Substituted pyrrolopyrimidines and pyrazolopyrimidines as Bruton's tyrosine kinase (BTK) degradation agents

Abstract

This invention provides substituted pyrrolopyrimidines and pyrazolopyrimidines as Bruton's tyrosine kinase (BTK) degradation agents. [Solution] A compound of formula (IB), or a tautomer, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof is provided. TIFF2026143716000178.tif3963

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 145,126, filed 3 February 2021, which is incorporated in its entirety by reference.

[0002] Areas of disclosure This invention relates to compounds that modulate Bruton's tyrosine kinase (BTK). In particular, this invention relates to compounds having a degrading effect on BTK, pharmaceutical compositions containing such compounds, and methods for using them. [Background technology]

[0003] Background of Disclosure Signaling via B cell receptors (BCRs) can lead to a wide range of biological production, depending in part on the developmental stage of B cells. Poor signaling via BCRs can cause dysregulation of B cell function and / or autoantibody formation, which can lead to autoimmune and / or inflammatory diseases. Therapies such as rituximab, which reduce B cell counts, are effective in treating inflammatory diseases such as rheumatoid arthritis. BTK is a Tec-family non-receptor protein kinase that is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages, but not in T cells, natural killer cells, and plasma cells. See Smith, CI et al. J Immunology, 152 (2), 557-65 (1994). BTK is a key component of the BCR and FcR signaling pathways, and targeted inhibition of BTK represents a novel approach for treating a wide range of human diseases, including B-cell malignancies, autoimmune diseases, and inflammatory disorders. For example, see Uckun, Fatih M. et al, Anti-Cancer Agents in Med Chem. 7(6):624-632 (2007); Shinohara et al, Cell 132(5):794-806 (2008); Pan, Z., Drug News & Perspectives, 21(7):357-362 (2008); Gilfillan et al, Immuno. Rev. 228(1):149-169 (2009); Davis RE et al, Nature, 463:88-92 (2010). BTK plays a role in B cell development and activation and is involved in multiple signaling pathways across a wide range of immune-mediated diseases. BTK activity is involved in the pathogenesis of several disorders and conditions, including B-cell-associated hematological cancers (e.g., non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjögren's syndrome, pemphigus, inflammatory bowel disease, lupus, and asthma). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Smith, CI et al. J Immunology, 152 (2), 557-65 (1994) [Non-Patent Document 2] Uckun, Fatih M. et al, Anti-Cancer Agents in Med Chem. 7(6):624-632 (2007) [Non-Patent Document 3] Shinohara et al., Cell 132(5):794-806 (2008) [Non-Patent Document 4] Pan, Z., Drug News & Perspectives, 21(7):357-362 (2008) [Non-Patent Document 5] Gilfillan et al, Immuno. Rev. 228(1):149-169 (2009) [Non-Patent Document 6] Davis RE et al, Nature, 463:88-92 (2010) [Overview of the project] [Means for solving the problem]

[0005] Summary of Disclosure In some embodiments, this disclosure relates to a compound of formula (I), or its tautomers, stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts, hydrates, or deuterated derivatives: [ka] (In the formula, X is either CH or N. Y is either CH or N. A is selected from -C(O)-, -SO2-, -S(O)-, -O-, -S-, -NH-, -N(C1~C5alkyl)- and -C(O)NH(C1~C5alkyl)-, B is [ka] And, However, B [ka] If that is the case, then, provided that A is not -O-, R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, dialkylamino group, amino group, -CN, hydroxyl, C1-C4 alkoxy, and halogen. R2 and R3 are independently selected from H, halogen, -CN, hydroxyl, dialkylamino group, C1-C5 alkyl, C1-C5 alkoxy, deuterated C1-C5 alkyl, deuterated C1-C5 alkoxy, and C1-C5 haloalkyl, respectively. Q is either L-W1 or L-W2. Here, L is a linker with a length of 2 to 20 carbon atoms, where one or more carbon atoms are independently replaced as needed by groups selected from C(=O), O, N(R6), S, S(O), SO2, C(O)NH, C(O)NCH3, C(O)NCH2CH3, C2-alkenyl, C2-alkynyl, cycloalkyl, heterocycloalkyl, heterocyclic, aryl, or heteroaryl, each independently substituted by 0, 1, 2, or 3 R7 groups. W1 is [ka] Selected from, R4 is selected from H, halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, and C1-C5 haloalkyl. W2 is [ka] R5 is either present or absent, and R5 is selected from H, halogen, -CN, C1-C5 alkyl, deuterated C1-C5 alkyl, C1-C5 alkoxy, deuterated C1-C5 alkoxy and C1-C5 haloalkyl. Each of the R6 groups is independently selected from H, C1-C3 alkyl, -C(=O)-(C1-C3 alkyl), -C(=O)-O-(C1-C3 alkyl), and -C(=O)-NH-(C1-C3 alkyl), and these are each substituted by 0, 1, 2, or 3 R7 groups. R7 is independently selected from halogen, hydroxyl, amino group, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R6)2, and -CN. This applies to the following.

[0006] In some embodiments, the compound of formula (I) is the compound of formula (IA): [ka] It can be done this way.

[0007] In some embodiments, the compound of formula (I) is the compound of formula (IB): [ka] It can be done this way.

[0008] In some embodiments, A is -O- or -C(O)-NH-CH2-.

[0009] In some embodiments, R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

[0010] In some embodiments, R2 and R3 are independently selected from H, -OCD3, -CD3, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups, respectively.

[0011] In some embodiments, R4 is selected from H, halogens, -CN, and C1-C4 haloalkyls.

[0012] In some embodiments, R5 is selected from H, halogens, deuterated C1-C5 alkoxys, and C1-C5 alkoxys. In some embodiments, L is a linker of length 2 to 12 carbon atoms, and one or more carbon atoms may be independently C(=O), O, S, S(O), SO2, C(O)NH, C(O)NCH3, C(O)NCH2CH3, NH, NCH3, NCH2CH3, C2-alkynyl [ka] [ka] It is replaced by an element selected from the following.

[0013] In some embodiments, the compound of formula (I) (e.g., formula (IA), formula (IB)) may encompass both stereoisomers and mixtures of stereoisomers. In some embodiments, the compound of formula (I) may encompass both racemic isomers and enantiomers.

[0014] Similarly, a method for treating a Bruton's tyrosine kinase (BTK)-modulated state in a subject requiring treatment of such a state is disclosed herein, comprising the step of administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., formula (IA), formula (IB)) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) or a pharmaceutically acceptable salt thereof. In at least one embodiment, the pharmaceutical composition of the present disclosure may be for use in the treatment of cancer, immunological disorders, autoimmune disorders and inflammatory disorders (or the manufacture of a pharmaceutical for treating them) in a subject requiring treatment of such disorders.

[0015] In at least one embodiment, a therapeutically effective amount of the pharmaceutical composition of the present disclosure can be administered to a subject suffering from a condition modulated by BTK. In some embodiments, the conditions modulated by BTK are selected from cancer, immunological disorders, autoimmune disorders and inflammatory disorders. In some embodiments, the conditions are selected from B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemias, non-Hodgkin lymphomas, mantle cell lymphomas, follicular lymphomas, hairy cell leukemias, B-cell non-Hodgkin lymphomas, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome and kidney transplant-related disorders.

[0016] The above summary of the invention and the modes for carrying out the invention described herein will be better understood when read in conjunction with the accompanying drawings. To illustrate this disclosure, the accompanying drawings illustrate some, but not all, alternative embodiments. However, it should be understood that this disclosure is not limited to the exact arrangements and means shown. These drawings, incorporated and constituting a portion of this specification, are intended to illustrate the principles of this disclosure. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 illustrates the BTK degradation activity of compounds 13, 25, 34, 42, 48, 49, 51, and 78 6 hours after administration in the RAMOS cell line.

[0018] [Figure 2] Figure 2 illustrates the BTK degradation activity of compounds 53, 54, 93, and 96 6 hours after administration in the RAMOS cell line. [Modes for carrying out the invention]

[0019] Detailed explanation of this disclosure definition A dash symbol ("-") that does not occur between two characters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached via the carbon atom.

[0020] When a range of values is recited, it is intended to encompass each value and sub-range within the range. For example, "C 1~ C6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 alkyl.

[0021] The term "acyl", as used herein, refers to a group R-C(O)- including, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)- and (heterocyclyl)-C(O)-, wherein said group is attached to the parent molecular structure via the carbonyl functional group. In some embodiments, it is C 1~10 acyl radical, which refers to the total number of chain or ring atoms formed by an alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heteroaryl moiety and the carbonyl carbon of the acyl group. For example, C4-acyl has 3 other ring or chain atoms plus the carbonyl group.

[0022] The term “alkenyl,” as used herein, refers to a linear or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2 to 8 carbon atoms, referred to herein as a (C2-C8) alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-buten)-pentenyl.

[0023] The term "alkyl" as used herein means C 1~8 The term "alkyl" refers to linear or branched saturated hydrocarbons, such as linear or branched groups of 1 to 8 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, "alkyl" refers to linear hydrocarbons. In some embodiments, "alkyl" refers to branched hydrocarbons.

[0024] The term "alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms with terminal "O" atoms in the chain, such as -O(alkyl). Examples of alkoxy groups include, non-limitingly, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0025] The term "alkylene," as used herein, refers to a divalent alkyl radical. 1~10Representative examples of alkylenes include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0026] The term "alkynyl," as used herein, refers to a linear or branched unsaturated hydrocarbon having at least one carbon-carbon triple bond, such as a linear or branched group of 2 to 8 carbon atoms, referred to herein as a (C2-C8) alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0027] The term "aryl," as used herein, refers to a monocyclic, bicyclic, or other polycyclic carbocyclic aromatic ring system having 5 to 14 ring atoms. The aryl group may be optionally condensed to one or more rings selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl groups. The aryl groups of this disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azlenyl, and naphthyl, as well as benzo-condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems, the rings comprising six carbon atoms, which are referred to herein as "C6-aryl".

[0028] The term "cyano" as used herein refers to -CN.

[0029] The term "cycloalkyl," as used herein, refers to saturated or unsaturated cyclic, bicyclic, or bridging bicyclic hydrocarbon groups consisting of 3 to 16 or 3 to 8 carbon atoms, derived from cycloalkanes and referred to herein as "(C3-C8) cycloalkyl." Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can condense with other cycloalkyl (saturated or partially unsaturated) aryl or heterocyclyl groups to form bicyclic, tetracyclic, and so on. The term "cycloalkyl" also includes cross-linked structures and spiro-condensed ring structures, which may or may not contain heteroatoms.

[0030] The term "halo" or "halogen" as used herein refers to -F, -Cl, -Br, and / or -I.

[0031] "Haloalkyl" refers to an alkyl group that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0032] The term “heteroaryl,” as used herein, refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing one or more heteroatoms, such as nitrogen, oxygen, and sulfur, e.g., 1 to 3 heteroatoms. Heteroaryls may be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls may also be condensed into non-aromatic rings. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, which contain 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred herein as “(C2-C5) heteroaryl.” Exemplary examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidylyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups also include, but are not limited to, a bicyclic aromatic ring, which in this specification is defined as "(C5-C 14 A heteroaryl compound, also known as a "heteroaryl," contains 5 to 14 carbon atoms and 1 to 3 heteroatoms. Representative examples of heteroaryl compounds include, but are not limited to, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0033] The terms “heterocycle,” “heterocyclyl,” or “heterocyclic formula,” as used herein, refer to a saturated or unsaturated ring of 3 to 18 members containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur, respectively. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Heterocycles can be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heterocyclic compounds also include bicyclic, tricyclic, and tetracyclic groups, in which case any of the above heterocyclic rings are fused to one or two rings independently selected from aryl, cycloalkyl, and heterocyclic compounds. Exemplary heterocyclic compounds include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, and This includes xazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridadinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidine-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranil, and triazolyl.

[0034] The terms "hydroxy" and "hydroxyl" refer to -OH as used herein.

[0035] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are linked by a single atom. These rings may differ in size and properties, or they may be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in the spiro ring may be fused to another ring, which may be a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring. (C 3~12 Spirocycloalkyls are spiro rings containing between 3 and 12 carbon atoms.

[0036] "Spiroheterocycloalkyl" or "spiroheterocyclyl" means a spiro ring in which at least one of the rings is heterocyclic and one or more carbon atoms may be substituted by heteroatoms (for example, one or more carbon atoms may be substituted by heteroatoms in at least one of the rings). One or both of the rings in the spiroheterocycle may be fused to another ring, which is a carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring.

[0037] An "isomer" is a compound that has the same number and type of atoms, and therefore the same molecular weight, but differs in terms of the arrangement or stereochemistry of its atoms in space.

[0038] "Stereoisomer" or "optical isomer" means a stable isomer having restricted rotation that gives rise to at least one chiral atom or perpendicular asymmetric plane (e.g., certain biphenyl, allene, and spiro compounds) and that can rotate plane-polarized light. Since chiral centers and other chemical structures are present in the compounds of this disclosure that can give rise to stereoisomerism, this disclosure intends to describe stereoisomers and mixtures thereof. The compounds of this disclosure and salts thereof contain a chiral carbon atom and may therefore exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-rich mixtures. As discussed in further detail below, individual stereoisomers of a compound are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparation of a mixture of enantiomer products, followed by separation or resolution (such as conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of enantiomers in a chiral chromatography column). Starting compounds for specific stereochemistrys are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0039] It is well known in the art that the biological and pharmacological activities of a compound are easily influenced by its stereochemistry. Therefore, enantiomers, for example, often exhibit significantly different biological activities, including differences in pharmacokinetic properties such as metabolism and protein binding, and pharmacological properties such as the type, degree, and toxicity of the activity exhibited. Accordingly, those skilled in the art will recognize that one enantiomer may be more active or exhibit beneficial effects when enriched with or separated from the other enantiomer. Furthermore, those skilled in the art will likely recognize from this disclosure methods for separating, enriching, or selectively preparing enantiomers of the compounds disclosed, as well as prior art knowledge.

[0040] Therefore, while racemic drugs may be used, they are often less effective than administering equal amounts of pure enantiomers. In fact, in some cases, one enantiomer may be pharmacologically inactive and merely act as a diluent. For example, ibuprofen has previously been administered as a racemic mixture, but it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (however, in the case of ibuprofen, the R-isomer is inactive but is converted to the S-isomer in vivo, and therefore the rapid action of racemic drugs is slower than that of pure S-isomers). Furthermore, the pharmacological activity of enantiomers may have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are advantageous over racemic mixtures because they have been reported to have faster transdermal penetration rates than racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0041] In some embodiments, the compound is a racemic mixture of (S)-isomers and (R)-isomers. In other embodiments, a mixture of compounds is provided herein in which the individual compounds of the mixture are predominantly present in either the (S)-isomer configuration or the (R)-isomer configuration. For example, the compound mixture has an excess of (S)-enantiomers of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In other embodiments, the compound mixture has a (S)-enantiomer excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or higher. In other embodiments, the compound mixture has a (R)-enantiomer purity of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In some other embodiments, the compound mixture has a (R)-enantiomer excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or higher.

[0042] Individual stereoisomers of the compounds of this disclosure can be prepared by synthesis from commercially available starting materials containing chiral or stereogenic centers, or by preparation of racemic mixtures and subsequent separation methods well known to those skilled in the art. These separation methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, or (3) direct separation of the optically enantiomer mixture on a chiral chromatography column. The stereoisomer mixture can also be separated into its constituent stereoisomers by well known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from sterically pure intermediates, reagents, and catalysts by well known asymmetric synthesis methods.

[0043] Therefore, if one enantiomer is pharmacologically more active, non-toxic, or has a preferred configuration in the body than the other, it appears that preferential administration of the former enantiomer would be more therapeutically beneficial. Thus, patients receiving treatment are likely to be exposed to a lower total dose of the drug, and a lower dose of the potentially toxic enantiomer or inhibitor of the other enantiomer.

[0044] The term "pharmaceutically acceptable carrier," as used herein, refers to any solvent, dispersion medium, coating agent, isotonic agent, and absorption retarder, etc., that is suitable for the administration of a pharmaceutical product. The use of such media and activators for pharmaceutically active substances is well known in the art. The composition may contain other active compounds that provide auxiliary, additional, or therapeutically enhanced functions.

[0045] The term "pharmaceutically acceptable composition" means, as used herein, a composition comprising at least one compound disclosed herein, which is formulated together with one or more pharmaceutically acceptable carriers.

[0046] The term “pharmaceutically acceptable prodrug” means, as used herein, a prodrug of a compound of the Disclosure that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reaction, within reasonable medical judgment, and that is balanced by a reasonable benefit / risk ratio and effective for its intended use, and, where possible, represents the zwitterionic form of the compound of the Disclosure. References are made in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and Roche, EB, ed. Bioreversible Carriers in Drug Design, American This information is presented in Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0047] The term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound used in the composition of the present invention. Compounds included in the composition of the present invention that are basic in nature can form a wide range of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, sulfates, citrates, malates, acetates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbic acidates, succinates, maleates, gentisinates, Fumarate, gluconate, glucuronate, sugar salt, formate, benzoin The compounds form salts containing pharmaceutically acceptable anions, including acid salts, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)). Compounds in the compositions of the present invention that contain an amino portion can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds in the compositions of the present invention that are acidic can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, and in particular salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron.

[0048] In this specification, the naming of compounds, including organic compounds, may be done using nomenclature, general names, IUPAC, IUBMB, or CAS recommendations. When a name is given, a person skilled in the art can use the nomenclature rules to systematically reduce the structure of the compound, or CHEMDRAW (trademark) (Cambridgesof The compound structure can be easily verified using commercially available software such as that from t Corporation (USA). The chemical name was generated using PerkinElmer ChemDraw® Professional, version 17.

[0049] The compounds of this disclosure may contain one or more chiral centers and / or double bonds and therefore exist as stereoisomers such as geometric isomers, enantiomers, or diastereomers. As used herein, the term “stereoisomer” encompasses all geometric isomers, enantiomers, or diastereomers. These compounds can be represented by the symbols “R” or “S” depending on the stereoconfiguration of substituents around the stereogenic carbon atom. This disclosure encompasses various stereoisomers and mixtures thereof of these compounds. Stereoiomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be represented in nomenclature as “(±)”, but those skilled in the art will recognize that the structure can implicitly represent a chiral center. In some embodiments, enantiomers or stereoisomers may be provided substantially without the corresponding enantiomer.

[0050] As used herein, “cancer” means a disease, disorder, or condition involving abnormal cell growth that may invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0051] As used herein, the term “subject” refers to an animal. Typically, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0052] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” mean a reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or biological process.

[0053] As used herein, the terms “to treat,” “to treat,” or “to treat” any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., slowing, inhibiting, or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, “to treat,” “to treat,” or “to treat” means mitigating or improving at least one physical parameter, including one that may not be perceived by the patient. In yet another embodiment, “to treat,” “to treat,” or “to treat” means modulating the disease or disorder either physically (e.g., by stabilizing recognizable symptoms), physiologically (e.g., by stabilizing physical parameters), or both. In yet another embodiment, “to treat,” “to treat,” or “to treat” means preventing or delaying the onset, development, or progression of the disease or disorder.

[0054] As used herein, an object “needs” a treatment if such object would benefit from such treatment biologically, medically, or in terms of quality of life.

[0055] Furthermore, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, hydrogen is replaced with deuterium ( 2 H) or tritium ( 3 Other than being replaced by H, or carbon 13 C- or 14 Compounds having current structures other than those substituted with C-carbon atoms are within the scope of this disclosure. Such compounds may be useful in biological assays, for example, as analytical instruments, probes, or therapeutic agents. compound

[0056] In some embodiments, the compound of formula (I), its tautomers, stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates or deuterated derivatives: [ka] (In the formula, X is either CH or N. Y is either CH or N. A is selected from -C(O)-, -SO2-, -S(O)-, -O-, -S-, -NH-, -N(C1~C5alkyl)- and -C(O)NH(C1~C5alkyl)-, B is [ka] And, However, B [ka] If that is the case, then, provided that A is not -O-, R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, dialkylamino group, amino group, -CN, hydroxyl, C1-C4 alkoxy, and halogen. R2 and R3 are independently selected from H, halogen, -CN, hydroxyl, dialkylamino group, C1-C5 alkyl, C1-C5 alkoxy, deuterated C1-C5 alkyl, deuterated C1-C5 alkoxy, and C1-C5 haloalkyl, respectively. Q is either L-W1 or L-W2. Here, L is a linker with a length of 2 to 20 carbon atoms, where one or more carbon atoms are independently replaced as needed by groups selected from C(=O), O, N(R6), S, S(O), SO2, C(O)NH, C(O)NCH3, C(O)NCH2CH3, C2-alkenyl, C2-alkynyl, cycloalkyl, heterocycloalkyl, heterocyclic, aryl, or heteroaryl, each independently substituted by 0, 1, 2, or 3 R7 groups. W1 is [ka] Selected from, R4 is selected from H, halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, and C1-C5 haloalkyl. W2 is [ka] R5 is either present or absent, and is selected from H, halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, and C1-C5 haloalkyl. Each of the R6 groups is independently selected from H, C1-C3 alkyl, -C(=O)-(C1-C3 alkyl), -C(=O)-O-(C1-C3 alkyl), and -C(=O)-NH-(C1-C3 alkyl), and these are each substituted by 0, 1, 2, or 3 R7 groups. R7 is independently selected from halogen, hydroxyl, amino group, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R6)2 and -CN, as provided herein. In some embodiments, the compound of formula (I) is the compound of formula (IA): [ka] It can be done this way.

[0057] In some embodiments, the compound of formula (I) is the compound of formula (IB): [ka] It can be done this way.

[0058] In some embodiments, A is -O- or -C(O)-NH-CH2. In some embodiments, A is -O-. In some embodiments, A is -C(O)-NH-CH2.

[0059] In some embodiments, R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl and halogen. In some embodiments, R1 is H, F, Cl, Br, I, -CF3, -CH3 and [ka] Selected from: In some embodiments, R1 is H. In some embodiments, R1 is Br. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is I.

[0060] In some embodiments, R2 and R3 are independently selected from H, -OCD3, -CD3, halogen, C1-C4 alkyl, and C1-C4 alkoxy, respectively. In some embodiments, R2 and R3 are each H. In some embodiments, R2 is H and R3 is F. In some embodiments, R2 is F and R3 is H. In some embodiments, R2 is -OCH3 and R3 is F. In some embodiments, R2 is F and R3 is -OCH3. In some embodiments, R2 is -OCD3 and R3 is F. In some embodiments, R2 is -F and R3 is -OCD3. In some embodiments, R2 is -CD3 and R3 is F. In some embodiments, R2 is -F and R3 is -CD3.

[0061] In some embodiments, R4 is selected from H, halogens, -CN, and C1-C4 haloalkyls. In some embodiments, R4 is H. In some embodiments, R4 is a halogen. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Br.

[0062] In some embodiments, R5 is selected from H, halogens, deuterated C1-C5 alkoxys, and C1-C5 alkoxys. In some embodiments, R5 is -OCH3 or -OCD3. In some embodiments, R5 is -OCH3.

[0063] In some embodiments, L is a linker of length 2 to 12 carbon atoms, and one or more carbon atoms may be independently C(=O), O, S, S(O), SO2, C(O)NH, C(O)NCH3, C(O)NCH2CH3, NH, NCH3, NCH2CH3, C2-alkynyl [ka] [ka] It is replaced by an element selected from the following.

[0064] In some embodiments, W2 is [ka] It is either or does not exist. In some embodiments, W2 is [ka] In some embodiments, W2 is [ka] In some embodiments, W2 is [ka] In some embodiments, W2 is absent.

[0065] In some embodiments, compounds or pharmaceutically acceptable salts thereof, selected from the compounds listed in Table 1, are provided herein. [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] Pharmaceutical composition

[0066] The pharmaceutical compositions of this disclosure include at least one compound of formula (I) (e.g., formula (IA), formula (IB)), or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts, hydrates, or deuterated derivatives, formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, oral, and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. In any given case, the most preferred form of administration depends on the degree and severity of the condition being treated, as well as the properties of the specific compound used.

[0067] Formulations suitable for oral administration may be supplied in discrete units such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the compound of the Disclosure as a powder or granule, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any preferred method of compounding, comprising the step of mixing at least one compound of the Disclosure as an activating compound with a carrier or excipient (which may constitute one or more minor components). The carrier must be acceptable in the sense that it is compatible with the other components of the formulation and is not harmful to the recipient. The carrier may be solid or liquid or both, and may be formulated together with at least one compound described herein as the active compound in a unit dose formulation, such as a tablet, and the unit dose formulation may contain at least one active compound in an amount of about 0.05% to about 95% by weight. Other pharmacologically active substances, including other compounds, may also be present. The formulations of this disclosure may be prepared by any well-known compounding technique that substantially consists of mixing the constituent components.

[0068] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. Liquid pharmaceutically administered compositions can be prepared, for example, by dissolving or dispersing, for example, at least one active compound of the Disclosure described herein, and a pharmaceutical adjuvant as needed, in an excipient such as water, physiological saline, aqueous dextrose, glycerol, or ethanol, thereby forming a solution or suspension. Generally, a suitable formulation may be prepared by uniformly and densely mixing at least one active compound of the Disclosure with a liquid carrier or a fine solid carrier, or both, and then, if necessary, molding it into a product. For example, tablets may be prepared by compressing or molding powder or granules of at least one compound of the Disclosure, which may be combined with one or more minor components as needed. Compressed tablets are, The tablets may be prepared by compressing at least one compound of the Disclosure in a free-flowing form, such as a powder or granules, in a suitable machine, which may be mixed as needed with a binder, lubricant, inert diluent and / or surfactant / dispersant. The molded tablets may be made by molding in a suitable machine, in which case the powder form of at least one compound of the Disclosure is moistened with an inert liquid diluent.

[0069] Formulations suitable for oral (sublingual) administration include flavored bases, lozenges typically containing at least one compound of the disclosure in sucrose and acacia or tragacanth, and pastels containing at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0070] Formulations of the present disclosure suitable for parenteral administration comprise a sterile aqueous preparation of at least one compound of formula (I) (e.g., formula (IA), formula (IB)), or a tautomer, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof, which is substantially isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by subcutaneous, intramuscular or intradermal injection. Such preparations may conveniently be prepared by mixing at least one compound described herein with water, rendering the resulting solution sterile and isotonic with blood. Injectable compositions according to the present disclosure may contain from about 0.1% to about 5% w / w of active compound.

[0071] Formulations suitable for rectal administration are presented as unit dose suppositories. These may be prepared by mixing at least one compound described herein with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.

[0072] Formulations suitable for topical application to the skin may take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers and excipients that may be used include petrolatum, lanolin, polyethylene glycol, alcohol, and combinations of two or more thereof. The active compound (i.e., at least one compound of formula (I) (e.g., formula (IA), formula (IB)), or a tautomer, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof) is generally present in the composition at a concentration of from about 0.1% to about 15% w / w, for example from about 0.5% to about 2% w / w.

[0073] The amount of the active compound to be administered may depend on the subject to be treated, the weight of the subject, the administration method and the judgment of the prescribing physician. For example, the administration schedule may include daily or semi-daily administration of the recognized dosage of the encapsulated compound ranging from about 1 μg to about 1000 mg. In another embodiment, intermittent administration of a certain dose of the encapsulated compound, such as on a monthly or yearly basis, may be used. Encapsulation facilitates access to the site of action, and allows simultaneous administration of active ingredients to theoretically generate a synergistic effect. A physician can comply with standard administration regimens, easily determine the optimal dosage, and easily modify the administration to achieve such a dosage.

[0074] A therapeutically effective amount of the compound or composition disclosed herein can be measured by the therapeutic efficacy of the compound. However, the dosage may vary depending on the patient's requirements, the severity of the condition being treated and the compound used. In one embodiment, a therapeutically effective amount of the disclosed compound is sufficient to establish the maximum plasma concentration. For example, the preliminary dosage determined in accordance with dose scaling for animal studies and human administration is carried out in accordance with work practices acceptable in the art.

[0075] Toxicity and therapeutic efficacy can be determined, for example, by LD 50 (dose lethal to 50% of the population) and ED 50 (dose therapeutically effective in 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio LD 50 / ED 50 Compositions exhibiting a large therapeutic index are preferred.

[0076] Data obtained from cell culture assays or animal studies can be used when formulating dosages for use in humans. A therapeutically effective dosage achieved in one animal model can be converted to use in other animals, including humans, using conversion factors known in this art (e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Equivalent Surface Area Dosage Factor). Please refer to the following table regarding the Area Dosage Factor. [Table 2]

[0077] The dosage of such compounds is low or no toxicity, ED 50 The circulating concentration is preferably within the range of [specific concentration]. The dose may vary within this range depending on the dosage form used and the route of administration utilized. In general, the therapeutically effective dose may vary depending on the age, condition, and sex of the subject, as well as the severity of the subject's medical condition. The dose may be determined by the physician and, if necessary, adjusted to suit the observed effect of the treatment. Treatment method

[0078] In some embodiments, in subjects requiring treatment of a BTK-modulated state, a compound of formula (I) (e.g., formula (IA), formula (IB)), or its tautomers, stereoisomers, or mixtures of stereoisomers, or a pharmaceutically acceptable salt, hydrate, or deuterated derivative thereof is administered to treat the BTK-modulated state. In some embodiments, the BTK-modulated state is selected from cancer, immunological diseases, autoimmune diseases, and inflammatory diseases.

[0079] In some embodiments, the disease is an inflammatory disease such as arthritis, a kidney disease, or cancers such as leukemia and lymphoma, for example, chronic lymphocytic leukemia (CLL), multiple myeloma and small lymphocytic lymphoma (SLL) and B-cell non-Hodgkin lymphoma.

[0080] In some embodiments, the disease is an autoimmune disease. In some embodiments, the disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is lupus.

[0081] In one embodiment, the subject in question suffers from a heterogeneous immune condition or disease, such as graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, hypersensitivity type I, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

[0082] In some embodiments, the subjects requiring treatment are those suffering from inflammatory diseases, such as asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, or conjunctivitis.

[0083] In some embodiments, the required subjects are suffering from cancer. In one embodiment, cancer is B-cell proliferative disorder, e.g., diffuse large B-cell lymphoma, follicular lymphoma, lymphoma, chronic lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Wandenstrom macroglobulinemia, spleen These include marginal zone lymphoma, plasmacytogenic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatous granuloma. In some embodiments, the condition is selected from B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemias, non-Hodgkin lymphomas, mantle cell lymphomas, follicular lymphomas, hairy cell leukemias, B-cell non-Hodgkin lymphomas, marginal zone lymphomas, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, and kidney transplant complications. In some embodiments, the condition is mantle cell lymphoma. In some embodiments, the conditions are chronic lymphocytic leukemias and small lymphocytic lymphomas. In some embodiments, the condition is Waldenström macroglobulinemia. In some embodiments, the condition is marginal zone lymphoma.

[0084] In some embodiments, the subject of interest is suffering from a heteroimmune condition or disease, such as graft-versus-host disease (GVHD). In some embodiments, the GVHD is acute GVHD. In some embodiments, the GVHD is chronic GVHD.

[0085] In some embodiments, a compound of formula (I) (e.g., formula (IA), formula (IB)), or its tautomers, stereoisomers, or mixtures of stereoisomers, or a pharmaceutically acceptable salt, hydrate, or deuterated derivative thereof, is administered as a pharmaceutical composition.

[0086] In some embodiments, the present invention provides a method for degrading BTK in cells, comprising the step of contacting cells with an effective amount of a compound of formula (I) (e.g., formula (IA), formula (IB)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contact is in vitro. In one embodiment, the contact is in vivo.

[0087] As used herein, the term “contact” means to bring together the indicated parts in an in vitro or in vivo system. For example, “contact” BTK with the compound provided herein includes administering the compound provided herein to an individual or patient, such as a human, having a state modulated by BTK, and introducing the compound provided herein into, for example, a cell-containing sample or a BTK-containing purified preparation.

[0088] The concentration and route of administration to the patient will vary depending on the condition being treated.

[0089] In one embodiment, the compound of formula (I) (e.g., formula (IA), formula (IB)), or a tautomer, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered in combination with other therapeutic agents. In one embodiment, these therapeutic agents are chemotherapeutic agents, steroids, immunotherapeutic agents, targeted therapeutic agents, antibody-drug conjugates, B-cell receptor pathway inhibitors, antibodies, B-cell receptor signaling inhibitors, PI3K inhibitors, IAP inhibitors, mTOR inhibitors, radioimmunotherapeutic agents, DNA damaging agents, proteosome inhibitors, histone deacetylase inhibitors, protein kinase inhibitors, hedgehog inhibitors, Hsp90 inhibitors, telomerase inhibitors, Jak1 / 2 inhibitors, protease inhibitors, BCL2 inhibitors, PKC inhibitors and PARP inhibitors. In some embodiments, these therapeutic agents are chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, bendamustine, cyclophosphamide, vincristine, venetoclax and lenalidomide.

[0090] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable known and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0091] Those skilled in the art will further recognize that in healthy patients and / or patients suffering from a given disorder, human clinical trials, including first-in-human, dose-range and efficacy trials, can be completed in accordance with methods well known in the clinical and medical arts. Examples

[0092] The examples and preparations presented below illustrate the compounds disclosed herein and the methods for preparing such compounds. It should be understood that the scope of this disclosure is not limited in any way to the following examples and preparations.

[0093] The chemical entities described herein can be synthesized in accordance with one or more exemplary schemes herein and / or techniques well known in the art. In particular, unless otherwise specified, the reactions described herein are carried out at atmospheric pressure, generally within a temperature range of about -10°C to about 200°C. Furthermore, unless otherwise specifically specified, reaction times and conditions are intended to be approximate and are carried out at a temperature range of about -10°C to about 200°C for a period of time that can be, for example, about 1 to about 24 hours, at approximately atmospheric pressure. Reactions carried out overnight may average a time of about 16 hours in some embodiments.

[0094] The isolation and purification of the chemical entities and intermediates described herein may be carried out by any suitable separation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination thereof. For example, Carey et al. Advanced Organic Chemistry, 3 rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 nd See Ed., 2005 Hoboken, NJ: J. Wiley & Sons. Specific examples of preferred isolation and separation procedures. The details are shown by reference to the following examples herein. However, other equivalent separation or isolation procedures may also be used.

[0095] In all methods, it is well understood that protecting groups for sensitive or reactive groups may be used where necessary, in accordance with general principles of chemistry. Protecting groups are described in *Protective Groups in Organic Synthesis* by TW Greene and PGM Wuts (1999) 3. rd These are operated in accordance with the standard method of Ed. John Wiley & Sons. The group may be removed at a conventional step in the compound synthesis using a method readily apparent to those skilled in the art.

[0096] If desired, non-limiting exemplary (R)- and (S)-isomers of compounds can be separated by methods known to those skilled in the art, for example, by the formation of diastereoisomer salts or complexes that can be separated by crystallization, for example, by the formation of diastereoisomer derivatives that can be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of one enantiomer with an enantiomer-specific reagent (e.g., enzymatic oxidation or reduction) and subsequent separation of modified and unmodified enantiomers, or separation by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica containing a bound chiral ligand, or in the presence of a chiral solvent. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation to convert one enantiomer to the other.

[0097] The compounds described herein may, if necessary, be contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt. Similarly, the compounds described herein may, if necessary, be contacted with a pharmaceutically acceptable base to form the corresponding base addition salt.

[0098] In some embodiments, the disclosed compounds can generally be synthesized by appropriate combinations of commonly known synthetic methods. Techniques useful for synthesizing these chemical entities are readily apparent and available to those skilled in the art based on this disclosure. Many of the starting compounds and other reagents, which may be substituted as needed, are commercially available, for example, from Millipore Sigma, or can be readily prepared by those skilled in the art using commonly used synthetic methodologies.

[0099] The following discussion is presented to illustrate a certain variety of methods available for use in preparing the disclosed compounds and is not intended to limit the range of reactions or reaction sequences that may be used in preparing the compounds presented herein. Those skilled in the art will understand that standard valencies apply to all compounds of the genus disclosed herein or named compounds unless otherwise specified. The following abbreviations have the definitions described below. [Table 5] General synthesis scheme

[0100] The claimed compounds can be prepared in accordance with the following scheme. The following scheme represents a general method used in preparing these compounds. However, their synthesis is not limited to these representative methods, as these compounds can also be prepared by various other methods by those skilled in synthetic chemistry. Scheme 1: Method for preparing compounds 1, 3, 4, 5, and 6 [ka] [ka] Scheme 2: Method for preparing compound 2 [ka] Scheme 3: Method for the preparation of compounds 7, 8, 11, and 19 [ka] Scheme 4: Method for the preparation of compounds 14, 16, 17, and 20 [ka] Scheme 5: Method for the preparation of compounds 9 and 10 [ka] Scheme 6: Method for the preparation of compounds 12 and 18 [ka]

[0101] The following compounds were prepared according to Scheme 3: Compounds 22, 23, 28, and 31.

[0102] The following compounds were prepared according to Scheme 4: Compounds 13, 21, 24, and 25.

[0103] The following compounds were prepared according to Scheme 6: Compounds 15, 26, 27, 29, 30, and 34. Scheme 7: Method for preparing compound 32 [ka] Compound 33 can be prepared using a method similar to that described in the synthesis of compound 32. Scheme 8: Method for the preparation of compounds 35, 36, and 38 [ka] Compounds 39, 40, and 41 can be prepared using the method described in Scheme 8. Scheme 9: Method for the preparation of compounds 37 and 48 [ka] Compounds 42 and 43 can be synthesized using a similar method described in Scheme 9. Scheme 10: Method for preparing compound 44 [ka] Compounds 45, 46, and 47 can be synthesized using a similar method to that described for the preparation of compound 44. Scheme 11: Method for the preparation of compounds 49, 50, 51, 59, and 70 [ka] Compounds 65, 66, 67, 68, 69, 81, 82, and 85 can be synthesized using similar methods described in Scheme 11. Scheme 12: Method for the preparation of compounds 52, 53, 54, 56, 57, 58, 60, and 61 [ka] Scheme 13: Method for the preparation of compounds 71, 72, 78, and 80 [ka] Compound 79 can be synthesized using a similar method described in Scheme 13. Scheme 14: Method for the preparation of compounds 73 and 74 [ka] Compounds 75, 76, and 77 can be prepared using a similar method described in Scheme 14. Scheme 15: Method for the preparation of compounds 83 and 84 [ka] Scheme 16: Method for the preparation of compounds 86 and 87 [ka] Scheme 17: Method for the preparation of compounds 88-91 and 100-101 [ka] Compounds 93, 94, 95, 96, 97, 98, 99, 102, 103, and 104 can be prepared using similar methods described in Scheme 11. Scheme 18: Method for the preparation of compounds 105-108 [ka] Compound 109 can be synthesized using a similar method described in Scheme 18. Preparation of intermediates Preparation of (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (intermediate A) [ka] Step 1: Preparation of methyl 2-chloro-4-phenoxybenzoate

[0104] A mixture of methyl 2-chloro-4-fluorobenzoate (20 g, 106.1 mmol), phenol (13 g, 137.9 mmol), and cesium carbonate (51.83 g, 156.1 mmol) in N,N-dimethylformamide (200 mL) was stirred at 90°C for 16 hours. This mixture was extracted with dimethyl phosphate (200 mL x 3). The organic layer was washed with saturated NaCl solution and dehydrated with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:1 → 5:1) to obtain methyl 2-chloro-4-phenoxybenzoate (18 g, 64.5%). Step 2: Preparation of (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone

[0105] 5-Bromo-4-chloro-7h-pyrrole[2,3-d]pyrimidine (1 (g, 4.3 mmol) was dissolved in tetrahydrofuran (25 mL), and n-BuLi (2.5 M, 2 equivalents in hexane) was slowly added dropwise under Ar at -78°C. The mixture was stirred at -78°C for 1 hour, and then a solution of methyl 2-chloro-4-phenoxybenzoate (1.1 equivalents) was added dropwise. The mixture was stirred at -78°C for 2 hours. The reaction product was quenched with 1N HCl and extracted with SiO2. The organic layer was washed with brine and dehydrated with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 1:1) to obtain (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (650 mg). LCMS:(ES+):m / z 383.02[M] + . Step 3: Preparation of tert-butyl(R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate

[0106] (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (1 g, 2.6 mmol), DIEA (3 equivalents), (R)-3-aminopiperidine-1-carboxylate tert-butyl (1.2 equivalents), and isopropanol (12 mL) were placed in a 20 mL microwave tube. This mixture was heated at 160 °C for 1.5 hours under microwave irradiation. After cooling to room temperature, the reaction product was extracted with SiO2 (40 mL x 4), the organic layer was washed with brine, and dehydrated with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Recrystallization of the residue with 25% ELISA in petroleum ether yielded tert-butyl(R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate (1.1 g). LCMS:(ES+):m / z 547.2[M] + . Step 4: Preparation of (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone

[0107] To a 250 mL solution of tert-butyl(R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate (11 g, 20.07 mmol) in dioxane, 50 mL of 4N HCl in dioxane was added. This mixed reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under vacuum and dried. The residue was powdered by DCM to obtain a crude product (9 g). Further purification of the solid by reverse-phase chromatography yielded 7.8 g of the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 12.91 (br, 1H), 8.91-8.81 (m, 3H), 8.31 (s, 1H), 7.70 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 - 7.05 (m, 3H), 7.05 (d, J = 6.7 Hz, 1H), 4.44 (s, 1H), 3.56 (br, 1H), 3.25 (br, 1H), 3.02 - 2.97 (m, 2H), 2.15 (br, 1H), 1.98 (br, 1H), 1.82 - 1.77 (m, 2H).LCMS:(ES+):m / z 448.2[M] + . Preparation of (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone hydrochloride (intermediate B) [ka] Step 1: Preparation of tert-butyl 4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate

[0108] In a 20 mL microwave tube, combine (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (4.4 g, 11.45 mmol), DIEA (3 equivalents), and 4-aminopiperidine-1-te rt-butyl carboxylate (1.2 equivalents) and isopropanol (12 ml) were added. This mixture was heated at 160°C for 1.5 hours under microwave irradiation. After cooling to room temperature, the reaction product was extracted with SiO4 (40 mL x 4), the organic layer was washed with brine, and dehydrated with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized with 25% SiO4 in petroleum ether to obtain tert-butyl 4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate (5 g). LCMS:(ES+):m / z 547.2[M] + . Step 2: Preparation of (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone hydrochloride

[0109] To a 250 mL solution of tert-butyl-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate (10 g, 18.3 mmol) in dioxane, 50 mL of 4N HCl in the dioxane was added. This mixed reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated to dryness under vacuum. The residue was powdered by DCM to obtain (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone hydrochloride (8 g). 1 H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 7.85 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.18 - 7.10 (m, 3H), 7.04 (d, J = 6.7 Hz, 1H), 4.44 (s, 1H), 3.57 (br, 2H), 3.34 (br, 2H), 2.47 (br, 2H), 2.06 (br, 2H).LCMS:(ES+):m / z 448.2[M] + . Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione (intermediate C) [ka]

[0110] Intermediate 2-1 was prepared as a hydrochloride salt according to the scheme above, using a similar method described in the literature. LC / MS 343.1[M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ ppm 7.76 (d, J = 8.36 Hz, 1 H), 7.47 (s, 1 H), 7.35 (dd, J = 8.36, 1.54 Hz, 1 H), 5.09 (br dd, J = 12.8, 5.40 Hz, 1 H), 3.67 - 3.74 (m, 4 H), 3.37 - 3.42 (m, 4 H), 2.63 - 2.94 (m, 3 H), 2.07 - 2.17 (m, 1 H). Synthesis of (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (intermediate D) [ka]

[0111] (S)-tert-butyl 4-(2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindorin-5-yl)piperazine-1-carboxylate (5.8 g, 12 mol) was dissolved in acetonitrile (90 mL) and benzenesulfonic acid (3.64 g, 23 mol) was added. This mixture was stirred at 85 °C for 12 hours. LC / MS indicated that the reaction was complete. This mixture was concentrated under vacuum. The residue was powdered with ethyl acetate to obtain (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dionebenzenesulfonate (5.2 g, 93%) as an off-white solid. LC / MS 329.1[M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 1H), 2.36-2.41 (m, 1H), 2.58-2.62 (d, 1H), 2.88-2.91 (m, 1H), 3.26 (s, 4H), 3.49-3.52 (m, 4H), 4.21-4.38 (dd, 2H), 5.05-5.10 (dd, 1H), 7.12-7.16 (m, 2H), 7.30-7.358 (m, 3H), 7.58-7.62 (m, 3H), 8.72 (s, 2H). Synthesis of N-(4-(4-amino-1-(4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (intermediate E) [ka] Step 1: Preparation of N-(4-bromobenzyl)-5-fluoro-2-methoxybenzamide

[0112] A solution of 5-fluoro-2-methoxybenzoic acid (30 g, 176 mmol, 1.0 equivalent), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.5 g, 212 mmol, 1.2 equivalents), and N,N-diisopropylethylamine (45.6 g, 353 mmol, 2 equivalents) in N,N-dimethylformamide (300 mL) was stirred at 25°C for 30 minutes. Next, (4-bromophenyl)methaneamine (32.8 g, 176 mmol, 1.0 equivalent) was added to this solution, and the mixture was stirred at 25°C for 12 hours. This solution was poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using 20%-30% ethyl acetate in petroleum ether as the eluent, yielding the desired compound (56 g, 94% yield) as a white solid. 1 HNMR (400 MHz, CDCl3): δ 8.26 (br s, 1H), 7.94 (q, J = 2.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 - 7.12 (m, 1H), 6.94 - 6.91 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H). Step 2: Preparation of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

[0113] To a 500 mL solution of dioxane containing N-[(4-bromophenyl)methyl]-5-fluoro-2-methoxybenzamide (46 g, 136 mmol, 1.0 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (51.8 g, 204 mmol, 1.5 equivalents), potassium acetate (26.7 g, 272 mmol, 2.0 equivalents) and 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.95 g, 13.6 mmol, 0.1 equivalent) were added. The suspension was degassed under vacuum and purged with nitrogen three times. The mixture was stirred under nitrogen at 90°C for 12 hours. The solution was poured into water (2 L) and extracted with ethyl acetate (1 L x 3). The combined organic phase was washed with brine (2 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The combined crude product was purified by silica gel chromatography using 20%-30% ethyl acetate in petroleum ether as the eluent. The crude product was powdered with petroleum ether (200 mL), filtered, and the filter cake was dried under vacuum to obtain the desired compound (50 g, 79% yield) as a white solid. LC / MS: 386.2[M+H] + . Step 3: Preparation of N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide A mixture consisting of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide (10.0 g, 26.0 mmol, 1.0 equivalent), 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (6.78 g, 26.0 mmol, 1.0 equivalent), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.80 g, 5.19 mmol, 0.2 equivalent), and potassium phosphate (16.5 g, 77.9 mmol, 3.0 equivalent) in dioxane (200 mL) and water (40 mL) was degassed, purged with nitrogen three times, and then stirred under a nitrogen atmosphere at 110°C for 60 hours. The reaction mixture was partitioned between ethyl acetate (1 L) and water (1 L). The organic phase was separated, washed with brine (1 L), dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The residue was powdered with acetonitrile (50 mL) and then with ethyl acetate (50 mL). The solid was collected and dried under vacuum to obtain the desired compound (6.0 g, 59% yield) as a pale yellow solid. LC / MS: 393.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 13.59 (s, 1H), 8.86 (t, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 - 7.47 (m, 3H), 7.37 - 7.31 (m, 1H), 7.19 (dd, J = 4.4, 9.2 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H). Step 4: Preparation of N-[[4-[4-amino-1-[4-[4-(dimethoxymethyl)-1-piperidyl]-3-fluorophenyl]pyrazolo[3,4-d]pyrimidine-3-yl]phenyl]methyl]5-fluoro-2-methoxybenzamide

[0114] To a dimethyl sulfoxide solution (150 mL) of N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)phenyl]methyl]-5-fluoro-2-methoxybenzamide (12.0 g, 30.6 mmol, 1.0 equivalent) and 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (11.6 g, 30.6 mmol, 1.0 equivalent), copper iodide (3.24 g, 17.0 mmol, 0.55 equivalent), 2-(dimethylamino)acetic acid (3.50 g, 33.98 mmol, 1.1 equivalent), and sodium carbonate (7.20 g, 68.0 mmol, 2.2 equivalents) were added. The suspension was degassed under vacuum and purged with nitrogen three times. The mixture was stirred under nitrogen at 110°C for 12 hours. This solution was partitioned between ethyl acetate (800 mL) and water (2.0 L). The separated aqueous layer was extracted with ethyl acetate (700 mL x 3). The combined organic layer was washed with brine (500 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (15 g). The crude product was dissolved in ethyl acetate (420 mL) under reflux. Next, this solution was cooled to ambient temperature with little precipitate formation, and the mixture was maintained in a refrigerator (approximately 5°C) for 48 hours. This solution was filtered, and the filter cake was washed with cold ethyl acetate (20 mL) to obtain the pure product (5.28 g). The mother liquor was concentrated, and the residue was recrystallized from ethyl acetate (100 mL) to obtain another harvest of the pure product (1.7 g) (total 6.98 g, 36% yield) as a gray solid. LC / MS: 644.2[M+H] + . 1HNMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 8.38 (t, J = 5.2 Hz, 1H), 7.99 (dd, J = 3.2, 9.2 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.92 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.22 - 7.14 (m, 1H), 7.08 (t, J = 8.8 Hz, 1H), 6.97 (dd, J = 4.4, 8.8 Hz, 1H), 5.60 (br s, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.12 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.53 (d, J = 12.0 Hz, 2H), 3.39 (s, 6H), 2.69 (t, J = 11.6 Hz, 2H), 1.88 Preparation of (S)-3-(6-fluoro-1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (intermediate F) (d, J = 12.0 Hz, 2H), 1.82 - 1.73 (m, 1H), 1.64 - 1.48 (m, 2H). [ka] Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate

[0115] To a mixture of 2-bromo-4,5-difluorobenzoic acid (20 g, 0.084 mol) in MeOH (60 mL), thionyl chloride (13 g, 0.11 mol) was slowly added at 10°C, and the mixture was then stirred at 80°C for 3 hours. TLC indicated that the reaction was complete. The mixture was cooled to room temperature and concentrated, and then partitioned between ethyl acetate and water. The organic layer was washed twice with saturated Na2CO3 and brine, dehydrated with Na2SO4, and concentrated to obtain the desired crude product (21 g, yield: 100%), which was used in the next step without further purification. Step 2: Preparation of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0116] A mixture of methyl 2-bromo-4,5-difluorobenzoate (21 g, 0.084 mol), tert-butyl piperazine-1-carboxylate (23.4 g, 0.125 mol), and K2CO3 (17.3 g, 0.125 mol) in N,N-dimethylacetamide (60 mL) was stirred at 80°C for 16 hours. TLC indicated that the reaction was complete. This mixture was added to water (200 mL) and stirred for 10 minutes. RINKAN (200 mL) was added. This mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dehydrated with Na2SO4, and concentrated to obtain the desired title product (31.6 g, yield: 90%). Step 3: Preparation of tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0117] A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (30.6 g, 0.073 mol) and CuCN (9.8 g, 0.11 mol) in DMF (120 mL) was stirred at 100 °C for 16 hours. TLC indicated that the reaction was complete. The mixture was cooled to room temperature. Ethyl acetate (200 mL) and ammonium hydroxide (200 mL) were added and the mixture was stirred for 30 minutes. The mixture was filtered. The organic layer was washed with water, dehydrated with Na₂SO₄, and concentrated to obtain the crude product (25.4 g). The crude product was placed in refluxed petroleum ether (100 mL). The mixture was filtered and dried in an oven at 50 °C to obtain the title compound (21.5 g, yield: 81%). Step 4: Preparation of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0118] To a solution of pyridine (39.1 g, 495 mmol), water (20 mL), and acetic acid (26.4 g, 440 mmol), tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (20 g, 55 mmol) and Raney nickel (85% in water, 10 g) were added at room temperature. The resulting mixture was heated to 60°C. Sodium hypophosphite (29.2 g in 50 mL of water) was added dropwise to this mixture. The mixture was stirred at 60°C for 16 hours. TLC indicated that the reaction was not complete. The mixture was stirred for a further 10 hours. The mixture was cooled to room temperature. Ethyl acetate and water were added. The mixture was filtered. The organic layer was washed with water, 1N HCl, and brine, dehydrated with Na2SO4, and concentrated under reduced pressure to obtain the crude product (20.8 g, crude). The resulting residue was purified using a silica gel pad to obtain the desired product (8.7 g, yield: 43%). Step 5: Preparation of tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-carboxylate

[0119] To a solution of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (8.15 g, 22 mmol) in methanol (50 mL) at room temperature, tert-butyl (S)-4,5-diamino-5-oxopentanoate (5.4 g, 27 mmol) was added. Acetic acid (1.98 g, 33 mmol) was added at 0°C. Sodium borohydride (2.76 g, 44 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours. TLC indicated that the reaction was complete. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated citric acid and brine, dehydrated with Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel pad to obtain the desired product (8 g, yield: 69%). Step 6: Preparation of (S)-3-(6-fluoro-1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dionebenzenesulfonic acid

[0120] To a solution of tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-carboxylate (6.7 g, 13 mmol) in acetonitrile (67 mL), benzenesulfonic acid (4.3 g, 26 mmol) was added. This mixture was stirred at 80 °C for 16 hours. LC / MS indicated that the reaction was complete. This mixture was cooled to room temperature. This mixture was filtered and dried to obtain the desired product (5.6 g, 86%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.73 (br s, 2H), 7.60 (m, 2H), 7.49 (d, 1H), 7.32 (m, 4H), 5.08 (dd, J = 13.2 and 5.2 Hz, 1H), 4.38 (d J = 17.2 Hz, 1H), 4.27 (d, J = 17.2 Hz, 1H), 3.30 (br s, 8H), 2.91 (m, 1H), 2.67 (m, 1H), 2.50 (m, 1H), 1.98 (m, 1H); LC / MS 347.3 [M+H] + Examples (Example 1) Preparation of 5-((7-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)heptyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 1) [ka] Step 1: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-hydroxyisoindoline-1,3-dione

[0121] To a solution of 3-aminopiperidine-2,6-dione HCl salt (4.1 g, 24.7 mmol) in acetic acid (45 mL), sodium acetate (4.1 g, 49.4 mmol) was added, and the mixture was stirred at 25°C for 1 hour. 4-hydroxyphthalic acid (3.0 g, 16.5 mmol) was added to this mixture, and the mixture was heated to 120°C for 11 hours. The mixture was concentrated and then poured into water (20 mL). The suspension was filtered. Purification of the crude product by column chromatography (dichloromethane:methanol = 50:1 to 10:1) yielded 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (3.9 g, 14.3 mmol, 86% yield) as a colorless solid. Step 2: Preparation of 6-(piperazin-1-yl)nicotinate tert-butyl

[0122] To a solution of tert-butyl 6-chloronicotinate (8.52 g, 40 mmol) in tert-butanol (100 mL), piperazine (17.2 g, 200 mmol) was added, and the mixture was heated to 60°C for 6 hours. The mixture was concentrated under vacuum, and the crude product was purified by column chromatography to obtain the title compound (10 g, 95%) as a colorless solid. LC-MS: m / z = 264.2 [M] + . Step 3: Preparation of 6-(4-(7-hydroxyheptyl)piperazin-1-yl)tert-butyl nicotinate

[0123] To a solution of 6-(piperazin-1-yl)nicotinate tert-butyl (526 mg, 2 mmol) and 7-bromoheptan-1-ol (468 mg, 2.4 mmol) in CH3CN (5 mL), K2CO3 was added at room temperature, and the reaction mixture was stirred at 85°C for 4 hours. This mixture was diluted with ethyl acetate and filtered through a Celite pad. Upon concentration of the filtrate, 6-(4-(7-hydroxyheptyl)piperazin-1-yl)nicotinate tert-butyl (630 mg, 83%) was obtained as a pale yellow solid. LCMS: m / z = 378.3 [M] + . Step 4: Preparation of tert-butyl 6-(4-(7-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)heptyl)piperazine-1-yl)nicotinate

[0124] To a solution of 6-(4-(7-hydroxyheptyl)piperazin-1-yl)nicotinate tert-butyl (377 mg, 1 mmol) in dry THF (3 mL), 2-(2,6-dioxopiperidine-3-yl)-5-hydroxyisoindoline-1,3-dione (383.6 mg, 1.4 mmol) and PPh3 (524 mg, 2.0 mmol) were added under nitrogen at 25°C. DIAD (404 mg, 2.0 mmol) was added to this mixture at room temperature. The resulting mixture was stirred at 45°C for 2 hours. After cooling to room temperature, the reaction product was quenched with H2O (10 mL) and extracted with ELISA (10 mL x 2). The combined organic layers were washed with brine (20 mL x 5), dehydrated with anhydrous sodium sulfate, and concentrated. Purification of the residue by preparative TLC yielded the desired product (80 mg, 12.6%) as a white solid. LCMS: m / z = 634.3 [M+1] + . Step 5: Preparation of 6-(4-(7-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)heptyl)piperazine-1-yl)nicotinic acid

[0125] A solution of tert-butyl 6-(4-(7-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)heptyl)piperazine-1-yl)nicotinate (80 mg, 0.13 mmol) in TFA / DCM (6.0 mL, 1:5) was stirred at room temperature for 3 hours. The reaction mixture was concentrated by rotary distillation to obtain the title product (70 mg), which was used in the next step without further purification. LCMS: m / z = 578.3 [M+1] + . Step 6: Preparation of 5-((7-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)heptyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0126] 6-(4-(7-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)heptyl)piperazine-1-yl)nicotinic acid (58 mg, 0.1 mmol), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (54 mg, 0.12 mmol), and DIEA (51.6 mg, 0.4 mmol) were dissolved in DMF (3 mL) and HATU (57 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature until LC-MS indicated completion of the reaction. The mixture was quenched with ice water and extracted by DCM (10 mL x 3). The organic layer was washed with water and brine, dehydrated with Na2SO4, filtered, and the solvent was removed by rotary evaporation. Purification of the residue by preparative TLC yielded the title product (21 mg, 20.8%) as a white solid. LC-MS: m / z = 1007.4 [M + H] + . 1 HNMR (400 MHz, CDCl3-d): δ9.05 (s, 1H), 8.36-8.30 (m, 2H), 7.77-7.65 (m, 2H), 7.41-7.31 (m, 5H), 7.23-7.16 (m, 2H), 7.10-7.07 (m, 3H), 6.95-6.93 (m, 1H), 6.50-6.48 (m, 1H), 4.96-4.95 (m, 1H), 4.38 (s, 1H), 4.08 (s, 3H), 3.90 (s, 1H), 3.58-3.44 (m, 6H), 2.91-2.74 (m, 3H), 2.52 (m, 4H), 2.36 (s, 2H), 2.19-2.01 (m, 4H), 1.18-1.75 (m, 5H), 1.51-1.36 (m, 8H). (Example 2) Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 2) [ka] Step 1: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione

[0127] To a solution of 5-fluoroisobenzofuran-1,3-dione (2 g, 12.05 mmol) in acetic acid (30 mL), sodium acetate (1.98 g, 24.08 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (1.98 g, 12.05 mmol) were added. This mixture was stirred at 120 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (60 mL) and stirred for 10 minutes. This solid was collected by filtration, washed with water (2 × 20 mL), and dried under vacuum to obtain the title compound (2.8 g, 94%) as a white solid. Step 2: Preparation of tert-butyl 6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)nicotinate

[0128] In a 20 mL microwave tube, 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (200 mg, 0.724 mmol), 6-(piperazine-1-yl)nicotinate tert-butyl (158 mg, 0.603 mmol), and K2CO3 (167 mg, 1.207 mmol) were suspended in DMF. This mixture was irradiated with microwaves at 120°C for 1 hour. The mixture was extracted with ELISA (30 mL x 3) and washed with brine (20 mL x 2). The combined organic phase was dehydrated with Na2SO4 and concentrated under vacuum. Purification of the residue by preparative TLC yielded tert-butyl 6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)nicotinate (200 mg). Step 3: Preparation of 6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)nicotinic acid

[0129] 180 mg, 0.346 mol of tert-butyl 6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)nicotinate was dissolved in 4N HCl / dioxane, and the mixture was stirred at room temperature for 1 hour. After concentration under vacuum, the title compound (130 mg) was obtained as a yellow solid and used directly in the next step. Step 4: Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0130] To a solution of 6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)nicotinic acid (130 mg, 0.281 mmol) in DMF (5 mL), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (163 mg, 0.337 mmol), HATU (128 mg, 0.337 mmol), and DIEA (145 mg, 1.12 mmol) were added. This mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate. The combined organic phase was washed with aqueous sodium chloride solution. After concentration under vacuum, the residue was purified by preparative HPLC, yielding the title compound (16.8 mg) as a yellow solid. LCMS:(ES + ):m / z 893.3[M+1] + . 1 HNMR (400 MHz, CDCl3): δ: 12.71 (s, 1H), 11.06(s, 1H), 8.87 (s, 1H), 8.17(m, 2H), 7.82 (d, J=13.6Hz, 1H),7.77-7.10(m, 12H)7.05 (br, 1H), 6,68(br,1H, 5.08-5.06(m, 1H), 4,25 (br, 1H), 3,79-3.51 (m, 14H), 2.93-2.89 (m, 1H),2.13-21.85 (m, 5H) (Example 3) Preparation of 5-((6-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)hexyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 3) [ka] Compound 3 was prepared in step 3 by replacing 7-bromoheptan-1-ol with 6-bromohexane-1-ol using the same procedure described for compound 1. LCMS: m / z = 993.4 [M] + . 1 HNMR (400 MHz, CDCl3-d): δ9.04 (s, 1H), 8.36-8.30 (m, 2H), 7.77-7.65 (m, 2H), 7.41-7.32 (m, 5H), 7.22-7.18 (m, 2H), 7.10-7.07 (m, 3H), 6.95-6.93 (m, 1H), 6.54-6.50 (m, 1H), 4.96-4.95 (m, 1H), 4.37 (s, 1H), 4.10-4.06 (m, 4H), 3.57-3.42 (m, 6H), 2.90-2.78 (m, 3H), 2.49 (s, 4H), 2.35 (s, 2H), 2.18-2.15 (m, 2H), 2.00 (s, 3H), 1.83-1.51 (m, 10H). (Example 4) Preparation of 5-(3-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)propoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 4) [ka] Compound 4 was prepared in step 3 by replacing 7-bromoheptan-1-ol with 3-bromopropan-1-ol using the same procedure described for compound 1. LCMS: m / z = 951.3 [M] + . 1HNMR (400 MHz, CDCl3-d): δ8.98-8.89 (m, 1H), 8.46-8.32 (m, 2H), 7.81-7.68 (m, 2H), 7.41-7.39 (m, 3H), 7.29-7.20 (m, 3H), 7.09-7.07 (m, 3H), 6.95-6.93 (m, 1H), 6.54-6.47 (m, 1H), 4.96-4.93 (m, 1H), 4.35-4.13 (m, 4H), 3.74-3.73 (m, 1H), 3.57 (s, 3H), 3.35-3.32 (m, 1H), 2.91-2.73 (m, 4H), 2.47 (s, 3H), 2.38-2.17 (m, 5H), 1.89-1.59 (m, 9H). (Example 5) Preparation of 5-(2-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)ethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 5) [ka] Step 1: Preparation of 6-(4-(2-hydroxyethyl)piperazin-1-yl)tert-butyl nicotinate

[0131] To a 20 mL solution of tert-butyl 6-(piperazin-1-yl)nicotinate (800 mg, 3.04 mmol) in acetonitrile, 452 mg of bromoethanol (3.65 mmol) and 839 mg of K2CO3 (6.08 mmol) were added. This mixture was stirred at 85°C for 12 hours. The mixture was diluted with ethyl acetate and then filtered. The filtrate was concentrated to obtain tert-butyl 6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinate (760 mg, 78.9%), which was used directly in the next step. LCMS: 308.2[M+H] + . Step 2: Preparation of tert-butyl 6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinate

[0132] To a solution of tert-butyl 6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinate (760 mg, 2.47 mmol) in THF (10 mL), 2-(2,6-dioxopiperidine-3-yl)-5-hydroxyisoindoline-1,3-dione (813 mg, 2.97 mmol) and PPh3 (1.01 g, 2.97 mmol), followed by DIAD (748 mg, 3.70 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain tert-butyl6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinate (130 mg, 87.1%). LCMS: 564.3[M+H] + . Step 3: Preparation of 6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinic acid

[0133] A DCM / TFA (3:1) solution of tert-butyl 6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinate (130 mg, 0.23 mol) was stirred at room temperature for 1 hour. After concentration under vacuum, 6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinic acid (120 mg) was obtained as a yellow oil and used directly in the next step. LCMS: 508.1[M+H] + . Step 4: Preparation of 5-(2-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)ethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0134] To a 30 mL solution of 6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazine-1-yl)nicotinic acid (120 mg, 0.236 mmol) in DMF (30 mL), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (137 mg, 0.283 mmol), HATU (90 mg, 0.283 mmol), and DIEA (121 mg, 0.944 mmol) were added. This mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate. The combined organic phase was washed with an aqueous sodium chloride solution. After concentration under vacuum, the residue was purified by preparative HPLC, yielding the title compound (19 mg, 9%) as a yellow solid. LC-MS: (ES + ):m / z 940.3[M+1] + . 1 HNMR (400 MHz, CDCl3): δ: 8.99 (s, 1H), 8.35(s, 1H),8.29(s, 1H)7.77 (d, J=8.4Hz, 1H), 7.65(s, 1H)7.49-7.39 (m, 4H),7.30(s, 1H),7.29-7.10(s, 2H)7.07-7.07 (m, 2H), 6.95 (d, J=1.6Hz, 1H), 6.47 (s, 1H), 5.36-5.34 (m, 1H),4.97-4.94 (m, 1H), 4.31 (s, 2H),4.15-4.06 (m, 1H),3.57(s, 6H),2.86(s, 4H), 2.63 (s, 4H), 2.25-2.12 (m, 2H), 2.08-2.01 (m, 2H) ,1.92(s, 1H),1.85(s, 1H) (Example 6) Preparation of 5-((5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 6) [ka] Compound 6 was prepared in step 3 by replacing 7-bromoheptan-1-ol with 5-bromopentan-1-ol using the same procedure described for compound 1. LCMS: m / z = 979.4 [M] + . 1 HNMR (400 MHz, CDCl3-d): δ9.06 (s, 1H), 8.36-8.30 (m, 2H), 7.77-7.64 (m, 2H), 7.43-7.38 (m, 3H), 7.33-7.31 (m, 2H), 7.23-7.15 (m, 2H), 7.10-7.06 (m, 3H), 6.95-6.93(m, 1H), 6.51-6.48 (m, 1H), 4.97-4.93 (m, 1H), 4.38 (s, 1H), 4.12-4.07 (m, 3H), 3.56-3.47 (m, 6H), 2.90-2.73 (m, 3H), 2.49(s, 4H), 2.36-2.35 (m, 2H), 2.19-2.01 (m, 4H),1.88-1.50 (m, 10H) (Example 7) Preparation of 5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 7) [ka] Step 1: Preparation of (R)-6-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one

[0135] A mixture consisting of 6-bromohexanoyl chloride (45 mg, 0.21 mmol), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (94 mg, 0.21 mmol), and DIEA (136 mg, 1 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (5 mL). The organic phase was collected and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (DCM / MeOH = 10:1) yielded the desired product as a white solid (150 mg, 98%). LC / MS: 624.5[M+H] + . Step 2: Preparation of 5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0136] A mixture consisting of (R)-6-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one (150 mg, 0.20 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (90.9 mg, 0.24 mmol), K2CO3 (165.9 mg, 1.2 mmol), and KI (7.9 mg, 0.05 mmol) in DMF (3 mL) was stirred at 60°C for 16 hours. The reaction mixture was filtered, and the solution was concentrated under vacuum. Purification of the residue by preparative TLC (DCM / MeOH = 10:1) yielded the desired product as a white solid (37 mg, 19.8%). LC / MS:885.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.78 (br, 1H), 11.11 (s, 1H), 8.92 - 8.89 (m, 1H), 8.30 - 8.25 (m, 1H), 7.71 - 7.61 (m, 2H), 7.59 - 7.52 (m, 1H), 7.51 - 7.39 (m, 2H), 7.37 (s, 1H), 7.32 - 7.23 (m, 2H), 7.22 - 7. 12 (m, 3H), 7.07 - 6.96 (m, 1H), 5.09 (dd, J = 12.9, 5.3 Hz, 1H), 4.31 - 4.13 (m, 1H), 3.89 - 3.71 (m, 1H), 3.67 - 3.37 (m, 6H), 2.96 - 2.81 (m, 1H), 2.70 - 2.54 (m, 2H), 2.49 - 2.17 (m, 5H), 2.03 (d, J = 4.9 Hz, 2H), 1.95 - 1.67 (m, 3H), 1.65 - 1.41 (m, 4H), 1.39 - 1.02 (m, 5H), 1.00 - 0.70 (m, 1H). (Example 8) Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 8) [ka] Step 1: (R)-7-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine(pyrimidin)-4-yl)amino) Preparation of piperidine-1-yl)heptan-1-one

[0137] To a 5 mL solution of 7-bromoheptanoyl chloride (60 mg, 0.26 mmol) in DCM, (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (145.8 mg, 0.26 mmol) and N,N-diisopropylethylamine (335.4 mg, 2.6 mmol) were added. This reaction mixture was stirred overnight at room temperature. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (45 mg, 27%) as a white oil. LC / MS: 639.6[M+H] + . Step 2: Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0138] To an acetonitrile solution of (R)-7-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one (45 mg, 0.07 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (23 mg, 0.06 mmol), stirred at room temperature, N,N-diisopropylethylamine (27.09 mg, 0.21 mmol) and KI (1.2 mg, 0.007 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (32 mg, 50.8%). LC / MS:899.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.81 (br, 1H), 11.10 (s, 1H), 8.95 - 8.85 (m, 1H), 8.32 - 8.25 (m, 1H), 7.70 - 7.61 (m, 2H), 7.59 - 7.53 (m, 1H), 7.51 - 7.49 (m, 2H), 7.40 - 7.25 (m, 3H), 7.24 - 7.15 (m, 3H), 7.12 - 7.03 (m, 1H), 5.14 - 5.07 (m, 1H), 4.27 - 4.16 (m, 1H), 3.82 - 3.74 (m, 1H), 3.62 - 3.41 (m, 4H), 3.29 - 3.27 (m, 2H), 2.95 - 2.85 (m, 1H), 2.70 - 2.62 (m, 2H), 2.45 - 2.12 (m, 5H), 2.08 - 1.98 (m, 2H), 1.90 - 1.70 (m, 3H), 1.65 - 1.40 (m, 4H), 1.31 - 1.10 (m, 7H), 0.95 - 0.82 (m, 1H). (Example 9) 5-(4-((5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 9) [ka] Step 1: Preparation of tert-butyl methylnicotinate

[0139] To a solution of 6-methylnicotinic acid (5.2 g, 37.9 mmol) in toluene (150 mL), DMAP (520 mg, 3.79 mmol) and Boc2O (12.37 g, 56.9 mmol) were added. This mixture was stirred at 110°C for 12 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and extracted with aqueous sodium chloride. The combined organic phase was concentrated under vacuum, and the residue was purified by silica gel column chromatography (elution with 3% siRNA in petroleum ether) to obtain the title product (5.09 g, 69%). LCMS: m / z 194.2 [M+1] + . Step 2: Preparation of tert-butyl 6-(bromomethyl)nicotinate

[0140] To a solution of tert-butyl 6-methylnicotinate (590 mg, 3.05 mmol) in carbon tetrachloride (10 mL), NBS (440 mg, 2.48 mmol) and AIBN (59 mg, 0.3 mmol) were added. This mixture was stirred at 70°C for 12 hours and then diluted with ethyl acetate. After extraction with aqueous sodium chloride solution, the combined organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography (elution with 3% ethyl acetate in petroleum ether) to obtain the title product (320 mg, 38.5%). Step 3: Preparation of tert-butyl 6-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)nicotinate

[0141] 520 mg, 1.52 mmol of 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione was dissolved in CH3CN (10 mL), to which DIEA (770 mg, 5.96 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. 6-(bromomethyl)nicotinate tert-butyl (316 mg, 1.16 mmol) was added to this reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction product was quenched with water and extracted with ELISA (100 mL x 3). The combined organic phases were washed with brine and dehydrated with Na2SO4. After filtration, the organic solvent was removed under vacuum. Purification of the residue by column chromatography (DCM / MeOH=50 / 1) yielded tert-butyl 6-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)nicotinate (480 mg, 59%). LCMS: m / z 534.3 [M+1] + . Step 4: Preparation of 6-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)nicotinic acid

[0142] 480 mg, 0.9 mmol of tert-butyl 6-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)nicotinate was dissolved in 30 mL of 4N HCl / dioxane and stirred at room temperature for 5 hours. The mixture was concentrated under vacuum to obtain the title product (470 mg), which was used in the next step without further purification. LC-MS: (ES + ):m / z 478.2[M+1] + . Step 5: Preparation of 5-(4-((5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0143] To a solution of 6-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)nicotinic acid (220 mg, 0.46 mmol) in DMF (5 mL), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (240 mg, 536 mmol), HOBT (120 mg, 0.88 mmol), EDCI (170 mg, 0.89 mmol), and DIEA (350 mg, 2.713 mmol) were added. This mixture was stirred at room temperature for 12 hours. This mixture was diluted with water and extracted with ELISA (100 mL x 3). The combined organic phase was washed with brine and dehydrated with Na2SO4. After filtration, the solvent was removed by rotary evaporation, and the residue was purified by preparative HPLC to obtain the title product (27 mg, 6%) as a yellow solid. LCMS: m / z 454.2 [M+1] + . 1 HNMR (400 MHz, CDCl3): δ: 8.91(s, 1H), 8.34 (s, 1H) 8.68 (d, J=8.4Hz, 1H) 8.20 (d, J=8Hz, 1H) 7.85-7.61 (m, 2H) 7.45-7.35 (m, 5H) 7.31 (s, 2H) 7.29-7.11(m, 2H) 7.10(s, 1H) 7.09-7.01 (m, 3H) 6.96 (d, J=8.0Hz, 1H) 5.98-5.91 (m, 1H) 4.21 (s, 1H) 4.11 (s, 1H) 4.12-3.89 (m, 1H) 3.72 (s, 3H) 3.35 (s, 6H) 2.92-2.71(m, 4H) 2.55 (s, 3H) 2.27-2.15(m, 1H) 2.14-2.09(m, 3H) (Example 10) Preparation of 5-(4-((1-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 10) [ka] Step 1: Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate

[0144] To a 20 mL solution of 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione (540 mg, 1.578 mmol) in DCM, tert-butyl 4-formylpiperidine-1-carboxylate (350 mg, 1.643 mmol) and sodium triacetoxyborohydride (990 mg, 4.691 mmol) were added. This mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (40 mL x 4) and washed with aqueous sodium chloride solution. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography in DCM / MeOH 100:1~50:1 to obtain the title compound (469 mg, 55.1%). LCMS:(ES + ):m / z 440[M+1-Boc] +. Step 2: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3-dione

[0145] tert-butyl 4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (400 mg, 0.74 mmol) was dissolved in HCl / dioxane (10 mL), and the mixture was stirred at room temperature for 1.5 hours. The solid was collected by filtration, yielding the title compound (450 mg) as the HCl salt. LC-MS: 440.2[M+H] + . Step 3: Preparation of tert-butyl 6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)nicotinate

[0146] To a DMSO (20 mL) solution of 2-(2,6-dioxopiperidine-3-yl)-5-(4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3-dione (350 mg, 0.797 mmol), tert-butyl 6-chloronicotinate (169 mg, 0.793 mmol), L-proline (70 mg, 10%), K2CO3 (220 mg, 1.59 mmol), and CuI (35 mg, 10%) were added. This mixture was stirred at 90°C for 12 hours. The mixture was extracted with ELISA (50 mL x 4), and the organic phase was washed with aqueous sodium chloride (40 mL x 3). The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (DCM / MeOH 20:1) to obtain the title compound (280 mg, 71.4%) as a yellow oil. LCMS:(ES + ):m / z 617.3[M+H] + . Step 4: Preparation of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinic acid

[0147] tert-Butyl 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinate (280 mg, 0.133 mmol) was dissolved in DCM (6 mL) and TFA (2 mL). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvent under vacuum, the residue was dissolved in DCE, then concentrated to dryness under vacuum. The residue was azeotroped three times with DCE to give the title compound (340 mg) as a pale yellow oil. LCMS: (ES + ): m / z 562.2 [M+1] + . Step 5: Preparation of 5-(4-((1-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carbonyl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0148] To a solution of 6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)nicotinic acid (110 mg, 0.196 mmol) in DMF (20 mL), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (70 mg, 0.156 mmol) and DIEA (300 mg, 2.34 mmol) were added, followed by the addition of HATU (89 mg, 0.234 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After extraction with ELISA (30 mL x 4), the mixture was washed with brine (20 mL x 3), and the organic phase was concentrated under vacuum. Purification of the residue by preparative HPLC yielded the title product (18.8 mg) as a yellow solid. LCMS:(ES + ):m / z 992.3[M+1] + , 1 HNMR (400 MHz, CDCl3): δ: 10.20 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.77 (d, J=8.4Hz, 1H), 7.22-7.12 (m, 5H), 7.11-6.19 (m, 2H), 5.35-5.33 (m, 1H), 4.97-4.93 (m, 1H), 4.51-4.21(m, 3H), 3.91-3.85(m, 3H), 3.76 (s, 5H), 3.41-3.03(m, 8H), 2.91-2.71 (m, 4H), 1.71-1.59 (m, 1H), 1.54(d, J=6.8Hz, 4H), 1.45 (s, 2H). (Example 11) Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 11) [ka] Step 1: Preparation of tert-butyl 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanoate

[0149] To a solution of tert-butyl 5-bromopentanoate (47 mg, 0.2 mmol) in ACN (10 mL), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (75.7 mg, 0.2 mmol) and N,N-diisopropylethylamine (38.7 mg, 0.3 mmol) were added. This reaction mixture was stirred overnight at 60°C. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (60 mg, 60.1%) as a yellow solid. LC / MS: 498.8[M+H] + . Step 2: Preparation of 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid

[0150] To a solution of tert-butyl 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanoate (40 mg, 0.08 mmol) in DCM (10 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. When this solution was concentrated under vacuum, the crude product (35 mg, yield: 100%) was obtained as a yellow solid. LC / MS: 442.7 [M+H] + Step 3: Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0151] To a solution of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid (35 mg, 0.08 mmol) and (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (44.88 mg, 0.08 mmol) in DMF (10 mL) stirred at room temperature under nitrogen were added HATU (36.48 mg, 0.096 mmol) and DIEA (15.48 mg, 0.12 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum to give a crude product. The crude product was purified by preparative TLC with MeOH:DCM=1:10 to give the title compound (40 mg, 57.4%). LC / MS: 871.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.84 (br, 1H), 11.12 (s, 1H), 9.57 - 9.51 (m, 1H), 8.96 - 8.90 (m, 1H), 8.38 - 8.35 (m, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 9.7 Hz, 1H), 7.57 (dd, J = 8.5, 3.0 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.38 - 7.15 (m, 5H), 7.08 - 7.01 (m, 1H), 5.14 - 5.06 (m, 1H), 4.26 - 4.16 (m, 3H), 3.99 - 3.85 (m, 2H), 3.56 - 3.52 (m, 2H), 3.27 - 3.03 (m, 5H), 2.94 - 2.84 (m, 1H), 2.69 - 2.54 (m, 3H), 2.45 - 2.41 (m, 1H), 2.37 - 2.31 (m, 1H), 2.10 - 1.99 (m, 2H), 1.80 - 1.50 (m, 6H), 1.30 - 1.23 (m, 2H), 0.90 - 0.80 (m, 1H). (Example 12) Preparation of 5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 12) [ka] Step 1: Preparation of 7-bromoheptanal

[0152] To a solution of 7-bromoheptan-1-ol (1 g, 5.52 mmol) in DMSO (30 mL), IBX (1.8 g, 6.62 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (30 mL) and filtered. The filtrate was extracted with SiO2. The combined organic phases were washed with aqueous sodium bicarbonate solution and brine. After dehydrating the solvent with Na2SO4, the mixture was concentrated under vacuum to obtain 7-bromoheptanal (780 mg, 4.062 mmol) as a yellow oily substance. Step 2: Preparation of 5-(4-(7-bromoheptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0153] To a 20 mL solution of 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione (260 mg, 0.76 mmol) in DCM, 7-bromoheptanal (161 mg, 0.83 mmol) was added at 0°C. The mixture was stirred for 30 minutes, and then Na(OAc)3BH (483 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 12 hours, then extracted with ethyl acetate and washed with sodium chloride solution. The combined organic phase was dehydrated with Na2SO4 and concentrated under vacuum to obtain 5-(4-(7-bromoheptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (410 mg, 89%) as a yellow solid. LCMS: m / z 519[M+1] + . Step 3: Preparation of 5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0154] To a 10 mL solution of 5-(4-(7-bromoheptyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (410 mg, 0.75 mmol) in DMSO (10 mL), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (472 mg, 0.97 mmol) and DIEA (483 mg, 3.75 mmol) were added. This mixture was stirred at 70°C for 12 hours and filtered. The filtrate was extracted with ethyl acetate and washed with brine. The organic phase was dehydrated with Na2SO4 and concentrated under vacuum. Purification of the residue by preparative HPLC yielded the desired product (42.8 mg, 6%) as a yellow solid. LCMS: m / z 443[M+1] 2+ . 1 HNMR (400 MHz, DMSO): δ: 12.85 (s, 1H), 11.09 (s, 1H),8.81 (d, J=7.2Hz, 1H) 8.29 (s, 1H),7.77 (d, J=8.4Hz, 1H) 7.68 (s, 1H),7.58 (d, J=8.4Hz, 1H),7.53-7.45 (m, 3H),7.39 (s, 1H),7.29-7.21 (m, 1H) 7.18(d, J=8.8Hz, 3H),7.05(d, J=2.4Hz, 1H),5.12-5.10 (m, 2H),4.32 (s, 1H),4.22 (s, 2H),3.59-3.48(m, 4H),3.21-3.09 (m, 8H),2.95-2.81(m, 1H),2.69-2.52 (m, 2H),2.36 (d, J=14.0Hz, 1H),2.15 (s, 2H),2.05-2.01 (m, 1H),2.71 (s, 4H),1.34 (s, 6H),1.23 (s, 2H) (Example 13) (S)-3-(5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 13) [ka] Step 1: Preparation of 6-bromo-1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one

[0155] To a 5 mL solution of (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (90 mg, 0.2 mmol) in DCM, stirred under argon, 6-bromohexanoyl chloride (43 mg, 0.2 mmol) and DIEA (130 mg, 1.0 mmol) were added at room temperature. This reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and purified by preparative TLC (DCM / MeOH = 10:1) to obtain the title compound (120 mg, 96%) as a white solid. LC / MS: 623.6[M+H] + . Step 2: Preparation of (S)-3-(5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0156] To a solution of 6-bromo-1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one (110 mg, 0.18 mmol) in ACN (2 mL), stirred at room temperature under argon, (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (88 mg, 0.18 mmol), DIEA (116 mg, 0.9 mmol), and potassium iodide (6.0 mg, 0.04 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours. The crude product was concentrated under vacuum and purified by preparative TLC (DCM / MeOH = 10:1) to obtain the title compound (13 mg, 8.3%). LC / MS: 872.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.97 (s, 1H), 10.49 (br, 1H), 8.84 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.18 - 7.15 (m, 1H), 7.07 - 7.00 (m, 1H), 5.07 (dd, J = 13.2, 5.0 Hz, 1H), 4.42 - 4.30 (m, 2H), 4.27 - 4.13 (m, 2H), 4.05 - 3.96 (m, 1H), 3.90 - 3.82 (m, 1H), 3.62 - 3.54 (m, 1H), 3.30 - 3.20 (m, 2H), 3.19 - 2.97 (m, 4H), 2.95 - 2.86 (m, 1H), 2.69 - 2.56 (m, 1H), 2.47 - 2.31 (m, 4H), 2.13 - 2.01 (m, 2H), 2.00 - 1.92 (m, 1H), 1.82 - 1.65 (m, 2H), 1.64 - 1.45 (m, 4H), 1.43 - 1.32 (m, 3H), 1.30 - 1.17 (m, 3H). (Example 14) (S)-3-(5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 14) [ka] Step 1: Preparation of tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate

[0157] To a MeCN (5 mL) solution of tert-butyl 5-bromopentanoate (50 mg, 0.21 mmol), stirred at room temperature, (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (103 mg, 0.21 mmol), KI (35 mg, 0.21 mmol), and DIEA (109 mg, 0.84 mmol) were added. This reaction mixture was stirred at 60°C for 12 hours. The mixture was cooled to room temperature, poured into water (45 mL), and extracted with ELISA (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (MeOH / DCM = 1:10) to obtain the desired product (100 mg, yield = 98.4%) as a yellow solid. LC / MS: 484.9 [M+H] + . Step 2: Preparation of (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid

[0158] A solution of tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate (100 mg, 0.20 mmol) in TFA / DCM (1:5, 12 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain the crude product (100 mg, crude). LC / MS: 428.8[M+H] + . Step 3: Preparation of (S)-3-(5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0159] (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid (100 mg, 0.20 mmol) in DMF (5 mL) was mixed with HATU (94 mg, 0.25 mmol), DIEA (107 mg, 0.828 mmol), and (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (116 mg, 0.187 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (45 mL) and extracted with ELISA (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH / DCM = 1:10) yielded the desired product (25 mg, 14.5% yield in 2 steps). LC / MS: 857.6[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.83 (br, 1H), 10.97 (s, 1H), 8.95 - 8.85 (m, 1H), 8.37 - 8.25 (m, 1H), 7.71 - 7.63 (m, 1H), 7.60 - 7.53 (m, 3H), 7.48 (t, J= 7.6 Hz, 2H), 7.25 (t, J= 7.6 Hz, 1H), 7.24 - 7.16 (m, 3H), 7.15 - 7.06 (m, 2H), 7.04 (dd, J= 8.4, 2.4 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.40 - 4.30 (m, 1H), 4.28 - 4.15 (m, 2H), 3.95 - 3.75 (m, 1H), 3.65 - 3.41 (m, 5H), 3.22 - 3.10 (m, 2H), 2.98 - 2.85 (m, 2H), 2.60 - 2.52 (m, 2H), 2.47 - 2.28 (m, 3H), 2.28 - 2.15 (m, 1H), 2.09 - 1.94 (m, 2H), 1.88 - 1.70 (m, 2H), 1.65 - 1.40 (m, 4H), 1.31 (t, J= 7.2 Hz, 2H), 1.26 - 1.21 (m, 1H). (Example 15) 5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 15) [ka] Step 1: Preparation of (R)-(2-chloro-4-phenoxyphenyl)(4-((1-(6,6-dimethoxyhexyl)piperidine-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone

[0160] A suspension of 6-bromo-1,1-dimethoxyhexane (21 mg, 0.09 mmol), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (50 mg, 0.09 mmol), KI (15 mg, 0.09 mmol), and DIEA (24 mg, 0.18 mmol) in DMF (2 mL) was stirred at 25°C for 16 hours. The solvent was removed under vacuum. The residue was purified by chromatography using DCM / MeOH = 20:1 elution, yielding the product (50 mg, 94%) as a yellow solid. LC / MS: 592.3[M+H] + . Step 2: Preparation of (R)-6-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexanal

[0161] (R)-(2-chloro-4-phenoxyphenyl)(4-((1-(6,6-dimethoxypentyl)piperidine-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (50 mg, 0.08 mmol) was dissolved in ACN (2 mL), to which TsOH (14 mg, 0.08 mmol) and HOAc (14 mg, 0.08 mmol) were added. The reaction mixture was stirred at 25 °C for 5 hours. The mixture was concentrated under vacuum. The residue was dissolved in ELISA (10 mL) and washed with saturated NaHCO3 solution. The organic phase was dehydrated with Na2SO4 and concentrated under vacuum to obtain the title product (35 mg, 80%) as a yellow solid. LC / MS: 546.2[M+H] + . Step 3: Preparation of 5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0162] A solution of (R)-6-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexanal (35 mg, 0.07 mmol), Et3N (14 mg, 0.14 mmol), and 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (27 mg, 0.07 mmol) in DCM (5 mL) was stirred at 25°C for 10 minutes. The mixture was cooled to 0°C, and NaBH(OAc)3 (22 mg, 0.11 mmol) was added in fractional amounts. The mixture was stirred at 25°C for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography using DCM / MeOH = 20:1 elution. The title product (15 mg, 24%) was obtained as a yellow solid. LC / MS: 872.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.79 (br, 1H), 10.97 (s, 1H), 10.60 (br, 1H), 8.83 (d, J = 7.5 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.60 - 7.46 (m, 3H), 7.26 (t, J = 7.4 Hz, 1H), 7.23 - 7.06 (m, 4H), 7.04 - 7.01 (m, 1H), 5.09 - 5.04 (m, 1H), 4.42 - 4.13 (m, 4H), 4.09 - 3.93 (m, 1H), 3.92 - 3.78 (m, 1H), 3.72 - 3.41 (m, 2H), 3.29 - 3.17 (m, 3H), 3.14 - 2.85 (m, 4H), 2.77 - 2.52 (m, 4H), 2.42 - 2.30 (m, 3H), 2.13 - 1.60 (m, 3H), 1.77 - 1.65 (m, 1H), 1.58 - 1.45 (m, 3H), 1.41 - 1.19 (m, 5H). (Example 16) Preparation of (S)-3-(5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 16) [ka] Step 1: Preparation of (R)-6-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one

[0163] A mixture of (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (113 mg, 0.20 mmol) and DIEA (77.8 mg, 0.60 mmol) in DCM (10 mL) was mixed with 6-bromohexanoyl chloride (42.8 mg, 0.20 mmol) at 0°C. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum. Purification of the crude product by silica gel chromatography with 4-8% MeOH in DCM yielded the desired compound (80 mg, 64%). LC / MS: 623.5[M+H] + . Step 2: Preparation of (S)-3-(5-(4-(6-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0164] A mixture consisting of (R)-6-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexane-1-one (50 mg, 0.08 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (38.8 mg, 0.08 mmol), DIEA (20 mg, 0.16 mmol), and NaI (1.2 mg, 0.008 mmol) in ACN (9 mL) was stirred at 90°C for 18 hours under an N2 atmosphere. This mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with 5-10% MeOH in DCM to obtain the desired compound (38 mg, 70%). LC / MS:871.4[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.75 (br, 1H), 10.96 (s, 1H), 8.91 (d, J = 6.8 Hz, 1H), 8.30 - 8.26 (m, 1H), 7.68 - 7.59 (m, 1H), 7.56 - 7.46 (m, 4H), 7.32 - 7.24 (m, 1H), 7.21 - 7.13 (m, 3H), 7.10 - 7.02 (m, 3H), 5.08 - 5.03 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.16 (m, 2H), 3.82 - 3.70 (m, 1H), 3.65 - 3.39 (m, 3H), 3.28 - 3.15 (m, 2H), 2.95 - 2.83 (m, 2H), 2.72 - 2.65 (m, 1H), 2.63 - 2.59 (m, 1H), 2.57 - 2.55 (m, 1H), 2.49 - 2.40 (m, 2H), 2.37 - 2.31 (m, 1H), 2.28 - 2.15 (m, 2H), 2.03-1.95 (m, 2H), 1.81 - 1.71 (m, 2H), 1.63 - 1.32 (m, 4H), 1.30 - 1.18 (m, 3H), 1.15 - 1.08 (s, 2H), 0.90 - 0.84 (m, 1H). (Example 17) 3-(5-(4-(7-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 17) [ka] Step 1: Preparation of (R)-7-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one

[0165] A mixture of (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (113 mg, 0.20 mmol) and DIEA (77.8 mg, 0.60 mmol) in DCM (10 mL) was mixed with 7-bromoheptanoyl chloride (45.7 mg, 0.20 mmol) at 0°C. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum. Purification of the crude product by silica gel chromatography with 4-8% MeOH in DCM yielded the desired compound (80 mg, 63%). LC / MS: 637.4[M+H] + . Step 2: Preparation of 3-(5-(4-(7-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0166] A mixture consisting of (R)-7-bromo-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one (50 mg, 0.08 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (38.8 mg, 0.08 mmol), DIEA (20 mg, 0.16 mmol), and NaI (1.2 mg, 0.008 mmol) in ACN (9 mL) was stirred at 90°C for 18 hours under an N2 atmosphere. This mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with 5-10% MeOH in DCM to obtain the desired compound (22 mg, 98% purity, 30% yield). Chiral chromatography analysis revealed partial racemization. LC / MS: 885.5[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.75 (br, 1H), 10.96 (s, 1H), 8.92 - 8.86 (m, 1H), 8.32 - 8.25 (m, 1H), 7.72 - 7.60 (m, 1H), 7.57 - 7.46 (m, 4H), 7.32 - 7.20 (m, 1H), 7.21 - 7.15 (m, 3H), 7.08 - 7.02 (m, 3H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 - 4.30 (m, 1H), 4.28 - 4.15 (m, 2H), 3.77 (d, J = 13.2 Hz, 1H), 3.61 - 3.45 (m, 3H), 3.29 - 3.21 (m, 2H), 3.02 - 2.79 (m, 2H), 2.69 - 2.55 (m, 2H), 2.40 - 2.29 (m, 3H), 2.25 - 2.12 (m, 2H), 2.07 - 1.91 (m, 3H), 1.88 - 1.73 (m, 2H), 1.63 - 1.55 (m, 1H), 1.50 - 1.32 (m, 4H), 1.28 - 1.23 (m, 3H), 1.17 - 1.08 (m, 3H), 0.89 - 0.78 (m, 1H). (Example 18) Preparation of 5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)hexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 18) [ka] Compound 18 was prepared in the same manner as described for compound 12. LCMS: m / z 436.8 [M+1] 2+ . 1HNMR (400 MHz, DMSO): δ: 12.91 (s, 1H), 11.12 (s, 1H), 8.81 (d, J=6.8Hz, 1H),8.31 (s, 1H), 7.77(d, J=8.8Hz, 1H) 7.72 (s, 1H),7.61 (s, 1H),7.51-7.48 (m, 3H),7.31 (s, 1H),7.15 (s, 1H),7.13 (s, 3H),7.05(d, J=2Hz, 1H),5.19-5.15 (m, 1H),4.35 (s, 1H),4.21 (s, 2H),3.61 (s, 6H),3.19 (s, 7H),2.91-2.87 (m, 1H),2.71-2.69 (m, 1H),2.50 (d, J=1.6Hz, 2H),2.12-2.08 (m, 2H),1.71(s, 4H),1.35(s, 4H),1.22(s, 3H) (Example 19) 5-(4-(4-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-4-oxobutyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 19) [ka] Compound 19 was prepared in the same manner as described for compound 14. LC / MS: 857.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.81 (br, 1H), 11.10 (s, 1H), 8.92 - 8.83 (m, 1H), 8.32 - 8.19 (m, 1H), 7.84 - 7.55 (m, 3H), 7.54 - 7.40 (m, 2H), 7.39 - 6.97 (m, 6H), 5.17 - 5.02 (m, 1H), 4.37 - 4.05 (m, 2H), 3.97 - 3.75 (m, 1H), 3.72 - 3.33 (m, 6H), 3.27 - 2.81 (m, 4H), 2.73 - 2.54 (m, 2H), 2.47 - 2.09 (m, 5H), 2.06 - 1.97 (m, 2H), 1.93 - 1.45 (m, 5H), 1.35 - 1.15 (m, 1H). (Example 20) (S)-3-(5-(4-(4-(((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-4-oxobutyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 20) [ka] Compound 20 was prepared in the same manner as described for compound 14. LC / MS:843.6[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.90 - 12.75 (m, 1H), 10.97 (s, 1H), 10.47 (br, 1H), 8.93 - 8.81 (m, 1H), 8.35 - 8.24 (m, 1H), 7.73 - 7.43 (m, 5H), 7.29 - 7.08 (m, 5H), 7.07 - 7.00 (m, 1H), 5.13 - 5.03 (m, 1H), 4.42 - 4.15 (m, 3H), 4.03 - 3.85 (m, 2H), 3.78 - 3.38 (m, 5H), 3.29 - 3.01 (m, 5H), 2.96 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.47 - 2.32 (m, 3H), 2.06 - 1.91 (m, 3H), 1.83 - 1.46 (m, 4H), 1.28 - 1.18 (m, 1H), 0.96 - 0.75 (m, 1H). (Example 21) Preparation of (S)-3-(5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 21) [ka] Step 1: Preparation of (S)-3-(5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0167] To a 5 mL solution of 7-bromo-1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one (80 mg, 0.13 mmol) in DMF, stirred under argon, (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (63 mg, 0.13 mmol), DIEA (50 mg, 0.39 mmol), and potassium iodide (20 mg, 0.13 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 15 hours. The crude product was concentrated under vacuum and purified by preparative TLC (DCM / MeOH = 10:1) to obtain the title compound (30 mg, 26.0%). LC / MS:886.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 10.97 (s, 1H), 10.25 (br, 1H), 8.83 (d, J = 7.3 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.60 - 7.46 (m, 3H), 7.26 (t, J = 7.4 Hz, 1H), 7.22 - 7.01 (m, 5H), 5.06 (dd, J = 13.4, 5.1 Hz, 1H), 4.38 - 4.15 (m, 4H), 4.08 - 3.92 (m, 1H), 3.90 - 3.77 (m, 1H), 3.75 - 3.50 (m, 2H), 3.45 - 3.35 (m, 1H), 3.32 - 3.18 (m, 3H), 3.14 - 2.85 (m, 4H), 2.75 - 2.53 (m, 5H), 2.42 - 2.31 (m, 3H), 2.15 - 1.95 (m, 3H), 1.77 - 1.62 (m, 1H), 1.57 - 1.47 (m, 3H), 1.45 - 1.27 (m, 5H). (Example 22) Preparation of 5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 22) [ka] Compound 22 was prepared in the same manner as described for compound 13. LC / MS:901.2[M+H] + . 1 H NMR (400 MHz, DMSO) δ = 12.87 (br, 1H), 11.10 (s, 1H), 8.83 (d, J=7.4, 1H), 8.26 (s, 1H), 7.78 - 7.67 (m, 1H), 7.65 - 7.56 (m, 2H), 7.50 - 7.45 (m, 2H), 7.35 - 7.23 (m, 2H), 7.22 - 7.14 (m, 3H), 7.06 - 7.01 (m, 1H), 5.15 - 5.05 (m, 1H), 4.38 - 4.30(m, 1H), 4.28 - 4.12 (m, 2H), 3.89 - 3.80 (m, 1H), 3.65 - 3.40 (m, 3H), 3.29 - 3.23 (m, 2H), 3.17 - 2.82 (m, 5H), 2.65 - 2.54 (m, 2H), 2.39 - 2.32 (m, 2H), 2.12 - 1.99 (m, 3H), 1.80 - 1.68 (m,1H), 1.60 - 1.44 (m, 4H), 1.40 - 1.20 (m, 7H), 0.94 - 0.73 (m, 1H). (Example 23) Preparation of 5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-4-oxobutyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 23) [ka] Compound 23 was prepared in the same manner as described for compound 11. LC / MS: 857.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.79 (br, 1H), 11.10 (s, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.27 (s, 1H), 7.72 (brs, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.46 - 7.35 (m, 1H), 7.34 - 7.23 (m, 2H), 7.23 - 7.15 (m, 3H), 7.08 - 7.00 (m, 1H), 5.14 - 5.03 (m, 1H), 4.40 - 4.31 (m, 1H), 4.28 - 4.07 (m, 2H), 3.93 - 3.81 (m, 1H), 3.70 - 3.39 (m, 3H), 3.10 - 2.85 (m, 3H), 2.71 - 2.56 (m, 2H), 2.36 - 2.32 (m, 1H), 2.14 - 1.97 (m, 4H), 1.94 - 1.75 (m, 2H), 1.68 - 1.48 (m, 2H), 1.48 - 1.15 (m, 4H), 1.06 - 0.74 (m, 2H). (Example 24) Preparation of (S)-3-(5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-4-oxobutyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 24) [ka] Compound 24 was prepared in the same manner as described for compound 14. LC / MS:843.4[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.81 (br, 1H), 10.96 (s, 1H), 8.84 (d, J = 7.3 Hz, 1H), 8.73 (s, 0.5H), 8.51 (d, J = 8.4 Hz, 0.5H), 8.27 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.23 - 7.15 (m, 3H), 7.14 - 7.06 (m, 2H), 7.03 (dd, J = 8.5, 2.3 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.39 - 4.30 (m, 2H), 4.25 - 4.17 (m, 2H), 3.89 - 3.82 (m, 1H), 3.50 - 3.32 (m, 4H), 3.06 - 3.00 (m, 1H), 2.94 - 2.88 (m, 3H), 2.76 - 2.66 (m, 2H), 2.62 - 2.56 (m, 1H), 2.47 - 2.33 (m, 3H), 2.18 - 1.92 (m, 4H), 1.89 - 1.80 (m, 2H), 1.59 - 1.52 (m, 1H), 1.47 - 1.34 (m, 2H). (Example 25) Preparation of (S)-3-(5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 25) [ka] Step 1: Preparation of tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate

[0168] To a solution of tert-butyl 5-bromopentanoate (200 mg, 0.84 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (410.37 mg, 0.84 mmol), and DIEA (326.87 mg, 2.53 mmol) in MeCN (20 mL), KI (14.00 mg, 0.084 mmol) was added at room temperature. This reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was evaporated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography using DCM / MeOH (50 / 1~10 / 1) to obtain the product (250 mg, 61%) as a yellow solid. LC / MS: 484.7 [M+H] + . Step 2: Preparation of (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid

[0169] tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate (250 mg, 0.52 mmol) was dissolved in DCM (10 mL) and TFA (2 mL). The reaction mixture was stirred at 25°C for 5 hours. Upon concentration of the mixture, the product (200 mg, 78%) was obtained as a brown solid. LC / MS: 428.8[M+H] + . Step 3: Preparation of (S)-3-(5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0170] (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid (50 mg, 0.10 mmol), HATU (53.24 mg, 0.14 mmol), and DIEA (45.23 mg, 0.35 mmol) were mixed in 15 mL of DCM and stirred for 10 minutes. (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (53.24 mg, 0.14 mmol) was added. The mixture was stirred at 25°C for 2 hours. After removing the solvent, the residue was purified by silica gel column (DCM / MeOH = 20 / 1) to obtain the product (35 mg, 0.04 mmol, 40%) as a yellow solid. LC / MS: 858.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 10.96 (s, 1H), 10.13 (br, 1H), 8.84 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.60 - 7.46 (m, 3H), 7.26 (t, J = 7.4 Hz, 1H), 7.23 - 6.97 (m, 5H), 5.06 - 5.01 (m, 1H), 4.48 - 4.12 (m, 4H), 4.061 - 3.81 (m, 2H), 3.66 - 3.49 (m, 1H), 3.34 - 3.11 (m, 5H), 3.10 - 2.76 (m, 3H), 2.67 - 2.52 (m, 3H), 2.50 - 2.24 (m, 6H), 2.17 - 2.08 (m, 2H), 2.01 - 1.87 (m, 1H), 1.74 - 1.46 (m, 4H), 1.43 - 1.31 (m, 1H). (Example 26) Preparation of 5-(4-(3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)propyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 26) [ka] Compound 26 was prepared in the same manner as described for compound 15. LC / MS:830.5[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 11.11 (s, 1H), 8.81 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.45 (m, 2H), 7.40 - 7.35 (m, 1H), 7.30 - 7.23 (m, 2H), 7.22 - 7.17 (m, 2H), 7.15 - 7.10 (m, 1H), 7.07 - 7.00 (m, 1H), 5.17 - 5.05 (m, 1H), 4.42 - 4.16 (m, 2H), 3.72 - 3.41 (m, 7H), 3.27 - 3.07 (m, 6H), 2.97 - 2.82 (m, 1H), 2.73 - 2.53 (m, 3H), 2.37 - 2.21 (m, 3H), 2.12 - 1.85 (m, 4H), 1.04 - 0.72 (m, 2H). (Example 27) Preparation of 5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)butyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 27) [ka] Compound 27 was prepared in the same manner as described for compound 15. LC / MS:844.4[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 11.11 (s, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 7.80 - 7.59 (m, 2H), 7.54 - 7.43 (m, 3H), 7.39 - 7.29 (m, 3H), 7.26 - 7.16 (m, 3H), 5.21 - 4.98 (m, 1H), 4.35-4.13 (m, 2H), 3.72 - 3.35 (m, 9H), 3.27 - 3.18 (m, 4H), 3.01 - 2.93 (m, 1H), 2.80 - 2.51 (m, 4H), 2.41 - 2.19 (m, 4H), 2.08 - 1.79 (m, 4H), 0.96 - 0.69 (m, 2H). (Example 28) Preparation of 5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 28) [ka] Compound 28 was prepared in the same manner as described for compound 11. LCMS: m / z = 886.3[M+1] + . 1 HNMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 8.85 (s, 1H), 8.229 (s, 1H), 7.69-7.67 (m, 1H), 7.58-7.56 (m, 1H), 7.51-7.49 (m, 2H), 7.32 (s, 1H), 7.28-7.21 (s, 2H), 7.19-7.15 (m, 3H), 7.01-6.99 (s, 1H), 6.65 (s, 1H), 5.32 (s, 2H), 5.11-5.08 (m, 1H), 4.35 (s, 1H), 4.19 (s, 1H), 3.91-3.88 (m, 2H), 2.68 (s, 1H), 2.39-2.31 (m, 5H), 2.09-1.99 (m, 8H), 1.60-1.42 (m, 8H), 0.85 (s, 4H). (Example 29) 5-(4-(7-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 29) [ka] Compound 29 was prepared in the same manner as described for compound 15. LC / MS:886.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.89 (br, 1H), 11.10 (s, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 7.77 - 7.65 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.44 - 7.32 (m, 1H), 7.30 - 7.17 (m, 4H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 5.09 (dd, J = 12.8, 5.3 Hz, 1H), 4.64 - 4.46 (m, 1H), 4.30 - 4.12 (m, 1H), 3.81 - 3.65 (m, 1H), 3.57 - 3.38 (m, 4H), 3.17 - 3.02 (m, 3H), 2.98 - 2.79 (m, 3H), 2.71 - 2.53 (m, 3H), 2.46 - 2.21 (m, 3H), 2.20 - 1.86 (m, 5H), 1.81 - 1.42 (m, 6H), 1.40 - 1.27 (m, 6H). (Example 30) Preparation of 5-(4-(5-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 30) [ka] Compound 30 was prepared in the same manner as described for compound 15. LC / MS:857.4[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.87 (br, 1H), 11.10 (s, 1H), 8.82 (br, 1H), 8.30 (s, 1H), 7.75 - 7.65 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.41 - 7.31 (m, 1H), 7.29 - 7.16 (m, 4H), 7.07 - 7.01 (m, 1H), 5.13 - 5.06 (m, 1H), 4.59 - 4.45 (m, 1H), 3.61 - 3.43 (m, 5H), 3.07 - 2.77 (m, 5H), 2.72 - 2.55 (m, 4H), 2.45 - 2.25 (m, 3H), 2.15 - 1.87 (m, 4H), 1.80 - 1.46 (m, 6H), 1.42 -1.17 (m, 4H). (Example 31) Preparation of 5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 31) [ka] Compound 31 was prepared in the same manner as described for compound 14. LCMS: m / z = 872.3[M+1] + . 1 HNMR (400 MHz, DMSO): δ: 12.91 (s, 1H), 11.09 (s, 1H), 9.71 (s, 1H), 9.01-8.98 (m, 1H), 8.31 (s, 1H), 7.81-7.79 (m, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.59-7.49 (m, 3H), 7.45-7.35 (m, 1H), 7.21 (s, 1H), 7.19-7.16 (m, 2H), 7.02 (s, 1H), 5.19-5.09 (m, 1H), 4.31 (s, 2H), 3.89(s, 2H), 3.61(s, 1H), 3.39-2.91 (m, 8H), 2.92-2.85 (m, 1H), 2.69-2.59 (m, 1H), 2.45-2.35 (s, 1H), 2.21-2.01 (s, 3H), 1.75 (s, 2H), 1.62-1.52 (m, 3H), 1.49-1.32(m, 1H), 1.25 (s, 1H). (Example 32) Preparation of (S)-3-(5-(4-((1-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 32) [ka] Step 1: Preparation of benzyl(S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate

[0171] To a 10 mL solution of benzyl 4-formylpiperidine-1-carboxylate (60 mg, 0.24 mmol) in DCM, stirred under argon at room temperature, (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (117 mg, 0.24 mmol), MgSO4 (288 mg, 2.4 mmol), and TEA (49 mg, 0.48 mmol) were added. This reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added. This reaction mixture was stirred at room temperature for 1 hour. The solid was filtered off and washed with DCM (5 mL x 3). The combined solution was concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC with PE:EA = 1:1 yielded the title product (100 mg, 74%) as a white solid. LC / MS: 560.8[M+H] + . Step 2: Preparation of (S)-3-(1-oxo-5-(4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-2-yl)piperidine-2,6-dione

[0172] A solution of benzyl(S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (100 mg, 0.18 mmol) in TFA (4 mL) was stirred overnight at 70°C. This mixture was concentrated under vacuum to obtain a crude product (136 mg) as a yellow solid, which was used in the next step without further purification. LC / MS: 426.8[M+H] + . Step 3: Preparation of (S)-3-(5-(4-((1-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0173] To a 5 mL solution of (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (90 mg, 0.16 mmol) stirred under argon, triphosgene (14 mg, 0.05 mmol) and DIEA (124 mg, 0.96 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. This solution was concentrated under vacuum. The residue was dissolved in 5 mL of DCM. (S)-3-(1-oxo-5-(4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (136 mg) and DIEA (124 mg, 0.96 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (2 mL), and the organic phase was separated. The organic phase was dehydrated with Na₂SO₄ and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC with a DCM / MeOH ratio of 10:1 yielded the product (30 mg, 20%) as a white solid. LC / MS: 898.4[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.81 (br, 1H), 10.97 (s, 1H), 8.90 (br, 1H), 8.29 (s, 1H), 7.64 (s, 1H), 7.62 - 7.44 (m, 4H), 7.29 - 7.15 (m, 4H), 7.13 - 7.01 (m, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.18 (m, 3H), 4.00 - 3.87 (m, 1H), 3.75 - 3.50 (m, 4H), 3.30 - 3.20 (m, 2H), 3.17 - 3.05 (m, 3H), 2.95 - 2.88 (m, 1H), 2.73 - 2.53 (m, 4H), 2.46 - 2.34 (m, 2H), 2.06 - 1.85 (m, 4H), 1.79 - 1.45 (m, 5H), 1.37 - 1.17 (m, 3H), 1.10 - 0.80 (m, 3H). (Example 33) Preparation of 5-(4-((1-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-((S)-2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 33) [ka] Compound 33 was prepared in the same manner as described for compound 32. LC / MS:913.2[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 11.11 (s, 1H), 8.90 (s, 1H), 8.28 (s, 1H), 7.76 - 7.62 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.40 - 7.31 (m, 1H), 7.30 - 7.15 (m, 4H), 7.12 - 7.00 (m, 1H), 5.14 - 5.05 (m, 1H), 4.35 - 4.12 (m, 2H), 3.68 - 3.40 (m, 6H), 3.02 - 2.84 (m, 5H), 2.70 - 2.61 (m, 2H), 2.59 - 2.54 (m, 1H), 2.46 - 2.33 (m, 2H), 2.19 - 1.84 (m, 5H), 1.72 - 1.48 (m, 4H), 1.33 - 1.14 (m, 3H), 0.99 - 0.72 (m, 3H). (Example 34) Preparation of 5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 34) [ka] Step 1: Preparation of 5-(4-(5,5-dimethoxypentyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0174] To a 10 mL solution of 5-bromo-1,1-dimethoxypentane (250 mg, 1.19 mmol) in DMSO (10 mL), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (340 mg, 0.994 mmol) and DIEA (350 mg, 2.71 mmol) were added. This mixture was stirred at 70°C for 12 hours and extracted with ethyl acetate. The combined organic phase was washed with an aqueous sodium chloride solution and then dehydrated with Na2SO4. The solvent was removed under vacuum, and the residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the desired product (135 mg, 24%) as a yellow solid. Step 2: Preparation of 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanal

[0175] 5-(4-(5,5-dimethoxypentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (360 mg, 0.762 mmol) was dissolved in 2N HCl / dioxane (10 mL), and the reaction mixture was stirred at room temperature for 3 hours. The pH of this mixture was adjusted to 8-9 with aqueous NaHCO3 solution, and then extracted with ELISA (40 mL x 3). The organic layer was washed with water and brine and dehydrated with Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanal (240 mg, 70%). Step 3: Preparation of 5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0176] Potassium acetate (72.3 mg, 0.738 mmol) was added to a 3 mL solution of (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (220 mg, 0.492 mmol) in DCM. The mixture was stirred for 30 minutes. A 5 mL solution of 5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentanal (210 mg, 0.492 mmol) and AcOH (44.28 mg, 0.738 mmol) in DCM was added. After stirring for 30 minutes, sodium triacetoxyborohydride (312 mg, 1.476 mmol) was added, and the mixture was stirred overnight at room temperature. This mixture was extracted with ELISA (30 mL x 3). The organic layer was washed with water and brine and dehydrated with Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by preparative HPLC to obtain 5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)pentyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (43.1 mg, 9.7%) as a white solid. LCMS: m / z = 860.3 [M + H] + . 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 11.09 (s, 1H),10.11 (s, 1H), 9.52 (s, 1H), 8.82 (d, J = 6.4 Hz, 1H), 8.29 (s, 1H), 7.69-7.59 (m, 1H) 7.58 (s, 1H), 7.56 (s, 1H), 7.50-7.48 (m, 2H), 7.45-7.44 (m, 1H), 7.42-7.40 (m, 1H), 7.25-7.23(m, 2H), 7.09-7.01 (s, 1H), 5.12-5.07 (m, 2H), 4.26-4.23 (m, 4H), 3.61 (s, 4H), 3.61-3.58(m, 2H), 3.21-3.12 (s, 9H), 2.99-2.81 (m, 2H), 2.69-2.52 (m, 2H), 2.40 (d, J = 2.4 Hz, 2H), 2.15(s, 1H), 2.09-1.98 (m, 2H), 1.35 (s, 2H). (Example 35) Preparation of 4-(9-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-9-oxonona-1-in-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (compound 35) [ka] Step 1: Preparation of nona-8-ic acid

[0177] To a solution of lithium acetylide-ethylenediamine complex (2.20 g, 21.5 mmol, 90%) in DMSO (5 mL), 7-bromoheptanoic acid (1.50 g, 7.17 mmol) in DMSO (7 mL) was added dropwise at 0°C. The solution was stirred at room temperature for 2 hours. The reaction mixture was poured into ice / water, acidified with 1N HCl, and extracted by DCM. The organic layer was dehydrated with Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (10-30% EA in PE) to obtain the title compound (713 mg, 64%) as a clear oil. LC / MS: 155.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 2.38 (t, J = 7.5 Hz, 2H), 2.21 (td, J = 7.0, 2.6 Hz, 2H), 1.96 (t, J = 2.6 Hz, 1H), 1.71 - 1.63 (m, 2H), 1.60 - 1.52 (m, 2H), 1.49 - 1.38 (m, 4H). Step 2: Preparation of tert-butyl nona-8-icate

[0178] In a solution of nona-8-ic acid (900 mg, 5.84 mmol) and anhydrous N,N-dimethylformamide (85 mg, 1.17 mmol) in anhydrous DCM (20 mL), which was stirred at room temperature under Ar, oxalyl chloride (1.5 g, 11.68 mmol) was added dropwise. This reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated under vacuum, and the residue was dissolved in anhydrous THF (20 mL). This solution was cooled to 0°C, and t-BuOK (1.3 g, 11.68 mmol) was added in small amounts. The mixture was stirred at room temperature for 1 hour. The reaction product was quenched by adding ice water and extracted with Et2O. The organic layer was dehydrated with Na2SO4 and evaporated under vacuum. The residue was purified by flash chromatography at PE / EA = 10:1, yielding the title compound (657 mg, 53%) as a clear oil. LC / MS: 232.9 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 2.26 - 2.17 (m, 4H), 1.96 (t, J = 2.6 Step 3: Preparation of tert-butyl 9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)nona-8-inoate. (Hz, 1H), 1.65 - 1.52 (m, 4H), 1.46 (s, 9H), 1.45 - 1.30 (m, 4H).

[0179] A suspension of tert-butyl nona-8-icate (63 mg, 0.3 mmol), 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione (50 mg, 0.15 mmol), copper(I) iodide (6.3 mg, 0.033 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.017 mmol), and Et3N (2 mL) in THF (5 mL) was stirred at 70 °C for 10 hours under an Ar atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum. The residue was purified by preparative TLC with PE / EA = 1:1 to obtain the title compound (48 mg, 68%) as a white solid. LC / MS: 488.7 [M + Na] + . Step 4: Preparation of 9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)nonano-8-ic acid

[0180] A solution of tert-butyl 9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)nona-8-inoate (30 mg, 0.06 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 2 hours. This mixture was evaporated under vacuum to obtain the crude product (33 mg), which was used in the next step without further purification. LC / MS: 432.7[M+Na] + . Step 5: Preparation of 4-(9-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-9-oxonona-1-in-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0181] A mixture consisting of 9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)nonano-8-ic acid (33 mg, 80% purity, 0.06 mmol), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (31 mg, 0.070 mmol), HATU (40 mg, 0.11 mmol), N,N-diisopropylethylamine (27 mg, 0.21 mmol), and DMF (5 mL) was stirred at room temperature for 2 hours. This mixture was concentrated under vacuum and purified by preparative TLC with DCM / MeOH = 10:1 to obtain the title compound (16.1 mg, 29%) as a white solid. LC / MS: 839.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.78 (br, 1H), 11.15 (br, 1H), 8.83 (s, 1H), 8.26 (s, 1H), 7.88 - 7.80 (m, 3H), 7.65 - 7 / 62 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.29 - 7.17 (m, 4H), 7.03 (d, J = 7.6 Hz, 1H), 5.18 - 5.12 (m, 1H), 4.35 - 4.06 (m, 2H), 3.91 - 3.76 (m, 1H), 3.05 - 2.85 (m, 2H), 2.70 - 2.57 (m, 2H), 2.37 - 2.35 (m, 2H), 2.30 - 2.20 (m, 3H), 1.63 - 1.48 (m, 8H), 1.36 - 1.25 (m, 5H). (Example 36) Preparation of 4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxohepta1-in-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 36) [ka] Compound 36 was prepared in the same manner as described for compound 35. LC / MS:811.4[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.78 (br, 1H), 11.16 (s, 1H), 8.82 (d, J = 6.5 Hz, 1H), 8.26 (s, 1H), 7.91 - 7.87 (m, 3H), 7.64 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.30 - 7.25 (m, 1H), 7.28 - 7.22 (m, 3H), 7.07 - 7.02 (m, 1H), 5.18 - 5.11 (m, 1H), 4.39 - 4.14 (m, 2H), 3.90 - 3.80 (m, 1H), 3.07 - 2.81 (m, 2H), 2.70 - 2.58 (m, 2H), 2.43 - 2.31 (m, 2H), 2.15 - 2.02 (m, 3H), 1.78 - 1.61 (m, 4H), 1.60 - 1.30 (m, 3H), 1.30 - 1.03 (m, 2H). (Example 37) Preparation of 5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 37) [ka] Step 1: Preparation of 3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutan-1-one

[0182] To a 10 ml solution of (3-oxocyclobutyl)acetic acid (250 mg, 1.95 mmol) in DMF (10 ml), stirred at room temperature, HATU (890 mg, 2.34 mmol), DIEA (756 mg, 5.85 mmol), and (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (944 mg, 1.95 mmol) were added. This reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into water (40 mL) and extracted with ELISA (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (1 g, 91.79%) as a yellow solid. LC / MS: 558.0 [M+H] + . Step 2: Preparation of 5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0183] To a solution of 3-{2-[4-({5-[(2-chloro-4-phenoxyphenyl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidine-4-yl}amino)piperidine-1-yl]-2-oxoethyl}cyclobutan-1-one (1 g, 1.79 mmol) in MeOH / DMF / AcOH (8 mL, 4 mL, 0.5 mL), stirred at room temperature, 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (678 mg, 1.79 mmol) and NaBH3CN (169 mg, 2.685 mmol) were added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (290 mg, 18.44%) as a yellow solid. LC / MS: 884.1[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 11.09 (s, 1H), 10.1 (br, 1H), 8.83 (d, J= 7.2 Hz, 1H), 8.26 (s, 1H), 7.85 - 7.72 (m, 1H), 7.64 (s, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.48 (t, J= 8.4 Hz, 2H), 7.35 - 7.30 (m, 1H), 7.26 (t, J= 7.6 Hz, 2H), 7.2-7.16 (m, 3H), 7.03 (dd, J= 8.4, 2.4 Hz, 1H), 5.18 - 5.05 (m, 1H), 4.40 - 4.30 (m, 1H), 4.19 - 4.13 (m, 1H), 3.86 - 3.82 (m, 1H), 3.48 - 3.39 (m, 3H), 3.29 - 3.25 (m, 2H), 3.05 - 2.80 (m, 4H), 2.64 - 2.53 (m, 3H), 2.43 - 2.30 (m, 4H), 2.27 - 2.21 (m, 2H), 2.18 - 1.95 (m, 4H), 1.61 - 1.48 (m, 2H), 1.40 - 1.35 (m, 1H). (Example 38) Preparation of 4-(8-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-8-oxoocta-1-in-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 38) [ka] Compound 38 was prepared in the same manner as described for compound 35. LC / MS:825.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.77 (br, 1H), 11.15 (s, 1H), 8.83 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 7.87 - 7.81 (m, 3H), 7.63 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.22 - 7.17 (m, 3H), 7.02 (dd, J = 8.5, 2.3 Hz, 1H), 5.15 (dd, J = 12.9, 5.3 Hz, 1H), 4.35 - 4.20 (m, 1H), 4.18 - 4.13 (m, 1H), 3.85 (d, J = 14.3 Hz, 1H), 3.32 - 3.26 (m, 1H), 3.05 - 2.98 (m, 1H), 2.92 - 2.84 (m, 1H), 2.63 - 2.53 (m, 3H), 2.42 - 2.32 (m, 3H), 2.09 - 2.01 (m, 3H), 1.64 - 1.51 (m, 6H), 1.44 - 1.29 (m, 2H). (Example 39) Preparation of 3-(4-(9-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-9-oxonona-1-in-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 39) [ka] Compound 39 was prepared in the same manner as described for compound 35. LC / MS:825.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.76 (br, 1H), 11.00 (br, 1H), 9.00 - 8.75 (m, 1H), 8.26 (br, 1H), 7.72 - 7.46 (m, 7H), 7.35 - 7.16 (m, 4H), 7.12 - 7.04 (m, 1H), 5.23 - 5.10 (m, 1H), 4.51 - 4.42 (m, 1H), 4.39 - 4.27 (m, 2H), 4.22 - 4.12 (m, 1H), 3.89 - 3.77 (m, 1H), 3.01 - 2.88 (m, 2H), 2.76 - 2.65 (m, 2H), 2.38 - 2.33 (m, 2H), 2.04 (s, 3H), 1.70 - 1.30 (m, 13H). (Example 40) Preparation of 3-(4-(8-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-8-oxoocta-1-in-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 40) [ka] Compound 40 was prepared in the same manner as described for compound 35. LC / MS:811.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.76 (br, 1H), 11.00 (s, 1H), 8.82 (d, J = 7.4 Hz, 1H), 8.26 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.64 (t, J = 3.4 Hz, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.54 - 7.43 (m, 3H), 7.28 - 7.24 (m, 1H), 7.20 - 7.18 (m, 2H), 7.02 (dd, J = 8.5, 2.4 Hz, 1H), 5.19 - 5.10 (m, 1H), 4.53 - 4.45 (m, 1H), 4.39 - 4.25 (m, 2H), 4.20 - 4.15 (m, 1H), 3.90 -3.81 (m, 1H), 3.29 - 3.25 (m, 1H), 3.04 - 2.85 (m, 3H), 2.70 - 2.66 (m, 1H), 2.62 - 2.54 (m, 2H), 2.40 - 2.33 (m, 2H), 2.10 - 1.98 (m, 3H), 1.63 - 1.36 (m, 8H), 1.29 - 1.21 (m, 1H). (Example 41) Preparation of 3-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxohepta1-in-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 41) [ka] Compound 41 was prepared in the same manner as described for compound 35. LC / MS:798.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 11.1-10.9(m, 1H), 8.82 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.63 (t, J = 3.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.54 - 7.43 (m, 3H), 7.30-7.23 (m, 1H), 7.23 - 7.14 (m, 3H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 5.15 (dd, J = 13.2, 4.6 Hz, 1H), 4.50-4.45 (m, 1H), 4.35-4.28 (m, 2H), 4.20-4.10 (m,1H), 3.89-3.80 (m, 1H), 3.65-3.57 (m, 1H), 3.33-3.25 (m, 1H), 3.15-3.08 (m, 1H), 3.02 - 2.87 (m, 2H), 2.62 - 2.53 (m, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.09 - 1.97 (m, 3H), 1.72 - 1.60 (m, 3H), 1.55-1.46 (m, 1H), 1.41 - 1.31 (m, 2H). (Example 42) Preparation of (S)-3-(5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 42) [ka] Step 1: Preparation of 3-(2-diazoacetyl)cyclobutan-1-one

[0184] To a solution of 3-oxocyclobutane-1-carboxylic acid (2 g, 17.54 mmol) in DCM (10 mL), SOCl2 (3.84 mL) was added. This reaction mixture was stirred at 20°C for 2 hours. The mixture was evaporated to dryness under reduced pressure. To a solution of the residue in THF (5 mL) and acetonitrile (5 mL), (diazomethyl)trimethylsilane (2 M in hexane, 17.5 mL) was added. This reaction mixture was stirred at 20°C overnight, and then evaporated under vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, PE / EA = 2:1) to obtain the title compound (1.6 g, 52.8% yield) as a yellow oil. LC / MS: 139.1[M+H]+. Step 2: Preparation of 2-(3-oxocyclobutyl)acetic acid

[0185] To a solution of 3-(2-diazoacetyl)cyclobutan-1-one (1.6 g, 9.27 mmol) in THF (30 mL) and water (15 mL), AgNO3 (1.87 g, 11.12 mmol) was added. The reaction mixture was stirred overnight at room temperature, then evaporated under vacuum to remove the THF. The aqueous phase was extracted using EA (20 mL × 3). The combined organic layers were dehydrated with Na2SO4 and evaporated under vacuum to obtain the title compound (1.0 g, 76.4% yield) as a yellow oil. LC / MS: 127.1 [MH] - . Step 3: Preparation of 3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutan-1-one

[0186] A solution of 2-(3-oxocyclobutyl)acetic acid (50 mg, 90% purity, 0.35 mmol), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (207.8 mg, 0.43 mmol), HATU (177.9 mg, 0.47 mmol), N,N-diisopropylethylamine (75.6 mg, 0.59 mmol), and DMF (10 mL) was stirred at room temperature for 4 hours. This mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM (1:10) to obtain the title compound (100 mg, 51%). LC / MS: 557.6[M+H] + . Step 4: Preparation of (S)-3-(5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0187] A solution of 3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutan-1-one (100 mg, 0.18 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (87.5 mg, 0.18 mmol), and sodium borohydride (21.6 mg, 0.36 mmol) in DMF / MeOH / HOAc (16 mL, 5:10:1) was stirred overnight at room temperature. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (40 mg, 25.6%). LC / MS: 869.5[M+H] +. 1 H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 10.96 (s, 1H), 8.83 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.21 - 7.16 (m, 3H), 7.08 - 7.01 (m, 2H), 5.06 (d, J = 12.7 Hz, 1H), 4.37 - 4.13 (m, 4H), 4.00 (s, 1H), 3.87 - 3.79 (m, 1H), 3.71-3.34 (m, 2H), 3.31 - 3.13 (m, 4H), 3.06 - 2.85 (m, 3H), 2.80 - 2.52 (m, 2H), 2.49 - 2.46 (m, 1H), 2.37 (s, 4H), 2.23 (s, 2H), 2.13 - 1.89 (m, 5H), 1.51 (br, 2H), 1.41 - 1.34 (m, 1H), 1.24 (s, 1H). (Example 43) Preparation of 5-(4-(3-(2-((R)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)cyclobutyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 43)

[0188] Compound 43 was prepared using the same method described for the preparation of Compound 42. LC / MS: 884.4[M+H]+ 1H NMR (400 MHz, DMSO) δ 12.81 - 12.75 (m, 1H), 11.09 (s, 1H), 8.92 - 8.86 (m, 1H), 8.33 - 8.25 (m, 1H), 7.67 - 7.63 (m, 2H), 7.59 - 7.42 (m, 3H), 7.35 - 7.30 (m, 1H), 7.29 - 7.11 (m, 5H), 7.07 - 7.01 (m, 1H), 5.10 - 5.06 (m, 1H), 4.28 - 4.20 (m, 1H), 3.79 - 3.35 (m, 8H), 2.94 - 2.84 (m, 1H), 2.68 - 2.55 (m, 3H), 2.46 - 2.08 (m, 9H), 2.05 - 1.80 (m, 3H), 1.78 - 1.72 (m, 3H), 1.27 - 1.20 (M, 1H). (Example 44) Preparation of 5-(4-(2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)ethyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 44) [ka] Step 1: Preparation of 2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)acetaldehyde

[0189] A solution of (2-chloro-4-phenoxyphenyl)(4-((4-(4-(2,2-dimethoxyethyl)piperidine-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (250 mg, 0.4 mmol) in THF / H2SO4 (10% aqueous solution) (30 mL, THF / H2SO4 = 1 / 1) was stirred at 70°C for 1 hour. The reaction mixture was adjusted to pH=10 with sodium hydroxide solution (2 M) and extracted with ELISA (15 mL x 3). The organic phase was dehydrated with sodium sulfate and concentrated under vacuum to obtain the desired product (200 mg, 82%) as a yellow solid. LC / MS: 583.[M+1] + . Step 2: Preparation of 5-(4-(2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)ethyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0190] A 20 mL solution of 2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)acetaldehyde (100 mg, 0.17 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (64 mg, 0.17 mmol), TEA (52 mg, 0.51 mmol), and MgSO4 (408 mg, 3.4 mmol) in DCM (20 mL) was stirred under nitrogen at room temperature for 30 minutes. Sodium triacetoxyborohydride (72 mg, 0.34 mmol) was added in small quantities at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and extracted with water. The organic phase was concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH:DCM=1:10) yielded the desired product (50 mg, 32%) as a yellow solid. LC / MS: 910.4[M+1] + . 1H NMR (400 MHz, DMSO) δ 13.06 (br, 1H), 11.12 (d, J = 18.0 Hz, 2H), 8.46 (s, 1H), 8.11 - 8.02 (m, 1H), 7.84 (s, 1H), 7.74 - 7.61 (m, 2H), 7.54 - 7.45 (m, 2H), 7.38 - 7.18 (m, 6H), 7.14 - 7.02 (m, 2H), 5.08 (dd, J = 12.8, 5.3 Hz, 1H), 3.52 - 3.37 (m, 2H), 3.36 - 3.28 (m, 7H), 2.95 - 2.82 (m, 1H), 2.71 - 2.53 (m, 4H), 2.45 - 2.27 (m, 3H), 2.04 - 1.97 (m, 1H), 1.85 - 1.73 (m, 2H), 1.55 - 1.3.0 (m, 5H), 1.28 - 1.20 (m, 1H). (Example 45) Preparation of (S)-3-(5-(4-(2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)ethyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 45) [ka]

[0191] A 20 mL solution of 2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)acetaldehyde (100 mg, 0.17 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (83 mg, 0.17 mmol), TEA (52 mg, 0.51 mmol), and MgSO4 (408 mg, 3.4 mmol) in DCM (20 mL) was stirred under nitrogen at room temperature for 30 minutes. Sodium triacetoxyborohydride (72 mg, 0.34 mmol) was added in small quantities at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The organic layer was washed with water and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH:DCM = 1:10) yielded the desired product (30 mg, 17.6%) as a yellow solid. LC / MS: 896.4[M+1] + . 1 H NMR (400 MHz, DMSO) δ 13.06 (br, 1H), 11.14 (s, 1H), 10.96 (s, 1H), 8.46 (s, 1H), 8.05 (dd, J = 15.0, 2.1 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.65 - 7.39 (m, 3H), 7.35 - 7.18 (m, 5H), 7.12 - 7.02 (m, 4H), 5.06 (dd, J = 13.2, 5.0 Hz, 1H), 4.39 - 4.19 (m, 2H), 3.35 - 3.25 (m, 7H), 2.94 - 2.85 (m, 1H), 2.70 - 2.53 (m, 4H), 2.49 - 2.25 (m, 4H), 1.95 - 1.85 (m, 1H), 1.80 - 1.75 (m, 2H), 1.62 - 1.30 (m, 5H), 1.25 - 1.15(m,1H). (Example 46) Preparation of (S)-3-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 46) [ka] Step 1: Preparation of 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0192] A solution of (2-chloro-4-phenoxyphenyl)(4-((4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (200 mg, 0.32 mmol) in THF / H2SO4 (10% aqueous solution) (20 mL, 1:1) was stirred at 70°C for 1 hour. The reaction mixture was adjusted to pH=10 with sodium hydroxide solution (2 M) and extracted with SiO2 (100 mL). The organic phase was dehydrated with sodium sulfate and evaporated under vacuum to obtain the desired product (150 mg, 82% yield) as a yellow solid. LC / MS: 570.1[M+1] + . Step 2: Preparation of (S)-3-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0193] A 10 mL solution of 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carboaldehyde (70 mg, 0.12 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (60 mg, 0.12 mmol), TEA (24 mg, 0.24 mmol), and MgSO4 (289 mg, 2.4 mmol) in DCM was stirred under nitrogen at room temperature for 30 minutes. Sodium triacetoxyborohydride (64 mg, 0.3 mmol) was added to this solution in small amounts at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The organic layer was washed with water and extracted with DCM (50 mL) to obtain the crude product. This was purified by preparative TLC (PE:EA = 5:1) to obtain the desired product (20 mg, 19% yield) as a yellow solid. LC / MS: 882.0[M+1] + 1 H NMR (400 MHz, DMSO) δ 13.05 (br, 1H), 11.14 (s, 1H), 10.96 (s, 1H), 8.46 (s, 1H), 8.04 (d, J = 16.6 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.39 - 7.14 (m, 5H), 7.11 - 7.03 (m, 3H), 5.05 (dd, J = 13.4, 5.1 Hz, 1H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 16.9 Hz, 1H), 3.30 - 3.27 (m, 6H), 2.96 - 2.86 (m, 1H), 2.71 - 2.53 (m, 4H), 2.46 - 2.31 (m, 3H), 2.26 (d, J = 6.5 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.88 - 1.78 (m, 2H), 1.76 - 1.62 (m, 2H), 1.38 - 1.19 (m, 3H). (Example 47) Preparation of 5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 47) [ka]

[0194] A 10 mL solution of 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carboaldehyde (70 mg, 0.12 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindorin-1,3-dione (45 mg, 0.12 mmol), TEA (24 mg, 0.24 mmol), and MgSO4 (289 mg, 2.4 mmol) in DCM (10 mL) was stirred under nitrogen at room temperature for 30 minutes. Sodium triacetoxyborohydride (64 mg, 0.3 mmol) was added in small quantities at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The organic layer was washed with water and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH:DCM=1:10) yielded the desired product (20 mg, 18%) as a yellow solid. LC / MS: 898.1[M+1] + . 1 H NMR (400 MHz, DMSO) δ 13.05 (s, 1H), 11.14 (s, 1H), 11.09 (s, 1H), 8.46 (s, 1H), 8.08 - 8.01 (m, 1H), 7.84 (s, 1H), 7.72 - 7.61 (m, 2H), 7.54 - 7.45 (m, 2H), 7.37 - 7.18 (m, 6H), 7.13 - 7.02 (m, 2H), 5.08 (dd, J = 13.0, 5.4 Hz, 1H), 3.50 - 3.41 (m, 3H), 3.33 - 3.29 (m, 2H), 2.93 - 2.84 (m, 1H), 2.75 - 2.58 (m, 3H), 2.57 - 2.52 (m, 2H), 2.47 - 2.30 (m, 2H), 2.29 - 2.20 (m, 2H), 2.10 - 1.92 (m, 2H), 1.90 - 1.64 (m, 4H), 1.39 - 1.22 (m, 3H). (Example 48) Preparation of 5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)azetidine-1-yl)piperidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound 48) [ka] Step 1: Preparation of benzyl 4-(3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-yl)piperidine-1-carboxylate

[0195] To a 5 mL solution of tert-butyl 2-(azetidine-3-yl)acetate (200 mg, 0.96 mmol) in DCM, stirred at room temperature, Et3N (194 mg, 1.92 mmol), MgSO4 (300 mg), and [3-(4-oxopiperidine-1-yl)phenyl]methylformate (224 mg, 0.96 mmol) were added. This mixture was stirred at room temperature for 30 minutes, after which NaBH(OAc)3 (406 mg, 1.92 mmol) was slowly added (0.5 equivalents per 30 minutes). The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under pressure. The residue was purified by flash chromatography (MeOH / DCM = 1:10) to obtain the desired product (255 mg, 68.37%) as a colorless oil. LC / MS: 388.8[M+H] + . Step 2: Preparation of 2-(1-(piperidine-4-yl)azetidine-3-yl) tert-butyl acetate

[0196] To a solution of tert-butyl 2-[1-(1-{3-[(formyloxy)methyl]phenyl}piperidine-4-yl)azetidine-3-yl]acetate (255 mg, 0.66 mmol) in MeOH (5 mL), which had been stirred at room temperature, Pd / C (70 mg, 0.66 mmol) was added. This reaction mixture was stirred under H2 at room temperature for approximately 3 hours. The mixture was filtered, and the filtrate was concentrated under pressure to obtain the desired product (160 mg, yield = 95.3%) as a white solid. LC / MS: 255.1[M+H] + . Step 3: Preparation of tert-butyl 2-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)azetidine-3-yl)acetate

[0197] To a 5 mL solution of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (140 mg, 0.55 mmol) in NMP (5 mL), stirred at room temperature, 2-[1-(piperidine-4-yl)azetidine-3-yl] tert-butyl acetate (140 mg, 0.55 mmol) and DIEA (142 mg, 1.1 mmol) were added. This reaction mixture was stirred at 90°C for 12 hours. The mixture was poured into 25 mL of water and extracted with ELISA (30 mL x 2). The combined organic layers were washed with brine, dehydrated with Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (MeOH / DCM = 1:10) to obtain the desired product (70 mg, yield = 25.4%) as a yellow solid. LC / MS: 510.8[M+H] + . Step 4: Preparation of 2-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)azetidine-3-yl)acetic acid

[0198] A solution of tert-butyl 2-(1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}azetidine-3-yl) acetate (70 mg, 0.14 mmol) in TFA / DCM (1:5, 6 mL) was stirred at room temperature for 2 hours. This solution was concentrated under vacuum to obtain the crude product (80 mg, crude). LC / MS: 455.1[M+H] + . Step 5: Preparation of 5-(4-(3-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)azetidine-1-yl)piperidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

[0199] To a 5 ml solution of DMF containing (1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl}azetidine-3-yl)acetic acid (70 mg, crude, 0.14 mmol), stirred at room temperature, HOBt (22 mg, 0.156 mmol), EDCI (30 mg, 0.156 mmol), NMM (53 mg, 0.52 mmol), and N-{5-[(2-chloro-4-phenoxyphenyl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidine-4-yl}piperidine-4-amine hydrochloride (63 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into 25 mL of water and extracted with ELISA (30 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH / DCM = 1:10) yielded the desired product (30 mg, yield = 24.2%) as a yellow solid. LC / MS: 884.1[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.75 (br, 1H), 11.09 (s, 1H), 8.83 (d, J= 7.2 Hz, 1H), 8.26 (s, 1H), 7.66-7.61 (m, 2H), 7.58 (d, J= 8.8 Hz, 1H), 7.47 (t, J= 8.0 Hz, 2H), 7.30 (s, 1H), 7.28 - 7.14 (m, 5H), 7.02 (dd, J= 8.8, 2.4 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.40 - 4.30 (m, 1H), 4.18 - 4.13 (m, 1H), 3.95 - 3.73 (m, 3H), 3.13 - 3.05 (m, 2H), 3.03 - 2.95 (m, 1H), 2.94 - 2.86 (m, 1H), 2.84 - 2.73 (m, 2H), 2.70 - 2.65 (m, 2H), 2.62 - 2.54 (m, 2H), 2.34 - 2.21 (m, 2H), 2.10 - 1.95 (m, 4H), 1.74 - 1.64 (m, 2H), 1.58 - 1.45 (m, 2H), 1.43 - 1.30 (m, 2H), 1.22 - 1.15 (m, 2H). (Example 49) Preparation of (S)-N-(4-(4-amino-1-(4-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 49) [ka] Step 1: Preparation of N-(4-bromobenzyl)-5-fluoro-2-methoxybenzamide

[0200] A solution of 5-fluoro-2-methoxybenzoic acid (30 g, 176 mmol, 1.0 equivalent), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.5 g, 212 mmol, 1.2 equivalents), and N,N-diisopropylethylamine (45.6 g, 353 mmol, 2 equivalents) in N,N-dimethylformamide (300 mL) was stirred at 25°C for 30 minutes. (4-bromophenyl)methaneamine (32.8 g, 176 mmol, 1.0 equivalent) was added to this solution, and the mixture was stirred at 25°C for 12 hours. This solution was poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated. When the residue was purified by silica gel chromatography using 20% ​​to 30% ethyl acetate in petroleum ether as the eluent, the desired compound (56 g, 94% yield) was obtained as a white solid. 1HNMR (400 MHz, CDCl3): δ 8.26 (br s, 1H), 7.94 (q, J = 2.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 - 7.12 (m, 1H), 6.94 - 6.91 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H). Step 2: Preparation of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

[0201] To a 500 mL solution of dioxane containing N-[(4-bromophenyl)methyl]-5-fluoro-2-methoxybenzamide (46 g, 136 mmol, 1.0 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (51.8 g, 204 mmol, 1.5 equivalents), potassium acetate (26.7 g, 272 mmol, 2.0 equivalents) and 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.95 g, 13.6 mmol, 0.1 equivalent) were added. The suspension was degassed under vacuum and purged with nitrogen three times. The mixture was stirred under nitrogen at 90°C for 12 hours. This solution was poured into water (2 L) and extracted with ethyl acetate (1 L x 3). The combined organic phase was washed with brine (2 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The combined crude product was purified by silica gel chromatography using 20%-30% ethyl acetate in petroleum ether as the eluent. The crude product was powdered with petroleum ether (200 mL), filtered, and the filter cake was dried under vacuum to obtain the desired compound (50 g, 79% yield) as a white solid. LC / MS: 386.2[M+H] + . Step 3: Preparation of N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0202] A mixture consisting of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide (10.0 g, 26.0 mmol, 1.0 equivalent), 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (6.78 g, 26.0 mmol, 1.0 equivalent), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.80 g, 5.19 mmol, 0.2 equivalent), and potassium phosphate (16.5 g, 77.9 mmol, 3.0 equivalent) in dioxane (200 mL) and water (40 mL) was degassed, purged with nitrogen three times, and stirred under a nitrogen atmosphere at 110°C for 60 hours. The reaction mixture was partitioned between ethyl acetate (1 L) and water (1 L). The organic phase was separated, washed with brine (1 L), dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The residue was successively powdered with acetonitrile (50 mL) and ethyl acetate (50 mL). This solid was collected and dried under vacuum to obtain the desired compound (6.0 g, 59% yield) as a pale yellow solid. LC / MS: 393.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 13.59 (s, 1H), 8.86 (t, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 - 7.47 (m, 3H), 7.37 - 7.31 (m, 1H), 7.19 (dd, J = 4.4, 9.2 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H). Step 4: Preparation of N-[[4-[4-amino-1-[4-[4-(dimethoxymethyl)-1-piperidyl]-3-fluorophenyl]pyrazolo[3,4-d]pyrimidine-3-yl]phenyl]methyl]5-fluoro-2-methoxybenzamide

[0203] To a dimethyl sulfoxide solution (150 mL) of N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)phenyl]methyl]-5-fluoro-2-methoxybenzamide (12.0 g, 30.6 mmol, 1.0 equivalent) and 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (11.6 g, 30.6 mmol, 1.0 equivalent), copper iodide (3.24 g, 17.0 mmol, 0.55 equivalent), 2-(dimethylamino)acetic acid (3.50 g, 33.98 mmol, 1.1 equivalent), and sodium carbonate (7.20 g, 68.0 mmol, 2.2 equivalents) were added. The suspension was degassed under vacuum and purged with nitrogen three times. The mixture was stirred under nitrogen at 110°C for 12 hours. The reaction mixture was partitioned between ethyl acetate (800 mL) and water (2.0 L). The aqueous layer was extracted with ethyl acetate (700 mL x 3). The combined organic layer was washed with brine (500 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (15 g). Under reflux, the crude product was dissolved in ethyl acetate (420 mL), and this solution was cooled to ambient temperature and then maintained in a refrigerator (approximately 5°C) for 48 hours. The suspension was filtered, and the wet cake was washed with cold ethyl acetate (20 mL) to obtain the pure product (5.28 g). The mother liquor was concentrated, and the residue was recrystallized from ethyl acetate (100 mL) to obtain another harvest of the pure product (1.7 g) (total 6.98 g, 36% yield) as a gray solid. LC / MS: 644.2[M+H] + . 1 HNMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 8.38 (t, J = 5.2 Hz, 1H), 7.99 (dd, J = 3.2, 9.2 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.92 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.22 - 7.14 (m, 1H), 7.08 (t, J = 8.8 Hz, 1H), 6.97 (dd, J = 4.4, 8.8 Hz, 1H), 5.60 (br s, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.12 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.53 (d, J = 12.0 Hz, 2H), 3.39 (s, 6H), 2.69 (t, J = 11.6 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.82 - 1.73 (m, 1H), 1.64 - 1.48 (m, 2H). Step 5: Preparation of N-(4-(4-amino-1-(3-fluoro-4-(4-formylpiperidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0204] A solution of N-(4-(4-amino-1-(4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (1.03 g, 1.60 mmol) in THF (20 mL) and H2SO4 (2 M, 20 mL) was stirred at 70 °C for 1 hour. The reaction mixture was diluted with DCM (50 mL), and the pH was adjusted to 8 by adding aqueous sodium hydroxide (2 M) dropwise. The organic layer was evaporated under vacuum to obtain the desired product as a yellow solid (900 mg, 96% yield). LC / MS: 598.1[M+1] + . Step 6: Preparation of (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0205] A solution of N-(4-(4-amino-1-(3-fluoro-4-(4-formylpiperidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (900 mg, 1.51 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (1.46 g, 3.02 mmol), and triethylamine (325 mg, 3.21 mmol) in DCM (60 mL) was stirred in air at room temperature for 1 hour. Sodium triacetoxyborohydride (956 mg, 4.53 mmol) was added to this solution in a fraction at 0°C. The reaction mixture was stirred overnight at room temperature, and then partitioned between water (50 mL) and DCM (60 mL). The organic phase was dehydrated with sodium sulfate and evaporated under vacuum. The crude product was powdered using MeOH, yielding a white solid (1.0 g, 1.10 mmol, 73% yield). LC / MS: 910.4[M+1] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.38 (s, 1H), 8.05 - 7.99 (m, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.57 - 7.50 (m, 4H), 7.37 - 7.32 (m, 1H), 7.25 - 7.18 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 5.05 (dd, J = 13.1, 4.9 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.33 (d, J = 17.2 Hz, 1H), 4.20 (d, J = 17.2 Hz, 1H), 3.91 (s, 3H), 3.42 (d, J = 10.4 Hz, 2H), 3.30 (br s, 4H), 2.96 - 2.85 (m, 1H), 2.77 - 2.67 (m, 2H), 2.64 - 2.52 (m, 5H), 2.43 - 2.30 (m, 1H), 2.24 (br d, J = 6.4 Hz, 2H), 2.01 - 1.66 (m, 4H), 1.38 - 1.25 (m, 2H). (Example 50) Preparation of N-(4-(4-amino-1-(4-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 50) [ka]

[0206] A 5.0 mL solution of N-[(4-{4-amino-1-[3-fluoro-4-(4-formylpiperidine-1-yl)phenyl]pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (60 mg, 0.1 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione hydrochloride (57 mg, 0.15 mmol), and triethylamine (30 mg, 0.3 mmol) in DCM (5.0 mL) was stirred in air at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added in small amounts at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (DCM:MeOH = 10:1) yielded the desired product as a white solid (31.8 mg, 0.034 mmol, 34% yield). LC / MS: 924[M+1] + . 1H NMR (400 MHz, DMSO) δ = 11.12 (s, 1H), 9.41 (s, 1H), 8.92 (t, J=6.2, 1H), 8.39 (s, 1H), 8.04 (dd, J=14.0, 2.4, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.76 (dd, J=19.5, 8.3 Hz, 3H), 7.53 (dd, J=9.2, 3.4 Hz, 3H), 7.39 - 7.33 (m, 2H), 7.20 (dd, J=9.2, 4.3 Hz, 2H), 5.11 (dd, J=13.1, 5.1 Hz, 1H), 4.60 (s, 2H), 4.23 (m, 2H), 3.92 (m, 8H), 3.64 (s, 2H), 3.45 (d, J=10.4, 2H), 3.14-3.22 (m, 3H), 2.84-2.95 (m, 2H), 2.78 (t, J=11.6 Hz, 2H), 1.85-2.06 (m, 3H), 1.33-1.47 (m, 2H). (Example 51) Preparation of (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 51) [ka]

[0207] N-[(4-{4-amino-1-[3-fluoro-4-(4-formylpiperidine-1-yl)phenyl]pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (60 mg, 0.1 mmol), (S)-2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindoline-1,3-dionebenzenesulfonic acid (76 mg, 0.15 mmol), and triethylamine (30 mg, 0.3 mmol) in a DCM (5.0 mL) solution were stirred in air at room temperature. This reaction mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added in small amounts at 0°C. This reaction mixture was stirred at room temperature for 2 hours. This reaction mixture was evaporated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (DCM:MeOH = 10:1) yielded the desired product as a white solid (29.7 mg, 0.032 mmol, 32% yield). LC / MS: 927[M+1] + . 1 H NMR (400 MHz, DMSO) δ = 11.01 (s, 1H), 9.45 (s, 1H), 8.92 (s, 1H), 8.40 (s, 1H), 7.95-8.20 (m, 2H), 7.74 (d, J=7.2 Hz, 2H), 7.53 (m, 3H), 7.46 - 7.04 (m, 4H), 5.10 (br d, J=9.0 Hz, 1H), 4.61 (d, J=4.9 Hz, 2H), 4.34 (m, 3H), 3.92 (m, 5H), 3.46 (m, 3H), 3.15 - 3.35 (m, 6H), 2.85 - 2.96 (m, 2H), 2.70 - 2.79 (m, 3H), 2.11 - 1.69 (m, 6H). (Example 52) Preparation of (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 52) [ka] Step 1: Preparation of N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0208] To a 10 mL solution of N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg, 0.42 mmol) in DMF (10 mL), which had been stirred at room temperature, 6-bromonicotinaldehyde (156 mg, 0.84 mmol) and K2CO3 (116 mg, 0.84 mmol) were added. The reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to room temperature, poured into 40 mL of water, and extracted with EA (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (100 mg, 41.0%). LC / MS: 581.0[M+H] + . Step 2: Preparation of (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0209] (S)-2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindoline-1,3-dionebenzenesulfonic acid (63 mg, 0.13 mmol) and Et3N (13 mg, 0.13 mmol) were added to MeOH (4 mL). This mixture was stirred at room temperature for 10 minutes. Next, N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (75 mg, 0.13 mmol), HOAc (155 mg, 2.58 mmol), and NaBH3CN (32 mg, 0.52 mmol) were added in DCM (4 mL). This mixture was stirred at room temperature for 2 days. The reaction mixture was quenched by adding water (10 mL) and extracted with EA (15 mL x 3). The organic layer was concentrated under vacuum. Purification of the residue by preparative HPLC (ACN (15-30%) in water (0.1% FA)) yielded the desired product as a white solid (16 mg, 13%). LC / MS: 893[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.98 - 10.91 (m, 1H), 8.89 - 8.82 (m, 1H), 8.26 - 8.25 (m, 1H), 8.07 - 8.02 (m, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.55 - 7.45 (m, 5H), 7.36 - 7.31 (m, 1H), 7.18 (dd, J = 9.1, 4.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.9 Hz, 1H), 5.08 - 4.96 (m, 2H), 4.57 (d, J = 6.1 Hz, 2H), 4.49 - 4.46 (m, 2H), 4.33 - 4.28 (m, 1H), 4.22 - 4.18 (m, 1H), 3.89 (s, 3H), 3.41 - 3.39 (m, 2H), 3.29 - 3.25 (m, 5H), 3.08 (t, J = 12.4 Hz, 2H), 2.94 - 2.85 (m, 1H), 2.62 - 2.52 (m, 4H), 2.40 - 2.30 (m, 1H), 2.18 - 2.06 (m, 2H), 2.10 - 1.92 (m, 3H). (Example 53) Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 53) [ka] Step 1: Preparation of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate

[0210] To a 20 mL solution of pyridine containing tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol), stirred at room temperature, TsCl (2.27 g, 11.93 mmol) was added. This reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into 80 mL of water and extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dehydrated with Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (PE / SiO₂=3:1) to obtain the desired product (2.2 g, 62%). LC / MS: 377.8[M+Na] + . Step 2: Preparation of tert-butyl 4-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carboxylate

[0211] To a 2 mL solution of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (2.2 g, 6.19 mmol) in DMF (2 mL), stirred at room temperature, Cs2CO3 (4.03 g, 12.38 mmol) and N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (2.43 g, 6.19 mmol) were added. This reaction mixture was stirred at 60 °C for 12 hours. The mixture was cooled to room temperature, poured into 75 mL of water, and extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (2.5 g, 70%). LC / MS: 575.8 [M+H] + . Step 3: Preparation of N-(4-(4-amino-1-(piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0212] A solution of tert-butyl 4-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carboxylate (2.5 g, 4.34 mmol) in TFA / DCM (1:5, 30 mL) was stirred at room temperature for 2 hours. This solution was concentrated under vacuum. The residue was dissolved in DCM (100 mL) and washed with saturated sodium bicarbonate solution (100 mL x 2). The organic layer was dehydrated with Na2SO4 and concentrated under vacuum to obtain the desired product (1.5 g, 72%). LC / MS: 476.0 [M+H] + . Step 4: Preparation of N-(4-(4-amino-1-(1-(4-formylphenyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0213] To a 10 mL solution of N-({4-[4-amino-1-(piperidine-4-yl)pyrazolo[3,4-d]pyrimidine-3-yl]phenyl}methyl)-5-fluoro-2-methoxybenzamide (700 mg, 1.47 mmol) in DMF (10 mL), which had been stirred at room temperature, 4-fluorobenzaldehyde (365 mg, 2.94 mmol) and K2CO3 (406 mg, 2.94 mmol) were added. This reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to room temperature, poured into 40 mL of water, and extracted with EA (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (300 mg, 35%). LC / MS: 580.0 [M+H] + . Step 5: Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0214] (S)-2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindoline-1,3-dionebenzenesulfonic acid (71 mg, 0.15 mmol) and Et3N (15 mg, 0.15 mmol) were added to MeOH (4 mL). This mixture was stirred at room temperature for 10 minutes. Next, N-(4-(4-amino-1-(1-(4-formylphenyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (85 mg, 0.15 mmol), HOAc (176 mg, 2.93 mmol), and NaBH3CN (37 mg, 0.59 mmol) were added in DCM (4 mL). This solution was stirred at room temperature for 2 days. The reaction mixture was quenched by adding water (10 mL) and extracted with EA (3 × 15 mL). The organic layers were combined and concentrated under vacuum. The residue was purified by preparative HPLC [ACN (20-40%) in water (0.1% FA)], yielding the desired product as a white solid (26 mg, 19%). LC / MS: 892[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.87 (t, J = 6.3 Hz, 1H), 8.26 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.55 - 7.47 (m, 4H), 7.37 - 7.31 (m, 1H), 7.18 (dd, J = 9.1, 4.3 Hz, 3H), 7.10 - 6.94 (m, 4H), 5.09 - 5.03 (m, 1H), 4.93 - 4.89 (m, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.35 - 4.10 (m, 2H), 3.95 - 3.80 (m, 5H), 3.48 - 3.35 (m, 2H), 3.31 - 3.19 (m, 3H), 3.15 - 2.85 (m, 4H), 2.63 - 2.53 (m, 4H), 2.44 - 2.34 (m, 2H), 2.47 - 2.25 (m, 2H), 2.09 - 1.95 (m, 3H). (Example 54) Preparation of (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 54) [ka] Step 1: Preparation of tert-butyl 3-(tosyloxy)azetidine-1-carboxylate

[0215] A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1270 mg, 7.33 mmol), Et3N (1113 mg, 11.00 mmol), and TsCl (1677 mg, 8.80 mmol) in DCM (20 mL) was stirred overnight at room temperature under N2. The reaction product was quenched by adding water (20 mL) and extracted by DCM (20 mL x 3). The organic phase was washed with brine and concentrated under vacuum. The residue was purified by flash chromatography (PE / EA=9 / 1) to obtain the desired product as a colorless oil (2.4 g, 100%). LC / MS: 328[M+H] + Step 2: Preparation of tert-butyl 3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)azetidine-1-carboxylate

[0216] A suspension of 3-(tosyloxy)azetidine-1-carboxylate tert-butyl (667 mg, 2.04 mmol), N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (800 mg, 2.04 mmol), and Cs2CO3 (1993 mg, 6.12 mmol) in DMF (10 mL) was stirred overnight at 80°C. The reaction mixture was quenched by adding water (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine and concentrated under vacuum. The residue was purified by flash chromatography (DCM / MeOH = 97 / 3) to obtain the desired product as a light brown solid (200 mg, 17.9%). LC / MS: 548[M+H] + . Step 3: Preparation of N-(4-(4-amino-1-(azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0217] A solution of tert-butyl 3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)azetidine-1-carboxylate (200 mg, 0.36 mmol) in DCM / TFA (8 mL, 3:1) was stirred at room temperature for 1 hour. This solution was concentrated under vacuum, and the desired product was obtained as a white solid (198 mg of TFA salt, 100%). LC / MS: 448[M+H] + . Step 4: Preparation of N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0218] N-(4-(4-amino-1-(azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (TFA salt, 198 mg, 0.36 mmol) and 6-bromonicotinaldehyde (136 mg, 0.73 mmol) were dissolved in DMF (4 mL) and K2CO3 (151 mg, 1.11 mmol) was added. The mixture was stirred overnight at 80°C. The reaction product was quenched by adding water (10 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine and concentrated under vacuum. The residue was purified by flash chromatography (DCM / MeOH = 75 / 15) to obtain the desired product as a yellow solid (100 mg, 50%). LC / MS: 553[M+H] + . Step 5: Preparation of (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0219] (S)-2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindoline-1,3-dionebenzenesulfonic acid (84 mg, 0.17 mmol) and Et3N (17 mg, 0.17 mmol) were added to MeOH (4 mL). This mixture was stirred at room temperature for 10 minutes. Next, N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (95 mg, 0.17 mmol), HOAc (206 mg, 3.44 mmol), and NaBH3CN (65 mg, 1.03 mmol) were added in DCM (4 mL). This mixture was stirred at room temperature for 2 days. The reaction product was quenched by adding water (10 mL) and extracted with EA (15 mL x 3). The organic phase was concentrated under vacuum. The residue was purified by preparative HPLC [ACN (15-25%) in water (0.1% FA)], and the desired product was obtained as a white solid (13.8 mg, 9.3%). LC / MS: 865[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.87 (t, J = 6.1 Hz, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.56 - 7.47 (m, 5H), 7.37 - 7.30 (m, 1H), 7.18 (dd, J = 9.2, 4.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.4 Hz, 1H), 5.87 (t, J = 7.5 Hz, 1H), 5.06 - 5.02 (m, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.55 - 4.37 (m, 4H), 4.35 - 4.17 (m, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 3.29 - 3.05 (m, 5H), 2.98 - 2.89 (m, 1H), 2.65 - 2.55 (m, 4H), 2.37 - 2.33 (m, 1H), 1.97 - 1.95 (m, 1H). (Example 55) Preparation of N-(4-(4-amino-1-(1-(5-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 55) [ka] Step 1: Preparation of tert-butyl 5-hydroxypentanoate

[0220] To a solution of 5-(tert-butoxy)-5-oxopentanoic acid (3.00 g, 6.96 mmol) cooled to 0°C in dry THF (60 mL), NaBH4 (630 mg, 16.74 mmol) was added. The solution was stirred until the generation of H2 ceased, and then BF3.OEt2 (2.71 g, 19.13 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by adding H2O (50 mL) at 0°C. The mixture was extracted using EA (50 mL x 3). The combined organic layers were washed with saturated Na2CO3 solution and brine, and then concentrated under vacuum to obtain the crude product (2.50 g, 90.0%) as a colorless oil. LC / MS: 197.2[M+Na] + . Step 2: Preparation of tert-butyl 5-oxopentanoate

[0221] To a 20 mL solution of tert-butyl 5-hydroxypentanoate (500 mg, 2.87 mmol) in DCM, stirred under argon at room temperature, PDC (1.62 g, 4.30 mmol) was added. This mixture was stirred at room temperature for 4 hours. The mixture was filtered, and the filtrate was collected. The filtrate cake was washed with 20 mL of DCM. The combined solution was concentrated under vacuum. The residue was purified by flash chromatography (0-65% EA in PE) to obtain the desired product (200 mg, 40.5%) as a colorless oil. LC / MS: 195.0[M+Na] + . Step 3: Preparation of tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate

[0222] NaBH3CN (66 mg, 1.05 mmol) was added to a solution of tert-butyl 5-oxopentanoate (90 mg, 0.52 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (254 mg, 0.52 mmol), and NaOAc (51 mg, 0.63 mmol) in MeOH (10 mL). This reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between DCM (50 mL) and water (30 mL). The organic layer was evaporated to obtain the crude product. The crude product was purified by flash chromatography (0-10% MeOH in DCM) to obtain the desired product (200 mg, 79.0% yield). LC / MS: 484.9[M+H] + . Step 4: Preparation of (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid

[0223] To a solution of tert-butyl(S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoate (200 mg, 0.41 mmol) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, yielding the desired product (170 mg, 96.1% yield) as a pale yellow solid. LC / MS: 428.9[M+H] + . Step 5: Preparation of N-(4-(4-amino-1-(1-(5-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0224] (S)-5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoic acid (177 mg, 0.41 mmol), N-(4-(4-amino-1-(pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (191 mg, 0.41 mmol), and DIEA (160 mg, 1.24 mmol) were dissolved in DMF (10 mL), to which HOBT (61 mg, 0.45 mmol) and EDCI (87 mg, 0.45 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between DCM (50 mL) and water (30 mL). The organic layer was evaporated to obtain the crude product. Purification of the crude product by preparative HPLC (20-22% ACN in H2O (0.1% FA)) yielded the desired product (25 mg, 6.64% yield) as a white solid. LC / MS: 872.6[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.87 (t, J = 5.9 Hz, 1H), 8.87 - 8.26 (m, 1H), 7.63 (dd, J = 7.3, 5.3 Hz, 2H), 7.55 - 7.48 (m, 4H), 7.34 (td, J = 8.7, 3.5 Hz, 1H), 7.18 (dd, J = 9.1, 4.3 Hz, 1H), 7.02 (dd, J = 10.7, 7.8 Hz, 2H), 5.55 - 5.39 (m, 1H), 5.10 - 4.95 (m, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.32 (d, J = 15.9 Hz, 1H), 4.19 (d, J = 16.9 Hz, 1H), 4.07 - 3.87 (m, 4H), 3.87 - 3.56 (m, 3H), 3.54 - 3.41 (m, 1H), 3.26 - 3.18 (m, 4H), 2.95 - 2.85 (m, 1H), 2.60 - 2.52 (m, 1H), 2.48 - 2.41 (m, 4H), 2.39 - 2.23 (m, 6H), 2.00 - 1.91 (m, 1H), 1.59 - 1.42 (m, 4H). (Example 56) Preparation of N-(4-(4-amino-1-(1-(6-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-3-yl)pyrroridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 58) [ka] Step 1: Preparation of tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate

[0225] To a solution of tert-butyl (3-hydroxypyrrolidine-1-yl)formate (5 g, 26.6 mmol) in pyridine (50 mL), TsCl (6.1 g, 31.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (100 mL) and then washed with water and brine. The organic phase was dehydrated with Na₂SO₄ and concentrated under vacuum to obtain the crude product. Purification of the crude product by flash chromatography (PE / EA=3:1) yielded the desired product (8 g, 87.9%) as a white solid. LC / MS: 364.0[M+Na] + . Step 2: Preparation of tert-butyl3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-carboxylate

[0226] To a 20 mL solution of tert-butyl(3-{[(4-methylbenzene)sulfonyl]oxy}pyrrolidine-1-yl)formate (2 g, 5.84 mmol) in DMF (20 mL), stirred at room temperature, N-[(4-{4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (2.3 g, 5.84 mmol) and Cs2CO3 (3.8 g, 11.68 mmol) were added. This reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was poured into water (80 mL) and then extracted with EA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. Purification of the crude product by flash chromatography (10% MeOH in DCM) yielded the desired product (2.3 g, 70.0%) as a yellow solid. LC / MS: 562.0[M+H] + . Step 3: Preparation of N-(4-(4-amino-1-(pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0227] A TFA / DCM (24 mL, 5:1) solution of tert-butyl-3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-carboxylate (2.3 g, 4.09 mmol) was stirred at room temperature for 2 hours. This mixture was concentrated under vacuum. The residue was dissolved in saturated sodium bicarbonate solution (100 mL) and then extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the desired product (1.2 g, 63.6%) as a brown solid. LC / MS: 462.0[M+H] + . Step 4: Preparation of 5-bromo-2-(dimethoxymethyl)pyridine

[0228] To a 10 mL solution of 5-bromopyridine-2-carboaldehyde (1 g, 5.37 mmol) in MeOH (10 mL), stirred at room temperature, trimethoxymethane (1.71 g, 16.13 mmol) and TsOH (278 mg, 1.61 mmol) were added. This reaction mixture was stirred at 70°C for 2 hours. The mixture was concentrated under vacuum to obtain the crude product. Purification of the crude product by flash chromatography (PE / EA = 10:1) yielded the desired product (600 mg, 48.1%). LC / MS: 232.0 [M+H] + . Step 5: Preparation of N-(4-(4-amino-1-(1-(6-(dimethoxymethyl)pyridine-3-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0229] To a toluene (10 mL) solution of N-({4-[4-amino-1-(pyrroridine-3-yl)pyrazolo[3,4-d]pyrimidine-3-yl]phenyl}methyl)-5-fluoro-2-methoxybenzamide (160 mg, 0.35 mmol) stirred at room temperature, 5-bromo-2-(dimethoxymethyl)pyridine (123 mg, 0.53 mmol), BINAP (130 mg, 0.21 mmol), t-BuONa (67 mg, 0.7 mmol), and Pd2(dba)3 (96 mg, 0.105 mmol) were added under Ar. This reaction mixture was stirred at 80°C for 12 hours. The mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (60 mg, 28.2%). LC / MS: 635.0 [M+H] + . Step 6: Preparation of N-(4-(4-amino-1-(1-(6-formylpyridine-3-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0230] HCl (0.2 mL) was added to a solution of N-{[4-(4-amino-1-{1-[5-(dimethoxymethyl)pyridine-2-yl]piperidine-4-yl}pyrazolo[3,4-d]pyrimidine-3-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (55 mg, 0.09 mmol) in THF (5 mL), which had been stirred at room temperature. The reaction mixture was stirred at 50 °C for 12 hours. This mixture was poured into H₂O (20 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (50 mL), dehydrated with Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (21 mg, 41.1%). LC / MS: 566.9 [M+H] + . Step 7: Preparation of N-(4-(4-amino-1-(1-(6-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-3-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0231] To a solution of N-(4-(4-amino-1-(1-(6-formylpyridine-3-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (21 mg, 0.03 mmol) in MeOH / DMF / HOAc (5 mL, 2:1:0.02), TEA (7.5 mg, 0.04 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (21.66 mg, 0.04 mmol) and NaBH3CN (6.99 mg, 0.11 mmol) were added. The mixture was stirred at 60°C for 1 hour. The reaction product was quenched by adding water (5 mL) and extracted by DCM (10 mL x 2). The organic phase was washed with brine and dehydrated with Na2SO4. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (ACN / H2O (0.1% FA), 10-40%) to obtain the desired compound (3 mg, 9.2%). LC / MS: 879.6[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.87 (t, J = 6.3 Hz, 1H), 8.39 - 8.27 (m, 2H), 7.91 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 9.8 Hz, 3H), 7.37 - 7.31 (m, 1H), 7.27 - 7.14 (m, 2H), 7.11 - 6.93 (m, 3H), 5.68 - 5.60 (m, 1H), 5.04 (dd, J = 13.1, 5.1 Hz, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.32 (d, J = 17.4 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1H), 3.94 - 3.82 (m, 4H), 3.69 - 3.64 (m, 2H), 3.53 - 3.50 (m, 4H), 3.29 - 3.25 (m, 3H), 2.94 - 2.86 (m, 1H), 2.68 - 2.52 (m, 6H), 2.42 - 2.28 (m, 2H), 1.99 - 1.90 (m, 1H). (Example 57) Preparation of (S)-N-(4-(4-amino-1-(6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 59) [ka] Step 1: Preparation of (1-(5-iodopyridine-2-yl)piperidine-4-yl)methanol

[0232] Potassium carbonate (3.7 g, 27.0 mmol) was added to a 50 mL solution of 2-fluoro-5-iodopyridine (2 g, 9.0 mmol) and piperidine-4-ylmethanol (1.2 g, 10.8 mmol) in DMF, which was stirred at 25°C under nitrogen. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was evaporated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain the desired product (2 g, 69.8%) as a white solid. LC / MS: 319.0[M+1] + . Step 2: Preparation of 1-(5-iodopyridine-2-yl)piperidine-4-carbaldehyde

[0233] To a 50 mL solution of [1-(5-iodopyridine-2-yl)piperidine-4-yl]methanol in dimethylamine (DCM) stirred under nitrogen at 25°C, des-martin periodinane (2.0 g, 4.6 mmol) was added in fractional amounts. This reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with Na₂S₂O₃ (2 M), extracted with DCM (200 mL), dehydrated with sodium sulfate, and evaporated under vacuum to obtain the crude product. Purification of the crude product by silica gel column (PE:EA = 10:1~1:1) yielded the desired product (0.7 g, 70.9%) as a white solid. LC / MS: 317.0[M+1] + . Step 3: Preparation of 2-(4-(dimethoxymethyl)piperidine-1-yl)-5-iodopyridine

[0234] A solution of 1-(5-iodopyridine-2-yl)piperidine-4-carboaldehyde (700 mg, 2.2 mmol) in trimethoxymethane (15 mL), stirred under nitrogen at 25°C, was to which TsOH (40 mg, 0.2 mmol) was added. This reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was evaporated under vacuum to obtain the crude product. Purification of the crude product by silica gel column chromatography (PE:EA = 10:1 to 1:1) yielded the desired product (0.6 g, 75.2%) as a white solid. LC / MS: 362.9[M+1] + . Step 4: Preparation of N-(4-(4-amino-1-(6-(4-(dimethoxymethyl)piperidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0235] 2-[4-(dimethoxymethyl)piperidine-1-yl]-5-iodopyridine (100 mg, 0.3 mmol), N-[(4-{4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (108.3 mg, 0.3 mmol) and N were stirred under nitrogen at 25°C. 1 ,N 1 To a solution of dimethylcyclohexane-1,2-diamine (39.3 mg, 0.3 mmol) in DMF (10 mL), copper(I) iodide (52.6 mg, 0.3 mmol) and cesium carbonate (269.8 mg, 0.8 mmol) were added. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was filtered and evaporated under vacuum to obtain the crude product. Purification of the crude product by silica gel column chromatography (DCM:MeOH = 100:1~10:1) yielded the desired product (20 mg, 11.5%) as a yellow solid. LC / MS: 627.0[M+1] + . Step 5: Preparation of N-(4-(4-amino-1-(6-(4-formylpiperidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0236] A solution of N-{[4-(4-amino-1-{6-[4-(dimethoxymethyl)piperidine-1-yl]pyridine-3-yl}pyrazolo[3,4-d]pyrimidine-3-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (15 mg, 0.023 mmol) in THF / H2SO4 (2N) (5 mL, 1:1) was stirred at 70°C for 1 hour. This mixture was diluted with EA (100 mL), neutralized with NaOH (2 M), dehydrated with sodium sulfate, and evaporated under vacuum to obtain the desired product (10 mg, 71.9%) as a yellow solid. LC / MS: 581.0[M+1] + . Step 6: Preparation of (S)-N-(4-(4-amino-1-(6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0237] Triethylamine (13.05 mg, 0.13 mmol) and NaBH3CN (8.11 mg, 0.13 mmol) were added to a CH3OH / DMF (2 mL, 1:1) solution of N-[(4-{4-amino-1-[6-(4-formylpiperidine-1-yl)pyridine-3-yl]pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (15 mg, 0.025 mmol), (3S)-3-[1-oxo-5-(piperazine-1-yl)-3H-isoindole-2-yl]piperidine-2,6-dione (8.47 mg, 0.025 mmol) and acetic acid (62 mg, 0.52 mmol) to which triethylamine (13.05 mg, 0.13 mmol) and NaBH3CN (8.11 mg, 0.13 mmol) were added. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was dissolved with EA (50 mL) and washed with water (10 mL x 2). The organic phase was dehydrated with sodium sulfate and evaporated under vacuum to obtain the crude product. Purification of the crude product by preparative HPLC yielded the desired product (5 mg, 21.7%) as a white solid. LC / MS: 893.0[M+1] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.90 (t, J = 6.1 Hz, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.58 - 7.48 (m, 3H), 7.40 - 7.32 (m, 1H), 7.23 - 7.17 (m, 1H), 7.08 - 6.96 (m, 3H), 6.61 - 6.49 (m, 3H), 5.15 - 5.01 (m, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.44 - 4.28 (m, 3H), 3.91 (s, 3H), 3.29 - 3.24 (m, 7H), 3.00 - 2.82 (m, 3H), 2.74 - 2.59 (m, 2H), 2.44 - 2.31 (m, 2H), 2.29 - 2.17 (d, J = 6.6 Hz, 2H), 2.02 - 1.73 (m, 4H), 1.34 - 1.05 (m, 2H). (Example 58) Preparation of N-(4-(4-amino-1-(1-(4-((4-((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 60) [ka] Step 1: Preparation of N-(4-(4-amino-1-(1-(4-formylphenyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0238] To a DMSO (5 mL) solution of N-({4-[4-amino-1-(pyrrolidine-3-yl)pyrazolo[3,4-d]pyrimidine-3-yl]phenyl}methyl)-5-fluoro-2-methoxybenzamide (300 mg, 0.65 mmol) stirred at room temperature, 4-fluorobenzaldehyde (121 mg, 0.98 mmol) and K2CO3 (180 mg, 1.3 mmol) were added. This reaction mixture was stirred at 80°C for 12 hours. This reaction mixture was poured into water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with water and brine, dehydrated with Na2SO4, and then concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (DCM / MeOH = 10:1) to obtain the desired product (100 mg, 27.2%). LC / MS: 566.0 [M+H] + . Step 2: Preparation of N-(4-(4-amino-1-(1-(4-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0239] To a MeOH / DMF / HOAc (12 mL, 2:1:0.06) solution of N-[(4-{4-amino-1-[1-(4-formylphenyl)pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (100 mg, 0.18 mmol) stirred at room temperature, (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (86 mg, 0.18 mmol), Et3N (36 mg, 0.36 mmol), and NaBH3CN (45 mg, 0.72 mmol) were added. The reaction mixture was stirred at 60°C for 1 hour. This mixture was concentrated under vacuum and poured into water (50 mL), and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative HPLC yielded the desired product (19 mg, 12.2%). LC / MS: 900.0[M+Na] + . 1 H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 8.86 (t, J= 6.0 Hz 1H), 8.30 (s, 1H), 8.28 (s, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.52 - 7.47 (m, 5H), 7.36 - 7.31 (m, 1H), 7.18 (dd, J= 9.2, 4.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 2H), 7.06 - 7.01 (m, 2H), 6.56 (d, J= 8.4 Hz, 2H), 5.65 - 5.60 (m, 1H), 5.04 (dd, J= 13.2, 5.2 Hz, 1H), 4.57 (d, J= 6.0 Hz, 2H), 4.32 (d, J= 16.8 Hz, 1H), 4.19 (d, J= 16.8 Hz, 1H), 3.89 (s, 3H), 3.84 - 3.79 (m, 1H), 3.66 - 3.60 (m, 2H), 3.48 - 3.39 (m, 2H), 3.30 - 3.20 (m, 5H), 2.95 - 2.83 (m, 2H), 2.64 - 2.59 (m, 2H), 2.57 - 2.54 (m, 2H), 2.47 (s, 3H), 1.96 - 1.90 (m, 1H). (Example 59) Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 61) [ka] Step 1: Preparation of N-(4-(4-amino-1-(1-(4-formylphenyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0240] A mixture of N-(4-(4-amino-1-(azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (60 mg, 0.13 mmol), 4-fluorobenzaldehyde (25 mg, 0.20 mmol), and K2CO3 (56 mg, 0.41 mmol) in DMSO (5 mL) was stirred overnight at 80°C. This reaction mixture was poured into water (5 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with water, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC at DCM / MeOH = 10:1 yielded the desired product (20 mg, 80% purity, 21.6% yield). LC / MS: 552.7[M+H] + . Step 2: Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0241] To a MeOH / DMF (2:1, 3 mL) solution of N-(4-(4-amino-1-(1-(4-formylphenyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (20 mg, 80% purity, 0.029 mmol) stirred at room temperature, (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (22 mg, 0.045 mmol) and Et3N (7 mg, 0.069 mmol) were added. This mixture was stirred at room temperature for 30 minutes, and then AcOH (0.1 mL) and NaBH3CN (4 mg, 0.064 mmol) were added. This reaction mixture was stirred at 60°C for 1 hour. This mixture was concentrated under vacuum. The residue was poured into water (4 ml) and extracted with EA (8 mL x 3). The combined organic layer was washed with brine (10 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC to obtain the desired product (8 mg, 31.9%). LC / MS: 864[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 8.33 - 8.20 (m, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.53 - 7.48 (m, 3H), 7.37 - 7.31 (m, 1H), 7.24 - 7.11 (m, 3H), 7.08 - 6.98 (m, 2H), 6.52 (d, J = 8.5 Hz, 2H), 5.88 - 5.81 (m, 1H), 5.05 - 5.02 (m, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.42 - 4.16 (m, 6H), 3.89 (s, 3H), 3.42 - 3.36 (m, 4H), 3.28 - 3.25 (m, 5H), 2.97 - 2.83 (m, 2H), 2.69 - 2.54 (m, 2H), 2.41 - 2.31 (m, 2H), 1.98 - 1.92 (m, 1H). (Example 60) Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 62) [ka] Step 1: Preparation of tert-butyl(S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoate

[0242] (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (100 mg, 0.2 mmol) was dissolved in DMF (10 mL) and TEA (41.51 mg, 0.4 mmol) was added. The mixture was stirred under nitrogen at room temperature for 5 minutes. Next, tert-butyl-4-formylbenzoate (42.38 mg, 0.2 mmol) and NaBH3CN (38.74 mg, 0.61 mmol) were added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction product was quenched by adding water (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine and dehydrated with Na2SO4. This solution was concentrated under vacuum, and the residue was purified by flash column chromatography with DCM:MeOH = 10:1 to obtain the desired product (100 mg, 90% purity, 86.7% yield) as a yellow solid. LC / MS: 519.1[M+H] + . Step 2: Preparation of (S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoic acid

[0243] A solution of tert-butyl(S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoate (100 mg, 90% purity, 0.17 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 2 hours. Concentration of this mixture yielded the title compound (70 mg, 80% purity, 69.5% yield) as a yellow oily substance. LC / MS: 462.8[M+H] + . Step 3: Preparation of tert-butyl3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)azetidine-1-carboxylate

[0244] To a 10 ml solution of N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (500 mg, 1.27 mmol) in DMF (10 ml), tert-butyl-3-(tosyloxy)azetidine-1-carboxylate (502 mg, 1.52 mmol) and Cs2CO3 (1.24 g, 3.82 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. The reaction product was quenched by adding water (20 mL) and extracted by DCM (20 mL x 2). The organic phase was washed with brine and dehydrated with Na2SO4. The solution was concentrated under vacuum, and the residue was purified by flash column chromatography with DCM:MeOH = 10:1 to obtain the desired product (230 mg, 90% purity, 29.7%) as a yellow oil. LC / MS: 547.8 [M+H] + . Step 4: Preparation of N-(4-(4-amino-1-(azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0245] A solution of tert-butyl 3-(4-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)azetidine-1-carboxylate (230 mg, 90% purity, 0.4 mmol) in DCM (8 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the compound was then dissolved in DCM (20 mL). The pH of the mixture was adjusted to approximately 10 with saturated Na2CO3 solution. The organic phase was concentrated under vacuum, yielding the title compound (100 mg, 60.3%) as a yellow solid. LC / MS: 448.1[M+H] + . Step 5: Preparation of (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0246] 4-[(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-3H-isoindole-5-yl}piperazine-1-yl)methyl]benzoic acid (44 mg, 80% purity, 0.07 mmol) in THF (5 mL), with N-({4-[4-amino-1-(azetidine-3-yl)pyrazolo[3,4-d]pyrimidine-3-yl]phenyl}methyl)-5-fluoro-2-methoxybenzamide (33.9 mg, 0.07 mmol), 1-hydroxybenzotriazole (Hydroxybenzotrizole) (15.3 (mg, 0.11 mmol), EDCI (21.8 mg, 0.11 mmol), and TEA (22.9 mg, 0.22 mmol) were added. This mixture was stirred at room temperature for 2 hours. The reaction product was quenched by adding water (15 mL) and extracted by DCM (10 mL x 3). The organic phase was washed with brine and dehydrated with Na2SO4. The solution was concentrated under vacuum, and the residue was purified by preparative HPLC (ACN / H2O (0.1% FA), 10-40%) to obtain the desired compound (10 mg, 14.3%) as a white solid. LC / MS: 892.6[M+H] + . 1H NMR (400 MHz, ) δ 10.95 (s, 1H), 8.88 (t, J = 6.0 Hz, 1H), 8.27 (s, 1H), 7.68 - 7.64 (m, 4H), 7.51 - 7.47 (m, 4H), 7.45 - 7.40 (m, 2H), 7.34 (td, J = 8.5, 3.3 Hz, 1H), 7.19 (dd, J = 9.1, 4.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 5.80 - 5.71 (m, 1H), 5.05 (dd, J = 13.2, 5.0Hz, 1H), 4.93 - 4.72 (m, 2H), 4.66 - 4.49 (m, 4H), 4.32 (d, J = 16.9 Hz, 1H), 4.20 (d, J = 16.9 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.32 - 3.25 (m, 4H), 2.96 - 2.84 (m, 1H), 2.68 - 2.56 (m, 4H), 2.44 - 2.29 (m, 2H), 1.99 -1.91 (m, 1H). (Example 61) Preparation of (N-(4-(4-amino-1-(1-(4-((4-((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)pyrroridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 63) [ka] Step 1: Preparation of (N-(4-(4-amino-1-(1-(4-((4-((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0247] To a solution of (S)-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoic acid (44 mg, 80% purity, 0.07 mmol) in THF (5 mL), N-(4-(4-amino-1-(pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (34.9 mg, 0.07 mmol), 1-hydroxybenzotriazole (15.3 mg, 0.11 mmol), EDCI (21.8 mg, 0.11 mmol), and TEA (22.9 mg, 0.22 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was quenched by adding water (10 mL) and extracted by DCM (10 mL x 2). The organic phase was washed with brine and dehydrated with Na2SO4. The solution was concentrated under vacuum, and the residue was purified by preparative HPLC (ACN / H2O (0.1% FA), 10-40%) to obtain the desired compound (4 mg, 6.3%). LC / MS: 906.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.94 - 8.86 (m, 1H), 8.25 - 8.12 (m, 1H), 7.75 - 7.28 (m, 11H), 7.25 - 7.15 (m, 1H), 7.10 - 6.97 (m, 2H), 5.62 - 5.35 (m, 1H), 5.05 (d, J = 8.7 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.32 (d, J = 16.2 Hz, 1H), 4.19 (d, J = 15.3 Hz, 1H), 4.06 - 3.72 (m, 6H), 3.67 (d, J = 6.4 Hz, 1H), 3.55 (d, J = 16.0 Hz, 2H), 3.32 - 3.18 (m, 4H), 2.90 (t, J = 12.8 Hz, 1H), 2.69 - 2.53 (m, 4H), 2.48 - 2.43 (m, 2H), 2.41 -2.28 (m, 2H), 2.02 - 1.86 (m, 1H). (Example 62) Preparation of N-(4-(4-amino-1-(1-(6-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)hexanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 64) [ka] Step 1: Preparation of (S)-6-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)hexanoic acid

[0248] A suspension of 6-bromohexanoic acid (100 mg, 0.51 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (168.3 mg, 0.51 mmol), K2CO3 (212.3 mg, 1.54 mmol), and KI (85.1 mg, 0.51 mmol) in DMF (3 mL) was stirred overnight at room temperature. This reaction mixture was concentrated under vacuum. The residue was dissolved in EA (50 mL), washed with water (10 mL), dehydrated with Na2SO4, and evaporated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (DCM / MeOH = 10:1) to obtain the desired product (50 mg, purity = 90%, yield = 19.8%) as a white solid. LC / MS: 442.9[M+H] + . Step 2: Preparation of N-(4-(4-amino-1-(1-(6-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)hexanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0249] (S)-6-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)hexanoic acid (50 mg, purity = 90%), N-(4-(4-amino-1-(pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (69.9 mg, 0.15 mmol), HATU (86.4 mg, 0.23 mmol), and DIEA (58.7 mg, 0.45 mmol) were mixed in DMF (5 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved with EA (50 mL), washed with water (10 mL), dehydrated with Na2SO4, and evaporated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (DCM / MeOH = 10:1) yielded the desired product (8 mg, 12.5%) as a white solid. LC / MS: 886.1[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.84 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 3.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.52 - 7.45 (m, 4H), 7.33 - 7.28 (m, 1H), 7.17 - 7.14 (m, 1H), 7.10 - 7.02 (m, 2H), 5.51 - 5.34 (m, 1H), 5.06 - 4.97 (m, 1H), 4.54 (d, J = 6.1 Hz, 2H), 4.33 - 4.15 (m, 2H), 4.05 - 3.57 (m, 8H), 3.50 - 3.41 (m, 1H), 3.24 - 3.05 (m, 2H), 2.93 - 2.78 (m, 2H), 2.60 - 2.48 (m, 3H), 2.45 - 2.14 (m, 9H), 1.96 - 1.88 (m, 1H), 1.56 - 1.44 (m, 4H), 1.33 - 1.17 (m, 3H). (Example 63) Preparation of N-(4-(4-amino-1-(4-(3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 65) [ka] Step 1: Preparation of (1-(2-fluoro-4-nitrophenyl)pyrrolidine-3-yl)methanol

[0250] To a solution of 1,2-difluoro-4-nitrobenzene (2 g, 12.57 mmol) in CH3CN (5 mL), pyrrolidine-3-ylmethanol (1.9 g, 13.83 mmol) and DIEA (4.9 g, 37.71 mmol) were added. The reaction mixture was stirred at 80°C for 3 hours. The solvent was removed under vacuum. The residue was purified by flash column chromatography with PE:EA = 1:1, yielding the desired product (1.8 g, 59.6%) as a yellow solid. LC / MS: 241.1[M+H] + . Step 2: Preparation of (1-(4-amino-2-fluorophenyl)pyrrolidine-3-yl)methanol

[0251] (1-(2-fluoro-4-nitrophenyl)pyrrolidine-3-yl)methanol (1.8 g, 7.49 mmol) was dissolved in MeOH (20 mL) and Pd / C (180 mg, 10%) was added. The reaction mixture was stirred under 1 atm H2 at room temperature for 2 hours. The catalyst was filtered off. Concentration of this solution under vacuum yielded the desired product (1.3 g, 82.5%) as a brown oily substance. LC / MS: 211.1[M+H] + . Step 3: Preparation of (1-(2-fluoro-4-iodophenyl)pyrrolidine-3-yl)methanol

[0252] To a solution of (1-(4-amino-2-fluorophenyl)pyrrolidine-3-yl)methanol (1.3 g, 6.1 mmol) in CH3CN (30 mL), 1.9 mL of concentrated HCl (1.9 mL) and NaNO2 (630 mg, 9.13 mmol, dissolved in 8 mL of H2O) were added at 0°C. The mixture was stirred at 0°C for 2 hours, and then KI (3.16 g, 19.03 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. The reaction product was quenched by adding water (20 mL) and extracted with EA (20 mL × 3). The organic phase was washed with brine and dehydrated with Na2SO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography with PE:EA = 3:1 to obtain the desired product (1.5 g, 75.5%) as a yellow solid. LC / MS: 321.9[M+H] + . Step 4: Preparation of 1-(2-fluoro-4-iodophenyl)pyrrolidine-3-carbaldehyde

[0253] To a solution of oxalyl chloride (1.19 g, 9.34 mmol) in DCM (20 mL), DMSO (1.46 g, 18.68 mmol) was added at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes, and then (1-(2-fluoro-4-iodophenyl)pyrrolidine-3-yl)methanol (1.5 g, 4.67 mmol) was added. The reaction mixture was stirred at -78 °C for another 15 minutes. TEA (1.9 g, 18.68 mmol) was added at -78 °C. The final mixture was stirred at -78 °C for 30 minutes. The reaction mixture was allowed to rise to room temperature and stirred for 1 hour. The reaction product was quenched by adding water (20 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum. The residue was purified by flash column chromatography with PE:EA = 1:1, yielding the desired product (1.2 g, 80.5%) as a yellow solid. LC / MS: 319.8[M+H] + . Step 5: Preparation of 3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)pyrrolidine

[0254] To a solution of 1-(2-fluoro-4-iodophenyl)pyrrolidine-3-carboaldehyde (1.2 g, 3.76 mmol) in MeOH (20 mL), trimethoxymethane (600 mg, 5.46 mmol) and PTSA (97 mg, 1.36 mmol) were added. The reaction mixture was stirred at 60°C for 12 hours. The solvent was removed under vacuum. The residue was dissolved in EA (20 mL), washed with NaHCO3 solution, and dehydrated with Na2SO4. The organic phase was concentrated and purified by flash column chromatography at PE:EA = 1:1 to obtain the desired product (720 mg, 41.9%) as a yellow solid. LC / MS: 365.8[M+H] + . Step 6: Preparation of N-(4-(4-amino-1-(4-(3-(dimethoxymethyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0255] To a solution of 3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)pyrrolidine (200 mg, 0.55 mmol) in 1,4-dioxane (5 mL), N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (429 mg, 1.09 mmol), Cs2CO3 (535 mg, 1.64 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (156 mg, 1.09 mmol), and CuI (104 mg, 0.55 mmol) were added. This reaction mixture was stirred under Ar at 100°C for 17 hours. The solid was filtered off, and the solution was concentrated under vacuum. The residue was purified by preparative TLC with a DCM:MeOH ratio of 10:1, yielding the desired product (100 mg, 60% purity, 17.3% yield) as a white solid. LC / MS: 629.9[M+H] + . Step 7: Preparation of N-(4-(4-amino-1-(3-fluoro-4-(3-formylpyrrolidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0256] N-(4-(4-amino-1-(4-(3-(dimethoxymethyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (80 mg, 60% purity, 0.076 mmol) was dissolved in THF (2 mL) and H₂SO₄ (4 mL, 3 M in water) was added. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to 0°C, neutralized with NaHCO₃ solution, and extracted using EA (10 mL x 3). The organic phase was washed with brine and dehydrated with Na₂SO₄. When this solution was concentrated under vacuum, the desired product (40 mg, crude) was obtained as a yellow solid. LC / MS: 584.2[M+H] + Step 8: Preparation of N-(4-(4-amino-1-(4-(3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0257] To a solution of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (11.26 mg, 0.034 mmol) in DMF (1 mL) and MeOH (1 mL), TEA (0.2 mL) was added. This mixture was stirred at room temperature for 30 minutes. Next, N-(4-(4-amino-1-(3-fluoro-4-(3-formylpyrrolidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (40 mg, crude), HOAc (0.5 mL), and NaBH3CN (21.55 mg, 0.343 mmol) were added. This reaction mixture was stirred at room temperature for 1 hour. The reaction product was quenched by adding H2O (10 mL) and extracted with EA (5 mL x 3). The combined organic phase was washed with brine and dehydrated with Na2SO4. This solution was concentrated under vacuum, and the residue was purified by preparative TLC with DCM:MeOH = 10:1 to obtain the desired product (6.9 mg, 10.1% in two steps) as a white solid. LC / MS: 896.5[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.90 (t, J = 6 Hz, 1H), 8.35 (s, 1H), 7.93 (d, J = 15.3 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.56 - 7.50 (m, 3H), 7.38 - 7.31 (m, 1H), 7.23 - 7.16 (m, 1H), 7.12 - 7.04 (m, 2H), 6.88 (t, J = 9.5 Hz, 1H), 5.05 (dd, J = 13.3, 5.0 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.36 - 4.17 (m, 2H), 3.91 (s, 2H), 3.57 - 3.49 (m, 1H), 3.48 - 3.40 (m, 2H), 3.31 (s, 3H), 3.22 - 3.15 (m, 1H), 2.93 - 2.83 (m, 1H), 2.66 - 2.53 (m, 4H), 2.45 - 2.30 (m, 3H), 2.13 - 1.90 (m, 3H), 1.73 - 1.66 (m, 1H), 1.50 - 1.40 (m, 1H), 1.27 - 1.17 (m, 5H). (Example 64) Preparation of N-(4-(4-amino-1-(6-(3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 66) [ka] Step 1: Preparation of (1-(5-iodopyridine-2-yl)pyrrolidine-3-yl)methanol

[0258] To a solution of 2-fluoro-5-iodopyridine (2 g, 9 mmol) in DMF (20 mL), pyrrolidine-3-ylmethanol (1.09 g, 10.8 mmol) and potassium carbonate (3.73 g, 2.7 mmol) were added. The reaction mixture was stirred at 100°C for 2 hours. The reaction product was quenched by adding water (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography with PE:EA = 5:1 to obtain the desired product (2 g, 73.0%) as a yellow solid. LC / MS: 304.9[M+H] + . Step 2: Preparation of 1-(5-iodopyridine-2-yl)pyrrolidine-3-carbaldehyde

[0259] To a 30 mL solution of [1-(5-iodopyridine-2-yl)pyrrolidine-3-yl]methanol in DCM, stirred under nitrogen at 0°C, des-martin periodinane (4.2 g, 9.9 mmol) was added in fractions. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was quenched by adding water (10 mL). The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum, and the title compound (1.5 g, 75.7% yield) was obtained as a yellow solid. LC / MS: 302.9[M+H] + . Step 3: Preparation of 2-(3-(dimethoxymethyl)pyrrolidine-1-yl)-5-iodopyridine

[0260] To a solution of 1-(5-iodopyridine-2-yl)pyrrolidine-3-carboaldehyde (1.5 g, 5.0 mmol) in trimethoxymethane (20 mL), stirred under nitrogen at 25°C, TsOH (90 mg, 0.5 mmol) was added. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by flash column chromatography with PE:EA = 5:1 to obtain the desired product (500 mg, 28.0%) as a yellow solid. LC / MS: 348.9[M+H] +. Step 4: Preparation of N-(4-(4-amino-1-(6-(3-(dimethoxymethyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0261] A solution of 2-(3-(dimethoxymethyl)pyrrolidine-1-yl)-5-iodopyridine (120 mg, 0.34 mmol) in DMF (20 mL) contains N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (135 mg, 0.34 mmol), Cs2CO3 (336.8 mg, 1.03 mmol), copper(I) iodide (65.3 mg, 0.34 mmol), and N 1 ,N 1 -Dimethylcyclohexane-1,2-diamine (49.02 mg, 0.34 mmol) was added. The reaction mixture was stirred at 110°C for 10 hours. The solid was filtered off and washed with DCM (10 mL x 3). This solution was concentrated under vacuum, and the residue was purified by flash column chromatography with DCM:MeOH = 1:0 to 10:1 to obtain the desired product (20 mg, 9.4%). LC / MS: 613.0[M+H] + . Step 5: Preparation of N-(4-(4-amino-1-(6-(3-formylpyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0262] A solution of N-(4-(4-amino-1-(6-(3-(dimethoxymethyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (15 mg, 0.025 mmol) in H2SO4 / H2O / THF (1 mL, 1 / 3 / 2) was stirred under nitrogen at 70°C for 1 hour. This mixture was diluted with EA (50 mL) and neutralized with NaOH (2N). The organic phase was dehydrated with Na2SO4. The solvent was removed under vacuum, and the title compound (12 mg, 86.5%) was obtained as a yellow solid. LC / MS: 567.0 [M+H] + . Step 6: Preparation of N-(4-(4-amino-1-(6-(3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0263] To a solution of N-(4-(4-amino-1-(6-(3-formylpyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (12 mg, 0.02 mmol) in MeOH / DMF / HOAc (2 mL, 2:1:0.02), 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione (7 mg, 0.02 mmol), TEA (21.5 mg, 0.21 mmol), and NaBH3CN (6.6 mg, 0.106 mmol) were added. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature, then quenched by adding water (5 mL), and extracted by DCM (5 mL x 3). The organic phase was washed with brine and dehydrated with Na2SO4. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:1~10:1) to obtain the desired compound (10 mg, 53.7%). LC / MS: 878.9[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.90 (m, 1H), 8.67 (d, J = 2.7 Hz, 1H), 8.31 (s, 2H), 8.07 (dd, J = 9.0, 2.7 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.58 - 7.50 (m, 3H), 7.38 - 7.30 (m, 1H), 7.21 - 7.18 (m, 1H), 7.10 - 7.05 (m, 2H), 6.62 (d, J = 9.1 Hz, 1H), 5.09 - 5.03 (m, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.33 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 16.9 Hz, 1H), 3.91 (s, 3H), 3.74 - 3.61 (m, 2H), 3.59 - 3.53 (m, 2H), 3.32 - 3.25 (m, 6H), 3.22 - 3.14 (m, 2H), 2.92 - 2.85 (m, 1H), 2.62 - 2.55 (m, 4H), 2.43 - 2.31 (m, 3H), 2.13 - 2.10 (m, 1H), 2.01 - 1.91 (m, 1H), 1.80 - 1.72 (m, 1H). (Example 65) Preparation of 1-(5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 71) [ka] Step 1: Preparation of tert-butyl 6-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)hexanoate

[0264] To a solution of tert-butyl 6-bromohexanoic acid (200 mg, 0.8 mmol) in DMF (10 mL), 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (392 mg, 0.88 mmol) and K2CO3 (336 mg, 2.4 mmol) were added. The reaction mixture was stirred at 90°C for 17 hours. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography with PE:EA = 1:2 to obtain the desired product (100 mg, 23%). LC / MS: 502.8[M+H] + . Step 2: Preparation of 6-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)hexanoic acid

[0265] To a solution of tert-butyl 6-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)hexanoate (100 mg, 0.2 mmol) in DCM (3 mL), TFA (1 mL) was added. This mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum to obtain the product (80 mg, crude). LC / MS: 446.7 [M+H] + . Step 3: Preparation of 1-(5-(4-(6-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-6-oxohexyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0266] To a solution of 6-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)hexanoic acid (80 mg, crude) in DCM (5 mL), HATU (102 mg, 0.27 mmol) and TEA (54 mg, 0.54 mmol) were added. This mixture was stirred at room temperature for 5 minutes, and then (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (80 mg, 0.18 mmol) was added. This mixture was stirred at room temperature for 2 hours. This mixture was extracted with brine and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative TLC in a DCM:MeOH = 10:1 ratio to obtain the desired product (19.5 mg, 11% in 2 steps). LC / MS:876.1[M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 7.4 Hz, 1H), 8.37 (s, 1H), 7.46 - 7.37 (m, 5H), 7.33 (s, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.02 - 6.93 (m, 2H), 4.40 - 4.48 (m, 1H), 4.31 - 4.38 (m, 1H), 3.89 (s, 3H), 3.77 - 3.87 (m, 2H), 3.71 (s, 4H), 3.34 (t, J = 10.7 Hz, 1H), 3.20 - 3.12 (m, 1H), 2.87 - 2.81 (m, 2H), 2.70 - 2.52 (m, 5H), 2.36 (t, J = 7.5 Hz, 2H), 2.11 - 2.21 (m, 2H), 1.53 - 1.75 (m, 8H), 1.40 - 1.25 (m, 2H). (Example 66) Preparation of 1-(5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 72) [ka] Step 1: Preparation of tert-butyl 5-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)pentanoate

[0267] A solution of tert-butyl 5-bromopentanoate (380 mg, 1.60 mmol), 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.07 g, 3.20 mmol), K2CO3 (1.11 g, 8.00 mmol), and KI (266 mg, 1.60 mmol) in DMF (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ELISA (50 mL x 3). The combined organic layer was dehydrated with Na2SO4, filtered, and evaporated to obtain the crude compound. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain the desired product as a pale yellow solid (130 mg, 17%). LC / MS: 488.7[M+H]+. Step 2: Preparation of 5-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)pentanoic acid

[0268] A solution of tert-butyl 5-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)pentanoate (130 mg, 0.27 mmol) in DCM (12 mL) and TFA (9 mL) was stirred at room temperature for 2 hours. When this mixture was concentrated under vacuum, the desired compound was obtained as a yellow oil (115 mg, 98%). LC / MS: 432.8[M+H]+ Step 3: Preparation of 1-(5-(4-(5-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-5-oxopentyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0269] A solution of 5-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)pentanoic acid (115 mg, 0.27 mmol), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (133 mg, 0.30 mmol), HATU (154 mg, 0.41 mmol), and N,N-diisopropylethylamine (174 mg, 1.35 mmol) in MeOH / DMF (2:1, 15 mL) was stirred at room temperature for 2 hours. This mixture was evaporated under vacuum and purified by preparative TLC in a MeOH:DCM ratio of 1:10 to obtain the title compound (40 mg, yield: 17%). LC / MS: 862.1[M+H]+. 1H NMR (301 MHz, DMSO) δ 12.74 (s, 1H), 10.33 (s, 1H), 8.80 (s, 1H), 8.24 (d, J = 3.6 Hz, 1H), 7.70 - 7.56 (m, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.38 - 7.29 (m, 2H), 7.28 - 7.23 (m, 1H), 7.19 - 7.11 (m, 4H), 7.02 - 6.95 (m, 1H), 4.31 - 4.14 (m, 3H), 3.90 - 3.75 (m, 4H), 3.58 - 3.46 (m, 6H), 2.70 - 2. 45 (m, 2H), 2.48 - 2.19 (m, 8H), 2.10 - 1.90 (m, 3H), 1.58 - 1.38 (m, 6H). (Example 67) Preparation of 1-(5-(4-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 73) [ka] Step 1: Preparation of benzyl 4-(2-(tert-butoxy)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carboxylate

[0270] 2-(piperidine-4-yl)acetate tert-butyl (500 mg, 2.51 mmol), 4-oxopiperidine-1-carboxylate benzyl (584.8 mg, 2.51 mmol), and TEA (507 mg, 5.02 mmol) were dissolved in DCM (15 mL) and MgSO4 (3 g, 25.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. NaBH(AcO)3 (1.3 g, 6.27 mmol) was added in fractions over 3 hours. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and washed with DCM (20 mL x 2). The solution was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound as a white solid (850 mg, 80% purity, 65.1% yield). LC / MS: 417.2[M+H] + . Step 2: Preparation of tert-butyl 2-([1,4'-bipiperidine]-4-yl)acetate

[0271] 850 mg of benzyl 4-(2-(tert-butoxy)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carboxylate (1.63 mmol) was added to a 20 mL solution of dried t-BuOH, to which Pd / C (100 mg) was added. The mixture was stirred overnight at 20°C under H2. The catalyst was filtered off. Concentration of this solution under vacuum yielded the title product (320 mg, 90% purity, 62% yield) as a white solid. LC / MS: 227.1[M-55] + . Step 3: Preparation of tert-butyl 2-(1'-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-[1,4'-bipiperidine]-4-yl) acetate

[0272] A solution of 2-([1,4'-bipiperidine]-4-yl) tert-butyl acetate (320 mg, 90% purity, 1.02 mmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoic acid (269 mg, 1.02 mmol), HATU (463.6 mg, 1.22 mmol), and N,N-diisopropylethylamine (197.4 mg, 1.53 mmol) in DMF (15 mL) was stirred at room temperature for 4 hours. This mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (30 mg, 5.5%) as a white solid. LC / MS: 529.2[M+H] + . Step 4: Preparation of 2-(1'-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-[1,4'-bipiperidine]-4-yl)acetic acid

[0273] A solution of tert-butyl 2-(1'-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-[1,4'-bipiperidine]-4-yl) acetate (30 mg, 0.056 mmol) in DCM (5 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. Concentration of this mixture under vacuum yielded the title compound (30 mg, 89.3% purity, 100% yield). LC / MS: 473.1[M+H] + . Step 5: Preparation of 1-(5-(4-(2-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0274] A solution of 2-(1'-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-[1,4'-bipiperidine]-4-yl)acetic acid (30 mg, 0.056 mmol), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (27.1 mg, 0.056 mmol), HATU (25.5 mg, 0.067 mmol), and N,N-diisopropylethylamine (11 mg, 0.084 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (15 mg, 29.4%) as a white solid. LC / MS:901.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.89 (br, 1H), 10.35 (s, 1H), 9.36 (br, 1H), 9.00 - 8.92 (m, 1H), 8.29 (s, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 8.1 Hz, 3H), 7.03 (d, J = 8.3 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.26 - 4.12 (m, 2H), 3.86 (s, 3H), 3.64 - 3.57 (m, 2H), 3.44 (d, J = 8.7 Hz, 2H), 3.33 - 3.25 (m, 1H), 3.07 - 2.98 (m, 3H), 2.73 - 2.65 (m, 2H), 2.40 - 2.31 (m, 2H), 2.16 - 1.83 (m, 8H), 1.72 - 1.31 (m, 8H), 1.27 - 1.20 (m, 1H). (Example 68) Preparation of 1-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 74) [ka] Step 1: Preparation of 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0275] (2-chloro-4-phenoxyphenyl)(4-((4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (200 mg, 0.33 mmol) was dissolved in THF (5 mL) and sulfuric acid (2 M, 5 mL, 10 mmol) was added. This mixture was stirred at 70°C for 30 minutes. NaOH (1 M) was added to adjust the pH to 9, and then the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product (152 mg, 81%). LC / MS: 569.6 [M + H] + . Step 2: Preparation of 1-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0276] 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carboaldehyde (90 mg, 0.16 mmol), 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (53.1 mg, 0.16 mmol), and TEA (48.5 mg, 0.48 mmol) were mixed in DCM (15 mL) with MgSO4 (192 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. NaBH(AcO)3 (101.7 mg, 0.48 mmol) was added in fractions over 3 hours. The reaction mixture was stirred at room temperature for 5 hours. When this reaction mixture was concentrated under vacuum, a crude product was obtained. Purification of the crude product by preparative TLC with MeOH:DCM = 1:10 yielded the title compound (40 mg, 98% purity, 25% yield). LC / MS: 885.4[M+H] + . 1H NMR (301 MHz, DMSO) δ 13.04 (s, 1H), 11.12 (s, 1H), 10.35 (s, 1H), 8.44 (s, 1H), 8.02 (d, J = 17.1 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.40 - 7.12 (m, 7H), 7.10 - 6.99 (m, 2H), 3.83 (s, 3H), 3.60 - 3.35 (m, 6H), 3.29 - 3.20 (m, 2H), 2.70 - 2.55 (m, 5H), 2.40 - 2.32 (m, 3H), 2.21 (d, J = 6.4 Hz, 2H), 1.80 (d, J = 12.3 Hz, 2H), 1.70 - 1.62 (m, 1H), 1.40 - 1.27 (m, 3H). (Example 69) Preparation of 1-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)-1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 75) [ka] Step 1: Preparation of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1,4-diazepan-1-carboxylate

[0277] To a solution of 3-(2,4-dioxo-1,3-diadinan-1-yl)-4-methoxybenzoic acid (500 mg, 1.89 mmol) in DMF (5 mL), HATU (862 mg, 2.268 mmol), DIEA (489 mg, 3.78 mmol), and tert-butyl (1,4-diazepan-1-yl)formate (380 mg, 1.89 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into water (45 mL) and extracted with SiO2 (50 mL x 2). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (MeOH / DCM = 1:10) to obtain the desired product (1 g, 94.7%). LC / MS: 391.2[M-55] + . Step 2: Preparation of 1-(5-(1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0278] A solution of tert-butyl(4-{[3-(2,4-dioxo-1,3-diadinane-1-yl)-4-methoxyphenyl]carbonyl}-1,4-diazepan-1-yl)formate (1 g) in TFA / DCM (1:5, 12 mL) was stirred at room temperature for 2 hours. This solution was concentrated under vacuum. The residue was dissolved in DCM (50 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dehydrated with Na2SO4 and concentrated under vacuum to obtain the desired product (500 mg, 83.0%). LC / MS: 347.1[M+H] + . Step 3: Preparation of 1-(5-(4-((1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)-1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0279] To a 5 mL solution of 1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-carboaldehyde (80 mg, 0.14 mmol) in DCM, 1-(5-(1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (97 mg, 0.28 mmol), Et3N (28 mg, 0.28 mmol), and MgSO4 (200 mg, 1.66 mmol) were added at room temperature. This mixture was stirred at room temperature for 30 minutes, after which NaBH(OAc)3 (59 mg, 0.28 mmol) was added in small quantities. This reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH / DCM = 1:10) yielded the desired product (80 mg, 63.5%). LC / MS: 900.1[M+H] + . 1 H NMR (400 MHz, DMSO) δ 13.06 (br, 1H), 11.14 (s, 1H), 10.36 (s, 1H), 8.46 (s, 1H), 8.04 (d, J= 14.8 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.49 (t, J= 7.6 Hz, 2H), 7.39 - 7.30 (m, 3H), 7.29 - 7.14 (m, 6H), 7.13 - 7.00 (m, 2H), 3.85 (s, 3H), 3.65 - 3.55 (m, 4H), 3.45 - 3.35 (m, 2H), 3.29 - 3.25 (m, 2H), 2.78 - 2.55 (m, 8H), 2.49 - 2.20 (m, 2H), 1.85 - 1.75 (m, 4H), 1.30 - 1.25 (m, 2H). (Example 70) Preparation of 1-(5-(4-(2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)ethyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 76) [ka]

[0280] A 20 mL solution of 2-(1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)-2-fluorophenyl)piperidine-4-yl)acetaldehyde (140 mg, 0.24 mmol), 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.24 mmol), TEA (121 mg, 1.2 mmol), and MgSO4 (408 mg, 3.4 mmol) in DCM (20 mL) was stirred under nitrogen at room temperature for 30 minutes. Sodium triacetoxyborohydride (163 mg, 0.72 mmol) was added in small quantities at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The organic layer was washed with water and concentrated under vacuum to obtain the crude product. Purification of the crude product by preparative TLC (MeOH:DCM = 1:10) yielded the desired product (55 mg, 25%) as a yellow solid. LC / MS: 900.0[M+1] + . 1 H NMR (400 MHz, DMSO) δ 13.06 (br, 1H), 11.14 (s, 1H), 10.36 (s, 1H), 10.05 (br, 1H), 8.46 (s, 1H), 8.04 (d, J = 14.8 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.45 - 7.37 (m, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.23 - 7.11 (m, 3H), 7.09 - 7.04 (m, 1H), 3.86 (s, 2H), 3.67 - 3.56 (m, 2H), 3.52 - 3.39 (m, 2H), 3.38 - 3.24 (m, 4H), 3.22 - 2.96 (m, 2H), 2.91 - 2.56 (m, 4H), 2.45 - 1.88 (m, 5H), 1.85 - 1.45 (m, 4H), 1.42 - 0.87 (m, 5H). (Example 71) Preparation of (R)-1-(5-(4-(2-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 77) [ka] Step 1: Preparation of (R)-1-(5-(4-(2-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0281] A solution of 2-(1'-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-[1,4'-bipiperidine]-4-yl)acetic acid (70 mg, 0.15 mmol), (R)-(2-chloro-4-phenoxyphenyl)(4-(piperidine-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (84 mg, 0.15 mmol), HATU (86 mg, 0.23 mmol), and N,N-diisopropylethylamine (116 mg, 0.9 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours. The mixture was evaporated under vacuum and purified by preparative TLC with MeOH:DCM = 1:10 to obtain the title compound (14 mg, 10%) as a white solid. LC / MS:902.4[M+H] + . 1 H NMR (301 MHz, DMSO) δ 12.86 (br, 1H), 10.37 (s, 1H), 8.87 (br, 1H), 8.32 - 8.24 (m, 1H), 7.67 - 7.62 (m, 1H), 7.60 - 7.52 (m, 1H), 7.51 - 7.43 (m, 2H), 7.42 - 7.34 (m, 2H), 7.29 - 7.12 (m, 5H), 7.05 - 6.98 (m, 1H), 4.32 - 4.21 (m, 1H), 4.20 - 4.13 (m, 1H), 3.84 (s, 3H), 3.63 - 3.53 (m, 3H), 3.33 - 3.24 (m, 2H), 3.21 - 3.13 (m, 1H), 3.07 - 3.01 (m, 1H), 2.94 - 2.77 (m, 3H), 2.67 (t, J = 6.4 Hz, 2H), 2.35 - 2.23 (m, 2H), 2.10 - 1.70 (m, 10H), 1.67 - 1.46 (m, 6H), 1.19 - 1.15 (m, 1H). (Example 72) Preparation of 1-(5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 78) [ka] Step 1: Preparation of 7-bromoheptanoyl chloride

[0282] A solution of 7-bromoheptanoic acid (1 g, 4.8 mmol) in thionyl chloride (20 mL) was stirred at 70°C for 5 hours. The reaction mixture was evaporated under vacuum, yielding the desired product as a brown oily substance (1 g, 91%). LC / MS: 223.0[M+H] + (Treatment with MeOH). Step 2: Preparation of 7-bromo-1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one

[0283] (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (106 mg, 0.22 mmol) and N,N-diisopropylethylamine (142.16 mg, 1.1 mmol) were stirred in ACN (10 mL) under nitrogen at room temperature, to which 7-bromoheptanoyl chloride (50 mg, 0.22 mmol) was added. This mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum. The residue was partitioned between siRNA and H2O. The organic phase was dehydrated with sodium sulfate and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography with CH2Cl2 / MeOH (100:1~10:1) to obtain the desired compound (60 mg, 41%) as a yellow solid. LC / MS: 637.9[M+H] + . Step 3: Preparation of 1-(5-(4-(7-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-7-oxoheptyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0284] Potassium iodide (3.1 mg, 0.02 mmol) was added to a 10 mL ACN solution of 7-bromo-1-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)heptan-1-one (60 mg, 0.09 mmol), 1-{2-methoxy-5-[(piperazin-1-yl)carbonyl]phenyl}-1,3-diadinane (31.20 mg, 0.09 mmol), and N,N-diisopropylethylamine (36.33 mg, 0.28 mmol) which had been stirred at room temperature under nitrogen. The reaction mixture was stirred at 70°C for 5 hours. After removing the solvent and purifying the residue by column chromatography (DCM / MeOH = 50:1~10:1), the product (21.3 mg, 0.024 mmol, 26%) was obtained as a yellow solid. LC / MS: 890.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 10.36 (s, 1H), 8.82 (d, J = 7.4 Hz, 1H), 8.26 (s, 1H), 7.64 (s, 1H), 7.60 - 7.55 (m, 1H), 7.51 - 7.44 (m, 2H), 7.43 - 7.31 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.23 - 7.11 (m, 4H), 7.05 - 7.00 (m, 1H), 4.38 - 4.33 (m, 1H), 4.19 - 4.12 (m, 1H), 3.93 - 3.80 (m, 4H), 3.60 (t, J = 6.6 Hz, 2H), 3.56 - 3.40 (m, 3H), 3.22 - 2.93 (m, 4H), 2.74 - 2.66 (m, 2H), 2.46 - 2.19 (m, 5H), 2.19 - 1.99 (m, 2H), 1.73 - 1.64 (m, 1H), 1.58 - 1.44 (m, 4H), 1.43 - 1.24 (m, 7H). (Example 73) Preparation of 1-(5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)benzyl)-1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 79) [ka] Step 1: Preparation of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1,4-diazepan-1-yl)methyl)benzoate

[0285] To a solution of 1-(5-(1,4-diazepane-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.23 mmol) in DMF (5 mL), tert-butyl 4-(bromomethyl)benzoate (69 mg, 0.25 mmol) and K2CO3 (64 mg, 0.46 mmol) were added. The reaction mixture was stirred at 75°C for 17 hours. The solvent was removed under vacuum, and the residue was purified by preparative TLC with PE:EA = 1:1 to obtain the desired product (72 mg, 58%). LC / MS: 537.2[M+H] + . Step 2: Preparation of 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1,4-diazepan-1-yl)methyl)benzoic acid

[0286] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1,4-diazepan-1-yl)methyl)benzoate (72 mg, 0.13 mmol) in DCM (3 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After removing the solvent under vacuum, the product (80 mg) was obtained and used in the next step without further purification. LC / MS: 481.0 [M+H] + . Step 3: Preparation of 1-(5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)benzyl)-1,4-diazepan-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0287] To a solution of 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1,4-diazepan-1-yl)methyl)benzoic acid (80 mg, crude) in DCM (5 mL), HATU (114 mg, 0.3 mmol) and DIEA (97 mg, 0.75 mmol) were added. This mixture was stirred at room temperature for 5 minutes, and (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (73 mg, 0.15 mmol) was added. This mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative TLC in a DCM:MeOH = 10:1 ratio to obtain the desired product (25 mg, 21% in 2 steps). LC / MS:910.1[M+H] + . 1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 10.34 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.44 - 7.31 (m, 6H), 7.26 (t, J = 7.6 Hz, 1H), 7.23 - 7.17 (m, 3H), 7.16 - 7.11 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.42 - 4.20 (m, 2H), 3.83 (s, 3H), 3.68 - 3.53 (m, 6H), 3.46 (s, 2H), 3.27 - 3.13(m, 2H), 2.75 - 2.60 (m, 4H), 2.59 - 2.53 (m, 1H), 2.23 - 1.92 (m, 3H), 1.86 - 1.66 (m, 3H), 1.60 - 1.48 (m, 2H). (Example 74) Preparation of 1-(5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)benzyl)piperazine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound 80) [ka] Step 1: Preparation of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)methyl)benzoate

[0288] A mixture consisting of tert-butyl 4-(bromomethyl)benzoate (150 mg, 0.55 mmol), 1-(2-methoxy-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (548 mg, 1.7 mmol), and DIEA (213 mg, 1.8 mmol) in DCM (20 mL) was stirred at room temperature for 4 hours. The solvent was removed under vacuum to obtain the crude product. Purification of the crude product by preparative TLC yielded the product (160 mg, 50%) as a yellow solid. LC / MS: 522.8[M+H] + . Step 2: Preparation of 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)methyl)benzoic acid

[0289] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)methyl)benzoate (160 mg) in DCM (20 mL), TFA (6 mL) was added. This mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to obtain the crude compound (180 mg), which was used in the next step without further purification. LC / MS: 466.7[M+H] + . Step 3: Preparation of 1-(5-(4-(4-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carbonyl)benzyl)piperazine-1-carbonyl)2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0290] A solution of 4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)methyl)benzoic acid (83 mg, purity: 70%, 0.12 mmol), (2-chloro-4-phenoxyphenyl)(4-(piperidine-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (60 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol), and DIEA (48 mg, 0.37 mmol) in DMF (10 mL) was stirred at room temperature for 3 hours. The solvent was removed under vacuum to obtain the crude product. Purification of the crude product by preparative TLC yielded the title product (24 mg, 22%) as a white solid. LC / MS: 895.5[M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 10.33 (s, 1H), 8.85 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.42 - 7.36 (m, 4H), 7.34 (s, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.22 - 7.10 (m, 4H), 7.05 - 7.00 (m, 1H), 4.36 - 4.31 (m, 2H), 3.84 (s, 3H), 3.65 - 3.45 (m, 8H), 3.32 (s, 3H), 3.29 - 3.17 (m, 2H), 2.67 (t, J = 6.5 Hz, 2H), 2.46 - 2.37 (m, 3H), 2.15 - 2.00 (m, 2H), 1.62 - 1.52 (m, 2H). (Example 75) Preparation of (S)-N-(4-(4-amino-1-(4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 85) [ka] Step 1: Preparation of (1-(2-fluoro-4-nitrophenyl)azetidine-3-yl)methanol

[0291] A mixture of 1,2-difluoro-4-nitrobenzene (2.0 g, 12.6 mmol), azetidine-3-ylmethanol (1.3 g, 15.1 mmol), and DIEA (4.9 g, 37.8 mmol) in ACN (15 mL) was stirred at 80°C for 3 hours. The solvent was removed under vacuum, and the residue was purified by flash column chromatography with PE:EA = 1:1 to obtain the desired product (2.5 g, 88.1%). LC / MS: 227.0 [M+H] + . Step 2: Preparation of (1-(4-amino-2-fluorophenyl)azetidine-3-yl)methanol

[0292] (1-(2-fluoro-4-nitrophenyl)azetidine-3-yl)methanol (2.5 g, 11.1 mmol) was dissolved in MeOH (30 mL) and Pd / C (0.25 g, 10%) was added. This mixture was stirred overnight at room temperature under 1 atm H2. The catalyst was filtered off, and the solution was concentrated under vacuum to obtain the product (2 g, 91.8%). LC / MS: 197.1[M+H] + . Step 3: Preparation of (1-(2-fluoro-4-iodophenyl)azetidine-3-yl)methanol

[0293] To a solution of (1-(4-amino-2-fluorophenyl)azetidine-3-yl)methanol (2.0 g, 10.2 mmol) in ACN (40 mL) and concentrated HCl (3.5 mL), an aqueous solution of NaNO2 (0.91 g, 13.2 mmol) (4 mL) was added at 0°C. This mixture was stirred at 0°C for 2 hours, and then an aqueous solution of KI (4.3 g, 25.5 mmol) (6 mL) was added dropwise. This mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted using DCM (40 mL × 3). The combined organic layers were concentrated under vacuum, and the residue was purified by flash column chromatography with PE:EA = 2:1 to obtain the desired product (1.0 g, 31.3%). LC / MS: 308.0[M+H] + . Step 4: Preparation of 1-(2-fluoro-4-iodophenyl)azetidine-3-carboaldehyde

[0294] To a 10 mL solution of (1-(2-fluoro-4-iodophenyl)azetidine-3-yl)methanol (1.0 g, 3.3 mmol) in DCM (10 mL), stirred under nitrogen at 0°C, des-martin periodinane (2.1 g, 4.9 mmol) was added in fractional amounts. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was quenched by adding water (10 mL). The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum to obtain the desired product (0.8 g, 78.7% yield). LC / MS: 306.0[M+H] + . Step 5: Preparation of 3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)azetidine

[0295] To a solution of 1-(2-fluoro-4-iodophenyl)azetidine-3-carboaldehyde (800 mg, 2.6 mmol) in MeOH (10 mL), acetyl chloride (310 mg, 3.9 mmol), stirred under nitrogen at 0°C, was added. The mixture was stirred at 25°C for 2 hours. The reaction product was quenched by adding TEA (1 mL). The solvent was removed under vacuum, and the residue was purified by flash column chromatography with PE:EA = 5:1 to obtain the desired product (500 mg, 53.8%). LC / MS: 352.0[M+H] + . Step 6: Preparation of N-(4-(4-amino-1-(4-(3-(dimethoxymethyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0296] To a DMSO (10 mL) solution of 3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)azetidine (400 mg, 1.14 mmol), N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (536.3 mg, 1.37 mmol), K2CO3 (472.3 mg, 3.41 mmol), copper(I) iodide (119.3 mg, 0.62 mmol), and N,N-dimethylglycine (129.2 mg, 1.25 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. The solid was filtered off and washed with DCM (20 mL x 3). The combined solution was concentrated under vacuum, and the residue was purified by flash with DCM:MeOH=10:1 to obtain the desired product (200 mg, 80% purity, 22.8% yield). LC / MS: 616.2[M+H] + . Step 7: Preparation of N-(4-(4-amino-1-(3-fluoro-4-(3-formylazetidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0297] To a solution of N-(4-(4-amino-1-(4-(3-(dimethoxymethyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg, 80% purity, 0.26 mmol), THF:H2O:H2SO4 (6 mL, 2:3:1) was added. This mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was diluted with DCM (20 mL). This organic phase was washed with saturated NaHCO3 solution and brine, and dehydrated with Na2SO4. The solvent was removed under vacuum. The residue was purified by silica gel chromatography using PE / EA=1:1 to obtain the desired product (100 mg, 67.5%). LC / MS: 570.1[M+H] + . Step 8: Preparation of (S)-N-(4-(4-amino-1-(4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0298] To a solution of N-(4-(4-amino-1-(3-fluoro-4-(3-formylazetidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (100 mg, 0.17 mmol), (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (63.4 mg, 0.19 mmol), and TEA (88 mg, 0.87 mmol) in MeOH / DMF (6 mL, 2:1), AcOH (0.5 mL) and NaBH3CN (44.1 mg, 0.70 mmol) were added. This mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding water (5 mL). This mixture was extracted using DCM (15 mL x 3). The organic phase was washed with brine and dehydrated with Na2SO4. After removing the solvent, the mixture was purified by preparative HPLC to obtain the desired compound (50 mg, 98.7% purity, 32.9% yield). LC / MS: 882.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.90 (t, J = 6.2 Hz, 1H), 8.35 (s, 1H), 7.93 - 7.89 (m, 1H), 7.85 - 7.83 (m, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.55 - 7.52 (m, 4H), 7.38 - 7.33 (m, 1H), 7.21 - 7.18 (m, 1H), 7.10 - 7.06 (m, 2H), 6.72 (t, J = 9.3 Hz, 1H), 5.08 - 5.03 (dd, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.34 (d, J = 17.2 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 4.12 - 4.10 (m, 2H), 3.91 (s, 3H), 3.69 - 3.63 (m, 2H), 3.32 - 3.27 (m, 3H), 3.04 - 2.85 (m, 3H), 2.68 - 2.55 (m, 6H), 2.39 - 2.33 (m, 2H), 1.96 - 1.91 (m, 1H). (Example 76) Preparation of N-(4-(4-amino-1-(1-(5-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 92) [ka] Step 1: Preparation of N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0299] To a DMSO (5 mL) solution of N-({4-[4-amino-1-(pyrrolidine-3-yl)pyrazolo[3,4-d]pyrimidine-3-yl]phenyl}methyl)-5-fluoro-2-methoxybenzamide (200 mg, 0.43 mmol) stirred at room temperature, 6-bromopyridine-3-carboaldehyde (121 mg, 0.65 mmol) and K2CO3 (120 mg, 0.86 mmol) were added. This reaction mixture was stirred at 80°C for 12 hours. This reaction mixture was poured into water (100 mL) and then extracted with EA (100 mL x 2). The combined organic layers were washed with water and brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (DCM / MeOH = 10:1) to obtain the desired product (150 mg, 61.1%). LC / MS: 566.9 [M+H] + . Step 2: Preparation of N-(4-(4-amino-1-(1-(5-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0300] To a MeOH / DMF / HOAc (12 mL, 2:1:0.05) solution of N-(4-(4-amino-1-(1-(5-formylpyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (130 mg, 0.23 mmol) stirred at room temperature, Et3N (36 mg, 0.36 mmol) was added, followed by (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (86 mg, 0.18 mmol) and NaBH3CN (45 mg, 0.72 mmol). The reaction mixture was stirred at 60°C for 1 hour. This mixture was concentrated under vacuum, then poured into water (50 mL) and extracted with EA (100 mL x 2). The combined organic layer was washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC to obtain the desired product (18 mg, 8.9%). LC / MS: 879.0 [M+H] + . 1H NMR (400 MHz, DMSO) δ = 10.94 (s, 1H), 8.85 (t, J= 6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.61 (d, J= 8.0 Hz, 2H), 7.53 - 7.45 (m, 5H), 7.36 - 7.31 (m, 1H), 7.18 (dd, J= 9.2, 4.4 Hz, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.50 (d, J= 8.4 Hz, 2H), 5.62 - 5.57 (m, 1H), 5.04 (dd, J= 13.2, 5.2 Hz, 1H), 4.57 (d, J= 6.0 Hz, 2H), 4.32 (d, J= 16.8 Hz, 1H), 4.19 (d, J= 16.8 Hz, 1H), 4.01 - 3.91 (m, 2H), 3.89 (s, 3H), 3.86 - 3.72 (m, 3H), 3.65 - 3.55 (m, 2H), 3.38 (s, 2H), 3.32 - 3.25 (m, 4H), 2.94 - 2.84 (m, 2H), 2.62 - 2.58 (m, 1H), 2.56 - 2.52 (m, 3H), 1.98 - 1.92 (m, 1H). (Example 77) Preparation of N-(4-(4-amino-1-(6-((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 93) [ka] Compound 93 was prepared in the same manner as described for compound 66. LC / MS:878.8[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.93 - 8.86 (m, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.59 - 7.49 (m, 4H), 7.38 - 7.32 (m, 1H), 7.20 (dd, J = 9.1, 4.2 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.62 (d, J = 9.0 Hz, 1H), 5.06 (dd, J = 13.0, 4.7 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.34 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 16.7 Hz, 1H), 3.91 (s, 3H), 3.71 - 3.50 (m, 3H), 3.49 - 3.36 (m, 3H), 3.27 - 3.15 (m, 2H), 2.89 (d, J = 11.8 Hz, 1H), 2.70 - 2.53 (m, 6H), 2.48 - 2.41 (m, 4H), 2.17 - 2.10 (m, 1H), 1.99 - 1.94 (m, 1H), 1.80 - 1.72 (m, 1H). (Example 78) Preparation of N-(4-(4-amino-1-(6-((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 94) [ka] Step 1: Preparation of 4-((5-fluoro-2-methoxybenzamide)methyl)benzoic acid

[0301] To a THF / water (100 mL, 1:1) solution of methyl 4-{[(5-fluoro-2-methoxyphenyl)formamide]methyl}benzoate (7.1 g, 22.37 mmol) stirred at room temperature, LiOH-H2O (4.7 g, 111.9 mmol) was added. This reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under vacuum to 50 mL and then acidified with HCl (5 M) to pH 5-6. The solid was filtered, washed with water, and dried under vacuum to obtain the desired product (6 g, 88.42%). LC / MS: 304.0[M+H] + . 1 H NMR (400 MHz, DMSO) δ = 8.89 (t, J= 6.0 Hz, 1H), 7.91 (d, J= 8.0 Hz, 2H), 7.50 (dd, J= 9.2, 3.2 Hz, 1H), 7.43 (d, J= 8.0 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.18 (dd, J= 9.2, 4.4 Hz, 1H), 4.56 (d, J= 6.0 Hz, 2H), 3.89 (s, 3H). Step 2: Preparation of 4-((5-fluoro-2-methoxybenzamide)methyl)benzoyl chloride

[0302] To a 50 mL solution of 4-{[(5-fluoro-2-methoxyphenyl)formamidomethyl}benzoic acid (3.9 g, 12.86 mmol) in DCM (50 mL), which had been stirred at room temperature, oxalyl chloride (2.2 mL, 25.72 mmol) was added. This reaction mixture was stirred at room temperature for 2 hours. When this reaction mixture was concentrated under vacuum, the title compound (4.0 g, crude) was obtained as a brown oily substance. Step 3: Preparation of N-(4-(2,2-dicyanoacetyl)benzyl)-5-fluoro-2-methoxybenzamide

[0303] To a 40 mL solution of 4-{[(5-fluoro-2-methoxyphenyl)formamide]methyl}benzoyl chloride (4 g, crude) and propanedinitrile (960 mg, 14.54 mmol) in acetone (40 mL), stirred at 5°C, NaOH (4 mL, 39.26 mmol, 40%) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (40 mL), and HCl (5 M) was added to adjust the pH to 2-3. The solid was filtered, washed with water, and dried under vacuum to obtain the desired product (3.8 g, 84.10% in two steps) as a white solid. LC / MS: 351.8[M+H] + . 1 H NMR (400 MHz, DMSO) δ = 10.89 (s, 1H), 8.86 (t, J= 6.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 2H), 7.50 (dd, J= 9.2, 3.2 Hz, 1H), 7.37 - 7.30 (m, 3H), 7.17 (dd, J= 9.2, 4.4 Hz, 1H), 4.52 (d, J= 6.0 Hz, 2H), 3.88 (s, 3H). Step 4: Preparation of N-(4-(2,2-dicyano-1-methoxyvinyl)benzyl)-5-fluoro-2-methoxybenzamide

[0304] To a solution of N-{[4-(2,2-dicyanoacetyl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (3.14 g, 8.94 mmol) in dioxane (40 mL), stirred at room temperature, NaHCO3 (6.0 g, 71.52 mmol) and dimethyl sulfate (8.45 g, 67.05 mmol) were added. The reaction mixture was stirred at 100°C for 2.5 hours. This mixture was poured into water (60 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain the title compound (3.5 g, crude) as a brown oily substance. LC / MS: 366.0 [M+H] + . Step 5: Preparation of N-(4-(5-amino-4-cyano-1H-pyrazole-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0305] In a sealed tube, a solution of N-{[4-(2,2-dicyano-1-methoxyethanol-1-en-1-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (6.2 g, crude) in MeOH / water (20 mL, 2:1), stirred at room temperature, was mixed with hydrazine (1.4 g, 34.16 mmol, 80%). The reaction mixture was stirred at 100°C for 12 hours. The mixture was poured into water (100 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (DCM:MeOH=10:1) to obtain the desired product (2.36 g, 36.1% in two steps). LC / MS: 366.0[M+H] + . 1 H NMR (400 MHz, DMSO) δ = 12.12 (s, 1H), 8.84 (s, 1H), 7.74 (d, J= 7.6 Hz, 2H), 7.51 (dd, J= 9.2, 3.2 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.36 - 7.30 (m, 1H), 7.18 (dd, J= 9.2, 4.4 Hz, 1H), 6.46 (s, 1H), 4.53 (d, J= 6.0 Hz, 2H), 3.89 (s, 3H). Step 6: Preparation of N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0306] N-{[4-(5-amino-4-cyano-1H-pyrazole-3-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (2.36 g, 6.46 mmol) in formamide (30 mL) was stirred at 160 °C for 2 hours. This mixture was poured into water (100 mL) and extracted with siRNA (100 mL x 2). The combined organic layer was washed with brine (200 mL), dehydrated with Na₂SO₄, and concentrated under vacuum. The residue was purified by flash chromatography (DCM:MeOH=10:1) to obtain the desired product (2.1 g, 82.8%). LC / MS: 393.0[M+H] + Step 7: Preparation of (R)-(1-(5-iodopyridine-2-yl)pyrrolidine-3-yl)methanol

[0307] To a 30 mL solution of 2-fluoro-5-iodopyridine (3 g, 13.45 mmol) in DMF (30 mL), stirred at room temperature, (3R)-pyrrolidine-3-ylmethanol (2.04 g, 20.18 mmol) and K2CO3 (5.6 g, 40.36 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours. This mixture was poured into 100 mL of water and extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (PE:ELISA = 3:1) to obtain the desired product (3.0 g, 73.3%). LC / MS: 304.8 [M+H] + . Step 8: Preparation of (R)-1-(5-iodopyridine-2-yl)pyrrolidine-3-carbaldehyde

[0308] To a 30 mL solution of oxalyl chloride (2.42 g, 19.07 mmol) in DCM, stirred at -78°C, DMSO (3 g, 38.14 mmol) was slowly added over 15 minutes at -78°C. Next, a 5 mL solution of [(3R)-1-(5-iodopyridine-2-yl)pyrrolidine-3-yl]methanol (2.9 g, 9.54 mmol) in DCM was slowly added. After 15 minutes, Et3N (3.86 g, 38.14 mmol) was added. This reaction mixture was stirred at -78°C for 30 minutes, then warmed to room temperature and stirred for 1 hour. The mixture was diluted with DCM (65 mL), washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the title compound (3.0 g, crude) as a brown solid. LC / MS: 302.7[M+H] + . Step 9: Preparation of (R)-2-(3-(dimethoxymethyl)pyrrolidine-1-yl)-5-iodopyridine

[0309] To a solution of (3R)-1-(5-iodopyridine-2-yl)pyrrolidine-3-carboaldehyde (3 g, crude) in MeOH (30 mL), stirred at 0°C, acetyl chloride (1.56 g, 19.86 mmol) was added. This reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with Et3N (2 mL) and concentrated under vacuum. The residue was purified by flash chromatography (PE:Â=5:1) to obtain the desired product (2.6 g, 78.3%). LC / MS: 348.7[M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.28 (d, J= 2.4 Hz, 1H), 7.61 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 8.8 Hz, 1H), 4.29 (d, J= 7.6 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.42 - 3.34 (m, 7H), 3.25 (dd, J= 10.8, 7.6 Hz, 1H), 2.73 - 2.63 (m, 1H), 2.16 - 2.05 (m, 1H), 1.94 - 1.84 (m, 1H). Step 10: Preparation of (R)-N-(4-(4-amino-1-(6-(3-(dimethoxymethyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0310] To a 10 mL solution of (R)-2-(3-(dimethoxymethyl)pyrrolidine-1-yl)-5-iodopyridine (300 mg, 0.86 mmol) in DMSO (10 mL), N-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (337 mg, 0.86 mmol), Na2CO3 (182 mg, 1.72 mmol), copper(I) iodide (82 mg, 0.43 mmol), and N,N-dimethylglycine (89 mg, 0.86 mmol) were added under nitrogen at 25 °C. The reaction mixture was stirred at 110 °C for 16 hours. The mixture was filtered and washed with DCM. This solution was concentrated under vacuum, and the residue was purified by flash column chromatography (DCM:MeOH=10:1) to obtain the desired product (460 mg, 87.2%) as a yellow solid. LC / MS: 612.7[M+H] + . Step 11: Preparation of (R)-N-(4-(4-amino-1-(6-(3-formylpyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0311] (R)-N-(4-(4-amino-1-(6-(3-(dimethoxymethyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (460 mg, 0.75 mmol) was dissolved in anhydrous THF (2.5 mL), to which HCl (4N, 2.5 mL in dioxane) was added. This reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the residue was dissolved by DCM. The organic phase was washed with NaHCO3 and brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the title compound (300 mg, crude) as a yellow solid. LC / MS: 566.8[M+H] + . Step 12: Preparation of N-(4-(4-amino-1-(6-((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0312] To a solution of (R)-N-(4-(4-amino-1-(6-(3-formylpyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (300 mg, crude) in MeOH / DMF (12 mL, 2:1), which had been stirred at room temperature, (S)-3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6-dione (260 mg, 0.53 mmol) and Et3N (107 mg, 1.06 mmol) were added. This mixture was stirred at room temperature for 30 minutes, and then AcOH (1 mL) and NaBH3CN (134 mg, 2.12 mmol) were added. This reaction mixture was stirred under nitrogen at 60°C for 1 hour. This mixture was diluted with water and extracted with DCM. The organic phase was washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired compound (30.5 mg, 6.9%). LC / MS: 878.8[M+H] + . 1 H NMR (400 MHz, DMSO) δ = 10.98 (s, 1H), 8.92 (t, J= 6.0 Hz, 1H), 8.70 (d, J= 2.4 Hz, 1H), 8.37 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 8.0 Hz, 2H), 7.61 (d, J= 8.4 Hz, 1H), 7.57 - 7.50 (m, 3H), 7.39 - 7.33 (m, 1H), 7.23 - 7.15 (m, 3H), 6.71 (d, J= 8.8 Hz, 1H), 5.07 (dd, J= 13.2, 4.8 Hz, 1H), 4.61 (d, J= 6.0 Hz, 2H), 4.37 (d, J=17.2, 1H), 4.25 (d, J=17.2, 1H), 4.10 - 4.02 (m, 2H), 3.91 (s, 3H), 3.41 - 3.37 (m, 2H), 3.27 - 3.22 (m, 4H), 2.95 - 2.85 (m, 2H), 2.77 (d, J= 5.2 Hz, 2H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 2H), 2.27 - 2.24 (m, 2H), 1.98 - 1.93 (m, 2H), 1.91 - 1.85 (m, 2H). (Example 79) Preparation of N-(4-(4-amino-1-(4-((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 95) [ka] Step 1: Preparation of (S)-(1-(2-fluoro-4-nitrophenyl)pyrrolidine-3-yl)methanol

[0313] To a solution of 1,2-difluoro-4-nitrobenzene (2.0 g, 12.6 mmol) in CH3CN (30 mL), (3S)-pyrrolidine-3-ylmethanol hydrochloride (1.91 g, 13.8 mmol) and DIEA (4.89 g, 37.8 mmol) were added. The reaction mixture was stirred at 80°C for 3 hours, and then quenched by adding water. The mixture was extracted with EA, washed with brine, and dehydrated with Na2SO4. The solvent was removed under vacuum, and the residue was purified by flash with PE:EA = 1:1 to obtain the desired product (2.8 g, 90% purity, 82.5% yield) as a yellow solid. LC / MS: 241.1[M+H] + . Step 2: Preparation of (S)-(1-(4-amino-2-fluorophenyl)pyrrolidine-3-yl)methanol

[0314] (S)-(1-(2-fluoro-4-nitrophenyl)pyrrolidine-3-yl)methanol (2.8 g, 90% purity, 10.5 mmol) was dissolved in methanol (40 mL) and Pd / C (0.28 g, 10%) was added. The reaction mixture was stirred at 25 °C for 16 hours under a 1 atm H2 atmosphere. The catalyst was filtered off and washed with MeOH. When this solution was concentrated under vacuum, the desired product (2.2 g, 99.6%) was obtained as a brown oily substance. LC / MS: 211.1[M+H] + . Step 3: Preparation of (S)-(1-(2-fluoro-4-iodophenyl)pyrrolidine-3-yl)methanol

[0315] To a solution of (S)-(1-(4-amino-2-fluorophenyl)pyrrolidine-3-yl)methanol (2.1 g, 9.98 mmol) in CH3CN (30 mL), concentrated HCl (2.5 mL) and NaNO2 (827 mg, 11.98 mmol, dissolved in 5 mL of H2O) were added at 0°C. The mixture was stirred at 0°C for 2 hours, and KI (4.14 g, 24.97 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. The reaction product was quenched by adding water (40 mL) and extracted with EA (40 mL × 3). The organic phase was washed with brine and dehydrated with Na2SO4. The solvent was removed under vacuum. The residue was purified by flash with PE:EA = 3:1 to obtain the desired product (2 g, 62.3%) as a yellow solid. LC / MS: 321.8[M+H] + . Step 4: Preparation of (S)-1-(2-fluoro-4-iodophenyl)pyrrolidine-3-carbaldehyde

[0316] To a solution of (S)-(1-(2-fluoro-4-iodophenyl)pyrrolidine-3-yl)methanol (1.9 g, 5.9 mmol) in DCM (20 mL), Dess-Martin periodinane (3.75 g, 8.8 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated Na₂S₂O₃ solution and then extracted with EA. The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash with PE:EA = 1:1 to obtain the desired product (2 g, 80% purity, 84.9% yield) as a white solid. LC / MS: 319.8[M+H] + . Step 5: Preparation of (S)-3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)pyrrolidine

[0317] To a solution of (S)-1-(2-fluoro-4-iodophenyl)pyrrolidine-3-carboaldehyde (2.0 g, 80% purity, 5.0 mmol) in MeOH (20 mL), acetyl chloride (1.04 g, 13.2 mmol), stirred under nitrogen at 0°C, was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with TEA, and the solvent was removed under vacuum. The residue was purified by flash column chromatography with PE:EA = 1:1 to obtain the desired product (1.0 g, 90% purity, 49.2% yield) as a white solid. LC / MS: 365.7[M+H] + . Step 6: Preparation of (S)-N-(4-(4-amino-1-(4-(3-(dimethoxymethyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0318] To a 10 mL solution of (S)-3-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)pyrrolidine (220 mg, 90% purity, 0.54 mmol) in DMSO (10 mL), N-[(4-{4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (257.89 mg, 0.65 mmol), Na2CO3 (127.72 mg, 1.2 mmol), copper(I) iodide (57.37 mg, 0.3 mmol), and N,N-dimethylglycine (62.13 mg, 0.6 mmol) were added under nitrogen at 25 °C. The reaction mixture was stirred at 110 °C for 16 hours. The mixture was filtered and washed with DCM. The solvent was removed under vacuum, and the residue was purified by flash with DCM:MeOH=10:1 to obtain the desired product (170 mg, 90% purity, 44.1% yield) as a yellow solid. LC / MS: 629.8[M+H] + . Step 7: Preparation of (S)-N-(4-(4-amino-1-(3-fluoro-4-(3-formylpyrrolidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0319] (S)-N-(4-(4-(4-amino-1-(4-(3-(dimethoxymethyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (170 mg, 90% purity, 0.24 mmol) was added to a 4 mL solution of DCM to which HCl (4N in dioxane, 4 mL), stirred under nitrogen at 25°C, was added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was made basic with a saturated NaHCO3 solution and extracted by DCM. The organic phase was washed with brine and dehydrated with Na2SO4. When this solution was concentrated under vacuum, the desired product (160 mg, crude) was obtained as a yellow solid. LC / MS: 583.8[M+H] + . Step 8: Preparation of N-(4-(4-amino-1-(4-(((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0320] To a solution of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindorin-2-yl)piperidine-2,6-dione (150 mg, 0.3 mmol) in MeOH / DMF / AcOH (5 mL, 2:1:0.02), (S)-N-(4-(4-amino-1-(3-fluoro-4-(3-formylpyrrolidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (150 mg, 0.25 mmol), TEA (52 mg, 0.51 mmol), and NaBH3CN (48 mg, 0.77 mmol) were added. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and then quenched with water. The mixture was extracted by DCM, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC with a DCM:MeOH ratio of 10:1 to obtain the desired product (60 mg, 26.0%) as a white solid. LC / MS: 896.7[M+H] + . 1 H NMR (400 MHz, ) δ 10.92 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 8.32 (s, 1H), 7.89 (dd, J = 15.2, 2.5 Hz, 1H), 7.79 (dd, J = 8.8, 2.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.52 - 7.47 (m, 4H), 7.34 - 7.28 (m, 1H), 7.16 (dd, J = 9.1, 4.3 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.84 (t, J = 9.5 Hz, 1H), 5.02 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.30 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 17.0 Hz, 1H), 3.88 (s, 3H), 3.51 - 3.45 (m, 1H), 3.42 - 3.37 (m, 2H), 3.27 - 3.25 (m, 3H), 3.21 - 3.11 (m, 2H), 2.90 - 2.81 (m, 1H), 2.60 - 2.52 (m, 6H), 2.41 - 2.24 (m, 4H), 2.07 - 2.01 (m, 1H), 1.95 - 1.89 (m, 1H), 1.69 - 1.62 (m, 1H). (Example 80) Preparation of N-(4-(4-amino-1-(4-(((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 96) [ka] Compound 96 was prepared in the same manner as described for compound 95. LC / MS:896.6[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.61 (bs, 1H), 8.93 - 8.90 (m, 1H), 8.38 (s, 1H), 7.99 - 7.85 (m, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.63 - 7.50 (m, 4H), 7.39 - 7.33 (m, 1H), 7.20 (m, 3H), 6.94 - 6.89 (m, 1H), 5.07 (m, 1H), 4.61 (d, J = 6.1 Hz, 2H), 4.39 - 4.35 (m, 1H), 4.26 - 4.22 (m, 1H), 4.08 - 4.02 (m, 2H), 3.91 (s, 3H), 3.74 - 3.63 (m, 3H), 3.54 - 3.36 (m, 4H), 3.28 - 3.13 (m, 5H), 2.95 - 2.76 (m, 3H), 2.64 - 2.56 (m, 1H), 2.43 - 2.34 (m, 1H), 2.26 - 2.18 (m, 1H), 2.00 - 1.94 (m, 1H), 1.82 - 1.74 (m, 1H). (Example 81) Preparation of (S)-N-(4-(4-amino-1-(6-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (compound 97) [ka] Step 1: Preparation of (1-(5-iodopyridine-2-yl)azetidine-3-yl)methanol

[0321] A DMA (100 mL) solution of 2-fluoro-5-iodopyridine (2.2 g, 9.86 mmol) was stirred at room temperature under argon, to which azetidine-3-ylmethanol (1.2 g, 9.86 mmol) and potassium carbonate (4.1 g, 29.59 mmol) were added. The reaction mixture was stirred overnight at 100°C. The reaction product was quenched by adding water (50 mL) and extracted by DCM (50 mL x 3). The organic phase was washed with brine and dehydrated with Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography at PE:EA=5:1 to obtain the desired product (1.5 g, 52.4%) as a yellow solid. LC / MS: 290.8[M+H] + . Step 2: Preparation of 1-(5-iodopyridine-2-yl)azetidine-3-carboaldehyde

[0322] Dess-Martin periodinane (3 g, 7.24 mmol) was added to a solution of [1-(5-iodopyridine-2-yl)azetidine-3-yl]methanol (1.4 g, 4.82 mmol) in DCM (80 mL), which had been stirred at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the residue was purified by flash with PE:EA = 5:1 to obtain the desired product (700 mg, 50.3%) as a yellow solid. LC / MS: 306.7[M+H2O] + . Step 3: Preparation of 2-(3-(dimethoxymethyl)azetidine-1-yl)-5-iodopyridine

[0323] A solution of 1-(5-iodopyridine-2-yl)azetidine-3-carboaldehyde (700 mg, 2.42 mmol) in MeOH (10 mL), stirred under argon at 0°C, was to which acetyl chloride (381 mg, 4.859 mmol) was added. This reaction was stirred at room temperature for 2 hours. The reaction was quenched with TEA (1 mL). The solvent was removed under vacuum, and the residue was purified by flash column chromatography with PE:EA = 5:1 to obtain the desired product (400 mg, 49.2%). LC / MS: 334.8 [M+H] + . Step 4: Preparation of N-(4-(4-amino-1-(6-(3-(dimethoxymethyl)azetidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0324] To a 13 mL solution of 2-[3-(dimethoxymethyl)azetidine-1-yl]-5-iodopyridine (200 mg, 0.59 mmol) in DMSO (13 mL), N-[(4-{4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl}phenyl)methyl]-5-fluoro-2-methoxybenzamide (282 mg, 0.71 mmol), Na2CO3 (139.5 mg, 1.31 mmol), copper(I) iodide (63 mg, 0.32 mmol), and N,N-dimethylglycine (67.89 mg, 0.65 mmol) were added under nitrogen at 25 °C. The reaction mixture was stirred overnight at 110 °C. The reaction mixture was quenched by adding water (50 mL) and extracted by DCM (50 mL x 3). The organic phase was washed with brine and dehydrated with Na2SO4. This solvent was removed under vacuum, and the residue was purified by flash column chromatography with DCM:MeOH=10:1 to obtain the desired product (200 mg, 55.8%) as a white solid. LC / MS: 599.2[M+H] + . Step 5: Preparation of N-(4-(4-amino-1-(6-(3-formylazetidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0325] To a 10 mL solution of N-{[4-(4-amino-1-{6-[3-(dimethoxymethyl)azetidine-1-yl]pyridine-3-yl}pyrazolo[3,4-d]pyrimidine-3-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (100 mg, 0.16 mmol) in DCM (10 mL), which had been stirred at room temperature, HCl / dioxane (10 mL) was added. This reaction mixture was stirred overnight at room temperature. When this solution was concentrated under vacuum, the title compound (110 mg, crude) was obtained as a yellow solid. LC / MS: 553.2[M+H] + . Step 6: Preparation of (S)-N-(4-(4-amino-1-(6-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluor...

Claims

1. A compound of formula (IB), or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof: 【Chemistry 141】 (In the formula, X is CH or N, Y is CH or N, R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, dialkylamino group, amino group, -CN, hydroxyl, C1-C4 alkoxy, and halogen. R2 and R3 are independently selected from H, halogen, -CN, hydroxyl, dialkylamino group, C1-C5 alkyl, deuterated C1-C5 alkyl, C1-C5 alkoxy, deuterated C1-C5 alkoxy, and C1-C5 haloalkyl, Q is L-W1, Here, L is an alkylene with a length of 3 to 8 carbon atoms, and one or more -CH2- groups are independently present as needed, C(=O). 【Chemistry 142】 It is replaced by an element selected from, W1 is, 【Chemistry 132】 Selected from, R4 is selected from H, halogens, -CN, C1-C5 alkyl, C1-C5 alkoxy, and C1-C5 haloalkyl.

2. The compound according to Claim 1, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R1 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl and halogen.

3. R1 is H, F, Cl, Br, I, -CF3, -CH3 and 【Chemistry 134】 A compound according to claim 2, selected from the above, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

4. The compound according to claim 3, wherein R1 is H, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

5. The compound according to claim 3, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R1 is Br.

6. The compound according to claim 3, wherein R1 is Cl, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

7. The compound according to claim 3, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R1 is F.

8. The compound according to claim 1, or a tautomer, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R2 and R3 are independently selected from H, -OCD3, -CD3, halogen, C1-C4 alkyl and C1-C4 alkoxy.

9. The compound according to claim 8, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R2 and R3 are each H.

10. The compound according to claim 8, wherein R2 is H and R3 is F, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

11. The compound according to claim 8, wherein R2 is F and R3 is H, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

12. The compound according to claim 8, wherein R2 is -OCH3 and R3 is F, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

13. The compound according to claim 8, wherein R2 is -F and R3 is -OCH3, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

14. The compound according to claim 8, wherein R2 is -OCD3 and R3 is F, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

15. The compound according to claim 8, wherein R2 is F and R3 is -OCD3, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

16. The compound according to claim 8, wherein R2 is -CD3 and R3 is F, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

17. The compound according to claim 8, wherein R2 is F and R3 is -CD3, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof.

18. The compound according to claim 1, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein R 4 is selected from H, halogen, -CN and C1-C4 haloalkyl.

19. The compound according to claim 18, wherein R4 is H, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

20. The compound according to claim 18, wherein R4 is a halogen, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

21. The compound according to claim 20, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, wherein the halogen is selected from F, Cl, Br and I.

22. The compound according to claim 21, wherein the halogen is F, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

23. The compound is (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(5-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(5-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)pentanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(((S)-1-(5-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-((R)-1-(5-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(6-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-3-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(4-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)phenyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)azetidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(4-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)benzoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(6-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)hexanoyl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(3-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(6-(3-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(6-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-((1R,5S,6s)-6-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-((1R,5S,6r)-6-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)picolinamide; N-(4-(4-amino-1-(4-(((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)picolinamide; N-(4-(4-amino-1-(4-(((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)picolinamide; N-(4-(4-amino-1-(1-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-[1,3'-biazethidine]-3-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1'-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)-[1,4'-bipiperidine]-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(1-(2-(4-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)ethyl)azetidine-3-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(1-(2-(4-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)ethyl)azetidine-3-yl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; Trans-N-(4-(4-amino-1-(1-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)cyclobutyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; Cis-N-(4-(4-amino-1-(1-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)cyclobutyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; Trans-N-(4-(4-amino-1-(1-((1S,3r)-3-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)cyclobutyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; Cis-N-(4-(4-amino-1-(1-(3-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)cyclobutyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(1-(5-((4-(2-(((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyridine-2-yl)pyrrolidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(6-(((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(6-(((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(((R)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(((S)-3-((4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(6-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)ethyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(1-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)piperazine-1-yl)ethyl)piperidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; (S)-N-(4-(4-amino-1-(4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; N-(4-(4-amino-1-(4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)methyl)piperazine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; and (S)-N-(4-(4-amino-1-(4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzyl)-5-fluoro-2-methoxybenzamide; A compound according to claim 1, selected from the above, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, and at least one additional component selected from a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle and a pharmaceutically acceptable excipient.

25. The pharmaceutical composition according to claim 24, wherein the compound is present in a therapeutically effective amount.

26. A composition for treating a state modulated by Bruton's tyrosine kinase (BTK) in an object that requires treatment of such a state, comprising a compound according to any one of claims 1 to 23, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof.

27. ​​The composition according to claim 26, wherein the state modulated by BTK is selected from cancer, lymphoma, leukemia, immunological disorders, autoimmune diseases and inflammatory disorders.

28. The composition according to claim 26, wherein the condition is selected from B-cell malignancy, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, chronic graft-versus-host disease, and kidney transplant-related disorders.

29. The composition according to claim 28, wherein the condition is mantle cell lymphoma.

30. The composition according to claim 28, wherein the condition is chronic lymphocytic leukemia or small lymphocytic lymphoma.

31. The composition according to claim 28, wherein the condition is Waldenström macroglobulinemia.

32. The composition according to claim 28, wherein the condition is marginal zone lymphoma.

33. The composition according to claim 28, wherein the condition is chronic graft-versus-host disease.

34. The composition according to claim 28, wherein the condition is multiple sclerosis.

35. Use of a compound according to any one of claims 1 to 23, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate or deuterated derivative thereof, in the preparation of a pharmaceutical.

36. A composition for degrading BTK in cells, comprising a compound according to any one of claims 1 to 23, or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or deuterated derivative thereof, characterized in that the compound comes into contact with the cells.

37. The composition according to claim 26, characterized in that the composition is administered to the subject in combination with another therapeutic agent.

38. The composition according to claim 37, wherein the therapeutic agent is selected from chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, bendamustine, cyclophosphamide, vincristine, venetoclax, and lenalidomide.

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