.22(m,2H),3.13(d,J=20.2Hz,3 LCMS:C 36 H 44 N 10 O4 theoretical value 680, measured value: m / z=681 [M+H] + . [ka]

[0275]

[0288] A mixture of piperidine (2.55 mL, 2194 mg, 25.76 mmol), 3,5-dichloropyrazine-2-carbonitrile (4075 mg, 23.42 mmol), N,N-diisopropylethylamine (8.16 mL, 46.84 mmol) and DMF (100 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 (4.08 g, 78%). LCMS: C 10 H 11 ClN4 theoretical value 222, measured value: m / z = 223 [M+H] + .

[0276]

[0289] A mixture of tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (1398.42 mg, 5.63 mmol), 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile (1254 mg, 5.63 mmol), (acetyloxy)paradioacetate (252.86 mg, 1.13 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane (701.32 mg, 1.13 mmol) and dicesium carbonate (5504 mg, 16.89 mmol) was degassed and filled with N2 five times. Dioxane (30 mL) was added and 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 (1.83 g, 74.8%). LCMS: C 24 H 30 N6O2 theoretical value 434, measured value: m / z = 435 [M+H] + .

[0277]

[0290] A 30% aqueous solution of H2O2 (7.11 mL) was added to a mixture of dicesium carbonate (1372 mg, 4.21 mmol), DMSO (2 mL), MeOH (40 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 (1.647 g, 86.4%). LCMS: C 24 H 32N6O3 theoretical value 452, measured value: m / z = 453 [M+H] + .

[0278]

[0291] 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 (1.28 g, 99.8%). LCMS: C 19 H 24 NO theoretical value: 352, measured value: m / z=353 [M+H] + .

[0279]

[0292] Sodium bis(acetyloxy)borane idyl acetate (32.47 mg, 0.15 mmol) was added to a mixture of triethylamine (0.03 mL, 0.20 mmol), rac-N-[(3R)-2,6-dioxopiperidin-3-yl]-5-(4-formylpiperidin-1-yl)pyridine-2-carboxamide (21.11 mg, 0.06 mmol), 5-(piperidin-1-yl)-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazine-2-carboxamide (18.00 mg, 0.05 mmol) and DCE (1 mL). The mixture was filtered through celite, washed with CHCl / EtOAc, concentrated and purified by HPLC (5-95% MeCN in H0 with 0.1% TFA) to give rac-3-[(2-{[1-(6-{[(3R)-2,6-dioxopiperidin-3-yl]carbamoyl}pyridin-3-yl)piperidin-4-yl]methyl}-3,4-dihydro-1H-isoquinolin-6-yl)amino]-5-(piperidin-1-yl)pyrazine-2-carboxamide (0.0130 g, 37.4%).

[0280]

[0293] compound 5 [ka]

[0294] Prepared similar procedure as 3-((4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide but with methyl 4-bromobenzoate as starting material. 3-((4-(1-((1-(4-(((RS)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (13 mg) was obtained. 1 H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),10.87(s,1H),7.76(d,J=2.9Hz,1H),7.67(s,1H),7.51(d,J=8.2Hz,2H),7.34(s,2H),7.17(d,J=8.2Hz,2H),6.95( d,J=8.3Hz,2H),5.01(s,1H),4.72(s,0H),4.37(d,J=12.3Hz,1H),4.29(d,J=13.3Hz,1H),3.82(d,J=12.3Hz,2H),3.63(ddt,J=10 .9,8.4,4.2Hz,1H),3.40-3.25(m,3H),3.03(dd,J=23.3,11.6Hz,1H),2.98-2.89(m,4H),2.73(s,9H),2.48-2.33(m,3H),2.21-2. 17(m,2H),2.09(s,1H),1.97(d,J=13.5Hz,3H),1.87-1.72(m,7H),1.65-1.52(m,3H),1.20(t,J=12.3Hz,2H),0.08(s,1H).LCMS:C 43 H 55 N 11 O5 theoretical value 805, actual value: m / z=806 [M+H]+ .

[0281]

[0295] Compound 6

change

[0296] 1 H NMR(500MHz,アセトトトリル-d3)δ 11.17(s,1H),8.91(s,1H),7.65(d,J=8.2Hz,2H),7.58(s,1H),7.41(s,1H),7.24(d,J=8.2Hz,2H),6.84(d,J=8.6H z,1H),6.41(s,1H),6.33(d,J=8.7Hz,1H),5.79(s,1H),5.14(dd,J=12.9,5.3Hz,1H),3.81-3.65(m,5H),3.61(t,J =8.3Hz,1H),3.49-3.39(m,2H),3.38-3.31(m,4H),3.27-3.20(m,2H),3.20-3.12(m,1H),3.10-2.96(m,2H),2.95- 2.80(m,3H),2.80-2.67(m,2H),2.54-2.01(m,6H),1.92-1.80(m,1H),1.78-1.70(m,2H),1.70-1.65(m,4H).LCMS:C 39 H 48 N 10 O4 theoretical value 720, measured value: m / z=721[M+H] + .

[0282]

[0297] Compound 7

change

[0298] 1H NMR (500MHz, acetonitrile-d3) δ 11.18(s,1H), 9.77(s,1H), 8.91(s,1H), 7.65(d,J=8.2Hz,2H), 7.58(s,1H), 7.41(s,1H), 7.24(d,J=8.2Hz,2H), 6.85(d,J=8.5Hz,1H), 6.41(s,1H), 6.33(d,J=8.5Hz,1H), 5.80(s,1H), 5.15(dd,J=12.8,5.4Hz,1H), 3.78-3.70(m,5H), 3.6 1(t,J=8.5Hz,1H),3.49-3.39(m,2H),3.38-3.31(m,4H),3.28-3.20(m,2H),3.20-3.13(m,1H),3.12-2.96(m,2H),2.9 2-2.84(m,3H),2.80-2.71(m,2H),2.57-2.03(m,6H),1.92-1.79(m,1H),1.80-1.71(m,2H),1.71-1.65(m,4H).LCMS:C 39 H 48 N 10 O4 theoretical value 720, measured value: m / z=721 [M+H] + .

[0283]

[0299] Intermediate 1 [ka]

[0300] Step 1: tert-Butyl (3R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]pyrrolidine-1-carboxylate

[0301] TBDPSCl (32.3 mL, 124 mmol) was added to a mixture of tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (25.0 g, 124 mmol) and imidazole (10.1 g, 149 mmol) in DCM (500 mL) at 0° C. under nitrogen. The mixture was stirred at 23° C. for 16 h and diluted with water (300 mL). The organic phase was washed with water (100 mL), brine (3×100 mL), dried (Na2SO4), filtered and concentrated to give the title product as an oil (54.0 g, 99%). m / z: ES + [M-C6H5-tBu+H]+ = 306.2, LCMS(A05);t R =2.47 minutes.

[0302] 1 H NMR(500MHz,CDCl3)δ 7.67-7.60(m,4H),7.46-7.34(m,6H),3.64-3.55(m,2H),3.45-3.37(m,1H),3.37-3.22(m,1H),3.17-3.0 7(m,1H),2.42(m,1H),1.97-1.86(m,1H),1.74-1.62(m,1H),1.60(s,1H),1.46(s,9H),1.08-1.02(m,9H);

[0284]

[0303] Step 2: tert-Butyl-diphenyl-[[(3R)-pyrrolidin-3-yl]methoxy]silane 2,2,2-trifluoroacetic acid

[0304] TFA (50 mL) was added to a mixture of tert-butyl (3R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]pyrrolidine-1-carboxylate (54.0 g, 123 mmol) in DCM (200 mL) at 23° C. under nitrogen. The mixture was stirred at 23° C. for 1.5 h and concentrated. The residue was diluted with PhMe (150 mL) and concentrated (process repeated twice) to give the title compound as an oil (55.7 g, quantitative). m / z: ES + [M+H-TFA] + = 340.3, LCMS(A05);t R =2.32 minutes. 1 H NMR(500MHz,CDCl3)δ 8.82(s,2H),7.65-7.57(m,4H),7.52-7.40(m,6H),3.65(d,J=6.4Hz,2H),3.35-3.27(m,1H),3.24-3 .10(m,2H),3.01-2.91(m,1H),2.58-2.52(m,1H),2.04-1.93(m,1H),1.74-1.63(m,1H),1.01(s,9H);

[0285]

[0305] Step 3: Dimethyl 2-bromopentanedioate

[0306] A solution of NaNO2 (25.5 g, 370 mmol) in water (50 mL) was added to a mixture of (2S)-2-aminopentanedioic acid (30 g, 204 mmol), NaBr (73.2 g, 711 mol) and HBr (50 mL, 48% in water) in water (100 mL) at 0 °C (internal temperature kept below 10 °C) under nitrogen. The mixture was stirred at 23 °C for 6 h and H2SO4 (25.0 mL) was added at 23 °C. The mixture was extracted with Et2O (4 × 70.0 mL) and the combined organic phase was washed with brine (2 × 50.0 mL), dried (Na2SO4), filtered and concentrated. H2SO4 (10.0 mL) was added to a mixture of the residue in MeOH (80.0 mL) at 23 °C under nitrogen. The mixture was refluxed for 16 h, cooled to 23 °C and concentrated. The residue was diluted with Et2O (100 mL) and water (100 mL). The aqueous phase was extracted with Et2O (4 x 50.0 mL). The combined organic layers were washed with water (60.0 mL), NaHCO3 (2 x 60.0 mL), brine (2 x 50.0 mL), dried (Na2SO4), filtered and concentrated to give the title compound as an oil (19 g, 39%). 1 H NMR(400MHz,CDCl3)δ 4.34(dd,J=8.5,5.8Hz,1H),3.75(s,3H),3.65(s,3H),2.52-2.45(m,2H),2.40-2.30(m,1H),2.26(m,1H).

[0286]

[0307] Step 4: 5-Bromo-N-methyl-2-nitro-aniline

[0308] Methylamine (56.6 mL, 455 mmol, 33 wt % in EtOH) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (50.0 g, 227 mmol) in EtOH (455 mL) at 23° C. under nitrogen. The mixture was stirred at 23° C. for 30 min, filtered and washed with cold EtOH (200 mL) to give the title compound as a solid (48.2 g, 92%). m / z (ES + ) [M+H] + = 231.0, LCMS(A05);t R =2.51 minutes.

[0309] 1H NMR(400MHz,DMSO-d6)δ 8.23(d,J=4.3Hz,1H),7.98(d,J=9.1Hz,1H),7.17(d,J=2.0Hz,1H),6.82(dd,J=9.1,2.1Hz,1H),2.95(d,J=5.0Hz,3H)

[0287]

[0310] Step 5: [(3R)-1-[3-(methylamino)-4-nitro-phenyl]pyrrolidin-3-yl]methanol

[0311] RuPhos-Pd-G3 (2.71 g, 3.25 mmol) was added to a mixture of 5-bromo-N-methyl-2-nitro-aniline (25 g, 108 mmol), tert-butyl-diphenyl-[[(3R)-pyrrolidin-3-yl]methoxy]silane 2,2,2-trifluoroacetic acid (60.0 g, 119 mmol, 90% purity) and Cs2CO3 (106 g, 325 mmol) in PhMe (600 mL) under nitrogen at 23 °C. The mixture was degassed by bubbling nitrogen for 15 min at 23 °C, stirred at 100 °C for 19 h, cooled to 23 °C, filtered and concentrated. The product was purified by silica gel chromatography (2 x 330 g cartridges in series) with hexanes and EtOAc (0-50%) to give the title compound as a solid (41.0 g, 77%). m / z: ES + [M+H] + =490.4.

[0312] 1 H NMR (400MHz, DMSO-d6) δ 8.36(d,J=4.9Hz,1H),7.91(d,J=9.6Hz,1H),7.64-7.57(m,4H),7.50-7.37( m,6H),6.07(dd,J=9.6,2.5Hz,1H),5.50(d,J=2.4Hz,1H),3.68(d,J=6.6Hz,2 H),3.54-3.46(m,1H),3.46-3.37(m,2H),3.27-3.21(m,1H),2.90(d,J=5.0H z,3H),2.64-2.55(m,1H),2.16-2.04(m,1H),1.90-1.79(m,1H),1.01(s,9H).

[0288]

[0313] Step 6: 4-[(3R)-3-Ethylpyrrolidin-1-yl]-N2-methyl-benzene-1,2-diamine

[0314] A solution of [(3R)-1-[3-(methylamino)-4-nitro-phenyl]pyrrolidin-3-yl]methanol (20.0 g, 40.8 mmol) in THF (100 mL) and EtOH (100 mL) was added to 10% Pd / C (4.4 g, 4.1 mmol, 50% wet) at 23° C. under nitrogen. The mixture was refluxed and hydrazine hydrate (16 mL, 163 mmol) was added (over 30 min). The mixture was refluxed for 2 h, cooled to 23° C., filtered (Celite), washed with EtOAc (200 mL) and EtOH (200 mL), and concentrated to give the title compound as an oil (18.0 g, 96%). m / z ESI + [M-Ph-tBu+H] + =328.16

[0315] 1 H NMR(400MHz,DMSO-d6)δ 7.65-7.59(m,4H),7.48-7.38(m,6H),6.45-6.40(m,1H),5.71(d,J=2.5Hz,1H),5.66 (dd,J=8.1,2.5Hz,1H),4.50(d,J=4.9Hz,1H),3.65(d,J=6.8Hz,2H),3.33(br.s,2H) ,3.21(dd,J=9.1,7.6Hz,1H),3.14-3.07(m,2H),2.97(dd,J=9.2,5.9Hz,1H),2.68(d ,J=4.2Hz,3H),2.56-2.51(m,1H),2.05-1.95(m,1H),1.76-1.67(m,1H),1.01(s,9H).

[0289]

[0316] Step 7: 5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-1H-benzimidazol-2-one

[0317] A mixture of triphosgene (8.09 g, 27.3 mmol) in DCM (30 mL) was added to a mixture of ISN-4-[(3R)-3-ethylpyrrolidin-1-yl]-N2-methyl-benzene-1,2-diamine (38.0 g, 82.7 mmol) and DIPEA (115 mL, 661 mmol) in DCM (300 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min and diluted with water (300 mL). The aqueous phase was extracted with DCM (2 x 100 mL) and the combined organic phases were washed with brine (50.0 mL), dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography (2 x 330 g cartridges) with DCM and MeOH (0-10%) to give the title compound as a solid (21 g, 52%). m / z: ES + [M+H] + =486.4.

[0290]

[0318] Step 8: Dimethyl 2-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]pentanedioate

[0319] Dimethyl 2-bromopentanedioate (10.9 g, 30.9 mmol, 68% purity) was added to a mixture of 5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-1H-benzimidazol-2-one (10.0 g, 20.6 mmol) and Cs2CO3 (20.3 g, 62.3 mmol) in DMF (100 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, and diluted with EtOAc (200 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL) and the combined organic phase was washed with brine (2 x 50 mL), dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography (220 g cartridge) with hexanes and EtOAc (0-50%) to give the title compound as a solid (9.00 g, 68%). m / z: ES + [M+H] + = 644.4, LCMS(A05);t R =2.33 minutes.

[0291]

[0320] Step 9: 2-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]pentanedioic acid

[0321] Aqueous NaOH (5M, 14.0 mL, 70.0 mmol) was added to a mixture of dimethyl 2-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]pentanedioate (9.00 g, 14.0 mmol) in a mixture of THF and water (200 mL, 1:1 v / v) at 23° C. under nitrogen. The mixture was stirred at 23° C. for 1 h and diluted with EtOAc (100 mL) and aqueous HCl (1 M, 80.0 mL). The aqueous phase was extracted with EtOAc (3×50.0 mL) and the combined organic phases were washed with brine (2×50.0 mL), dried (Na2SO4), filtered and concentrated to give the title compound as a solid (8.6 g, quantitative). 1 H NMR (500MHz, DMSO-d6) δ 7.67-7.58(m,4H),7.51-7.36(m,6H),6.93-6.81(m,1H),6.41-6.30(m,1H), 6.27-6.17(m,1H),4.95(dd,J=10.8,5.0Hz,1H),3.69(d,J=6.6Hz,2H),3.38- 3.31(m,1H),3.29(s,3H),3.27-3.19(m,2H),3.12-3.03(m,1H),2.65-2.55( m,1H),2.41-2.21(m,2H),2.21-2.02(m,3H),1.86-1.79(m,1H),1.02(s,9H).

[0292]

[0322] Step 10: 3-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

[0323] HATU (6.792 g, 17.9 mmol) was added to a mixture of 2-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]pentanedioic acid (5.0 g, 8.12 mmol), trifluoroacetamide (1.01 g, 8.93 mmol) and DIPEA (5.66 mL, 32.5 mmol) in DMF (50.0 mL) under nitrogen at 23° C. The mixture was stirred at 23° C. for 18 h and concentrated. The product was purified by silica gel chromatography (120 g cartridge) with DCM and MeOH (0-5%) to give the title compound as a solid (3.30 g, 68%). 1 H NMR(500MHz,DMSO-d6)δ 11.04(s,1H),7.65-7.60(m,4H),7.50-7.39(m,6H),6.93-6.87(m,1H),6.35(d,J=2.1H z,1H),6.20(dd,J=8.6,2.2Hz,1H),5.26(dd,J=12.8,5.4Hz,1H),3.69(d,J=6.6Hz,2H) ,3.29(s,3H),3.26-3.20(m,2H),3.08-3.02(m,1H),2.93-2.85(m,1H),2.70(s,2H),2. 67-2.55(m,2H),2.13-2.04(m,1H),1.98-1.95(m,1H),1.86-1.76(m,1H),1.02(s,9H).

[0293]

[0324] Step 11: 3-[5-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

[0325] TBAF (8.00 mL, 8.00 mmol, 1 M in THF) was added to a mixture of 3-[5-[(3R)-3-ethylpyrrolidin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (3.20 g, 5.36 mmol) in THF (20 mL) at 23° C. under nitrogen. The mixture was stirred at 23° C. for 3 h and concentrated. The product was purified by silica gel chromatography (220 g cartridge) with DCM and MeOH (0-12%) to give the title compound as a solid (1.30 g, 67%). m / z: ES + [M] + =358.2.

[0326] 1 H NMR(400MHz,DMSO-d6)δ 11.03(s,1H),6.89(d,J=8.5Hz,1H),6.37(d,J=2.2Hz,1H),6.21(dd,J=8.6,2.2H z,1H),5.25(dd,J=12.9,5.4Hz,1H),4.69(t,J=5.2Hz,1H),3.48-3.36(m,2H),3. 37-3.32(m,1H),3.29(s,3H),3.27-3.15(m,2H),3.05-2.97(m,1H),2.95-2.83(m ,1H),2.73-2.55(m,2H),2.48-2.37(m,1H),2.08-1.92(m,2H),1.79-1.68(m,1H).

[0294]

[0327] Step 12: (3R)-1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine-3-carbaldehyde

[0328] To a mixture of (3RS)-3-{5-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl}piperidine-2,6-dione (33.50 mg, 0.09 mmol) in DMSO (1.00 mL) was added triethylamine (0.26 mL, 0.19 g, 1.87 mmol) followed by sulfur trioxide pyridine complex (148.77 mg, 0.93 mmol). After 25 min, water was added and the mixture was extracted twice with DCM. The combined organic layers were concentrated to give the title compound without further purification. m / z: ES + [M] + =357.2.

[0295]

[0329] compound 8 [ka]

[0330] To a mixture of 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide (27.28 mg, 0.06 mmol) in DCM (1.00 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). The mixture became basic to pH paper. The resulting suspension was added to (3R)-1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine-3-carbaldehyde (20.31 mg, 0.06 mmol) followed by sodium triacetoxyborohydride (36.24 mg, 0.17 mmol). After 45 min, water was added. The mixture was extracted twice with DCM. The combined organic layers were concentrated and purified by HPLC (MeCN / H2O with 0.1% TFA) to give 3-((4-(1-(((3S)-1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (22.3 mg, 47%). 1H NMR (500MHz, acetonitrile-d3) δ 11.14(s,1H), 9.07(s,1H), 8.92(s,1H), 7.66-7.56(m,3H), 7.43(s,1H), 7.23(d,J=8.3Hz,2H), 6.85(d,J=8.4Hz,1H), 6.44(s,1H), 6.36(s,1H), 5.83(s,1H), 5.15(dd,J=12.8,5.2Hz,1H), 4.42(d,J=12.4Hz, 1H),4.31(d,J=13.5Hz,1H),3.77-3.67(m,3H),3.62-3.56(m,1H),3.50-3.12(m,8H),3.13-2.96(m,4H) ,2.95-2.68(m,6H),2.69-2.19(m,6H),2.18-2.09(m,5H),1.97-1.85(m,5H),1.70-1.64(m,1H).LCMS:C 43 H 54 N 12 O5 theoretical value 818, measured value: m / z=819 [M+H] +

[0296]

[0331] compound 9 [ka]

[0332] A mixture of [(1s,4s)-4-aminocyclohexyl]methanol hydrochloride (230 mg, 1.39 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (319 mg, 1.15 mmol), N,N-diisopropylethylamine (0.60 mL, 3.46 mmol) and DMF (10 mL) was stirred at 80 °C for 7 h. EtOAc and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated and purified by MPLC (0-10% MeOH in CHCl2) to give 2-(2,6-dioxopiperidin-3-yl)-4-{[(1s,4s)-4-(hydroxymethyl)cyclohexyl]amino}isoindole-1,3-dione (0.135 g, 30.3%). LCMS: C 20 H 23 N3O5 theoretical value 385, measured value: m / z = 386 [M+H] + .

[0297]

[0333] A mixture of 1,1-bis(acetyloxy)-3-oxo-1-lambda 5,2-benzoiodoxol-1-yl acetate (297 mg, 0.70 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-{[(1s,4s)-4-(hydroxymethyl)cyclohexyl]amino}isoindole-1,3-dione (135 mg, 0.35 mmol) and CHCl (12 mL) was stirred at room temperature for 1 h. The mixture was concentrated and purified by MPLC (0-10% MeOH in CHCl) to give (1s,4s)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}cyclohexane-1-carbaldehyde (0.1320 g, 98.3%). LCMS: C 20 H 21 N3O5 theoretical value: 383, measured value: m / z = 384 [M+H] + .

[0298]

[0334] Sodium bis(acetyloxy)borane idyl acetate (22 mg, 0.10 mmol) was added to a mixture of 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide (25 mg, 0.05 mmol), triethylamine (0.06 mL, 0.42 mmol), (1s,4s)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}cyclohexane-1-carbaldehyde (30 mg, 0.08 mmol) and DCE (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed with CHCl / EtOAc, concentrated and purified by HPLC (5-95% MeCN in H0 with 0.1% TFA) to give 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(1-{[(1s,4s)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}cyclohexyl]methyl}piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide (0.0082 g, 18.6%). 1 H NMR (500MHz, acetonitrile-d3) δ 11.13(s,1H), 8.93(s,1H), 8.68(s,1H), 7.68-7.53(m,4H), 7.43(s,1H), 7.22(d,J=8.1Hz,2H), 7.08(d,J=7.9Hz,2H), 6.47(s,1H), 5.82(s,1H), 4.98(dd,J=12.4,5.4Hz,1H), 4.4 2(d,J=13.2Hz,1H),4.32(d,J=13.5Hz,1H),3.86(s,1H),3.69(d,J=12.9Hz,3H),3.48-3. 25(m,4H),3.15-2.94(m,6H),2.89-2.64(m,7H),2.09(s,5H),1.93-1.39(m,15H).LCMS:C 45 H 55 N 11 O6 theoretical value 845, measured value: m / z=846 [M+H] + .

[0299] Biological Example 1

[0335] Compounds 1-24 were tested for BTK degradation in TMD8 cells using the protocol described in PCT Application WO 2020 / 081450 (Example 66). All showed DC activity below 100 nM. 50 A subset of these compounds were tested for BTK degradation in other cells and were shown to degrade BTK in a dose-dependent manner in microglia, monocytes, and macrophages.

[0300]

[0336] Additionally, compounds 1-24 were assayed for IMiD activity. 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 exhibited little or no measurable IMiD activity, as shown in the table below. DC50 is the compound concentration that degrades 50% of Aiolos. Dmax is the maximum percent Aiolos degradation in the assay. Compounds 20-22 exhibited little or no measurable IMiD activity by Western blotting (data not shown).

[0301] [Table 8]

[0302] Biological Example 2

[0337] Compound 1 provided significant benefit in a mouse CIA model with minimal effects on body weight.

[0303]

[0338] Immunization with collagen type II (CII) in adjuvant induces polyarthritis in rodents. This model, known as the collagen-induced arthritis (CIA) model, has been used extensively to study arthritis and resembles many aspects of the human disease. High levels of anti-collagen II correlate with disease severity. In Figure 1, CIA was induced by immunization with collagen type II in complete Freund's adjuvant on day 0. A second booster was given on day 21. Treatment with vehicle or therapeutic agent began on day 18 and continued until day 35. Serum was collected at the end of the study on day 36.

[0304]

[0339] A) Daily oral treatment with Compound 1 at 30 mg / kg resulted in lower mean arthritis scores than ibrutinib at 30 mg / kg. The effect of Compound 1 achieved similar clinical benefit 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.

[0305]

[0340] Compound 1 also produced lower mean arthritis scores than the standard of care agents: rilzabrutinib 10 mg / kg and 30 mg / kg; tofacitinib 30 mg / kg BID and Enbrel 10 mg / kg in the same model.

[0306] Biological Example 3

[0341] Compound 1 shows a dose-dependent reduction in clinical scores in EAE that is superior to ibrutinib.

[0307]

[0342] Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS).

[0308]

[0343] EAE was induced in C57BL / 6 mice by immunization with an emulsion of MOG1-125 in complete Freund's adjuvant (CFA) followed by administration of pertussis toxin in PBS, first on the day of immunization (day 0) and then again the following day (day 1).

[0309]

[0344] Dosing of all mice began on day 1 and continued until day 22. Fingolimod (FTY720, Gilenya) is a commonly used positive control in this model. In Figure 2, prophylactic treatment with daily oral Compound 1 demonstrated a dose-dependent reduction in EAE clinical scores.

[0310]

[0345] Treatment with Compound 1 at 30 mg / kg resulted in lower mean clinical scores than ibrutinib dosed at 30 mg / kg. Statistical significance was determined between vehicle control and treatment groups based on final clinical scores using the Wilcoxon non-parametric test.

[0311]

[0346] On day 22, histological analysis was performed on spinal cords harvested from mice treated with 30 mg / kg Compound 1 or 30 mg / kg ibrutinib.

[0312]

[0347] Compound 1, dosed at 30 mg / kg, caused a significant reduction in the number of inflammatory foci or apoptotic cells per spinal cord section and substantially reduced the demyelination score compared to vehicle controls.

[0313]

[0348] Ibrutinib treatment at 30 mg / kg did not result in statistically significant changes in histological features compared to vehicle controls.

[0314]

[0349] Statistical analysis: demyelination (anti-MBP) by Wilcoxon nonparametric test; inflammatory lesions or apoptosis by two-tailed Student's t test.

[0315] [Table 9]

[0316] Biological Example 4

[0350] MRL / lpr mice, genetically characterized by defective Fas-mediated apoptosis, exhibit spontaneous systemic autoimmune disease that mimics human SLE, including a predominance in female animals, circulating nuclear autoantibodies, and pathology in multiple end organs. Compound 1 significantly ameliorated kidney disease in the MRL / lpr model.

[0317]

[0351] Treatment of MRL-lpr mice with Compound 1 administered orally daily starting at 10 weeks of age resulted in a dose-dependent reduction in urinary protein scores. Compound 1 given at 30 mg / kg, but not ibrutinib, results in a statistically significant reduction in proteinuria scores. Dexamethasone was used as a positive control. Statistical significance is shown as an asterisk next to the group symbol in the figure legend for treatment with P<0.05 as determined between vehicle control and treatment groups based on urinary protein score AUC using Kruskal-Wallis test with Dunn's post-hoc analysis.

[0318]

[0352] Compound 1 at 30 mg / kg and ibrutinib at 10 mg / kg resulted in a statistically significant reduction in anti-ds DNA autoantibodies measured at the end of the serum study. Statistical significance was determined between vehicle control and treatment groups by ANOVA with Dunnett's post-hoc analysis.

[0319]

[0353] Histological examination of H&E stained kidney tissue from treated mice collected at the end of the study revealed that Compound 1 was more effective than ibrutinib in reducing glomerular size and overall total histological score in treated mice. Glomerular size is a quantitative measure that correlates well with histopathological grade and severity of nephritis in this model. Statistical significance was determined between vehicle control and treatment groups by ANOVA with Dunnett's post-hoc analysis (glomerular diameter) or Kruskal-Wallis test with Dunn's post-hoc analysis (total score). * p<0.05, ** p<0.01, *** p<0.001 **** p<0.0001.

[0320] Biological Example 5

[0354] Assessment of the effects of dosing with Compound 1, a comparator compound, and ibrutinib on the B cell compartment. The comparator compound has IMiD activity and was prepared as described in PCT / US2019 / 56112, filed October 14, 2019.

[0321]

[0355] Female C57BL / 6 mice were dosed with Compound 1, a control compound, or ibrutinib formulated at 30 mg / kg in a water bottle. A separate group of mice received vehicle formulation as a control. Blood, spleen, and femur for each treated mouse were collected at the end of the study. Peritoneal lavage was also performed with PBS to collect peritoneal resident lymphocytes.

[0322]

[0356] It is shown that treatment with both Compound 1 and the control compound resulted in robust BTK degradation in the blood, spleen, peritoneum and bone marrow of treated mice. Ibrutinib induces minimal reduction in BTK levels in B cells. To assess the levels of BTK in B cells, single lymphocyte cell suspensions from each tissue were permeabilized and stained for lineage markers and intracellular BTK. B cells were gated on B220+TCR beta-, and T cells were gated on B220- and TCR beta+. Percentage BTK remaining was calculated by subtracting the mean fluorescence intensity (MFI) of BTK in T cells that do not express BTK from the mean fluorescence intensity of BTK in B cells, and then normalizing this value to the vehicle group.

[0323]

[0357] Treatment with Compound 1, the comparator compound, or ibrutinib does not significantly affect B cell percentages in the blood, spleen, peritoneum, and bone marrow of treated animals.

[0324]

[0358] The results show that the BTK inhibitor, ibrutinib, or the BTK degrader, the control compound, do not alter the number of plasma cells in the bone marrow of treated animals. However, treatment with Compound 1 significantly reduces plasma cells in the bone marrow of treated animals. It is plausible that Compound 1 affects one or more proteins involved in plasma cell production or survival, and this effect is independent of its ability to degrade the BTK protein. Left, representative dot plots showing the gating strategy to identify plasma cells in the bone marrow. Right, histogram showing cumulative data from multiple treated animals.

[0325]

[0359] Ordinary one-way ANOVA with Tukey's multiple comparison test was performed to compare all groups with each other. * p<0.05, ** p<0.01, **** p<0.001. All comparisons without an asterisk were not significant.

[0326] Biological Example 6

[0360] The effects of Compound 1, comparator compounds, and ibrutinib on Ab affinity maturation and plasma cell production were assessed by immunization with the T cell-dependent model Ag NP-KLH. The results show that the BTK inhibitor ibrutinib or the BTK degrader comparator compound have no effect on plasma cell production, while Compound 1 significantly reduces the number of plasma cells generated by immunization.

[0327]

[0361] In a T cell-dependent immunization model, IgG1+ antibody responses are not significantly reduced by BTK inhibitors, such as ibrutinib. (www.jimmunol.org / content / 193 / 1 / 185). It is therefore surprising to find out what the specific effect of Compound 1 is. It is plausible that Compound 1 affects one or more proteins involved in plasma cell production or survival, and this effect is independent of its ability to degrade BTK protein. The success of current B cell-targeted therapies highlights the important role that B cells play in the pathogenesis of autoimmune diseases. Thus, a treatment that specifically depletes pathogenic B cells, such as plasma cells, could have great potential for the treatment of autoimmune diseases. A treatment that affects BTK levels and can also deplete plasma cells while preserving other B cell populations is expected to have a therapeutic effect on autoantibody-mediated diseases.

[0328]

[0362] Mice were immunized by intraperitoneal injection of 200 μL of immunogen containing 100 μg NP-32-KLH (Biosearch Technologies, catalog N-5060-25, lot 156285-01) and 1% Alum (Alhydrogel, 2%, Invivogen catalog Vac-alu-250, batch 0001715532, expiry July 2022) prepared in phosphate-buffered saline. Mice in group 1 were not immunized and served as controls. Mice in groups 2-5 were dosed orally once daily on days 1-7 with compound or vehicle for an additional 6 days and then sacrificed the following day. Splenocytes and bone marrow were collected 24 hours after the final dose of compound on day 7. Spleens collected at the end of the study were isolated and red blood cells were lysed with ammonium chloride potassium (ACK) lysis buffer. One million cells per tissue were stained for each flow cytometry panel.

[0329]

[0363] Treatment with Compound 1 and the control compound resulted in robust BTK degradation in the spleens of treated animals. Cells were permeabilized and stained for lineage markers and intracellular BTK. B cells were gated on CD19+TCR beta-, and T cells were gated on CD19- and TCR beta+. Percentage BTK remaining was calculated by subtracting the mean fluorescence intensity (MFI) of BTK in T cells not expressing BTK from the mean fluorescence intensity of BTK in B cells, then normalizing this value to the untreated group. 24 hours after the final dose of compound, BTK levels were suppressed to 13.4% of baseline in the Compound 1 group and 21.1% of baseline in the control compound group.

[0330]

[0364] Ibrutinib-mediated BTK inhibition or Compound 1 or control compound-mediated BTK degradation does not affect the number of B cells in the spleen or germinal center formation following immunization. Splenocytes were stained with fluorophore-conjugated antibodies for lineage markers and phycoerythrin-conjugated NP (NP-PE) for NP hapten reactivity. Live single lymphocytes were gated for B cells (CD19+B220+) and then gated for IgD+ and IgD- B cells. IgD- B cells were then gated for germinal center B cells (Fas+GL-7+) and germinal center B cells were gated for NP+ cells based on staining with NP-PE.

[0331]

[0365] Treatment with Compound 1 significantly reduces the numbers of total and IgG1+ plasma cells in the spleens of immunized mice.

[0332]

[0366] Ordinary one-way ANOVA with Tukey's multiple comparison test was performed to compare all groups with each other. * p<0.05, ** p<0.01, **** p<0.001. All comparisons not marked with an asterisk were not significant.

[0333] Biological Example 7

[0367] The effect of Compound 1 was measured in a well-established mouse model of arthritis. Compound 1 given at 10mg / kg or 30mg / kg strongly suppressed disease when started after arthritis was already established. Compound 1 was able to control disease to a similar extent as ibrutinib (both given at a dose of 30mg / kg), but was more potent than anti-TNF-alpha blocking antibody (Enbrel) or BTK inhibitors rilzabrutinib and tofacitinib.

[0334]

[0368] (A) Arthritis was induced in male DBA / 1 mice by two intradermal injections of type II collagen in Freund's complete adjuvant on study days 0 and 21, then mice were randomized and enrolled into treatment arms on study days 25-27 when the first clinical signs of arthritis occurred, and treatment was initiated (defined as arthritis day 1). In Figure 6A, once-daily oral treatment was administered at the doses indicated for vehicle, Compound 1, rilzabrutinib, or ibrutinib; tofacitinib was administered orally twice daily at 30 mg / kg for each dose; Enbrel was administered by daily intraperitoneal injection at 10 mg / kg. Treatment continued until arthritis day 14, and the study was terminated on arthritis day 15.

[0335]

[0369] (B) Spleens collected at the end of the study were separated and red blood cells were lysed with ammonium chloride potassium (ACK) lysis buffer. 1.5 million cells per spleen were stained for flow cytometry, and live single lymphocytes were gated for plasma cells (CD138+IgD-). Plasma cell numbers were normalized to total B cells (CD19+B220+) in the spleen. As shown in Figure 6B, mice treated with Compound 1 at both doses had significantly fewer plasma cells than vehicle-treated mice, and mice treated with 30 mg / kg Compound 1 had significantly fewer plasma cells than mice treated with equivalent doses of BTK inhibitors (rilzabrutinib and ibrutinib).

[0336]

[0370] (C) Bone marrow was isolated from femurs harvested at the end of the study, and samples were processed and analyzed as in (B). As shown in Figure 6C, Compound 1 significantly reduced plasma cell counts in bone marrow compared to vehicle and compared to equivalent doses of BTK inhibitors (rilzabrutinib and ibrutinib).

[0337]

[0371] In (B) and (C), ordinary one-way ANOVA with Dunnett's multiple comparison test was performed comparing vehicle with both doses of Compound 1, and comparing 30 mg / kg Compound 1 with 30 mg / kg rilzabrutinib and 30 mg / kg ibrutinib.** p<0.01, *** p<0.001, **** p<0.001.

[0338] Biological Example 8

[0372] Certain bifunctional BRK decomposition compounds cross the blood-brain barrier. The ability of compound 1 to cross the blood-brain barrier was evaluated in a mouse model. As shown in Figure 7, compound 1 crosses the blood-brain barrier and shows exposure in cerebrospinal fluid (CSF) following administration of a single oral dose in mice.

[0339]

[0373] Male C57BL / 6 mice were orally dosed with Compound 1 at 300 mg / kg, and CSF and plasma were collected from three mice at 4, 8, or 24 hours post-dose. Compound 1 concentrations in CSF and plasma were determined by LC / MS / MS; free plasma concentrations were calculated by multiplying the total plasma concentration by the previously determined percentage of Compound 1 not bound to plasma proteins.

[0340] Biological Example 9

[0374] The effect of Compound 1 on brain tumors was evaluated in a cell line model. Treatment with Compound 1 in mice bearing intracranial TMD8 tumors resulted in the degradation of tumor-expressed BTK and a reduction in tumor burden.

[0341]

[0375] TMD8 is a human activated B cell (ABC) type diffuse large B-cell lymphoma (DLBCL) cell line that is dependent on BTK signaling for survival (Davis, RE, Ngo, VN, Lenz, G., Tolar, P., Young, RM, Romesser, PB, Staudt, LM (2010). Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature, 463(7277), 88-92. doi:10.1038 / nature08638).

[0342]

[0376] TMD8 cells were implanted into female CB.17 SCID mice by intracranial injection of 5E5TMD8 cells. Treatment with Compound 1 began the next day. Mice were treated orally with vehicle or 90 mg / kg Compound 1 daily for 12 days. Brains were then harvested and dissociated into single cell suspensions, and BTK levels in TMD8 cells were assessed by flow cytometry. TMD8 cells in dissociated brain tissue were identified by human specific surface area markers (CD20+HLA+), and the total number of TMD8 cells per brain is reported in (A, tumor burden). Percentage of BTK remaining in TMD8 cells (B) was calculated by the formula below. 100 * (Tumor BTK MFI-Background MFI) / (Peak MFI-Background MFI) Here, background MFI and peak MFI were calculated using TMD8 cells treated overnight in vitro with 1 μM Compound 1 or DMSO control, respectively. **** p<0.0001; Welch's t-test was used to compare mice treated with compound 1 to mice treated with vehicle. As shown in Figure 8, compound 1 significantly reduced TMD8 tumor cells (Figure 8A) and degraded BTK (Figure 8B) in vitro.

[0343] Other embodiments

[0377] 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 the treatment or prevention of 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 little or no IMiD activity, the bifunctional compound being administered over a treatment period of two weeks or more, the bifunctional compound having the formula (A) 【Chemical 1】 (wherein, W is CH or N; D is a bond or -NH-; ring A is phenyl, 9- to 10-membered bicyclic aryl, 5- to 6-membered partially or fully unsaturated monocyclic heterocyclic or 9- to 10-membered bicyclic heteroaryl, the monocyclic heterocyclic and bicyclic heteroaryl of ring A each having 1 to 3 heteroatoms independently selected from N, O and S, ring A being 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- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 8- to 10-membered spirobicyclic heterocyclic, ring B being unsubstituted or substituted, the heteroaryl and heterocycloalkyl of ring B having 1 to 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-, 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, 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-, a 4-6 membered monocyclic cycloalkyl or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S; X3 is a bond, -C1-8 alkyl-, -C≡C-, a 4-6 membered cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2)p-, -(CH2-CH2-O)p-, a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, and the heterocycloalkyl is unsubstituted or substituted with -CH3; X4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C1-4 alkyl-, -(O-CH2-CH2-CH2)m-, a 5-6 membered saturated, partially unsaturated or fully unsaturated carbocyclic ring or a 5-6 membered saturated, partially unsaturated or fully unsaturated heterocyclic ring having 1-3 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 2】 wherein Each J is independently aryl or heteroaryl; and Each K is independently absent, -CH2-, -NH-, -NMe- or -O-) A pharmaceutical composition which is a compound of or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the disease is selected from the group consisting of acoustic neuroma, astrocytoma, pilocytic astrocytoma, juvenile pilocytic astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma, chordoma, craniopharyngioma, glioma, brainstem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET), rhabdoid tumor, schwannoma, warm autoimmune hemolytic anemia (wAIHA), systemic sclerosis, and systemic sclerosis membranous nephropathy. **Claim 3**: The bifunctional compound is formulated for chronic administration, and the frequency of the chronic administration is once a week, twice a week, once a day, twice a day, three times a day, or four times a day. The pharmaceutical composition according to claim 1. **Claim 4** The bifunctional compound is administered over a period of one month or more, or one year or more. The pharmaceutical composition according to claim 1. **Claim 5** The bifunctional compound is administered 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. **Claim 6** The disease is cancer, an autoimmune disease or an inflammatory disease. The pharmaceutical composition according to claim 1. **Claim 7**: The disease is cancer, and the cancer includes solid tumors. The pharmaceutical composition according to claim 1. **Claim 8**: The disease is cancer, and the cancer is a B-cell malignancy. The pharmaceutical composition according to claim 1. **Claim 9**: The disease is cancer, and the cancer is 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 cancer, mesothelioma, cervical cancer, microsatellite stable colorectal cancer (MSS CRC), and multiple myeloma (MM). The pharmaceutical composition according to claim 1. **Claim 10** The disease is a brain tumor. The pharmaceutical composition according to claim 1. **Claim 11** The disease is selected from the group consisting of acoustic neuroma, astrocytoma, pilocytic astrocytoma, juvenile pilocytic astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma, chordoma, CNS lymphoma, craniopharyngioma, glioma, brainstem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET), rhabdoid tumor, and schwannoma. The pharmaceutical composition according to claim 1.

12. The pharmaceutical composition according to claim 1, wherein the disease is selected from the group consisting of Waldenström macroglobulinemia, marginal zone lymphoma, mantle cell lymphoma, primary central nervous system lymphoma, and chronic lymphocytic leukemia.

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

14. The pharmaceutical composition according to claim 1, wherein the disease is an autoimmune disease, and the autoimmune disease is selected from the group consisting of warm autoimmune hemolytic anemia (wAIHA), systemic sclerosis, and membranous nephropathy.

15. The pharmaceutical composition according to claim 1, wherein the Bruton's tyrosine kinase is C481 mutant Bruton's tyrosine kinase.

16. The pharmaceutical composition according to claim 1, wherein the disease is cancer, and the cancer is ibrutinib-resistant.

17. 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.

18. 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.

19. Ring B is 【Chemical Formula 3】 selected from, R １０ is 【Chemical Formula 4】 and R １ is a C １～４ alkyl group and / or Ring B is [Chemical Formula 5] selected from, R10 is 【Chemical Formula 6】 is and / or Ring B is [Chemical Formula 7] is and / or R10 is 【Chemical Formula 8】 is, the pharmaceutical composition according to claim 1.

20. Ring A is 【Chemical Formula 9】 is, 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 10】 is, the pharmaceutical composition according to claim 1.

21. 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, -C≡C-, -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 11】 is, and / or, X2 is a bond, -C(O)-, -C1-5 alkyl-, 【Chemical 12】 is, and / or, X3 is a bond, -C1-4 alkyl-, 4-6 membered cycloalkyl or -N(R)-, and / or, X3 is a bond, -C1-4 alkyl-, -NH-, 【Chemical Formula 13】 or -C≡C-, and / or, X4 is a bond, 【Chemical Formula 14】 , -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)-, the pharmaceutical composition according to claim 1.

22. L is, 【Chemical Formula 15】 【Chemical Formula 16】 【Chemical 17】 【Chemical Formula 18】 is, the pharmaceutical composition according to claim 1.

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

24. J is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazanyl, pyrazinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl or thiazolyl, the pharmaceutical composition according to claim 1.

25. K is -CH ２ -, -NH-, -NMe- or -O-, the pharmaceutical composition according to claim 1.

26. The compound of formula (A) is a compound of formula (B) 【Chemical 20】 (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 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, 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 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from bonding, -C １～４ alkyl-, -C≡C-, 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ -, and 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 Formula 21】 is, and ring B1 is unsubstituted or substituted with 1 to 3 groups selected from -CH3, -CH2OH, -C(OH)OH, -CF3, fluorine, 【Chemical 22】 is substituted with 1 to 3 groups selected from, and / or Ring B1 is, 【Chemical 23】 is, and / or Ring B1 is, 【Chemical 24】 is, and / or X1 is, 【Chemical 25】 is, and / or X2 is a bond, -C1-5 alkyl-, 4-6 membered monocyclic cycloalkyl or 4-6 membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O and S, and / or X2 is a bond, -C1-3 alkyl-, -C(O)-, 【Chemical 26】 is, and / or X3 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 -CH3, and / or X3 is a bond, 【Chemical 27】 is and / or L is 【Chemical Formula 28】 is and / or W is N and D is a bond, the pharmaceutical composition according to claim 1.

27. The compound of formula (A) is a compound of formula (C) 【Chemical Formula 29】 wherein W is CH or N; Ring C is phenyl or a saturated, partially unsaturated or fully unsaturated 5- to 6-membered monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, and each of the phenyl and heterocyclic ring of Ring C is unsubstituted or substituted; 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 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from bonding, -C １～４ alkyl-, -C≡C-, 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ -, and 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 C is 【Chemical Formula 30】 is and / or Ring C is 【Chemical 31】 is and / or X1 is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and / or X1 is 【Chemical 32】 is and / or X2 is a bond, -C1-5alkyl-, 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, and / or X2 is a bond or -C1-3alkyl-, and / or X3 is 4- to 6-membered cycloalkyl, -N(R)- or 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 -CH3, and / or X3 is 【Chemical 33】 is and / or L is 【Chemical 34】 is, the pharmaceutical composition according to claim 1.

28. The compound of formula (A) is a compound of formula (D) 【Chemical 35】 wherein W is CH or N; Ring A is 【Chemical 36】 is 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 a bond, -C １～５ alkyl - or 1 to 2 heteroatoms independently selected from N, O, and S, and X １ said monocyclic heterocycloalkyl of is unsubstituted or substituted with -CH ３ ; X ３ is a bond, -C １～４ alkyl-, a 4- to 6-membered monocyclic cycloalkyl or 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 -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 37】 is) or a pharmaceutically acceptable salt thereof, or The compound of formula (D) is a compound of formula (D-1) 【Chemical Formula 38】 wherein W is CH or N; Ring A is 【Chemical 39】 is L is -X1-X2-X3-; X1 is 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from -C1-5 alkyl-, N, O, and S, and said monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3; X2 is a bond, -C1-5 alkyl-, or 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and said monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3; X3 is a bond, -C1-4 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, and said heterocycloalkyl is unsubstituted or substituted with -CH3; and R10 is 【Chemical 40】 is a compound of or a pharmaceutically acceptable salt thereof, or the compound of formula (D) is a compound of formula (D-2) 【Chemical 41】 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 1.

29. Ring A is 【Chemical Formula 42】 is and / or X1 is 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, and said monocyclic heterocycloalkyl of X1 is unsubstituted or substituted with -CH3, and / or X1 is 【Chemical 43】 is and / or X2 is a bond, -C1-5 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, and / or X2 is a bond or -C1-4 alkyl-, and / or X3 is a bond, 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, and / or X3 is 【Chemical 44】 is and / or L is 【Chemical 45】 is and / or R10 is 【Chemical Formula 46】 is and / or R10 is 【Chemical 47】 is, the pharmaceutical composition according to claim 28.

30. The compound of formula (A) is of formula (E) 【Chemical 48】 wherein D is a bond or -NH-; W is N or CH; Ring A is phenyl, 9-10 membered bicyclic aryl, 5-6 membered partially or fully unsaturated monocyclic heterocyclic or 9-10 membered bicyclic heteroaryl, and said monocyclic heterocyclic and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O and S; Ring B is an unsubstituted or substituted 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic heterocyclic or an unsubstituted or substituted 8-10 membered spirobicyclic heterocyclic, and ring B has 1-3 heteroatoms independently selected from N, O and S; L is -X １ -X ２ -X ３ -X ４ -X ５ - and; 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-, and is a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S, or a 7- to 12-membered spiro bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S. 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 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from bonding, -C １～４ alkyl-, -C≡C-, 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ), ｐ -(CH ２ -CH ２ -O) ｐ -, and 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) a compound of or a pharmaceutically acceptable salt thereof, and / or Ring B is 【Chemical 49】 and R10 is 【Chemical Formula 50】 and R1 is a C1-4 alkyl group, and / or Ring B is 【Chemical 51】 and R10 is 【Chemical 52】 and / or Ring B is and / or 【Chemical 53】 R10 is and / or Ring A is 【Chemical 54】 and / or X5 is -N(R)-, 【Chemical 55】 and / or X5 is -C(O)-N(R)-, and / or X5 is a bond, and / or L is and / or Y is the pharmaceutical composition according to claim 1. 【Chemical 56】 【Chemical 57】 【Chemical 58】 【Chemical 59】

31. The compound of formula (A) is a compound of formula (F) (wherein, 【Chemical Formula 60】 W is CH or N; Each of m, n and p is independently an integer from 1 to 3) a compound of or a pharmaceutically acceptable salt thereof, 【Chemical Formula 61】 and / or W is N, L is -X １ -X ２ -X ３ - and; 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, and is 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. Each of the monocyclic and bicyclic heterocycloalkyls of X １ is unsubstituted or substituted with -CH ３ ; X ２ is a group selected from the group consisting of a bond, -C １～５ alkyl-, -(O-CH ２ -CH ２ ) ｎ -, -(CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C １～５ alkyl-, a 4- 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 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from bonding, -C １～４ alkyl-, -C≡C-, 4- to 6-membered cycloalkyl, -N(R)-, -(O-CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ -, and is unsubstituted or substituted with -CH ３ ; Each R is independently hydrogen or -C １～３ alkyl; and and / or Y is and / or X1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 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 62】 and / or X1 is and / or X2 is a bond or -C1-5 alkyl-, and / or 【Chemical Formula 63】 X3 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, and / or X3 is 【Chemical Formula 64】 and / or X3 is and / or L is the pharmaceutical composition according to claim 1.

32. The compound of formula (A) is a compound of formula (G) 【Chemical Formula 65】 a compound of or a pharmaceutically acceptable salt thereof, and / or R1 is methyl, 【Chemical Formula 66】 and / or Y is ​ 【Chemical Formula 67】 ​ ​ ​ 【Chemical Formula 68】 ​ ​ ​ ​ ​ 【Chemical Formula 69】 ​ and / or The pharmaceutical composition according to claim 1, wherein W is N.

33. The compound of formula (A) is a compound of formula (J) 【Chemical 70】 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 1.

34. The compound of formula (A) is a compound of formula (K) 【Chemical Formula 71】 (wherein ring A is 【Chemical Formula 72】 and ring A is unsubstituted or is independently substituted with up to three substituents selected from halo, CN, carboxyl, NH ２ and unsubstituted or substituted C １～６ alkyl; V is a bond or -CH ２ -; and E and G are each independently a 5- to 6-membered heterocycloalkyl, and each heterocycloalkyl contains at least one nitrogen atom) or a pharmaceutically acceptable salt thereof, and / or D is a bond and W is a nitrogen atom, the pharmaceutical composition according to claim 1.

35. The bifunctional compound is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof, the pharmaceutical composition according to claim 1. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】

36. 【Fig. 80】 【Chemical Formula 81】 【Chemical 82】 a compound selected from the group consisting of

37. A compound selected from one of the following compounds or a pharmaceutically acceptable salt thereof. 【Table 8】 【Table 9】

38. The pharmaceutical composition according to any one of claims 1 to 35, comprising 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.

39. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 36 or 37 and one or more selected from the group consisting of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

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