HPK1 DEGRADERS, COMPOSITIONS THEREOF, AND METHODS OF USING SAME

Abstract

Provided are compounds of formula I and I', pharmaceutical compositions containing the compounds, and methods of using same in treating diseases, disorders, or conditions mediated by the degradation of protein kinases, such as, for example, hematopoietic progenitor kinase 1 (HPK1). JPEG2024531439000175.jpg78170

Description

[Technical Field]

[0001] This disclosure relates to novel compounds that are useful in treating certain diseases. Specifically, this disclosure relates to novel compounds that bind to hematopoietic progenitor kinases (HPKs), such as HPK1, induce HPK1 degradation, and treat HPK1-dependent disorders. [Background technology]

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a serine / threonine kinase predominantly expressed in hematopoietic cells such as T cells, B cells, and dendritic cells (DCs). HPK1 kinase activity can be induced by various receptor stimuli, including TCR, BCR, EP2 / 4, and CD95 (Sawasdikosol & Burakoff, 2020). After TCR engagement, HPK1 is phosphorylated by ZAP70 at tyrosine 379, allowing it to bind to the SH2 domain of SLP76. HPK1 subsequently phosphorylates serine 376 of SLP76 and threonine 262 of Gad (DiBartolo et al., 2007; Lasserre et al., 2011), creating a binding site for SLP76 and 14-3-3 disruption of the LAT complex (diBartolo et al., 2007; Lasserre et al., 2011). This acts as a negative feedback signal to TCR activation. The function of HPK1 has been validated by various genetic evidence. HPK1- / - T cells have a lower activation threshold along with increased proinflammatory cytokine and hyperproliferative responses (Liu et al., 2019). HPK1- / - T cells also exhibit resistance to PGE2-mediated suppression (Alzabin et al., 2009). HPK1- / - dendritic cells have demonstrated superior antigen-presenting capacity in vitro, leading to antitumor responses in vivo. In addition, HPK1- / - mice exhibited better antitumor activity than wild-type mice in several tumor models (Liu et al., 2019). These findings highlight the importance of HPK1 activity in enhancing immune cell function and preventing tumor progression. In addition to autoimmune diseases, MAP4K1 expression has also been reported to be a novel resistance mechanism and an independent prognostic marker in AML (Knight et al., 2021; Ling et al., 2021). Therefore, HPK1 may be a novel target for cancer and other disorders.

[0003] Structurally, HPK1 contains an N-terminal kinase domain, a proline-rich domain, and a C-terminal citron homology domain. Traditionally, HPK1 activity can be modulated by the kinase domain. HPK1 binds to many adaptor proteins, including Grb2, Nck, Crk, and SLP-76, as well as the actin-binding adaptor HIP-55. The proline-rich domain can bind to proteins containing SH3 domains. HPK1 can prevent the formation of an ADAP and SLP76 complex by interacting with IKK-α / β. Bivalent heterobifunctional molecules, also known as protein degradation targeting chimeras (PROTACs), not only inhibit enzymatic activity but also eliminate the scaffolding function of proteins. Therefore, molecules that bind to and induce HPK1 degradation not only have better efficacy than those that inhibit kinase activity but can also overcome inhibition-induced or acquired resistance. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 2013 / 075083 [Patent Document 2] WO 2013 / 075084 [Patent Document 3] WO 2013 / 078320 [Patent Document 4] WO 2013 / 120104 [Patent Document 5] WO 2014 / 124418 [Patent Document 6] WO 2014 / 151142 [Patent Document 7] WO 2015 / 023915 [Patent Document 8] U.S. Patent No. 4,938,949 [Non-patent literature]

[0005] [Non-Patent Document 1] SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19 [Non-patent document 2] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-patent document 3] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia [Non-patent document 4] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick [Non-patent document 5] J.C. Boylan, 1988–1999, Marcel Dekker, New York Summary of the Invention [Means for solving the problem]

[0006] One aspect of the present disclosure provides a compound selected from the group consisting of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used in the treatment of diseases mediated by the degradation of hematopoietic progenitor kinase 1 (HPK1). For example, a compound of the following structural formula I: [ka] Disclosed herein is a compound of the formula: (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, CORx , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) Each R 2 , R 3 and R 4 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 independently selected; (iii) R 5 is hydrogen, R x , -CH2OC(O)R x - and -CH2OC(O)C(R x R y )NH2; (iv) Each W 1 , W 2 , W 3 and W 4 is C(R w )2 and C(O); (v) V is N and CR x Selected from; (vi) When V is N, X is absent, or -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -, -S(O)2-, and -S(O)2R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (vii) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (viii) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (ix) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (x) Ring A is selected from aryl groups and heteroaryl groups; (xi) Ring B is absent or selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups.

[0007] One aspect of the present disclosure provides a compound selected from the group consisting of a compound of formula I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used in the treatment of diseases mediated by the degradation of hematopoietic progenitor kinase 1 (HPK1). For example, a compound of the following structural formula I': [ka] Disclosed herein is a compound of the formula: (xii) R 1is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (xiii) Each R 2 and R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 independently selected; (xiv) V is N and CR x Selected from; (xv) When V is N, X is absent, or —C(O)—, —C(O)R x -, -C(S)-, -C(S)R x -, -S(O)2-, and -S(O)2R x or V is selected from CR x When X is absent, or -O-, -S-, -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (xvi) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (xvii) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (xviii) Each R w , Rx , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xix) Ring A is selected from aryl groups and heteroaryl groups; (xx) ring B is , absent, or selected from aryl groups, heteroaryl groups, cycloalkyl groups, and heterocycloalkyl groups; (xxi) Ring C is [ka] (In the formula, R c is selected from hydrogen, linear, branched, and cyclic alkyl groups; each R' and R" is selected from hydrogen, a halogen group, OR x , independently selected from linear, branched and cyclic alkyl groups Selected from; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups.

[0008] In one aspect of the disclosure, the compounds of formulas I and I' are selected from compounds 1 to 106 shown below, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0009] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I and I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can comprise a compound selected from Compounds 1 to 106 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. These compositions can further comprise an additional active pharmaceutical agent.

[0010] Another aspect of the present disclosure provides methods of treating a disease, disorder, or condition mediated by the degradation of hematopoietic progenitor kinase 1 (HPK1) in a subject, comprising administering a therapeutically effective amount of a compound of Formula I or I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a compound selected from compounds 1 to 106 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0011] In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of Formula I and I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof a compound selected from Compounds 1 to 106 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or in the same composition or in a separate composition, with the additional active pharmaceutical agent.

[0012] Additionally, disclosed herein are methods for decreasing HPK1 activity comprising administering to a subject a therapeutically effective amount of a compound of Formula I or I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method for degrading HPK1 comprises administering to a subject a compound selected from Compounds 1 to 106 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method for decreasing HPK1 activity comprises contacting said HPK1 with a compound of Formula I or I', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, a method of degrading HPK1 comprises contacting HPK1 with a compound selected from compounds 1 to 106 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0013] The foregoing summary, as well as the following detailed description of the present disclosure, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, the accompanying drawings show some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. These drawings, which are incorporated in and constitute a part of this specification, serve to explain the principles of the present disclosure. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 illustrates IL-2 production in primary murine CD3+ T cells. [Figure 2] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 1 of the present disclosure. [Figure 3]FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 16 of the present disclosure. [Figure 4] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 21 of the present disclosure. [Figure 5] FIG. 1 illustrates HPK1 degradation according to Example 31 of the present disclosure in primary mouse CD3+ T cells. [Figure 6] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 35 of the present disclosure. [Figure 7] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 51 of the present disclosure. [Figure 8] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 56 of the present disclosure. [Figure 9] FIG. 1 illustrates HPK1 degradation in primary mouse CD3+ T cells according to Example 79 of the present disclosure. [Figure 10] FIG. 1 illustrates HPK1 degradation in human PBMCs according to Example 31 of the present disclosure. [Figure 11] FIG. 1 illustrates HPK1 degradation in human PBMCs according to Example 58 of the present disclosure. [Figure 12] FIG. 1 illustrates HPK1 degradation in human PBMCs according to Example 63 of the present disclosure. [Figure 13] FIG. 1 illustrates HPK1 degradation in human PBMCs according to Example 73 of the present disclosure. [Figure 14] FIG. 1 illustrates HPK1 degradation in human PBMCs according to Example 78 of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0015] I. Definition The terms "a" or "an" when used herein to refer to a noun include "at least one," and thus include both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means a single or two or more additional pharmaceutical agents.

[0016] The term "protein kinase" refers to an enzyme that catalyzes the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The serine / threonine kinases, which are specific for phosphorylating serine and threonine residues, constitute an important family of protein kinases.

[0017] The term "HPK1" or "hematopoietic progenitor kinase 1," also known as MAP4K1, as used herein, is a serine / threonine kinase that is predominantly expressed in hematopoietic cells such as T cells, B cells, and dendritic cells (DCs). HPK1 is involved in modulating various downstream signaling pathways, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB), all of which are associated with the regulation of cell proliferation and immune cell activation.

[0018] The compounds disclosed herein degrade protein kinase HPK1.Therefore, the compounds disclosed herein are generally useful in treating diseases or conditions associated with such kinases.In one embodiment, the compounds disclosed herein are HPK1 degraders and are useful for treating diseases such as cancer associated with such kinases.

[0019] The term "degrading agent," as used herein, refers to a molecular agent that binds to hematopoietic precursor kinase 1 and subsequently reduces the steady-state protein level of the kinase. In some embodiments, a degrading agent as disclosed herein reduces steady-state HPK1 protein levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, a degrading agent as disclosed herein reduces steady-state HPK1 protein levels by at least 65%. In some embodiments, a degrading agent as disclosed herein reduces steady-state HPK1 protein levels by at least 85%.

[0020] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variations among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown will also contain lesser amounts of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on numerous factors, including, for example, the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0021] As used herein, the term "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with a specified substituent group. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified groups, the substituents may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0022] The term "isotopically enriched" refers to species whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise stated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms as well. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon by C, are within the scope of this disclosure.

[0023] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0024] The term "tautomer," as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the movement of an atom, e.g., a hydrogen atom or group, within the molecule.

[0025] "Stereoisomers," as used herein, refers to enantiomers and diastereomers.

[0026] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, except that one or more hydrogen atoms have been replaced with a deuterium atom ("D" or " 2 "H" refers to a compound in which at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. It is recognized that some variation in natural isotopic abundance will occur in synthetic compounds depending on the origin of the chemical materials used in their synthesis. The concentration of naturally abundant stable hydrogen isotopes, despite this variation, is small and insignificant when compared to the degree of stable isotopic substitution of the deuterated derivatives disclosed herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium designation), at least 4500 (67.5% deuterium incorporation at each deuterium designation), at least 5000 (75% deuterium incorporation at each deuterium designation), at least 5500 (82.5% deuterium incorporation at each deuterium designation), at least 6000 (90% deuterium incorporation at each deuterium designation), at least 6333.3 (95% deuterium incorporation at each deuterium designation), at least 6466.7 (97% deuterium incorporation at each deuterium designation), or at least 6600 (99% deuterium incorporation at each deuterium designation).

[0027] The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0028] The term "alkyl," as used herein, means a straight-chain or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, alkyl groups contain 1 to 30 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms. In other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms. And in still other embodiments, alkyl groups contain 1 to 2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are straight-chain or unbranched. In some embodiments, alkyl groups are branched.

[0029] The term "cycloalkyl" refers to a fully saturated, monocyclic C 3~8 hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 "cycloalkyl" refers to a hydrocarbon, wherein any individual ring in the bicyclic ring system has 3 to 7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is a C3 to C6 alkyl group. 12 In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0030] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to monocyclic C alkyl groups that are fully saturated or that contain one or more units of unsaturation but are not aromatic and are therefore partially saturated. 3~8 hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 "Carbocyclyl" refers to a hydrocarbon, wherein any individual ring in the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes, for example, a combination of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is a C3 to C6 12 In some embodiments, the carbocyclyl is a carbocyclyl of the formula C3 to C 10 In some embodiments, the carbocyclyl is a C3 to C8 carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.

[0031] The term "alkylene," as used herein, refers to a divalent alkyl group. 1~10 Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, 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.

[0032] The term "alkenyl," as used herein, refers to a straight or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is straight-chained, linear, or unbranched. In some embodiments, an alkenyl group is branched.

[0033] The term "alkynyl" as used herein includes, but is not limited to, C 2~8 Alkynyl refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 8 carbon atoms. 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.

[0034] The term "heterocyclyl," as used herein, means a non-aromatic (i.e., fully saturated, or partially saturated because it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system, where one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to a phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members, wherein one or more ring members are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, a heterocyclic ring has one heteroatom that is a nitrogen atom. In some embodiments, a heterocyclic ring has one heteroatom that is an oxygen atom. In some embodiments, a heterocyclic ring has two heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring has three heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring is substituted. In some embodiments, a heterocyclic ring is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl.In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, and the like.

[0035] The term "heteroatom" refers to any oxidized form of nitrogen or sulfur, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + It refers to one or more of oxygen, sulfur, and nitrogen, including (as in N-substituted pyrrolidinyl).

[0036] The term "unsaturated," as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are filled by substituents, and thus the compound contains double or triple bonds.

[0037] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, where one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is linked between two carbon atoms.

[0038] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0039] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0040] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system with a delocalized pi orbital composed of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, further defined as follows.

[0041] The term "aryl," used alone or as part of a larger moiety, as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, where every ring in the system is an aromatic ring containing only carbon atoms, and where each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) rings and naphthyl (C 10 ) ring. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0042] The term "heteroaryl" refers to a monocyclic, spirocyclic, fused, or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Bicyclic heteroaryl groups include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to phenyl. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, heteroaryl groups are monocyclic ring systems having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0043] "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, wherein any two rings share only one common atom.

[0044] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0045] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0046] Pharmaceutically acceptable salts of the disclosed compounds are disclosed herein. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0047] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0048] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts include, therefore, sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-diol ... Included are oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0049] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4(Alkyl) quaternary salts are also included. The present disclosure further contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0050] The term "subject" refers to an animal, including, but not limited to, a human.

[0051] The term "therapeutically effective amount" refers to the amount of a compound for which it is administered that produces the desired effect (e.g., amelioration of symptoms of diseases, disorders, and conditions mediated by HPK1 degradation, reducing the severity of diseases, disorders, and conditions mediated by HPK1 degradation or symptoms thereof, and / or reducing the progression of diseases, disorders, and conditions mediated by HPK1 degradation or symptoms thereof). The exact amount of the therapeutically effective amount will depend on the purpose of the treatment, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0052] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. As used herein, "treatment" and its cognates include, but are not limited to: complete or partial remission of, or lower risk of, diseases, disorders, and conditions mediated by HPK1 degradation, and disease-related complications. Improvement in or reduction in the severity of any of these symptoms can be readily determined according to methods and techniques known or subsequently developed in the art.

[0053] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the specified dose, amount, or weight percent value, or a range of doses, amounts, or weight percent that would be recognized by one of skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent.

[0054] II. Compounds and Compositions In a first embodiment, the compounds of the present disclosure have the following structural formula I: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) Each R 2 , R 3 and R 4 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 independently selected; (iii) R 5 is hydrogen, Rx , -CH2OC(O)R x - and -CH2OC(O)C(R x R y )NH2; (iv) Each W 1 , W 2 , W 3 and W 4 is C(R w )2 and C(O); (v) V is N and CR x Selected from; (vi) When V is N, X is absent, or -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -, -S(O)2-, and -S(O)2R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (vii) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (viii) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (ix) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (x) Ring A is selected from aryl groups and heteroaryl groups; (xi) Ring B is absent or selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups.

[0055] In a second embodiment, the compound of the present disclosure has the following structural formula I': [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) Each R 2 and R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 independently selected; (iii) V is N and CR x Selected from; (iv) When V is N, X is absent, or —C(O)—, —C(O)R x -, -C(S)-, -C(S)R x -, -S(O)2-, and -S(O)2R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (v) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (vi) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (vii) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (viii) Ring A is selected from aryl and heteroaryl groups; (ix) ring B is , absent, or selected from aryl groups, heteroaryl groups, cycloalkyl groups, and heterocycloalkyl groups; (x) Ring C is [ka] (In the formula, R c is selected from hydrogen, linear, branched, and cyclic alkyl groups; each R' and R" is selected from hydrogen, a halogen group, OR x , linear, branched and cyclic alkyl groups) Selected from; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups.

[0056] In a third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the first and second embodiments.

[0057] In a fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from C1-C6 straight chain, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in all of the preceding embodiments.

[0058] In a fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from methyl, ethyl, cyclopropyl, and cyclobutyl; all other variables not specifically defined herein are as defined in the fourth embodiment.

[0059] In a sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is a halogen group; all other variables not specifically defined herein are as defined in the previous embodiments.

[0060] In a seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is chloro; all other variables not specifically defined here are as defined in the sixth embodiment.

[0061] In an eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is hydrogen; all other variables not specifically defined herein are as defined in any one of the first through fifth embodiments.

[0062] In a ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is a halogen group; all other variables not specifically defined herein are as defined in the previous embodiments.

[0063] In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is chloro; all other variables not specifically defined here are as defined in the ninth embodiment.

[0064] In an eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is hydrogen; all other variables not specifically defined herein are as defined in any one of the first through eighth embodiments.

[0065] In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is a halogen group; all other variables not specifically defined herein are as defined in the previous embodiments.

[0066] In a thirteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is fluoro; all other variables not specifically defined here are as defined in the previous embodiments.

[0067] In a fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is hydrogen; all other variables not specifically defined herein are as defined in any one of the first through thirteenth embodiments.

[0068] In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is selected from C1 to C6 straight chain, branched and cyclic alkyl groups; all other variables not specifically defined here are as defined in any one of the first to thirteenth embodiments.

[0069] In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl; all other variables not specifically defined herein are as defined in the fifteenth embodiment.

[0070] In a seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is -CH2OC(O)R x - all other variables not specifically defined herein are as defined in any one of the first through thirteenth embodiments.

[0071] In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R xis selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl; all other variables not specifically defined herein are as defined in the seventeenth embodiment.

[0072] In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is -CH2OC(O)C(R x R y )NH2; all other variables not specifically defined herein are as defined in any one of the first to thirteenth embodiments.

[0073] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R x is hydrogen; all other variables not specifically defined herein are as defined in the nineteenth embodiment.

[0074] In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R y is selected from hydrogen, methyl, iso-propyl, and benzyl; all other variables not specifically defined here are as defined in the nineteenth and twentieth embodiments.

[0075] In a twenty-second embodiment, X is absent; all other variables not specifically defined herein are as defined in the previous embodiments.

[0076] In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is —C(O)—; all other variables not specifically defined herein are as defined in any one of the first through twenty-first embodiments.

[0077] In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is selected from linear, branched, and cyclic alkylene groups; all other variables not specifically defined herein are as defined in the previous embodiments.

[0078] In a twenty-fifth embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is C1-C 10 straight chain alkylene groups; all other variables not specifically defined herein are as defined in the twenty-third embodiment.

[0079] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is selected from a PEG group; all other variables not specifically defined herein are as defined in any one of the first through fifth embodiments.

[0080] In a twenty-seventh embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is [ka] all other variables not specifically defined herein are as defined in the twenty-fifth embodiment.

[0081] In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is absent; all other variables not specifically defined herein are as defined in the previous embodiments.

[0082] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is —C(O)—; all other variables not specifically defined herein are as defined in any one of the first through twenty-sixth embodiments.

[0083] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is O; and all other variables not specifically defined herein are as defined in any one of the first through twenty-seventh embodiments.

[0084] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is NR z and all other variables not specifically defined herein are as defined in any one of the first through twenty-seventh embodiments.

[0085] In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R z is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-first embodiment.

[0086] In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R z is hydrogen; all other variables not specifically defined herein are as defined in the thirty-first embodiment.

[0087] In a thirty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R z is methyl; all other variables not specifically defined herein are as defined in the thirtieth embodiment.

[0088] In a thirty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring B is absent; all other variables not specifically defined herein are as defined in the previous embodiments.

[0089] In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring B is selected from optionally substituted heterocycloalkyl; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment.

[0090] In a thirty-seventh embodiment, Ring B is [ka] all other variables not specifically defined herein are as defined in the thirty-sixth embodiment.

[0091] In a thirty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 1 is C(R w ) 2; all other variables not specifically defined herein are as defined in the previous embodiments except for embodiment 2.

[0092] In a thirty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R w is hydrogen; all other variables not specifically defined herein are as defined in the 38th embodiment.

[0093] In a fortieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 1 is C(O); all other variables not specifically defined herein are as defined in any one of the first to thirty-sixth embodiments.

[0094] In a forty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 2 is C(R w ) 2; all other variables not specifically defined herein are as defined in the previous embodiments except for embodiment 2.

[0095] In a forty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R w is hydrogen; all other variables not specifically defined herein are as defined in the forty-first embodiment.

[0096] In a forty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 2 is C(O); all other variables not specifically defined herein are as defined in any one of the first to fortieth embodiments.

[0097] In a forty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 3 is C(R w ) 2; all other variables not specifically defined herein are as defined in the previous embodiments except for embodiment 2.

[0098] In a forty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R w is hydrogen; all other variables not specifically defined herein are as defined in the forty-fourth embodiment.

[0099] In a forty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 3 is C(O); all other variables not specifically defined herein are as defined in the previous embodiments except for embodiment 2.

[0100] In a forty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 4 is C(R w) 2; all other variables not specifically defined herein are as defined in the previous embodiments except for embodiment 2.

[0101] In a forty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R w is hydrogen; all other variables not specifically defined herein are as defined in the 47th embodiment.

[0102] In a forty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, W 4 is C(O); all other variables not specifically defined herein are as defined in any one of the first to forty-sixth embodiments.

[0103] In a 50th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is a 5- or 6-membered heteroaryl group; all other variables not specifically defined herein are as defined in any one of the 1 through 46 embodiments.

[0104] In a fifty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is [ka] and each U 1 and U 2 is CR u or N; U 3 are O, S, and NR u Selected from; R u are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; all other variables not specifically defined herein are as defined in the 50th embodiment.

[0105] In a fifty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is CR u and U 3 is O; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0106] In a fifty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is CR u and U 3 is S; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0107] In a fifty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 CR u and U 3 is O; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0108] In a fifty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is CR u and U 3 is S; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0109] In a fifty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is N and U 3is O; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0110] In a fifty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is N and U 3 is S; all other variables not specifically defined herein are as defined in the 51st embodiment.

[0111] In a fifty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is [ka] and each U 1 and U 3 is CR u or N; U 2 are O, S, and NR u Selected from; R u are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; all other variables not specifically defined herein are as defined in the fortieth embodiment.

[0112] In a fifty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is O and U 3 is CR u and all other variables not specifically defined herein are as defined in the 58th embodiment.

[0113] In a sixtieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR uand U 2 is S and U 3 is CR u and all other variables not specifically defined herein are as defined in the 57th embodiment.

[0114] In a sixty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is O and U 3 is CR u and all other variables not specifically defined herein are as defined in the 58th embodiment.

[0115] In a sixty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is S and U 3 is CR u and all other variables not specifically defined herein are as defined in the 58th embodiment.

[0116] In a sixty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR z and U 2 is O and U 3 is N; all other variables not specifically defined herein are as defined in the 58th embodiment.

[0117] In a sixty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR z and U 2 is S and U 3 is N; all other variables not specifically defined herein are as defined in the 58th embodiment.

[0118] In a sixty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is [ka] and all other variables not specifically defined herein are as defined in the 51st embodiment.

[0119] In a sixty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is [ka] and each U 1 , U 2 , U 3 and U 4 is CR z or N; R u are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; all other variables not specifically defined herein are as defined in the 50th embodiment.

[0120] In a sixty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is CR u and U 3 is CR u and U 4 is CR u and all other variables not specifically defined herein are as defined in the 66th embodiment.

[0121] In a sixty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is N and U 3 is CR u and U 4is CR u and all other variables not specifically defined herein are as defined in the 66th embodiment.

[0122] In a sixty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is CR u and U 3 is N and U 4 is CR u and all other variables not specifically defined herein are as defined in the 66th embodiment.

[0123] In a seventieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is CR u and U 3 is CR u and U 4 is N; all other variables not specifically defined herein are as defined in the 66th embodiment.

[0124] In a seventy-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is N and U 3 is CR u and U 4 is CR u and all other variables not specifically defined herein are as defined in the 66th embodiment.

[0125] In a seventy-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is CR u and U 3 is N and U4 is CR u and all other variables not specifically defined herein are as defined in the 66th embodiment.

[0126] In a seventy-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is CR u and U 2 is CR u and U 3 is CR u and U 4 is N; all other variables not specifically defined herein are as defined in the 66th embodiment.

[0127] In a seventy-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is N and U 2 is CR u and U 3 is CR u and U 4 is N; all other variables not specifically defined herein are as defined in the 66th embodiment.

[0128] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 106 shown in Table 1 below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0129] [Table 1A]

[0130] [Table 1B]

[0131] [Table 1C]

[0132] [Table 1D]

[0133] [Table 1E]

[0134] [Table 1F]

[0135] [Table 1G]

[0136] [Table 1H]

[0137] [Table 1I]

[0138] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of Formulas I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0139] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant, hi some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0140] It will also be recognized that the pharmaceutical compositions of the present disclosure can be used in combination therapy; i.e., the pharmaceutical compositions disclosed herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of Formulas I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered as a separate composition simultaneously with, before, or after a composition comprising an additional active pharmaceutical agent.

[0141] As discussed above, the pharmaceutical compositions disclosed herein include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. As used herein, pharmaceutically acceptable carriers can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants that are appropriate for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphate, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxylates, cellulose derivative ... sodium dimethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, perfumes, preservatives, and antioxidants.

[0142] III. Methods of Treatment and Use In another aspect of the disclosure, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formula I and I', compounds 1 to 106, tautomers, deuterated derivatives of the compounds or tautomers thereof, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is for use in treating a disease, disorder, or condition mediated by degradation of HPK1. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formula I and I', compounds 1 to 106, tautomers, deuterated derivatives of the compounds or tautomers thereof, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease, disorder, or condition mediated by degradation of HPK1. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by the degradation of HPK1 in a subject comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formulas I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof.

[0143] In some embodiments, the disease, disorder, or condition is selected from an HPK1-associated disease. In some embodiments, the disease, disorder, or condition is selected from cancer, a dysregulated immune response, or a disease involving aberrant HPK1 expression, activity, and / or signaling. In some embodiments, the cancer is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, kidney cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, parathyroid cancer, lymphoma, sarcoma, and leukemia.

[0144] In some embodiments, the brain cancer is selected from brainstem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma multiforme, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor. In some embodiments, the liver cancer is selected from hepatocellular carcinoma (with or without fibrolamellar variant), biliary adenocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma. In some embodiments, the respiratory cancer and / or lung cancer is selected from small cell lung cancer, non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma. In some embodiments, the gastrointestinal cancer is selected from anal cancer, colon cancer, rectal cancer, gallbladder cancer, gastric cancer, esophageal cancer, stomach cancer, pancreatic cancer, salivary gland cancer, small intestine cancer, and colorectal cancer. In some embodiments, the kidney cancer is selected from renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini ductal carcinoma, clear cell sarcoma of the kidney, mesodermal nephroma, and Wilms' tumor. In some embodiments, the skin cancer is selected from malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer. In some embodiments, the head and neck cancer is selected from squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell. In some embodiments, the reproductive cancer is selected from prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma. In some embodiments, the ovarian cancer is selected from serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenic tumors. In some embodiments, the cervical cancer is selected from squamous cell carcinomas, adenocarcinomas, adenosquamous carcinomas, small cell carcinomas, neuroendocrine tumors, hyaloid cell carcinomas, and choriocarcinomas. In some embodiments, the bone cancer is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumors. In some embodiments, the breast cancer is selected from triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.In some embodiments, the sarcoma is selected from soft tissue sarcoma, chondrosarcoma, Ewing's sarcoma, angiosarcoma, fibrosarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, teratoma, osteosarcoma, malignant fibrous histiocytoma, liposarcoma, lymphosarcoma, and rhabdomyosarcoma. In some embodiments, the eye cancer is selected from intraocular melanoma and retinoblastoma. In some embodiments, the hematological cancer is selected from lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including NHL, relapsed or refractory NHL), Hodgkin's lymphoma, multiple myeloma, and combinations of the foregoing cancers. In some embodiments, the nervous system cancer is selected from skull cancer, meningeal cancer, brain cancer, glioblastoma, spinal cancer, neuroblastoma, and Lhermitte-Duclos disease.

[0145] In another aspect of the disclosure, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formula I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, is for use in decreasing HPK1 activity. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formula I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or a pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for decreasing HPK1 activity. In yet another aspect, disclosed herein is a method of decreasing HPK1 activity comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formulas I and I', compounds 1 to 106, tautomers, deuterated derivatives of the compounds or tautomers thereof, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of decreasing HPK1 activity comprising contacting said HPK1 with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of Formulas I and I', compounds 1 to 106, tautomers, deuterated derivatives of the compounds or tautomers thereof, or a pharmaceutical composition thereof.

[0146] The compounds of Formulas I and I', compounds 1 to 106, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered once daily, twice daily, or three times daily, for example, for the treatment of diseases, disorders, or conditions mediated by the degradation of HPK1.

[0147] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I and I', compounds 1 to 106, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, is administered once daily, twice daily, or three times daily.

[0148] Compounds of Formulas I and I', Compounds 1 to 106, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, intravaginally, transdermally, by patch, pump administration, or via an implanted reservoir, where the pharmaceutical composition is appropriately formulated. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are as described in International Patent Application Nos. WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0149] The useful dosage or therapeutically effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models.Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0150] Those skilled in the art will recognize that when a compound amount is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the compounds of Formulas I and I' and pharmaceutically acceptable salts thereof" includes 1000 mg of the compounds of Formulas I and I' and a concentration of the pharmaceutically acceptable salts of the compounds of Formulas I and I' equivalent to 1000 mg of the compounds of Formulas I and I'.

[0151] Non-limiting illustrative embodiments 1. Formula (I): [ka] a compound of the formula: (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) Each R 2 , R 3 and R 4 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 independently selected; (iii) R 5 is hydrogen, R x , -CH2OC(O)R x - and -CH2OC(O)C(R x R y )NH2; (iv) Each W 1 , W 2 , W 3 and W 4 is C(R w )2 and C(O); (v) V is N and CR x Selected from; (vi) When V is N, X is absent, or -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -, -S(O)2-, and -S(O)2R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (vii) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (viii) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (ix) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (x) Ring A is selected from aryl groups and heteroaryl groups; (xi) Ring B is absent or selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups). 2. R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 3. R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 2, wherein is selected from C1 to C6 straight chain, branched, and cyclic alkyl groups. 4. R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 3, wherein is selected from methyl, ethyl, cyclopropyl, and cyclobutyl. 5. R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-4, wherein is a halogen group. 6. R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 5, wherein is chloro. 7. R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-5, wherein is hydrogen. 8. R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-7, wherein is a halogen group. 9. R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 8, wherein is chloro. 10. R 3The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-7, wherein is hydrogen. 11. R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-10, wherein is a halogen group. 12. R 4 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-11, wherein is fluoro. 13. R 5 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-12, wherein is hydrogen. 14. R 5 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-12, wherein is selected from C1-C6 straight chain, branched, and cyclic alkyl groups. 15. R 5 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. 16. R 5 But -CH2OC(O)R x 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-12, wherein: 17. R x 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 16, wherein is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. 18. R 5 But -CH2OC(O)C(R x R y 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-12, wherein R is 1 or 2; 19. R x The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 18, wherein is hydrogen. 20. R yThe compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiments 18 and 19, wherein is selected from hydrogen, methyl, i-propyl, and benzyl. 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-20, wherein X is absent. 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-20, wherein X is —C(O)—. 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein Y is selected from linear, branched, and cyclic alkylene groups. 24. Y is C1~C 10 24. The compound of embodiment 23, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein: 25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein Y is selected from a PEG group. 26. Y, [ka] 26. The compound of embodiment 25, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, selected from: 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-26, wherein Z is absent. 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-26, wherein Z is —C(O)—. 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-26, wherein Z is O. 30. Z is NR z 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-26, wherein: 31. R z The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 32. R z The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein is hydrogen. 33. R z The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein is methyl. 34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-33, wherein Ring B is absent. 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-34, wherein Ring B is selected from optionally substituted heterocycloalkyl. 36. Ring B is [ka] 36. The compound of embodiment 35, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, selected from: 37. W 1 is C(R w 37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-36, wherein: 38. R w The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 37, wherein is hydrogen. 39. W 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-36, wherein is C(O). 40. W 2 is C(R w 40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-39, wherein: 41. R w The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 40, wherein is hydrogen. 42. W 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-39, wherein is C(O). 43. W 3is C(R w 43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-42, wherein: 44. R w The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 43, wherein is hydrogen. 45. W 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-44, wherein is C(O). 46. ​​W 4 is C(R w 46. ​​The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-45, wherein: 47. R w The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 46, wherein is hydrogen. 48. W 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-45, wherein is C(O). 49. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-45, wherein Ring A is a 5- or 6-membered heteroaryl group. 50. Ring A is [ka] and each U 1 and U 2 But, CR u or N; U 3 O, S, and NR u Selected from; R u is independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. 51. U 1 is CR u and U 2 is CR u and U 3The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is O. 52. U 1 is CR u and U 2 is CR u and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is S. 53. U 1 is N and U 2 is CR u and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is O. 54. U 1 is N and U 2 is CR u and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is S. 55. U 1 is CR u and U 2 is N and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is O. 56. U 1 is CR u and U 2 is N and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 50, wherein is S. 57. Ring A is [ka] and each U 1 and U 3 But, CR u or N; U 2 O, S, and NR u Selected from; R uis independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. 58. U 1 is CR u and U 2 is O and U 3 is CR u 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein: 59. U 1 is CR u and U 2 is S and U 3 is CR u 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein: 60. U 1 is N and U 2 is O and U 3 is CR u 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein: 61. U 1 is N and U 2 is S and U 3 is CR u 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein: 62. U 1 is CR z and U 2 is O and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein is N. 63. U 1 is CR z and U 2 is S and U 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 57, wherein is N. 64. Ring A is [ka] 50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 49, wherein: 65. Ring A is [ka] and each U 1 , U 2 , U 3 and U 4 But, CR z or N; R u is independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. 66. U 1 is N and U 2 is CR u and U 3 is CR u and U 4 is CR u 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein: 67. U 1 is CR u and U 2 is N and U 3 is CR u and U 4 is CR u 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein: 68. U 1 is CR u and U 2 is CR u and U 3 is N and U 4 is CR u 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein: 69. U 1 is CR u and U 2 is CR u and U 3 is CR u and U4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein is N. 70. U 1 is N and U 2 is N and U 3 is CR u and U 4 is CR u 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein: 71. U 1 is N and U 2 is CR u and U 3 is N and U 4 is CR u 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein: 72. U 1 is CR u and U 2 is CR u and U 3 is CR u and U 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein is N. 73. U 1 is N and U 2 is CR u and U 3 is CR u and U 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 65, wherein is N. 74. A compound selected from the compounds of Table 1, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing. 75. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 74, and at least one pharmaceutically acceptable carrier. 76. A method for treating or alleviating a disease, disorder, or condition mediated by degradation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 74, or a pharmaceutical composition according to embodiment 75. 77. A method for reducing HPK1 activity in a disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 74, or a pharmaceutical composition according to embodiment 75. 78. The method of embodiment 145, wherein the disease, disorder, or condition is selected from HPK1-related diseases. 79. The method of embodiment 145, wherein the HPK1-associated disease is selected from cancer, a dysregulated immune response, or a disease involving aberrant HPK1 expression, activity, and / or signaling. 80. The method of embodiment 79, wherein the cancer is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, kidney cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, parathyroid cancer, lymphoma, sarcoma, and leukemia. 81. The method of embodiment 80, wherein the brain cancer is selected from brainstem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma multiforme, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor. 82. The method of embodiment 80, wherein the liver cancer is selected from hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), biliary adenocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma. 83. The method of embodiment 80, wherein the respiratory and / or lung cancer is selected from small cell lung cancer, non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma. 84. The method of embodiment 80, wherein the gastrointestinal cancer is selected from anal cancer, colon cancer, rectal cancer, gallbladder cancer, gastric cancer, esophageal cancer, stomach cancer, pancreatic cancer, salivary gland cancer, small intestine cancer, and colorectal cancer. 85. The method of embodiment 80, wherein the kidney cancer is selected from renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini ductal carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor. 86. The method of embodiment 80, wherein the skin cancer is selected from malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer. 87. The method of embodiment 80, wherein the head and neck cancer is selected from squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell. 88. The method of embodiment 80, wherein the reproductive cancer is selected from prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma. 89. The method of embodiment 88, wherein the ovarian cancer is selected from serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenic tumors. 90. The method of embodiment 88, wherein the cervical cancer is selected from squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, hyaloid cell carcinoma, and choriocarcinoma. 91. The method of embodiment 80, wherein the bone cancer is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor. 92. The method of embodiment 80, wherein the breast cancer is selected from triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. 93. The method of embodiment 80, wherein the sarcoma is selected from sarcoma of the soft tissue, chondrosarcoma, Ewing's sarcoma, angiosarcoma, fibrosarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, teratoma, osteosarcoma, malignant fibrous histiocytoma, liposarcoma, lymphosarcoma, and rhabdomyosarcoma. 94. The method of embodiment 80, wherein the eye cancer is selected from intraocular melanoma and retinoblastoma. 95. The method of embodiment 80, wherein the hematological cancer is selected from lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (NHL, including relapsed or refractory NHL), Hodgkin's lymphoma, multiple myeloma, and combinations of said cancers. 96. The method of embodiment 80, wherein the nervous system cancer is selected from skull cancer, meningeal cancer, brain cancer, glioblastoma, spinal cancer, neuroblastoma, and Lhermitte-Duclos disease. 97. The method of embodiment 76, further comprising administering to the subject an existing standard of care or FDA-approved therapy. [Example]

[0152] Compound synthesis In order to provide a more complete understanding of the present disclosure, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any manner.

[0153] All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of this disclosure.

[0154] The compounds of the present disclosure can be made according to standard chemical practices or as disclosed herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing the compounds of Formulas I and I', compounds 1 through 106, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing: Abbreviation ACN = acetonitrile Boc2O = di-tert-butyl dicarbonate DCE = 1,2-dichloroethane DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMA = N,N-dimethylformamide DMAP = dimethylaminopyridine DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = ethyl acetate EtOH = ethanol HOAc = acetic acid KOAc = potassium acetate MeOH = methanol NaOAc = sodium acetate NMP = N-methyl-2-pyrrolidone PE = petroleum ether Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) rt = room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBA = tertiary butyl alcohol TEA = triethylamine TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran TLC = thin layer chromatography TsCl = p-toluenesulfonyl chloride

[0155] General preparation: Synthesis of intermediates: Intermediate A: 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0156] [ka]

[0157] Step 1. Preparation of tert-butyl 4-(3-bromophenyl)-3-oxopiperazine-1-carboxylate: To a solution of 1-bromo-3-iodobenzene (77.33 g, 0.273 mol), tert-butyl 3-oxopiperazine-1-carboxylate (50 g, 0.248 mol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (17.62 g, 0.074 mol) in dioxane (1000 mL) was added Cu(OAc) (9 g, 0.05 mol) and CsCO (162 g, 0.5 mol) under N. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated. The residue was slurried in EA / PE (1:10, 550 mL) for 2 h. The solid was filtered to give the product (70 g, 79% yield) as a yellow solid. Mass (m / z): 376.7 [M+Na] + .

[0158] Step 2. Preparation of tert-butyl 3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate: To a solution of tert-butyl 4-(3-bromophenyl)-3-oxopiperazine-1-carboxylate (107 g, 0.3 mol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (91.5 g, 0.36 mol), and KOAc (88.45 g, 0.9 mol) in dioxane (1500 mL) was added Pd(dppf)Cl (14.9 g, 0.018 mol) under N. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered and concentrated. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with EA (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by Combiflash using EA / PE (1:2) to give the product (92 g, 75.9% yield) as a white solid. Mass (m / z): 402.6 [M+H] + .

[0159] Step 3. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.25 mol) in DCM (550 mL) was added AlCl (101.27 g, 0.76 mol) and acetyl chloride (21.92 g, 0.28 mol) at 0 °C under N. The reaction mixture was stirred at room temperature for 7 h under N. MeOH (300 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The reaction solution was adjusted to pH 6-7 with 3N aqueous NaOH and extracted with EA (500 mL × 3). The combined organic layers were washed with brine (300 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the crude product was purified by Combiflash (PE / EtOAc=2:1) ​​to give the product 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one as a yellow solid (43.24 g, 71%). Mass (m / z): 241.0 [M+H] + .

[0160] Step 4. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of AlCl (27.8 g, 0.20 mol) in DME (200 mL) was added LiAlH (4.39 g, 0.1 mol) and 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (10 g, 0.04 mol) at 0 °C. The reaction mixture was stirred at room temperature under N for 3 h. After the reaction was complete, HO (500 mL) was added to the reaction mixture, which was then extracted with EA (200 mL × 3). The combined organic layer was washed with brine (100 mL × 2) and then dried over anhydrous NaSO. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the compound product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (11.5 g, 74%). Mass (m / z): 225.0 [M+H] + .

[0161] Step 5. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (25 g, 0.11 mol) in EA (100 mL) was added 3-chloroperoxybenzoic acid (26.84 g, 0.155 mol). The reaction mixture was stirred at room temperature for 3 hours. The solution was washed with saturated Na2CO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give the desired product as a white solid (17.4 g, yield: 64.6%). Mass (m / z): 240.7 [M+H] + .

[0162] Step 6. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (17.3 g, 71.8 mmol) in NMP (15 mL) was added phosphoryl trichloride (55.05 g, 35.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (50 mL), extracted with EA (30 mL × 3), washed with saturated brine, filtered, concentrated, and the residue was purified by flash column (PE / EA = 5:1) to give the desired product as a white solid (4.1 g, yield: 22%). Mass (m / z): 258.7 [M+H] + .

[0163] Step 7. (General Step A) Preparation of tert-butyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a mixture of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (4.1 g, 15.8 mmol), tert-butyl 3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (7.01 g, 17.38 mmol) and KCO (6.55 g, 4.74 mmol) in dioxane / HO (10:1, 50 mL) was added Pd(dppf)Cl (1.16 g, 1.58 mmol) under N. The reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was filtered and concentrated. The residue was purified by Combiflash using DCM / PE (1:2) to give the product (5.8 g, yield: 80%) as a yellow solid. Mass (m / z): 455.2 [M+H] + .

[0164] Step 8. (General Step B1) Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: To a mixture of tert-butyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (5.8 g, 12.7 mmol) in DCM (20 mL) was added HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was slurried with DCM (10 mL) for 1 hour. The solid was filtered to give Intermediate A HCl salt (4.1 g, yield: 91%) as a yellow solid. Mass (m / z): 354.7 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 10.25 (s, 2H), 8.17 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 19.0, 10.0 Hz, 4H), 4.00 (t, J = 5.0 Hz, 2H), 3.87 (s, 2H), 3.55 (s, 2H), 2.97 - 2.90 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H).

[0165] Intermediate B: 1-(3-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0166] [ka]

[0167] Step 1. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (27 g, 120 mmol) in TBA / HO (20 / 1) (63 mL) was added NaBr (0.37 g, 3.6 mmol) and oxone (55.35 g, 90 mmol). The reaction mixture was stirred at room temperature under N for 3 h. After the reaction was complete, HO (500 mL) was added to the reaction mixture, which was then extracted with EA (500 mL × 3). The combined organic layer was washed with brine (300 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was suction filtered and the crude product was purified by Combiflash (DCM / MeOH=0-30%) to obtain the product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide as a brown solid (3.5 g, 12%), mass (m / z): 240.9 [M+H] + The product, 5-bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, was obtained as a white solid (8.9 g, 30%). Mass (m / z): 240.9 [M+H] + .

[0168] Step 2. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 5-Bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (3.5 g, 14.5 mmol) was dissolved in POCl3 (30 mL). The reaction mixture was stirred at 90 °C under N2 for 16 h. After the reaction was complete, HO (200 mL) was added to the reaction mixture, which was then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and then dried over anhydrous Na2SO4. After filtration, the solution was suction filtered, and the crude product was purified by Combiflash (PE / EA = 0-50%) to give the by-product as a yellow solid (1.24 g, 33%), mass (m / z): 260.9 [M+H]. + The desired product, 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine, was obtained as a white solid (1.63 g, 43%). Mass (m / z): 260.9 [M+H] + .

[0169] Step 3. Preparation of tert-butyl 4-(3-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(3-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (1.5 g, 84.7% yield). Mass (m / z): 455.2 [M+H] + .

[0170] Step 4. Preparation of 1-(3-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (Intermediate B): Following general step B1, the product was prepared as a yellow solid (1.2 g, 92% yield). Mass (m / z): 355.1 [M+H] + . 1HNMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.62 (s, 1H), 7.80 - 7.72 (m, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 4.08 - 4.04 (m, 4H), 3.77 - 3.68 (m, 2H), 2.88 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).

[0171] Intermediate C: 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0172] [ka]

[0173] Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine: To a solution of compound 4-chloropyridin-2-amine (300 g, 2.34 mol, 1.0 equivalent) in acetonitrile (3000 mL) was added NBS (458 g, 2.57 mol, 1.1 equivalent) in several portions. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then poured into water and filtered. The filter cake was washed with PE and dried to obtain compound 5-bromo-4-chloropyridin-2-amine (407 g, 83.9% yield) as a yellow solid. Mass (m / z): 207 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.67 (s, 1H), 6.45 (s, 2H).

[0174] Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine: To a solution of compound 5-bromo-4-chloropyridin-2-amine (407 g, 1.97 mol, 1.0 equiv.) in AcOH (2000 mL) was added NIS (666 g, 2.96 mol, 1.5 equiv.) in several portions. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured into ice water (5000 mL), adjusted to pH > 7 with KCO, extracted with EA (5000 mL × 3), and washed with NaSO solution (5000 mL) and brine (5000 mL). The organic phase was concentrated in vacuo to give compound 5-bromo-4-chloro-3-iodopyridin-2-amine (500 g, 76.3% yield) as a yellow solid. Mass (m / z): 332.7[M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.62 (s, 2H).

[0175] Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine: To a solution of 5-bromo-4-chloro-3-iodopyridin-2-amine (100 g, 0.300 mol, 1.0 equiv.) and DABCO (101 g, 0.900 mol, 3.0 equiv.) in DMF (2000 mL) was added Pd(PPh3)2Cl2 (21.1 g, 0.03 mol, 0.1 equiv.) under N2. Then (cyclopropylethynyl)trimethylsilane (166 g, 1.20 mol, 4.0 equiv.) was added. The reaction mixture was degassed three times under N2. The reaction mixture was stirred at 120 °C for 10 h. The reaction mixture was filtered, quenched with water (2000 mL), extracted with EA (2000 mL x 3), washed with brine (2000 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using THF / PE (1:15) to give the compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 26.2% yield) as a yellow solid. Mass (m / z): 344.9 [M+H] + .

[0176] Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine: To a mixture of compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 79.0 mmol, 1.0 equiv.) in THF (237 mL), TBAF in THF (1.0 M, 237 mL, 3.0 equiv.) and HO (4.27 g, 237 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (1000 mL), extracted with EA (1000 mL × 3), washed with brine (1000 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel using THF / PE (1:4) to give the product compound 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (15 g, 70.4% yield) as a slightly yellow solid. Mass (m / z): 272.9 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.36 (s, 1H), 7.33 - 7.34 (d, J = 4.0 Hz, 1H), 2.11 - 2.16 (m, 1H), 0.84 - 0.86 (m, 2H), 0.62 - 0.64 (m, 2H).

[0177] Step 5. Preparation of tert-butyl 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: General Step A was followed to give the product tert-butyl 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (250 mg, 21%) as a black oil. MS: m / z=466.9 (M+1, ESI+).

[0178] Step 6. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B1, the product 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (14 mg, 6.4% yield) was obtained as a yellow solid. MS: m / z=367 (M+1, ESI+).

[0179] Intermediate D: 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0180] [ka]

[0181] Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone: To a solution of 3-bromo-4-chloro-7H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mol) in DCM (10 mL) was added AlCl (863.78 mg, 6.48 mmol) and 2,2-difluoroacetyl 2,2-difluoroacetate (751.9 mg, 4.32 mol) at 0 °C. The reaction mixture was stirred at 25 °C under N for 7 h. MeOH (30 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was adjusted to pH 6-7 with 3N aqueous NaOH and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and then dried over NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by Combiflash (eluted with PE / EtOAc=2:1) ​​to give the product as a yellow solid (200 mg, 11.67%). Mass (m / z): 308.7 [M+H]+.

[0182] Step 2. Preparation of 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine: To a solution of AlCl (200 mg, 0.65 mmol) in DME (10 mL) was added LiAlH (64.62 mg, 1.62 mmol) and 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone (430.69 g, 3.23 mmol) at 0 °C. The reaction mixture was stirred at 25 °C under N for 3 h. After the reaction was complete, HO (100 mL) was added, followed by extraction with EA (20 mL × 3). The combined organic layer was washed with brine (10 mL × 2) and then dried over NaSO. The reaction mixture was filtered, and the filtrate was concentrated under vacuum and purified by Combiflash eluting with PE / EA (1:1) to give the compound product 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 13.09%) as a brown solid compound. Mass (m / z): 295.0 [M+H]+.

[0183] Step 3. Preparation of tert-butyl 4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step A, the product tert-butyl 4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was obtained as a brown solid (70 mg, yield: 33%). Mass (m / z): 491.1 [M+H] + .

[0184] Step 4. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B1, the product 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was obtained as a yellow solid (5 mg, 8%). Mass (m / z): 391.0 [M+H]+ .

[0185] Intermediate E: 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one

[0186] [ka]

[0187] Step 1. Preparation of tert-butyl 4-(6-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate: To a solution of 2,6-dibromopyridine (117.5 g, 0.50 mol, 2.0 equiv.), tert-butyl 3-oxopiperazine-1-carboxylate (50.0 g, 0.25 mol, 1.0 equiv.), and CsCO (163 g, 0.50 mol, 2.0 equiv.) in dioxane (1000 mL) was added Pd(dba) (11.5 g, 0.0125 mol, 0.05 equiv.) and Xantphos (14.5 g, 0.025 mol, 0.1 equiv.) under N. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and concentrated. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with EA (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using EA / PE (1:4) to give the product (63 g, 70.9% yield) as a slightly yellow solid. Mass (m / z): 356 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 8.04 - 8.06 (m, 1H), 7.55 - 7.59 (t, J = 8.0 Hz, 1H), 7.27 - 7.30 (t, J = 6.0 Hz, 1H), 4.28 (s, 2H), 4.11 - 4.14 (m, 2H), 3.73 - 3.76 (m, 2H), 1.49 (s, 9H).

[0188] Step 2. Preparation of tert-butyl 3-oxo-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate: To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate (5.0 g, 14.1 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (10.0 g, 39.5 mmol, 2.8 equiv.), and KOAc (4.14 g, 42.3 mmol, 3.0 equiv.) in dioxane (150 mL) was added Pd(dppf)Cl (0.52 g, 0.705 mmol, 0.05 equiv.) under N. The reaction mixture was stirred at 110 °C for 1.5 hours. The reaction mixture was filtered and concentrated. The residue was slurried with PE and filtered. The filtrate was concentrated to give the product (1.8 g, 39.8% yield) as a yellow oil. Mass (m / z): 322.1 [M+H-82] + .

[0189] Step 3. Preparation of tert-butyl 4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, the product tert-butyl 4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (800 mg, 33.7% yield) was obtained as a yellow oil. Mass (m / z): 468.1 [M+H] + .

[0190] Step 4. Preparation of 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one: Following general step B1, the product 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one (4.70 g, 67.2% yield) was obtained as a yellow semi-solid. Mass (m / z): 367 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.88 - 7.92(m, 1H), 7.78 - 7.80 (m, 1H), 7.56 - 7.58 (m, 1H), 7.14 - 7.15 (m, 1H), 4.00 - 4.03 (m, 2H), 3.60 (s, 2H), 3.16 - 3.19 (m, 2H), 2.21 - 2.25 (m, 1H), 0.86 - 0.91 (m, 2H), 0.61 - 0.65 (m, 2H).

[0191] Intermediate F: 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0192] [ka]

[0193] Step 1. Preparation of tert-butyl 4-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a brown solid (15 g, 77% yield). MS: m / z=426.9 (M+1, ESI+).

[0194] Step 2. Preparation of tert-butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a solution of tert-butyl [4-(3-{4-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazine-1-yl]formate (15 g, 35.1 mmol) in acetone (300 mL) was added NIS (8.69 g, 38.6 mmol). The resulting mixture was stirred at 25 °C for 4 hours and then concentrated. The residue was diluted with EA (200 mL), washed with water (100 mL × 2), dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (EA:PE=1:1) to give tert-butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (8 g, 39% yield) as a yellow solid. MS: m / z=552.7. (M+1, ESI+).

[0195] Step 3. Preparation of tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: A mixture of tert-butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (5 g, 9 mmol), 4-DMAP (0.11 g, 0.9 mmol), (Boc)O (2.95 g, 13.5 mmol) and TEA (01.82 g, 18 mmol) in DCM (50 mL) was stirred at room temperature under nitrogen overnight. The mixture was concentrated, and the residue was purified by column chromatography (eluted with EA:PE=1:1) to give tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.5 g, 40%) as a yellow solid. MS: m / z=652.7 (M+1, ESI+).

[0196] Step 4. Preparation of tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: A mixture of tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (208.9 mg, 0.32 mmol), 2-ethynylpyridine (164.8 mg, 1.6 mmol), bis(triphenylphosphine)palladium(II) chloride (22.4 mg, 0.032 mmol), and copper(I) iodide (12.2 mg, 0.064 mmol) in TEA (2 mL) and DMF (2 mL) was stirred at room temperature under nitrogen for 18 hours. Methyl tert-butyl ether was added. A white solid precipitated and was filtered. The residue was purified by column chromatography (MeOH:DCM = 1:10) to give the crude product, which was further purified by preparative HPLC (xbridge-c18 150 × 19 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), gradient: 20-40) to give tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a gray solid (150 mg, 74%). MS: m / z = 627.8 (M+1, ESI+).

[0197] Step 5. Preparation of 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: A solution of tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (165 mg, 0.27 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 18 hours. After concentration, the residue was purified by preparative HPLC (xbridge-c18 150 × 19 mm, 5 μm, mobile phase: ACN-HO (0.1% TA), gradient: 10–40) to give 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one as a gray solid (80 mg, 71%). MS: m / z=427.8 (M+1, ESI+).

[0198] Intermediate G: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate

[0199] [ka]

[0200] Step 1. tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a mixture of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (1 g, 3.1 mmol), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (1.92 g, 6.2 mmol), and KPO (1.32, 6.2 mmol) in dioxane / HO (10:1, 20 mL) was added Pd(dppf)Cl (0.23 g, 0.3 mmol) under N. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was filtered and concentrated. The residue was purified by Combiflash using EA / PE (1:2) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, yield: 70.97%) as a brown solid. Mass (m / z): 425.9 [M+H] + .

[0201] Step 2. tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate: To a solution of tert-butyl {4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}formate (500 mg, 1.1724 mmol) in DMF (50 mL), MeOH (50 mL), and THF (50 mL) was added Pd(OH) / C (65.86 mg, 0.4689 mmol) and AcOH (2 mL). The reaction was then stirred at 40 °C under an atmosphere of H for 18 h. Suction filtration and concentration in vacuo afforded tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (500 mg, 94.55%) as a black oil. Mass (m / z): 499.9 [M+H] + .

[0202] Intermediate H: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate

[0203] [ka]

[0204] Step 1. tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1 g, 3 mmol), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (1.12 g, 3.6 mmol), and KPO (0.76 g, 3.6 mmol) in dioxane / HO (10:1, 20 mL) was added Pd(dppf)Cl (0.12 g, 0.1 mmol) under N. The reaction mixture was stirred at 90° C. for 18 hours. 5% aqueous citric acid (20 mL) was added and extracted with DCM (20 mL×2). The DCM layer was washed with brine (20 mL×2), dried over Na2SO4, concentrated, and the residue was purified by CombiFlash using MeOH:DCM (1:10) to give the product (1 g, 73.33%) as a brown solid: mass (m / z): 462 [M+Na] + .

[0205] Step 2. tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate: To a solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 1.1378 mmol) in MeOH (10 mL) and THF (10 mL) was added Pd / C (48.43 mg, 0.4551 mmol). The reaction was then stirred at 40° C. under an atmosphere of H for 18 hours. After suction filtration, the filtrate was concentrated in vacuo to give the product (400 mg, 75.65%) as a gray solid. Mass (m / z): 464 [M+Na] + .

[0206] Intermediate I: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0207] [ka]

[0208] Step 1. Preparation of tert-butyl {4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}formate: To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.5 g, 5.4 mmol) in NMP (20 mL) was added tert-butyl piperazin-1-ylformate (1.01 g, 5.4 mmol) and DIEA (2.09 g, 0.016 mol). The reaction mixture was stirred at 90 °C under N for 6 h. The reaction solution was extracted with EA (100 mL × 3). The combined organic layer was washed with brine (30 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum and the crude product was purified by Combiflash (PE / EA=1:1) to give the product as a yellow solid (1.8 g, 72%). Mass (m / z): 464.6 [M+Na] + .

[0209] Step 2. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione:

[0210] To a solution of tert-butyl {4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}formate (1.8 g, 4.06 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature (25 ° C) for 2 hours. The solvent was removed under reduced pressure and lyophilized to dryness to give the crude product as a yellow solid (1.2 g, 93%). Mass (m / z): 426.7 [M+H]+.

[0211] Intermediate J: 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0212] [ka]

[0213] Step 1. Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10 g, 0.031 mol), tert-butyl piperazine-1-carboxylate (20.25 g, 0.11 mol), CsCO (30.2 g, 0.093 mol), Ruphos (2.88 g, 0.006 mol), and 4A molecular sieves (410 mg, 0.9 mmol) in dioxane (600 mL) was added RuPhos Pd G (4.8 g, 0.006 mol). The reaction mixture was stirred at 100 °C under N for 48 h. After the reaction was completed, HO (1000 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (500 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate as a yellow solid (6.7 g, 50%). Mass (m / z): 429.2 [M+H] + .

[0214] Step 2. 3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl {4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}formate (700 mg, 1.62 mmol) in DCM (15 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature under N for 18 hours. Methyl tert-butyl ether (10 mL) was added to precipitate a brown solid, and the desired product (500 mg, 88%) was obtained by suction filtration as a brown solid. Mass (m / z): 329 [M+H] + .

[0215] Intermediate K: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)naphthalen-2-yl)piperazine-1-carboxylate

[0216] [ka]

[0217] Step 1. Preparation of 6-bromonaphthalen-1-amine: To a mixture of 6-bromo-1-nitronaphthalene (5.00 g, 0.0198 mol) in EtOH / HO (3:1, 50 mL) was added NH4Cl (7.73 g, 0.145 mol). The reaction mixture was warmed to 60 °C, and then zinc powder (9.45 g, 0.145 mol) was added portionwise. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL), then extracted with EtOAc (150 mL × 3), washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA = 0-40%) to give the product, 6-bromonaphthalen-1-amine, as a brown solid (3.87 g, 83%). Mass (m / z): 221.9[M+H] + .

[0218] Step 2. Preparation of 3-[(6-bromonaphthalen-1-yl)amino]propanoic acid: To a mixture of 6-bromonaphthalen-1-amine (3.87 g, 0.0174 mol) in toluene (40.0 mL) was added propa-enoic acid (7.52 g, 0.104 mol). The reaction was degassed with N2 and stirred at 110 °C for 21 h. The reaction mixture was concentrated under reduced pressure to give the product, 3-[(6-bromonaphthalen-1-yl)amino]propanoic acid, as a brown solid (8.00 g, 93%). Mass (m / z): 293.9 [M+H] + .

[0219] Step 3. Preparation of 1-(6-bromonaphthalen-1-yl)-1,3-diazinan-2,4-dione: To a mixture of 3-[(6-bromonaphthalen-1-yl)amino]propanoic acid (8.7 g, 0.0296 mol) in AcOH (180 mL) was added urea (4.44 g, 0.0740 mol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was slowly poured into water (200 mL) at 0 °C and then filtered. The cake was evaporated to dryness under reduced pressure to give the product, 1-(6-bromonaphthalen-1-yl)-1,3-diazinan-2,4-dione, as a brown solid (7.5 g, 71%). Mass (m / z): 318.8 [M+H] + .

[0220] Step 4. Preparation of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperazin-1-yl}formate: To a mixture of 1-(6-bromonaphthalen-1-yl)-1,3-diazinan-2,4-dione (500 mg, 1.57 mmol) in dioxane (10.0 mL), KPO (998 mg, 4.70 mmol), tert-butyl piperazin-1-yl formate (586 mg, 3.133 mmol), and RuPhos Pd G (262 mg, 0.313 mmol) were added. The reaction mixture was degassed with N three times and stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EA (25 mL) and HO (50 mL), then extracted with EA (50 mL × 3), washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA = 0-30%) to give the product tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperazin-1-yl}formate as a white solid (360 mg, 49%). Mass (m / z): 424.9 [M+H] + .

[0221] Intermediate L: 1-[6-(piperidin-4-yl)naphthalen-1-yl]-1,3-diazinan-2,4-dione

[0222] [ka]

[0223] Step 1. Preparation of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]-3,6-dihydro-2H-pyridin-1-yl}formate: To a mixture of 1-(6-bromonaphthalen-1-yl)-1,3-diazinan-2,4-dione (20.0 g, 0.063 mol) in dioxane / HO (10:1, 400 mL) was added KPO (26.6 g, 0.125 mol), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (23.3 g, 0.075 mol) and Pd(dppf)Cl (2.29 g, 0.003 mol). The reaction mixture was degassed with N2 and stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and then extracted with EA (500 mL × 3). The organic layer was washed with brine (300 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column flash (PE / EA = 0-80%) to give the product tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]-3,6-dihydro-2H-pyridin-1-yl}formate (12.0 g, 43%) as a yellow solid. Mass (m / z): 366.2 [M-55] + .

[0224] Step 2. Preparation of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperidin-1-yl}formate: To a mixture of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]-3,6-dihydro-2H-pyridin-1-yl}formate (8.0 g, 0.019 mol) in MeOH (500 mL) was added Pd(OH) / C (1.6 g, 20% w / w). The reaction was stirred under H at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperidin-1-yl}formate (6.8 g, 76%) as a yellow solid. Mass (m / z): 368.2 [M-55] + .

[0225] Step 3. Preparation of 1-[6-(piperidin-4-yl)naphthalen-1-yl]-1,3-diazinan-2,4-dione: A solution of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperidin-1-yl}formate (6.8 g, 0.016 mol) in DCM / TFA (3:1, 100 mL) was stirred at 25° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE (100 mL) and filtered. The filter cake was evaporated to dryness under reduced pressure to give the product 1-[6-(piperidin-4-yl)naphthalen-1-yl]-1,3-diazinan-2,4-dione (6.0 g, 99%) as an off-white solid. Mass (m / z): 324.2 [M+H] + .

[0226] Intermediate M: tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate

[0227] [ka]

[0228] Step 1. tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate: To a mixture of [4-(4-bromophenyl)piperidin-1-yl]tert-butyl formate (1 g, 2.9 mmol), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (1.47 g, 5.8 mmol), and KOAc (0.85 g, 8.7 mmol) in dioxane (20 mL) was added Pd(dppf)Cl (0.2 g, 0.2 mmol) under N. The reaction mixture was stirred at 90 °C for 18 h. 5% aqueous citric acid (20 mL) was added and extracted with DCM (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over Na2SO4, concentrated, and the residue was purified by CombiFlash with MeOH / DCM (1:10) to give the product (0.8 g, 68.97%) as a brown solid: mass (m / z): 410 [M+Na] + .

[0229] Step 2. tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylate: To a mixture of 2,6-bis(benzyloxy)-3-bromopyridine (500 mg, 1.3505 mmol), tert-butyl {4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-1-yl}formate (786.66 g, 2.0257 mmol), and NaCO (286.27 mg, 2.701 mmol) in dioxane / HO (10:1, 10 mL) was added Pd(dppf)Cl (49.41 mg, 0.0675 mmol) under N. The reaction mixture was stirred at 90 °C for 18 h. 5% aqueous citric acid (20 mL) was added and extracted with DCM (20 mL x 2). The organic layer was washed with brine (20 mL x 2), dried over Na2SO4, concentrated, and the residue was purified by CombiFlash using MeOH / DCM (1:10) to give the target compound (500 mg, yield: 63.75%) as a brown solid. Mass (m / z): 550.9 [M+H]+ .

[0230] Step 3. tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate: To a solution of (4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-1-yl)tert-butyl formate (250 mg, 0.4531 mmol) in MeOH (10 mL) and THF (10 mL) was added Pd / C (19.29 mg, 0.1812 mmol). The reaction was then stirred at 40° C. under an atmosphere of H for 18 hours. After suction filtration and concentration in vacuo, the residue was purified by Combiflash using MeOH / DCM (1:10) to give the desired compound (400 mg, 75.65%) as a gray solid. Mass (m / z): 395 [M+Na] + .

[0231] Intermediate N: tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate

[0232] [ka]

[0233] Step 1. Preparation of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate: To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (3 g, 8.10 mmol) and tert-butyl {4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazin-1-yl}formate (3.15 g, 8.10 mmol) in dioxane (50 mL) and water (5 mL) was added KCO (2.24 g, 16.20 mmol) and Pd(dppf)Cl (593 mg, 0.81 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=3:1) to give the product as a yellow solid (4.6 g, 93%). Mass (m / z): 496.1 [M-55] + .

[0234] Step 2. Preparation of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate: To a solution of (4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1-yl)tert-butyl formate (4.5 g, 8.14 mmol) in EtOH (45 mL) and EA (45 mL) was added 10% Pd / C (1.73 g, 1.62 mmol). The reaction mixture was stirred at 25 °C under H (1 atm) for 16 h. After filtration, the filtrate was concentrated to give the product as a white solid (2.2 g, 64%). Mass (m / z): 374.2 [M+H] + .

[0235] Intermediate O: tert-butyl(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)formate

[0236] [ka]

[0237] Step 1. Preparation of tert-butyl [4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]formate: To a solution of 1,2-difluoro-4-nitrobenzene (5 g, 31.4 mmol) in DMF (50 mL), tert-butyl piperazin-1-ylformate (11.76 g, 62.8 mmol) and K2CO3 (8.68 g, 62.8 mmol) were added. The reaction was stirred at 80 °C under N2 for 12 h. The reaction mixture was quenched with ice water. The precipitated solid was filtered and evaporated to dryness in vacuo to give the product as a yellow solid (10 g, 93%). Mass (m / z): 326.1 [M+H] + .

[0238] Step 2. Preparation of [4-(4-amino-2-fluorophenyl)piperazin-1-yl]tert-butyl formate: To a solution of tert-butyl [4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]formate (5 g, 15.3 mmol) in MeOH was added Pd / C (0.16 g, 1.5 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction was stirred at room temperature under H2 for 24 hours. The solution was filtered through Celite and concentrated to give the product as a yellow solid (3 g, 63%). Mass (m / z): 296.1 [M+H] + .

[0239] Step 3. Preparation of tert-butyl (4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)formate: To a solution of [4-(4-amino-2-fluorophenyl)piperazin-1-yl]tert-butyl formate (500 mg, 1.69 mmol) in DMF (50 mL) was added 3-bromopiperidine-2,6-dione (972 mg, 5.06 mmol) and NaHCO (1417 mg, 16.9 mmol). The reaction mixture was stirred at 85 °C for 12 hours. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA=1:1) to give the product as a white solid (300 mg, 41.8%). Mass (m / z): 407.2 [M+H] + .

[0240] Intermediate P: tert-butyl(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)formate

[0241] [ka]

[0242] Step 1. Preparation of tert-butyl (4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)formate: To a solution of [4-(4-aminophenyl)piperidin-1-yl]tert-butyl formate (500 mg, 1.8 mmol) in DMF (5 mL) was added 3-bromopiperidine-2,6-dione (692 mg, 3.6 mmol) and NaHCO (1514 mg, 18 mmol). The reaction mixture was stirred at 85 °C for 12 hours. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a white solid (300 mg, 39.8%). Mass (m / z): 388.2[M+H]+.

[0243] Intermediate Q: tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[0244] [ka]

[0245] Step 1. Preparation of 6-bromo-1-methylindazol-3-amine: To a solution of 4-bromo-2-fluorobenzonitrile (3.0 g, 15 mmol) in EtOH (50 mL) was added methylhydrazine (2.1 g, 45 mmol). The reaction was stirred in a microwave reactor (120 °C) for 50 minutes. The reaction mixture was quenched with ice water and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 2:1) to give the product as a yellow solid (2.5 g, 70%). Mass (m / z): 227.9 [M+H] + .

[0246] Step 2. Preparation of ethyl 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoate: To a solution of tert-butyl 6-bromo-1-methylindazol-3-amine (2.5 g, 11 mmol) in THF, ethyl prop-2-enoate (11 g, 110 mmol) and DBU (16.9 g, 110 mmol) were added. The reaction mixture was stirred at 80 °C for 5 days. The reaction mixture was quenched with ice water and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a yellow solid (1.2 g, 31%). Mass (m / z): 326.1 [M+H] + .

[0247] Step 3. Preparation of ethyl 3-[(6-bromo-1-methylindazol-3-yl)(cyano)amino]propanoate: To a solution of ethyl 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoate (2, 1.1 g, 3.4 mmol) in EtOH (20 mL) was added carbononitridic acid bromide (540 mg, 5 mmol) and NaOAc (560 mg, 6.8 mmol). The reaction mixture was stirred at 90 °C for 48 h. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product (500 mg, 41%). Mass (m / z): 353.0 [M+H] + .

[0248] Step 4. Preparation of ethyl 3-[(6-bromo-1-methylindazol-3-yl)(carbamoyl)amino]propanoate: To a solution of ethyl 3-[(6-bromo-1-methylindazol-3-yl)(cyano)amino]propanoate (500 mg, 1.4 mmol) in toluene (10 mL) was added (E)-N-ethylidenehydroxylamine (252 mg, 4.2 mmol) and InCl (31 mg, 0.14 mmol). The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a yellow solid (330 mg, 60%). Mass (m / z): 369.0[M+H] + .

[0249] Step 5. Preparation of 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione: To a solution of ethyl 3-[(6-bromo-1-methylindazol-3-yl)(carbamoyl)amino]propanoate (330 mg, 0.9 mmol) in MeCN (5 mL) was added benzyltrimethylammonium hydroxide (224 mg, 1.35 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a white solid (247 mg, 82%). Mass (m / z): 323.0 [M+H] + .

[0250] Step 6. Preparation of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]-3,6-dihydro-2H-pyridin-1-yl}formate: To a solution of 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione (230 mg, 0.7 mmol) in 10:1 dioxane / HO (5 mL) was added tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (441 mg, 1.4 mmol), KPO (297 mg, 1.4 mmol), and Pd(dppf)Cl (52 mg, 0.07 mmol). The solution was stirred at 100°C under N2 for 1.5 hours. The reaction mixture was quenched with ice water and extracted with EA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a white solid (200 mg, 63%). Mass (m / z): 426.2 [M+H] + .

[0251] Step 7. Preparation of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl}formate: To a solution of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]-3,6-dihydro-2H-pyridin-1-yl}formate (100 mg, 0.2 mmol) in MeOH, Pd / C (2.50 mg, 0.02 mmol) was added under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was stirred at room temperature under H2 for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the product as a white solid (70 mg, 66%). Mass (m / z): 428.2 [M+H] + .

[0252] Intermediate R: tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[0253] [ka]

[0254] Step 1. Preparation of [4-(3a,7a-dihydro-1H-indazol-6-yl)-3,6-dihydro-2H-pyridin-1-yl]tert-butyl formate: To a solution of 6-bromo-3a,7a-dihydro-1H-indazole (6 g, 30 mmol) in 10:1 dioxane / HO (60 mL) was added tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (14 g, 45 mmol), Pd(dppf)Cl (2.5 g, 3 mmol), and NaCO (6.4 g, 60 mmol). The reaction was stirred at 105 °C under N for 12 h. The reaction mixture was quenched with ice water and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 10:1) to give the product as a yellow solid (6 g, 63%). Mass (m / z): 300.2 [M+H] + .

[0255] Step 2. Preparation of tert-butyl [4-(3-iodo-1-methylindazol-6-yl)-3,6-dihydro-2H-pyridin-1-yl]formate: To a solution of [4-(3a,7a-dihydro-1H-indazol-6-yl)-3,6-dihydro-2H-pyridin-1-yl]tert-butyl formate (7.5 g, 24.8 mmol) in DMF (50 mL) was added NaOH (3.0 g, 74.4 mmol) and I2 (9.4 g, 37.2 mmol). The reaction was stirred at room temperature for 12 hours. MeI (17.6 g, 124 mmol) was added. The reaction was stirred at 25 °C for an additional hour. The reaction mixture was quenched with ice water and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA=1:1) to give the product as a yellow solid (1 g, 9%). Mass (m / z): 440.1 [M+H] + .

[0256] Step 3. Preparation of (4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}-3,6-dihydro-2H-pyridin-1-yl) tert-butyl formate: To a solution of tert-butyl [4-(3-iodo-1-methylindazol-6-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (1 g, 2.3 mmol) in 10:1 dioxane / HO (10 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.4 g, 3.5 mmol), Pd(dppf)Cl (170 mg, 0.23 mmol), and CsCO (1.5 g, 4.2 mmol). The solution was stirred at 100° C. under N for 12 h. The reaction mixture was quenched with ice water and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA=10:1) to give the product as a yellow solid (1 g, 69%). Mass (m / z): 603.3 [M+H] + .

[0257] Step 4. Preparation of (4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}-3,6-dihydro-2H-pyridin-1-yl) tert-butyl formate: To a solution of (4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}-3,6-dihydro-2H-pyridin-1-yl) tert-butyl formate (1 g, 1.7 mmol) in MeOH, Pd / C (20 mg, 0.17 mmol) was added under N atmosphere. The suspension was degassed and purged with H three times. The reaction mixture was stirred at room temperature under H for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA=1:1) to give the product as a white solid (124 mg, 18%). Mass (m / z): 427.2[M+H] + .

[0258] Intermediate S: tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)piperidine-1-carboxylate

[0259] [ka]

[0260] Step 1. Preparation of tert-butyl (4-{imidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate: To a solution of 7-bromoimidazo[1,2-a]pyridine (5 g, 25.4 mmol) in 10:1 dioxane / HO (50 mL) was added tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]formate (11.82 g, 38 mmol), KPO (10.78 g, 50.8 mmol), and Xphos Pd G1 (2.15 g, 2.5 mmol). The reaction was stirred at 90 °C under N for 12 h. The reaction mixture was quenched with ice water and extracted with EA (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH = 10:1) to give the product as a yellow solid (7.2 g, 90%). Mass (m / z): 300.2 [M+H] + .

[0261] Step 2. Preparation of tert-butyl (4-{3-iodoimidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate: To a solution of tert-butyl (4-{imidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate (7 g, 23.3 mmol) in MeCN was added NIS (5.77 g, 25.6 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered. The filter cake was evaporated to dryness in vacuo to give the product as a yellow solid (9 g, 87%). Mass (m / z): 426.1 [M+H] + .

[0262] Step 3. Preparation of tert-butyl (4-{3-[3-(2-methoxy-5-methylphenyl)-2,4-dioxo-1,3-diazinan-1-yl]imidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate: To a solution of tert-butyl (4-{3-iodoimidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate (4.8 g, 17.5 mmol) in dioxane (50 mL) was added 3-(2-methoxy-5-methylphenyl)-1,3-diazinan-2,4-dione (3.18 g, 13.5 mmol), CuI (0.43 g, 2.3 mmol), and KPO (4.80 g, 22.6 mmol). The reaction mixture was stirred at 95°C under N2 for 24 hours. The reaction mixture was quenched with ice water and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 1:1) to give the product as a yellow solid (2.4 g, 38%). Mass (m / z): 532.3 [M+H] + .

[0263] Step 4. Preparation of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]-3,6-dihydro-2H-pyridin-1-yl}formate: To tert-butyl (4-{3-[3-(2-methoxy-5-methylphenyl)-2,4-dioxo-1,3-diazinan-1-yl]imidazo[1,2-a]pyridin-7-yl}-3,6-dihydro-2H-pyridin-1-yl)formate (2 g, 3.8 mmol) was added 20% TfOH in TFA (10 mL), and the resulting mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove TFA. The red residue was dissolved in water (15 ml) and stirred at room temperature for 5 minutes. The mixture was filtered. The filter cake was washed with water (2 × 5 mL). The aqueous solution was then neutralized to pH 7 with solid NaHCO3. THF (20 mL) was added to the aqueous mixture, followed by (Boc)2O (1.66 g, 7.6 mol) and 4-DMAP (50 mg, 0.3 mmol). The reaction was stirred at room temperature for 1 h and then diluted with EtOAc (15 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (1% Et3N / EtOAc) to give the product as an off-white solid (500 mg, 32%). Mass (m / z): 412.1 [M+H] + .

[0264] Step 5. Preparation of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidin-1-yl}formate: To a solution of tert-butyl {4-[3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]-3,6-dihydro-2H-pyridin-1-yl}formate (160 mg, 0.39 mmol) in MeOH (4 mL) was added Pd / C (4 mg, 0.04 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was stirred at room temperature under H2 for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the product as a white solid (130 mg, 78%). Mass (m / z): 414.3[M+H] + . Synthesis of Examples

[0265] Example 1 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Scheme 20

[0266] Step 1. (General Step C1) Preparation of tert-butyl 8-hydroxyoctanoate: To a solution of 8-hydroxyoctanoic acid (3.5 g, 0.022 mol) in toluene (50 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (8.94 g, 0.044 mol). The reaction mixture was stirred at 80° C. for 16 hours. The solution was concentrated, and the residue was purified by flash column (PE / EA=10:1) to give the desired product (1.9 g, 29% yield) as a yellow oil. Mass (m / z): 239.2 [M+Na] + .

[0267] Step 2. (General Step D) Preparation of tert-butyl 8-(tosyloxy)octanoate: To a solution of tert-butyl 8-hydroxyoctanoate (1.9 g, 8.79 mmol), DMAP (11 mg, 0.088 mmol), and TEA (1.77 g, 17.58 mmol) in DCM (15 mL) was added TsCl (2 g, 10.54 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. Then, filtered, and the filtrate was concentrated. The residue was purified by flash column (PE / EA = 1:1) to give the desired product as a pale yellow oil (1.5 g, yield: 37%). Mass (m / z): 393.0 [M+Na] + .

[0268] Step 3. (General Step E) Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoate: A mixture of tert-butyl 8-(tosyloxy)octanoate (200 mg, 0.54 mmol), 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140 mg, 0.54 mmol), and K2CO3 (112 mg, 0.81 mmol) in DMF (15 mL) was stirred at 50 °C under N2 for 16 h. The reaction was filtered and concentrated. The crude product was purified by preparative HPLC (CAN-H2O 0.1% FA) to give the desired product (100 mg, 9% yield) as a pale yellow solid. Mass (m / z): 481.0 [M+Na] + .

[0269] Step 4. (General Step B2) Preparation of 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoic acid: To a mixture of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoate (100 mg, 0.22 mmol) in DCM (20 mL) was added TFA (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in a lyophilizer overnight to give the desired product (90 mg, 84% yield). Mass (m / z): 403.0 [M+H] + .

[0270] Step 5. (General Step F) Preparation of 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a mixture of compound 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoic acid (45 mg, 0.11 mmol), 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (42 mg, 0.11 mmol), and DIEA (42 mg, 0.33 mmol) in DMF (10 mL) was added T3P (140 mg, 0.22 mmol, 50% in EA) under N2. The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3) and dried over Na2SO4. It was then filtered, and the filtrate was concentrated. The reaction is purified by preparative HPLC (ACN-HO, 0.1% FA) to give the desired product (15 mg, 16% yield) as a pale yellow solid. Mass (m / z): 739.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.98 (s, 1H), 8.12 (s, 1H), 7.47-7.24 (m, 7H), 5.09 (s, 1H), 4.23-4.10 (m, 7H), 3.84 (s, 3H), 2.91(s, 3H), 2.38(s, 2H), 1.98-1.27 (m, 7H).

[0271] Example 2 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione

[0272] [ka]

[0273] Step 1. Preparation of tert-butyl 8-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoate: A mixture of compound tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoate (130 mg, 0.28 mmol), CHI (43 mg, 0.31 mmol), and KCO (78 mg, 0.56 mmol) in DMF (10 mL) was stirred at room temperature under N for 16 hours. Water (30 mL) was added, and the mixture was extracted with EA (20 mL × 3). The combined organic layer was washed with brine (20 mL × 3) and dried over NaSO. It was then filtered, and the filtrate was concentrated to give compound 2 (120 mg, 89% yield) as a pale yellow solid. Mass (m / z): 496.0[M+Na] + .

[0274] Step 2. Preparation of 8-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoic acid: Following general step B2, 8-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)octanoic acid was prepared as a yellow solid (100 mg, 94% yield). Mass (m / z): 417.0 [M+H] + .

[0275] Step 3. Preparation of 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione: Following general step F, 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione was prepared as a pale yellow solid (25 mg, 19% yield). Mass (m / z): 752.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.12-8.11 (m, 1H), 7.52-7.21 (m, 8H), 5.16 (dd, J = 12 H Z , 4Hz, 1H), 4.37-4.08 (m, 6H), 3.83 (s, 2H), 3.77 (d, J = 8H Z , 2H), 2.98 (s, 3H), 2.94-2.88 (m, 2H), 2.74-2.66 (m, 2H), 2.39-2.32 (m, 2H), 1.99-1.96 (m, 1H), 1.72-1.71 (m, 2H), 1.52-1.22(m, 12H).

[0276] Example 3 3-Ethyl-1H-pyrrolo-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0277] [ka]

[0278] Step 1. Preparation of 3-(4-{[2-(tert-butoxy)prop-2-en-1-yl]oxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione: Following general step E, 3-(4-{[2-(tert-butoxy)prop-2-en-1-yl]oxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione was prepared as a white solid (610 mg, 38%). Mass (m / z): 375.0 [M+H] + .

[0279] Step 2. Preparation of {[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oxy}acetic acid: According to general step B2, {[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oxy}acetic acid was prepared as a white solid (410 mg, 72%). Mass (m / z): 319.0 [M+H] + .

[0280] Step 3. Preparation of 3-(4-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione was prepared as a white solid (18 mg, 19%). Mass (m / z): 654.8 [M+H] + .

[0281] Example 4 3-(4-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0282] [ka]

[0283] Step 1. Preparation of tert-butyl 4-(tosyloxy)butanoate: Following general step D, tert-butyl 4-(tosyloxy)butanoate was prepared as a pale yellow oil (600 mg, yield: 61%). Mass (m / z): 336.9 [M+H] + .

[0284] Step 2. Preparation of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)butanoate: Following general step E, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)butanoate was prepared as a pale yellow solid (150 mg, 19% yield). Mass (m / z): 424.8 [M+Na]+ .

[0285] Step 3. Preparation of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)butanoic acid: Following general step B2, 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)butanoic acid was prepared as a yellow solid (110 mg, 85% yield). Mass (m / z): 346.9 [M+H] + .

[0286] Step 4. Preparation of 3-(4-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a pale yellow solid (50 mg, 33% yield). Mass (m / z): 682.7 [M+H] + .

[0287] Example 5 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0288] [ka]

[0289] Step 1. Preparation of tert-butyl 6-hydroxyhexanoate: Following general step C1, tert-butyl 6-hydroxyhexanoate was prepared as a pale yellow oil (1.1 g, 25% yield). Mass (m / z): 211.0 [M+Na] + .

[0290] Step 2. Preparation of tert-butyl 6-(tosyloxy)hexanoate: Following general step D, tert-butyl 6-(tosyloxy)hexanoate was prepared as a pale yellow oil (700 mg, yield: 35%). Mass (m / z): 365.0 [M+Na] + .

[0291] Step 3. Preparation of tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoate: Following general step E, tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoate was prepared as a pale yellow solid (90 mg, 23% yield). Mass (m / z): 453.0 [M+Na] + .

[0292] Step 4. Preparation of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoic acid: Following general step B2, 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoic acid was prepared as a pale yellow oil (70 mg, 64% yield). Mass (m / z): 375.0 [M+H] + .

[0293] Step 5. Preparation of 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a pale yellow solid (12 mg, 24% yield). Mass (m / z): 710.9 [M+H] + .

[0294] Example 6 3-(4-((7-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-7-oxoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0295] [ka]

[0296] Step 1. (General Step C2) Preparation of tert-butyl 7-bromoheptanoate: To a solution of 7-bromoheptanoic acid (2 g, 9.56 mmol) in DCM (20 mL) was added TFAA (4.6 g, 22.00 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. Then, tert-butyl alcohol (2.52 g, 34.43 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. Then, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain the product tert-butyl 7-bromoheptanoate as a yellow oil (2 g, 70%).

[0297] Step 2. Preparation of tert-butyl 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoate: To a solution of tert-butyl 7-bromoheptanoate (509 mg, 1.92 mmol) and 3-(4-hydroxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (500 mg, 1.92 mmol) in DMF (5 mL) was added potassium carbonate (398 mg, 2.88 mmol). The reaction mixture was stirred at 55° C. for 16 h. Water (100 mL) was added, and the reaction mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and dried over Na2SO4. It was then filtered, and the filtrate was concentrated. The crude product was concentrated from the organic phase and purified by preparative HPLC [chromatography column: Gemini-C 18 Purification using a column chromatography (150 × 21.2 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), gradient: 45-70) gave the product tert-butyl 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoate as a brown solid (200 mg, 22%). Mass (m / z): 466.9 [M+Na]. + .

[0298] Step 3. Preparation of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoic acid: Following general step B2, 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoic acid was prepared as a yellow oil (200 mg, 91%). Mass (m / z): 388.9 [M+H] + .

[0299] Step 4. Preparation of 3-(4-((7-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-7-oxoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((7-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-7-oxoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (9 mg, 3.5%). Mass (m / z): 724.7 [M+H] + .

[0300] Example 7 3-(4-((10-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-10-oxodecyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0301] [ka]

[0302] Step 1. Preparation of tert-butyl 10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)decanoate: Following general step E, tert-butyl 10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)decanoate was prepared as a pale yellow solid (400 mg, 54% yield). Mass (m / z): 508.8 [M+Na] + .

[0303] Step 2. Preparation of 10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)decanoic acid: Following general step B2, 10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)decanoic acid was prepared as a pale yellow oil (300 mg, 84% yield). Mass (m / z): 431.0 [M+H] + .

[0304] Step 3. Preparation of 3-(4-((10-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-10-oxodecyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((10-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-10-oxodecyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a pale yellow solid (18 mg, 9% yield). Mass (m / z): 767.0 [M+H] + .

[0305] Example 8 3-Ethyl-1H-pyrrolo-3-(4-((8-(4-(3-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0306] [ka]

[0307] Step 1. Preparation of 3-[4-({8-[4-(3-{6-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-8-oxooctyl}oxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione: Following general step F, 3-[4-({8-[4-(3-{6-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-8-oxooctyl}oxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione was prepared as a pale yellow solid (70 mg, 99% yield). Mass (m / z): 739.0[M+H] + .

[0308] Example 9 4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0309] [ka]

[0310] Step 1. Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octanoate: Following general step E, tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octanoate was prepared as a pale yellow solid (90 mg, 11% yield). Mass (m / z): 494.8 [M+Na] + .

[0311] Step 2. Preparation of 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octanoic acid: Following general step B2, 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octanoic acid was prepared as a pale yellow oil (70 mg, 88% yield). Mass (m / z): 417.0 [M+H] + .

[0312] Step 3. Preparation of 4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a pale yellow solid (20 mg, 15% yield). Mass (m / z): 752.9 [M+H] + .

[0313] Example 10 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0314] [ka]

[0315] Step 1. (General Step G1) Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoate: To a solution of tert-butyl 8-bromooctanoate (600 mg, 2.14 mmol) and 3-(4-hydroxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (557 mg, 2.14 mmol) in NMP (10 mL) was added DIEA (833 mg, 6.44 mmol). The reaction mixture was stirred at 110° C. for 16 hours. Water (100 mL) was added, and the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine (50 mL×2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC [chromatography column: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), gradient: 50-80] to give the product as a white solid (200 mg, 19%). Mass (m / z): 480.0 [M+Na] + .

[0316] Step 2. Preparation of 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid: Following general step B2, 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid was prepared as a yellow oil (200 mg, 91%). Mass (m / z): 401.9 [M+H] + .

[0317] Step 3. Preparation of 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (42 mg, 10%). Mass (m / z): 737.8 [M+H] + .

[0318] Example 11 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0319] [ka]

[0320] Step 1. (General Step H) Preparation of tert-butyl 3-(4-((8-(tert-butoxy)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: To a solution of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoate (200 mg, 0.43 mmol) in THF (5 mL) was added 4-DMAP (14 mg, 0.043 mmol), BocO (105 mg, 0.48 mmol), and TEA (88 mg, 0.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1) to give the product as a yellow oil (100 mg, 41%). Mass (m / z): 580.0 [M+Na] + .

[0321] Step 2. (General Step I) Preparation of tert-butyl 3-(4-((8-(tert-butoxy)-8-oxooctyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: To a solution of tert-butyl 3-(4-((8-(tert-butoxy)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate (100 mg, 0.18 mmol) in DCM (3 mL) was added paraformaldehyde (54 mg, 1.79 mmol) and glacial acetic acid (1 drop). The reaction mixture was stirred at room temperature for 4 hours. NaBH(AcO)3 (76 mg, 0.35 mmol) was then added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1) to give the product as a yellow oil (100 mg, 97%). Mass (m / z): 572.0 [M+H] + .

[0322] Step 3. Preparation of 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)octanoic acid: Following general step B2, 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)octanoic acid was prepared as a yellow oil (70 mg, 96%). Mass (m / z): 416.0 [M+H] + .

[0323] Step 4. Preparation of 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (16.8 mg, 16%). Mass (m / z): 751.7[M+H] + .

[0324] Example 12 3-(4-(2-(2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0325] [ka]

[0326] Step 1. Preparation of tert-butyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate: Following general step D, tert-butyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate was prepared as a colorless oil (1.5 g, 90%). Mass (m / z): 411.1 [M+Na] + .

[0327] Step 2. Preparation of tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoate: Following general step E, tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoate was prepared as a white solid (276 mg, 45%). Mass (m / z): 421.0 [M-55] + .

[0328] Step 3. Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoic acid: Following general step B2, 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoic acid was prepared as a white solid (110 mg, 98%). Mass (m / z): 421.1 [M+H] + .

[0329] Step 4. Preparation of 3-(4-(2-(2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-(2-(2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (20 mg, 44%). Mass (m / z): 757.0[M+H] + .

[0330] Example 13 3-(4-(4-((2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0331] [ka]

[0332] Step 1. Preparation of tert-butyl 3-[2-(prop-2-yn-1-yloxy)ethoxy]propanoate: To a solution of 2-(prop-2-yn-1-yloxy)ethanol (976 mg, 9.75 mmol) and tert-butyl prop-2-enoate (500 mg, 3.90 mmol) in MeCN, Trition B (40 wt % in water) (24 mg, 0.14 mmol) was added and stirred under nitrogen at 25 °C for 72 hours. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography eluting with DCM:MeOH = 20:1 to obtain tert-butyl 3-[2-(prop-2-yn-1-yloxy)ethoxy]propanoate as a pale yellow oil (470 mg, 50% yield). Mass (m / z): 251.1 [M+Na] + .

[0333] Step 2. Preparation of tert-butyl 3-[2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]-1,2,3-triazol-4-yl}methoxy)ethoxy]propanoate: To a stirred solution of tert-butyl 3-[2-(prop-2-yn-1-yloxy)ethoxy]propanoate (470 mg, 2.06 mmol), 3-(4-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (881 mg, 3.09 mmol) in DMA under nitrogen at 100 °C was added a solution of CuSO (153 mg, 0.62 mmol) and L-ascorbic acid sodium salt (122.7 mg, 0.62 mmol) in water. The reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature, extracted with EA (200 mL×2), and washed with water (20 mL×2) and saturated brine. The organic layer was concentrated, and the residue was purified by column chromatography using DCM:MeOH=30:1 to give tert-butyl 3-[2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]-1,2,3-triazol-4-yl}methoxy)ethoxy]propanoate as a brown solid (600 mg, 30% yield). Mass (m / z): 514.2 [M+H]+.

[0334] Step 3. Preparation of 3-[2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]-1,2,3-triazol-4-yl}methoxy)ethoxy]propanoic acid: Following general step B2, 3-[2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]-1,2,3-triazol-4-yl}methoxy)ethoxy]propanoic acid was prepared as a pale yellow solid (400 mg, 40% yield). Mass (m / z): 458.1 [M+H]+.

[0335] Step 4. Preparation of 3-(4-(4-((2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione): Following general step F, 3-(4-(4-((2-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a pale yellow solid (60 mg, 34% yield). Mass (m / z): 793.9 [M+H] + .

[0336] Example 14 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0337] [ka]

[0338] Step 1. Preparation of tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoate: Following general step G1, tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoate was prepared as a yellow solid (854 mg, 51%). Mass (m / z): 451.9 [M+Na] + .

[0339] Step 2. Preparation of tert-butyl 3-(4-((6-(tert-butoxy)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step H, tert-butyl 3-(4-((6-(tert-butoxy)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was prepared as a yellow solid (550 mg, 53%). Mass (m / z): 552.8 [M+Na] + .

[0340] Step 3. Preparation of tert-butyl 3-(4-((6-(tert-butoxy)-6-oxohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step I, tert-butyl 3-(4-((6-(tert-butoxy)-6-oxohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was prepared as a yellow oil (244 mg, 79%). Mass (m / z): 543.8 [M+H] + .

[0341] Step 4. Preparation of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)hexanoic acid: Following general step B2, 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)hexanoic acid was prepared as a yellow oil (300 mg, 86%). Mass (m / z): 387.8 [M+H] + .

[0342] Step 5. Preparation of 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (20 mg, 15%). Mass (m / z): 723.6 [M+H] + .

[0343] Example 15 3-(4-((4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0344] [ka]

[0345] Step 1. Preparation of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoate: Following general step G1, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoate was prepared as a yellow solid (1.1 g, 47%). Mass (m / z): 401.8 [M+H] + .

[0346] Step 2. Preparation of tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step H, tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was prepared as a yellow oil (654 mg, 47%). Mass (m / z): 523.9 [M+Na] + .

[0347] Step 3. Preparation of tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step I, tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was prepared as a yellow oil (272 mg, 88%). Mass (m / z): 515.8 [M+H] + .

[0348] Step 4. Preparation of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)butanoic acid: Following general step B2, 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)butanoic acid was prepared as a yellow oil (310 mg, 79%). Mass (m / z): 359.9 [M+H] + .

[0349] Step 5. Preparation of 3-(4-((4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, 3-(4-((4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was prepared as a white solid (48 mg, 8%). Mass (m / z): 695.7 [M+H] + .

[0350] Example 16 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0351] [ka]

[0352] Step 1. (General Step J1) Preparation of benzyl 4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxylate: To a mixture of NaH (60% in oil, 920 mg, 38.3 mmol) in DMF (50 mL) was added benzyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 0.021 mol) at 0 °C. The reaction was stirred at 0 °C for 15 minutes, and then tert-butyl 2-bromoacetate (4.57 g, 0.023 mol) was added. The reaction was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl solution (80 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed three times with saturated NaCl solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE / EtOAc (0-10%) to give benzyl 4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxylate as a yellow oil (3.67 g, 30%). Mass (m / z): 294.0 [M-55] + .

[0353] Step 2. (General Step K) Preparation of tert-butyl 2-(piperidin-4-yloxy)acetate: To a mixture of benzyl 4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxylate (3.70 g, 10.6 mmol) in MeOH (40 mL) was added 10% Pd / C (370 mg, 10% w / w). The reaction was degassed with N three times and then stirred under H (0.1 MPa) at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(piperidin-4-yloxy)acetate as a yellow oil (2.10 g, 90%).

[0354] Step 3. (General Step L) Preparation of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)acetate: To a mixture of tert-butyl 2-(piperidin-4-yloxy)acetate (500 mg, 2.32 mmol) in DMSO (6.0 mL), DIEA (360 mg, 2.78 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (769 mg, 2.78 mmol) were added. The reaction was stirred at 115 °C for 1 h. The reaction mixture was diluted with HO (20 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed three times with saturated NaCl solution, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE / EtOAc (0-50%) to give tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)acetate as a white solid (480 mg, 39%). Mass (m / z): 471.9 [M+H] + .

[0355] Step 4. Preparation of ({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)acetic acid: Following general step B2, ({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)acetic acid was prepared as a brown oil (400 mg, 85%), which was used directly in the next step without further purification. Mass (m / z): 415.9 [M+H] + .

[0356] Step 5. Preparation of 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a yellow solid (43 mg, 13%). Mass (m / z): 751.7[M+H] + .

[0357] Example 17 4-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0358] [ka]

[0359] Step 1. Preparation of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl}oxy)acetate: Following general step L, tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl}oxy)acetate was prepared as a yellow oil (700 mg, 48%). Mass (m / z): 471.9 [M+H] + .

[0360] Step 2. Preparation of ({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl}oxy)acetic acid: According to general step B2, ({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl}oxy)acetic acid was prepared as a yellow oil (520 mg, 71%). Mass (m / z): 415.8 [M+H] + .

[0361] Step 3. Preparation of 4-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 4-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a white solid (22.5 mg, 15%). Mass (m / z): 751.7[M+H] + .

[0362] Example 18 4-(3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0363] [ka]

[0364] Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate: Following general step J1, tert-butyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate was prepared as a yellow oil (900 mg, 11%).

[0365] Step 2. Preparation of 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)acetic acid: To a solution of tert-butyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate (100 mg, 0.38 mmol) in a mixture of MeOH and HO (3 mL, 2:1 (v / v)), LiOH . H2O (80.6 mg, 1.92 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was acidified to pH 3 with 1 M HCl solution. The reaction solution was extracted with EA (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2) and dried over Na2SO4. The solvent was removed under reduced pressure and the mixture was frozen to give 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)acetic acid as a yellow oil (40 mg, 36%). Mass (m / z): 230.0 [MH] - .

[0366] Step 3. Preparation of tert-butyl 3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)azetidine-1-carboxylate: Following general step F, tert-butyl 3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)azetidine-1-carboxylate was prepared as a pale yellow solid (25 mg, 20%). Mass (m / z): 567.9 [M+H] + .

[0367] Step 4. Preparation of 4-(2-(azetidin-3-yloxy)acetyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B2, 4-(2-(azetidin-3-yloxy)acetyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow oil (16 mg, 69%). Mass (m / z): 467.8 [M+H] + .

[0368] Step 5. Preparation of 4-(3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step L, 4-(3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a yellow solid (4 mg, 16%). Mass (m / z): 723.6[M+H] + .

[0369] Example 19 5-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0370] [ka]

[0371] Step 1. Preparation of tert-butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate: Following general step L, tert-butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate was prepared as a yellow solid (600 mg, 15%). Mass (m / z): 465.9 [M+Na] + .

[0372] Step 2. Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoic acid: Following general step B2, 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoic acid was prepared as a yellow oil (180 mg, 62%). Mass (m / z): 387.8 [M+H] + .

[0373] Step 3. Preparation of 5-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 5-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a pale yellow solid (23 mg, 6%). Mass (m / z): 723.6 [M+H]+.

[0374] Example 20 4-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0375] [ka]

[0376] Step 1. Preparation of benzyl 4-(3-(tert-butoxy)-3-oxopropyl)piperazine-1-carboxylate: To a solution of [3-(piperazin-1-yl)phenyl]methyl formate (1 g, 4.5 mmol) in EtOH (3.5 mL) under nitrogen, tert-butyl prop-2-enoate (0.75 g, 5.8 mmol) was added. The reaction mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was dried to give benzyl 4-(3-(tert-butoxy)-3-oxopropyl)piperazine-1-carboxylate as a gray solid (1.5 g, 95%). MS (ESI) (m / z) = 348.9 [M+H] + .

[0377] Step 2. Preparation of tert-butyl 3-(piperazin-1-yl)propanoate: Following general step K, tert-butyl 3-(piperazin-1-yl)propanoate was prepared as a colorless oil (0.5 g, 76%). MS (m / z) = 215.0 [M + H] + .

[0378] Step 3. Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoate: Following general step L, tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoate was prepared as a yellow solid (1 g, 27%). MS (m / z) = 471.2 [M+H] + .

[0379] Step 4. Preparation of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoic acid: Following general step B1, 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoic acid was prepared as a yellow solid (0.5 g, 77%). MS (m / z) = 415.1 [M+H] + .

[0380] Step 5. Preparation of 4-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 4-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a yellow solid (45 mg, 12%). MS: (m / z)=751.2[M+H] + .

[0381] Example 21 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0382] [ka]

[0383] Step 1. Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoate: Following general step L, tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoate was prepared as a yellow solid (0.5 g, 27%). MS: m / z=471.2 (M+1, ESI+).

[0384] Step 2. Preparation of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoic acid: Following general step B1, 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoic acid was prepared as a yellow solid (200 mg, 43%). MS: m / z=414.9 (M+1, ESI+).

[0385] Step 3. Preparation of 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step F, 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared as a yellow solid (27 mg, 14%). MS: m / z=750.8 (M+1, ESI+).

[0386] Example 22 3-(4-((4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0387] [ka]

[0388] Step 1. Preparation of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoate: Following general step G1, the product tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoate was obtained as a yellow solid (1.1 g, 47%). Mass (m / z): 401.8 [M+H] + .

[0389] Step 2. Preparation of tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step H, the product tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was obtained as a yellow oil (654 mg, 47%). Mass (m / z): 523.9 [M+Na] + .

[0390] Step 3. Preparation of tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate: Following general step I, the product tert-butyl 3-(4-((4-(tert-butoxy)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate was obtained as a yellow oil (272 mg, 88%). Mass (m / z): 515.8 [M+H] + .

[0391] Step 4. Preparation of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)butanoic acid: Following general step B2, the product 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)butanoic acid was obtained as a yellow oil (310 mg, 79%). Mass (m / z): 359.9 [M+H] + .

[0392] Step 5. Preparation of 3-(4-((4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Followed general step F to obtain the product as a white solid (48 mg, 8%). Mass (m / z): 696.7 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.58 - 7.53 (m, 1H), 7.48 - 7.44 (m, 2H), 7.41 (dd, J = 14.0, 5.8 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.21 - 5.13 (m, 1H), 4.60 (dd, J = 21.8, 11.2 Hz, 2H), 4.34 - 4.23 (m, 2H), 4.12 (q, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 2.97 (s, 3H), 2.93 - 2.86 (m, 1H), 2.82 (s, 1H), 2.59 (d, J = 13.0 Hz, 1H), 2.49 (t, J = 6.8 Hz, 2H), 2.21 (dd, J = 9.8, 5.2 Hz, 1H), 2.04 (d, J = 8.8 Hz, 2H), 1.95 (dd, J = 13.8, 6.8 Hz, 2H), 1.36 (d, J = 7.4 Hz, 3H).

[0393] Example 23 3-Ethyl-1H-pyrrolo5-((6-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0394] [ka]

[0395] Step 1. Preparation of tert-butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate: To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.97 g, 7.1 mmol) and tert-butyl 6-aminohexanoate (1.46 g, 7.8 mmol) in NMP (20 mL) was added DIEA (2.75 mg, 0.02 mol). The reaction mixture was placed in a microwave synthesizer at 130 °C for 50 min. Water (100 mL) was added, and the mixture was extracted with EA (150 mL × 3). The combined organic layers were washed with brine (50 mL × 2) and dried over Na2SO4. The mixture was then filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (PE / EA=3:1) to give the product as a yellow solid (600 mg, 15%). Mass (m / z): 465.9 [M+Na]+.

[0396] Step 2. Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoic acid: Following general step B2, the product was obtained as a yellow oil (180 mg, 62%). Mass (m / z): 387.8 [M+H] + .

[0397] Step 3. Preparation of 5-({6-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-6-oxohexyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: Following general step F, the product was obtained as a pale yellow solid (23 mg, 6%). Mass (m / z): 723.6 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 11.80 (d, J = 1.8 Hz, 1H), 11.06 (s, 1H), 8.12 (s, 1H), 7.60 - 7.45 (m, 3H), 7.40 (t, J = 8.6 Hz, 3H), 7.24 - 7.01 (m, 1H), 6.94 (s, 1H), 6.84 (dd, J = 8.4, 1.6 Hz, 1H), 5.02 (dd, J = 12.9, 5.3 Hz, 1H), 4.29 (s, 1H), 4.19 (s, 1H), 3.85 (s, 2H), 3.83 - 3.74 (m, 2H), 3.53 (d, J = 10.7 Hz, 4H), 3.16 (dd, J = 7.3, 5.9 Hz, 2H), 2.92 (q, J = 7.4 Hz, 2H), 2.40 (dd, J = 15.4, 7.6 Hz, 2H), 1.58 (dt, J = 16.0, 8.1 Hz, 4H), 1.46 - 1.36 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H).

[0398] Example 24 3-Ethyl-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanoyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0399] [ka]

[0400] Step 1. Preparation of tert-butyl (4-{3-[4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)formate: A mixture of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (300 mg, 0.85 mmol), tert-butyl prop-2-enoate (140.88 mg, 1.1 mmol), and DIEA (218.54 mg, 1.69 mmol) in EtOH (3.5 mL) was stirred at 100° C. under N for 36 hours. The reaction was filtered and concentrated. The residue was purified by Combiflash using DCM / MeOH (20:1) to give the product (260 mg, yield: 39%) as a brown solid. Mass (m / z): 482.8 [M+H] + .

[0401] Step 2. Preparation of 3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanoic acid: Following general step B2, the crude product was obtained as a yellowish solid (200 mg, 72%). Mass (m / z): 426.7 [M+H]+.

[0402] Step 3. Preparation of 5-(4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanoyl}piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: Following general step F, the product was obtained as a pale yellow solid compound (50 mg, 14%). Mass (m / z): 750.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 11.09 (s, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.42 - 7.34 (m, 4H), 7.26 (d, J = 8.6 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 3.75 - 3.70 (m, 2H), 3.67 (s, 2H), 3.63 (s, 2H), 3.50 (d, J = 28.6 Hz, 6H), 3.25 (s, 2H), 2.96 - 2.83 (m, 5H), 2.73 - 2.61 (m, 5H), 1.27 (t, J = 7.4 Hz, 3H).

[0403] Example 25 3-Ethyl-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0404] [ka]

[0405] Step 1. (General Step G2) Preparation of tert-butyl 4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazine-1-carboxylate: To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (300 mg, 0.845 mmol) and TEA (256 mg, 2.536 mmol) in EtOH (10 mL) was added tert-butyl 4-(3-(tosyloxy)propyl)piperazine-1-carboxylate (371 mg, 0.93 mmol). The reaction mixture was stirred at 80° C. under N for 16 h. The mixture was concentrated, and the residue was purified by flash column (DCM / MeOH=10:1) to give the product as a yellow solid (280 mg, 56%). Mass (m / z): 580.9 [M+H] + .

[0406] Step 2. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(3-(piperazin-1-yl)propyl)piperazin-2-one: Following general step B2, the product was obtained as a brown solid (300 mg, purity: 70%). Mass (m / z): 481.1 [M+H] + .

[0407] Step 3. Preparation of 5-(4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step L was followed to give the product as a yellow solid (150 mg, 74%). Mass (m / z): 755.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.80 (d, J = 2.2 Hz, 1H), 11.12 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.39 (dd, J = 12.2, 9.2 Hz, 3H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.25 (s, 4H), 3.19 (s, 2H), 2.92 (dd, J = 14.6, 7.2 Hz, 3H), 2.82 - 2.78 (m, 2H), 2.61-2.50 (m, 6H), 2.49 - 2.35 (m, 4H), 2.06 - 2.00 (m, 1H), 1.74 - 1.63 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H).

[0408] Example 26 3-Ethyl-1H-pyrrolo5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0409] [ka]

[0410] Step 1. Preparation of benzyl 4-(2,2-diethoxyethoxy)piperidine-1-carboxylate: From the compound benzyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.12 mmol), the desired product (147 mg, 19%) was obtained as a pale yellow oil according to the general step J1. Mass (m / z): 325.5 [M+H] + .

[0411] Step 2. Preparation of 4-(2,2-diethoxyethoxy)piperidine: From benzyl 4-(2,2-diethoxyethoxy)piperidine-1-carboxylate (147 mg, 0.41 mmol), following general step K, the product (118 mg, 98%) was obtained as a yellow oil. Mass (m / z): 218.3 [M+H] + .

[0412] Step 3. Preparation of 5-(4-(2,2-diethoxyethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: From 4-(2,2-diethoxyethoxy)piperidine (118 mg, 0.543 mmol), following general step L, the product (125 mg, 45%) was obtained as a yellow oil. Mass (m / z): 492.2 [M+H] + .

[0413] Step 4. Preparation of 2-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)acetaldehyde: A solution of 5-(4-(2,2-diethoxyethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (125 mg, 0.254 mmol) in 1N HCl / THF (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated in vacuo, and water (10 mL) was added. The mixture was adjusted to pH 7 with 1N aqueous NaOH and extracted with EA (10 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography (PE / EA=4:1) to give the product (61 mg, 57%) as a yellow oil. Mass (m / z): 418.3 [M+H] + .

[0414] Step 5. (General Step M1) Preparation of 5-(4-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethoxy}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: To a solution of 2-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)acetaldehyde (61 mg, 0.146 mmol) in MeOH / HOAc (10:1, 5.5 mL) was added Intermediate A (52 mg, 0.146 mmol) and sodium cyanoborohydride (18 mg, 0.292 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (10 mL), and dried over anhydrous sodium sulfate. It was then filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN—HO (0.1% FA), 30–45] to give the product (40 mg, 36%) as a yellow solid. Mass (m / z): 757.3 [M+H] + . 1 H NMR (400Hz, CD3OD): δ 8.11 (s, 1H), 7.59-7.33 (m, 6H), 7.26 (s, 1H), 5.07 (s, 1H), 4.61(s, 1H), 3.79 (dt, J =24.8 Hz, 4H), 3.61 (s, 1H), 3.53 (s, 2H), 3.47 (s, 2H), 3.04 (m, 6H), 2.78 (m, 5H), 2.08 (s, 3H), 1.78 (m, 2H), 1.32 (m, 4H).

[0415] Example 27 3-Ethyl-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0416] [ka]

[0417] Step 1. Preparation of tert-butyl [4-(3-{[(4-methylbenzene)sulfonyl]oxy}propyl)piperazin-1-yl]formate: To a mixture of tert-butyl [4-(3-hydroxypropyl)piperazin-1-yl]formate (2.0 g, 8.20 mmol) and TEA (2.82 g, 27.8 mmol) in DCM (40 mL) was added 4-methylbenzenesulfonyl chloride (2.66 g, 13.9 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the desired product, tert-butyl [4-(3-{[(4-methylbenzene)sulfonyl]oxy}propyl)piperazin-1-yl]formate, as a yellow oil (1.97 g, 47%). Mass (m / z): 398.9 [M+H] + .

[0418] Step 2. Preparation of tert-butyl (4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)formate: Following general step G2, the product tert-butyl (4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)formate was obtained as a pale yellow solid (440 mg, 75%). Mass (m / z): 580.8 [M+H] + .

[0419] Step 3. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-4-[3-(piperazin-1-yl)propyl]piperazin-2-one: Following general step B2, the product 1-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-4-[3-(piperazin-1-yl)propyl]piperazin-2-one was obtained as a brown solid (470 mg, 90%). Mass (m / z): 481.0 [M+H] + .

[0420] Step 4. Preparation of 5-(4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: Following general step L, the product 5-(4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione was obtained as a yellow solid (10 mg, 8%). Mass (m / z): 736.7 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (dd, J = 9.0, 1.6 Hz, 3H), 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.27 (s, 1H), 5.09 (dd, J = 12.6, 5.6 Hz, 1H), 3.84-3.82 (m, 2H), 3.66 (s, 4H), 3.37 (s, 2H), 3.21 (s, 4H), 3.09 - 3.05 (m, 2H), 3.00 (d, J = 4.0 Hz, 1H), 2.96 (t, J = 5.4 Hz, 2H), 2.88 - 2.82 (m, 1H), 2.78 - 2.76 (m, 1H), 2.74 - 2.72 (m, 1H), 2.66 (dd, J = 8.8, 4.4 Hz, 2H), 2.16 - 2.09 (m, 1H), 2.01 - 1.94 (m, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0421] Example 28 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0422] [ka]

[0423] Step 1. Preparation of tert-butyl 4-(2,2-dihydroxyethyl)piperazine-1-carboxylate: To a stirred solution of oxalyl chloride (5.49 g, 43.2 mmol) in DCM (90 mL) was added DMSO (6.74 g, 86.4 mmol) at -78 °C. The reaction mixture was stirred for 10 min, followed by the addition of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5 g, 21.6 mmol, dissolved in DCM (10 mL)). The reaction mixture was stirred at the same temperature for 15 min. TEA (13.09 g, 129.6 mmol) was then added, and stirring was continued for an additional 1 h, allowing the reaction mixture to reach room temperature. Water (100 mL) was added, and the mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and dried over Na2SO4. It was then filtered and the filtrate was concentrated to dryness to give the product as a brown oil (5.8 g, purity: 80%). Mass (m / z): 247.1 [M+H] + .

[0424] Step 2. Preparation of tert-butyl 4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperazine-1-carboxylate: A solution of tert-butyl 4-(2,2-dihydroxyethyl)piperazine-1-carboxylate (200 mg, 0.542 mmol), 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (201 mg, 0.81 mmol), NaOAc (133 mg, 1.63 mmol), and NaBH(OAc) (344 mg, 1.63 mmol) in DCE (10 mL) was stirred at room temperature for 3 h. The mixture was concentrated, and the residue was purified by flash column (DCM / MeOH=20:1) to give the product tert-butyl 4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperazine-1-carboxylate (140 mg, 31%). Mass (m / z): 566.9 [M+H] + .

[0425] Step 3. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(piperazin-1-yl)ethyl)piperazin-2-one: Following general step B2, the product was obtained as a yellow solid (220 mg, purity: 50%). Mass (m / z): 469.9 [M+H] + .

[0426] Step 4. 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: General step L was followed to give the product as a yellow solid (160 mg, 74%). Mass (m / z): 722.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.76 (d, J = 2.0 Hz, 1H), 11.06 (s, 1H), 8.09 (s, 1H), 7.73 - 7.64 (m, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.36 (q, J = 8.4 Hz, 4H), 7.27 (s, 1H), 5.04 (dd, J = 13.0, 5.0 Hz, 1H), 3.72 (s, 2H), 3.50 - 3.37 (m, 4H), 2.93 - 2.80 (m, 6H), 2.66 - 2.52 (m, 4H), 2.50 (s, 3H), 2.44 - 2.35 (m, 2H), 2.04 - 1.89 (m, 2H), 1.24 (t, J = 7.4 Hz, 3H).

[0427] Example 29 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0428] [ka]

[0429] Step 1. Preparation of tert-butyl 2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]acetate: A solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (90 mg, 0.25 mmol), tert-butyl 2-bromoacetate (49 mg, 0.25 mmol), and DIEA (65 mg, 0.50 mmol) in DCM (5 mL) was prepared. The resulting mixture was stirred at 25° C. under N for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=2:1) ​​to give the product (60 mg, 31%) as a yellow solid. Mass (m / z): 469 [M+H] + .

[0430] Step 2. Preparation of 2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)acetic acid: Following general step B2, the product (50 mg, 76%) was obtained as a yellow oil. Mass (m / z): 413 [M+H] + .

[0431] Step 3. Preparation of 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: Followed general step F to obtain the product (13 mg, 28%) as a yellow solid. Mass (m / z): 755 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 9.71(s, 1H), 9.00 (s, 1H), 8.16 (s, 1H), 7.52-7.40 (m, 2H), 7.38-7.12 (m, 4H), 7.00 (s, 1H), 4.96-4.92 (m, 1H), 3.82-3.40 (m, 6H), 3.27 (s, 2H), 3.14 (s,2H), 3.02-2.92 (m, 4H), 2.89-2.80 (m, 4H), 2.70-2.78 (m, 3H), 2.16-2.08 (m, 1H), 1.34-1.25 (m,3H).

[0432] Example 30 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanoyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0433] [ka]

[0434] Step 1. Preparation of ethyl 3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanoate: To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (50 mg, 0.14 mmol) and ethyl prop-2-enoate (140 mg, 0.14 mmol) in THF (5 mL) was added DBU (21 mg, 0.14 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain the product (30 mg, 24%) as a yellow solid. Mass (m / z): 455 [M+H]+.

[0435] Step 2. Preparation of 3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanoic acid: To a solution of ethyl 3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanoate (30 mg, 0.065 mmol) in MeOH (3 mL) and HO (1 mL) was added NaOH (26 mg, 0.65 mmol). The resulting mixture was stirred at 25 °C for 1 h. MeOH was removed, and water (10 mL) was added. The mixture was adjusted to pH 7 with aqueous HCl (1 N) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL x 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo to give the product (25 mg, 85%) as a yellow solid. Mass (m / z): 426 [M+H] + .

[0436] Step 3. Preparation of 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanoyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: Followed general step F to obtain the product (12 mg, 21%) as a yellow solid. Mass (m / z): 769 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 9.73 (s, 1H), 9.08 (s, 1H), 8.16 (s, 1H), 7.52-7.49 (m, 2H), 7.47-7.35 (m, 4H), 7.12 (s, 1H), 4.97-4.93 (m, 1H), 3.83-3.76 (m, 4H), 3.69 (s, 2H) ,3.41 (s, 2H), 3.27-3.27 (m, 4H), 3.02-2.75 (m, 7H), 2.71-2.67 (m, 2H), 2.65-2.62 (t, J = 4.8 Hz, 2H), 2.18 (s, 1H), 1.34-1.25 (m, 3H).

[0437] Example 31 3-Ethyl-1H-pyrrolo5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0438] [ka]

[0439] Step 1. Preparation of 5-(4-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: General step F was followed to provide the desired product, 5-(4-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (18 mg, 4.24%) as a yellow solid. Mass (m / z): 763.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 7.64 (dd, J = 19.6, 8.4 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.45 - 7.40 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.05 - 6.97 (m, 2H), 4.98 - 4.94 (m, 1H), 4.44 (d, J = 15.2 Hz, 2H), 4.31 - 4.24 (m, 3H), 4.02 - 3.99 (m, 2H), 3.89 - 3.85 (m, 2H), 3.74 (s, 2H), 3.29 - 3.18 (m, 2H), 2.93 - 2.74(m, 4H), 2.24 - 2.20 (m, 1H), 2.01 (dd, J = 10.6, 7.8 Hz, 3H), 1.63 - 1.60 (m, 2H), 0.92 - 0.88 (m, 2H), 0.64 (d, J = 5.0 Hz, 2H).

[0440] Example 32 3-Ethyl-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0441] [ka]

[0442] Step 1. Preparation of tert-butyl 3-[(1-{3-[(formyloxy)methyl]phenyl}piperidin-4-yl)oxy]propanoate: To a solution of [3-(4-hydroxypiperidin-1-yl)phenyl]methyl formate (2 g, 8.5 mmol) and tert-butyl prop-2-enoate (1.63 g, 0.012 mol) in MeCN (20 mL) was added benzyltrimethylammonium hydroxide (0.13 g, 0.31 mmol). The reaction mixture was stirred at 25 °C for 16 hours. Water (100 mL) was added, and the mixture was extracted with EA (300 mL × 2). The combined organic layers were washed with brine (30 mL × 2) and dried over Na SO . Then, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (PE / EA = 1:1) to give the product as a yellow solid (1.8 g, 49.4%). Mass (m / z): 385.9[M+Na] + .

[0443] Step 2. Preparation of tert-butyl 3-(piperidin-4-yloxy)propanoate: Following general step K, the product was obtained as a pale yellow containing oily compound (600 mg, 52%). Mass (m / z): 230.8 [M+H] + .

[0444] Step 3. Preparation of tert-butyl 3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)propanoate: Following general step L, the product was obtained as a yellow solid (450 mg, 39%). Mass (m / z): 485.8 [M+H] + .

[0445] Step 4. Preparation of 3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)propanoic acid: Following general step B2, the product was obtained as a yellow solid (380 mg, 83%). Mass (m / z): 430.1 [M+H] + .

[0446] Step 5. Preparation of 5-(4-{3-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-3-oxopropoxy}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: Followed general step F to obtain the product as a yellow solid (36 mg, 18%). Mass (m / z): 766.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.08 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.61 (dd, J = 12.7, 8.5 Hz, 1H), 7.49 (dd, J = 15.0, 7.4 Hz, 2H), 7.39 (s, 3H), 7.30 (d, J = 6.4 Hz, 1H), 7.24 - 7.13 (m, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.33 (d, J = 12.1 Hz, 1H), 4.20 (s, 1H), 3.85 (dd, J = 15.2, 5.0 Hz, 4H), 3.73 (dd, J = 13.2, 7.0 Hz, 4H), 3.60 (s, 1H), 3.27 (d, J = 9.4 Hz, 4H), 2.95 - 2.86 (m, 2H), 2.72 - 2.55 (m, 4H), 1.88 (s, 2H), 1.49 (d, J = 8.9 Hz, 2H), 1.26 (dd, J = 14.2, 6.8 Hz, 3H).

[0447] Example 33 3-Ethyl-1H-pyrrolo5-(4-(2-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0448] [ka]

[0449] Step 1. Preparation of 3-(2,2-diethoxyethoxy)propane-1,2-diol: To a solution of propane-1,2,3-triol (1.7 g, 18 mmol) in DMF (20 mL) was added NaH (60% in oil, 1.44 g, 36 mmol) at 0 °C. After 10 min, a solution of 2-bromo-1,1-diethoxyethane (1.65 g, 18 mmol) was added. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was complete, HO (50 mL) was added to the reaction mixture, which was then extracted with EA (30 mL × 5). The combined organic layer was washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo to give the product 3-(2,2-diethoxyethoxy)propane-1,2-diol (2 g, 54%) as a colorless oil. Mass (m / z): 209 [M+H] + .

[0450] Step 2. Preparation of 2-(2,2-diethoxyethoxy)acetaldehyde: To a solution of 3-(2,2-diethoxyethoxy)propane-1,2-diol (1 g, 4.8 mmol) was added NaIO (2 g, 9.6 mmol) in HO (30 mL). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo to give the product 2-(2,2-diethoxyethoxy)acetaldehyde (400 mg, 31%) as a colorless oil. Mass (m / z): 177 [M+H] + .

[0451] Step 3. Preparation of 5-{4-[2-(2,2-diethoxyethoxy)ethyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: From 2-(2,2-diethoxyethoxy)acetaldehyde (400 mg, 2.27 mmol), according to general step M1, the product (268 mg, 31%) was obtained as a yellow solid. Mass (m / z): 521 [M+H] + .

[0452] Step 4. Preparation of 2-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl}ethoxy)acetaldehyde: A solution of 5-{4-[2-(2,2-diethoxyethoxy)ethyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione (268 mg, 0.515 mmol) in 1 N HCl / THF (5 mL) was stirred at 25 °C for 1 h. After the reaction was complete, HO (10 mL) was added to the reaction mixture, which was then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo to give the product (50 mg, 20%) as a colorless oil. Mass (m / z): 447 [M+H] + .

[0453] Step 5. Preparation of 5-[4-(2-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethoxy}ethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step M1 was followed to give the product (13 mg, 28%) as a yellow solid. Mass (m / z): 785 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 11.78 (s, 1H), 11.11 (s, 1H), 7.91 (t, J = 8.4 Hz, 1H), 7.57 (t, J = 9.2 Hz 1H), 7.45-7.35 (m, 5H), 5.12-5.08 (m, 1H), 3.74-3.71 (m, 2H), 3.60-3.58 (m, 3H), 3.33-3.25 (m, 7H), 2.93-2.84 (m, 4H), 2.56-2.47 (m, 12H), 2.07-2.02 (m, 1H), 1.28-1.23 (m, 3H).

[0454] Example 34 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0455] [ka]

[0456] Step 1. Preparation of 5-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Followed general step F to obtain the product (6 mg, 10%) as a yellow solid. Mass (m / z): 737 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 11.79 (s, 1H),11.08 (s, 1H), 8.12 (s, 1H), 7.71-7.50 (m, 1H), 7.48-7.25 (m, 7H), 5.10-5.05 (m, 1H), 3.75-3.33 (m, 13H), 2.91-2.84 (m, 5H), 2.67-2.07 (m, 2H), 2.03-2.00 (m, 1H), 1.29-1.23 (m, 4H).

[0457] Example 35 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0458] [ka]

[0459] Step 1. Preparation of tert-butyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate: To a solution of tert-butyl (4-hydroxypiperidin-1-yl)formate (3000 mg, 14.8316 mmol) in acetonitrile (30 mL), ethyl prop-2-enoate (2970 mg, 29.66 mmol) and benzyltrimethylammonium hydroxide (248 mg, 0.59 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA = 2:1) to give the product as a colorless oil (3000 mg, 46%). Mass (m / z): 246.0 [M-55] + .

[0460] Step 2. Preparation of tert-butyl 4-(3-hydroxypropoxy)piperidine-1-carboxylate: To a solution of ethyl 3-{[1-(tert-butyl-$l^{3}-oxy)piperidin-4-yl]oxy}propanoate (3000 mg, 9.9211 mmol) in THF (20 mL) was added LAH (414 mg, 10.9132 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with 15 wt% NaOH (aq) (0.5 mL) and water (0.5 mL). The resulting mixture was filtered, and the filtrate was concentrated to give the product as a colorless oil (2500 mg, 67%). Mass (m / z): 204.0 [M-55] + .

[0461] Step 3. Preparation of tert-butyl 4-(3-(tosyloxy)propoxy)piperidine-1-carboxylate: To a solution of tert-butyl [4-(3-hydroxypropoxy)piperidin-1-yl]formate (2200 mg, 8.45 mmol) in DCM (20 mL) was added TsCl (1933 mg, 10.14 mmol) and TEA (1710 mg, 16.90 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was washed with water (50 mL) and extracted with DCM (20 mL). The organic phase was collected and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give the product as a colorless oil (2200 mg, 56%). Mass (m / z): 358.1 [M-55] + .

[0462] Step 4. Preparation of tert-butyl 4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidine-1-carboxylate: Following general step G2, the product was obtained as a colorless oil (120 mg, 32%). Mass (m / z): 595.8 [M+H] + .

[0463] Step 5. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(3-(piperidin-4-yloxy)propyl)piperazin-2-one: Following general step B2, the product was obtained as a colorless oil (80 mg, 86%). Mass (m / z): 495.9 [M+H] + .

[0464] Step 6. Preparation of 5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: General step L was followed to give the product as a white solid (33 mg, 26%). Mass (m / z): 751.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.05 (s, 1H), 8.08 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 15.9, 8.2 Hz, 2H), 7.33 (dd, J = 20.8, 11.1 Hz, 4H), 7.21 (d, J = 8.7 Hz, 1H), 5.03 (dd, J = 12.9, 5.3 Hz, 1H), 3.79 - 3.66 (m, 4H), 3.58 - 3.43 (m, 4H), 3.23 - 3.13 (m, 4H), 2.92 - 2.82 (m, 3H), 2.78 - 2.72 (m, 2H), 2.59 - 2.49 (m, 2H), 2.12 - 1.75 (m, 4H), 1.73 - 1.63 (m, 2H), 1.52 - 1.42 (m, 2H), 1.24 (t, J = 7.4 Hz, 3H).

[0465] Example 36 3-(2,2-Difluoroethyl)-1H-pyrrolo5-(4-(2-(4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0466] [ka]

[0467] Step 1. Preparation of 5-{4-[2-(4-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)-2-oxoethoxy]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: Following general step F, the product was obtained as a yellow solid (36 mg, 18%). Mass (m / z): 787.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 12.57 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.42 - 7.36 (m, 3H), 7.06 (t, J = 7.4 Hz, 1H), 6.08 (tt, J = 56.4, 4.3 Hz, 1H), 4.94 (dd, J = 12.2, 5.2 Hz, 1H), 4.44 (d, J = 5.0 Hz, 2H), 4.29 (s, 2H), 4.01 (d, J = 5.2 Hz, 2H), 3.86 (d, J = 5.8 Hz, 2H), 3.73 (s, 3H), 3.59 (td, J = 16.6, 4.2 Hz, 2H), 3.30 - 3.25 (m, 2H), 2.91 - 2.70 (m, 3H), 2.15 - 2.11 (m, 1H), 2.03-2.01 (m, 2H), 1.79 - 1.66 (m, 2H).

[0468] Example 37 3-Ethyl-1H-pyrroloN-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide

[0469] [ka]

[0470] Step 1. Preparation of tert-butyl 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxylate: Following general step L, the product tert-butyl 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxylate (580 mg, 73%) was obtained as a yellow solid. Mass (m / z): 441.9 [M+H] + .

[0471] Step 2. Preparation of 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxylic acid: Following general step B2, the product 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxylic acid (400 mg, 86%) was obtained as a brown solid. Mass (m / z): 386.1 [M+H] + .

[0472] Step 3. Preparation of tert-butyl (2-{[(4-methylbenzene)sulfonyl]oxy}ethyl)aminoformate: To a mixture of tert-butyl (2-hydroxyethyl)aminoformate (1.0 g, 6.20 mmol) in DCM (15 mL) at 0 °C, TEA (1.88 g, 18.6 mmol) and 4-methylbenzenesulfonyl chloride (1.77 g, 9.3 mmol) were added. The reaction mixture was stirred at room temperature under N2 for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column (PE / EA = 0-13%) to give the product tert-butyl (2-{[(4-methylbenzene)sulfonyl]oxy}ethyl)aminoformate (1.1 g, 56%) as a colorless oil. Mass (m / z): 337.9 [M+Na] + .

[0473] Step 4. Preparation of tert-butyl {2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}aminoformate: To a mixture of tert-butyl (2-{[(4-methylbenzene)sulfonyl]oxy}ethyl)aminoformate (1.0 g, 3.1 mmol) in DMF (15 mL) was added CsCO (3.0 g, 9.30 mmol) and 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (0.75 g, 2.1 mmol). The reaction was stirred at 80 °C under N for 16 h. After the reaction was completed, HO (30 mL) was added to the reaction mixture, which was then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and then dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (PE / EA = 0-50%) to give the product tert-butyl {2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}aminoformate (700 mg, 39%) as a yellow solid. Mass (m / z): 487.9 [M+H] + .

[0474] Step 5. Preparation of 4-(2-aminoethyl)-1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one: Following general step B2, the product 4-(2-aminoethyl)-1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (550 mg, 89%) was obtained as a brown solid. Mass (m / z): 398.0 [M+H] + .

[0475] Step 6. Preparation of N-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}-1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxamide: Followed general step F to obtain the product (5.0 mg, 1%) as a yellow solid. Mass (m / z): 764.7 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.98 (t, J = 5.8 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.49 - 7.41 (m, 3H), 7.31 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 7.19 - 7.16 (m, 1H), 4.42 - 4.40 (m, 2H), 4.02 (s, 3H), 3.96 (d, J = 13.0 Hz, 2H), 3.69 (s, 2H), 3.64 (dd, J = 11.2, 5.8 Hz, 1H), 3.01 - 2.68 (m, 7H), 2.34 (t, J = 11.2 Hz, 1H), 2.11 - 2.09 (m, 1H), 1.70 (d, J = 12.2 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.32 (t, J = 7.4 Hz, 5H).

[0476] Example 38 5-(4-((4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0477] [ka]

[0478] Step 1. Preparation of tert-butyl 4-((4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate: From 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (300 mg, 0.85 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (362 mg, 1.69 mmol), following general step M1, the product tert-butyl 4-((4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate was obtained as a yellow oil (277 mg, 59%). Mass (m / z): 522.0 [M+H] + .

[0479] Step 2. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(piperidin-4-ylmethyl)piperazin-2-one: Following general step B2, the product 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(piperidin-4-ylmethyl)piperazin-2-one was obtained as a yellow oil (400 mg, purity: 60%). Mass (m / z): 451.9 [M+H] + .

[0480] Step 3. Preparation of 5-(4-((4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to give the product as a yellow solid (60 mg, 18%). Mass (m / z): 726.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.67 - 7.46 (m, 5H), 7.32 (s, 1H), 5.11 (dd, J = 12.6, 5.4 Hz, 1H), 4.94 (s, 1H), 4.89 - 4.86 (m, 2H), 4.16 (dd, J = 18.8, 13.6 Hz, 4H), 3.94 - 3.67 (m, 4H), 3.08 - 2.97 (m, 3H), 2.91 - 2.83 (m, 1H), 2.76 (dd, J = 22.2, 7.8 Hz, 2H), 2.27 - 2.09 (m, 2H), 2.06 - 1.97 (m, 2H), 1.60 (d, J = 9.0 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H), 1.31 (d, J = 3.4 Hz, 1H).

[0481] Example 39 5-(4-(3-(4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0482] [ka]

[0483] Step 1. Preparation of tert-butyl 4-(3-(4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidine-1-carboxylate: Following general step G2, the product was obtained as a yellow oil (100 mg, 39%). Mass (m / z): 632.2 [M+H] + .

[0484] Step 2. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(3-(piperidin-4-yloxy)propyl)piperazin-2-one: Following general step B2, the product was obtained as a yellow oil (140 mg, 99%). Mass (m / z): 532.2 [M+H] + .

[0485] Step 3. Preparation of 5-(4-(3-(4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to give the product as a yellow solid (41 mg, 20%). Mass (m / z): 805.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.12 (s, 1H), 8.19 (s, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.64 - 7.39 (m, 6H), 6.29 (tt, J = 56.7, 4.5 Hz, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.14 - 4.11 (m, 2H), 4.02 - 3.98 (m, 2H), 3.82 - 3.65 (m, 2H), 3.60 - 3.45 (m, 7H), 3.38 - 3.28 (m, 2H), 3.07 (t, J = 9.9 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.64 - 2.51 (m, 2H), 2.08 - 1.93 (m, 5H), 1.69 - 1.56 (m, 2H).

[0486] Example 40 5-(4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0487] [ka]

[0488] Step 1. Preparation of tert-butyl 4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidine-1-carboxylate: Following general step G2, the product was obtained as a yellow oil (850 mg, 54%). Mass (m / z): 607.8 [M+H] + .

[0489] Step 2. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(3-(piperidin-4-yloxy)propyl)piperazin-2-one: Following general step B2, the product was obtained as a yellow oil (1000 mg, 98%). Mass (m / z): 508.2 [M+H] + .

[0490] Step 3. Preparation of 5-(4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to give the product as a yellow solid (620 mg, 40%). Mass (m / z): 781.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.4 Hz, 1H), 11.12 (s, 1H), 8.12 (s, 1H), 7.69 (d, J = 11.5 Hz, 1H), 7.53 - 7.37 (m, 5H), 7.32 - 7.28 (m, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 - 3.69 (m, 2H), 3.57 - 3.36 (m, 9H), 3.09 - 3.02 (m, 2H), 2.93 - 2.82 (m, 2H), 2.64 - 2.51 (m, 3H), 2.23 - 2.16 (m, 1H), 2.05 - 1.93 (m, 3H), 1.81 - 1.70 (m, 2H), 1.65 - 1.55 (m, 2H), 0.87 - 0.81 (m, 2H), 0.66 - 0.61 (m, 2H).

[0491] Example 41 3-(2,2-Difluoroethyl)-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0492] [ka]

[0493] Step 1. Preparation of tert-butyl {4-[3-(4-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)propyl]piperazin-1-yl}formate: General step G2 was followed to give the product (120 mg, 79.24%) as a yellow oil. Mass (m / z): 617.1 [M+H]+.

[0494] Step 2. Preparation of 1-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-4-[3-(piperazin-1-yl)propyl]piperazin-2-one: Following general step B2, the desired product (100 mg, 88.67%) was obtained as a yellow solid. Mass (m / z): 517.1 [M+H]+.

[0495] Step 3. Preparation of 5-{4-[3-(4-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)propyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: Followed general step L to obtain the desired product (46 mg, 30%) as a yellow solid. Mass (m / z): 791.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (d, J = 2.2 Hz, 1H), 11.13 (s, 1H), 8.18 (s, 1H), 7.83 (d, J = 11.1 Hz, 1H), 7.61 (dd, J = 8.6, 4.9 Hz, 2H), 7.55 (m, 1H), 7.48 (s, 1H), 7.42 (dd, J = 7.7, 1.4 Hz, 2H), 6.43 - 6.15 (m, 0H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 3.88 (s, 2H), 3.55 (s, 10H), 3.24 (m, 4H), 2.86 (m, 2H), 2.62 (m, 2H), 2.38 (m, 2H), 2.04 (m, 4H).

[0496] Example 42 3-Cyclopropyl-1H-pyrrolo 5-(4-((2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)(methyl)amino)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0497] [ka]

[0498] Step 1. Preparation of tert-butyl 4-((2-(benzyloxy)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate: To a mixture of tert-butyl [4-(methylamino)piperidin-1-yl]formate (5.0 g, 0.023 mol) in THF (35 mL), TEA (7.04 g, 0.069 mol) and benzyl 2-bromoacetate (6.38 g, 0.027 mol) were added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column (PE / EA=0-13%) to give the product tert-butyl 4-((2-(benzyloxy)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate as a white solid (3.0 g, 32%). Mass (m / z): 363.0 [M+H] + .

[0499] Step 2. Preparation of benzyl 2-[methyl(piperidin-4-yl)amino]acetate: From tert-butyl 4-((2-(benzyloxy)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate (1.0 g, 2.8 mmol), the product benzyl 2-[methyl(piperidin-4-yl)amino]acetate (1.5 g, 93%) was obtained as a brown solid according to general step B2. Mass (m / z): 263.0 [M+H]+ .

[0500] Step 3. Preparation of benzyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl}(methyl)amino)acetate: General step L was followed to obtain the product benzyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl}(methyl)amino)acetate (1.0 g, 46%) as a yellow solid. Mass (m / z): 536.8 [M+H] + .

[0501] Step 4. Preparation of ({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl}(methyl)amino)acetic acid: Followed general step K to obtain the product (50.0 mg, 99%) as a white solid. Mass (m / z): 477.1 [M+H] + .

[0502] Step 5. Preparation of 5-[4-({2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethyl}(methyl)amino)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: Followed general step F to obtain the product (12 mg, 13%) as a yellow solid. Mass (m / z): 794.7 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.58 (dd, J = 9.2, 3.8 Hz, 2H), 7.51 (dd, J = 16.2, 7.6 Hz, 3H), 7.43 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 5.10 (dd, J = 12.4, 5.4 Hz, 1H), 4.55 (d, J = 16.8 Hz, 1H), 4.43 (s, 1H), 4.34 (s, 1H), 4.29 (d, J = 16.0 Hz, 1H), 3.99 (d, J = 5.5 Hz, 1H), 3.92 (d, J = 4.6 Hz, 2H), 3.85 (d, J = 12.0 Hz, 2H), 3.58 (s, 1H), 3.00 (dd, J = 14.8, 7.6 Hz, 5H), 2.90 - 2.82 (m, 1H), 2.77 - 2.66 (m, 2H), 2.27-2.03 (m, 7H), 0.93-0.89 (m, 2H), 0.67-0.63 (m, 2H).

[0503] Example 43 3-Cyclopropyl-1H-pyrrolo5-(4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0504] [ka]

[0505] Step 1. Preparation of tert-butyl (4-{3-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)formate: Following general step G2, the product (50 mg, 28%) was obtained as a yellow solid. Mass (m / z): 593.3 [M+H] + .

[0506] Step 2. Preparation of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-4-[3-(piperazin-1-yl)propyl]piperazin-2-one: Following general step B2, the product (450 mg, 98%) was obtained as a brown solid. Mass (m / z): 492.9 [M+H] + .

[0507] Step 3. Preparation of 5-(4-{3-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propyl}piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step L was followed to give the product (137 mg, 19%) as a yellow solid. Mass (m / z): 766.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.4 Hz, 1H), 11.12 (s, 1H), 8.13 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 2H), 7.31 (d, J = 1.6 Hz, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.75 - 3.73 (m, 2H), 3.26 (s, 5H), 3.20 (s, 2H), 2.93-2.88 (m, 1H), 2.81-2.79 (m, 2H), 2.59 (s, 4H), 2.54 (s, 3H), 2.45 (d, J = 7.0 Hz, 2H), 2.23-2.17 (m, 1H), 2.07-1.98 (m, 1H), 1.73-1.66 (m, 2H), 0.87 - 0.82 (m, 2H), 0.66 - 0.62 (m, 2H).

[0508] Example 44 3-Ethyl-1H-pyrrolo 5-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)(methyl)amino)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0509] [ka]

[0510] Step 1. Preparation of 5-[4-({2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-fluorophenyl)-3-oxopiperazin-1-yl]-2-oxoethyl}(methyl)amino)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: Followed general step F to obtain the product (40 mg, 18%) as a yellow solid. Mass (m / z): 801.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.13 (s, 1H), 9.57 (s, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 11.2 Hz, 1H), 7.47 (m, 4H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H), 4.28 (t, J = 14.8 Hz, 3H), 3.83 (m, 8H), 2.91 (m, 9H), 2.13 (d, J = 18.0Hz, 2H), 2.03 (m, 1H), 1.90 (d, J = 11.2 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H).

[0511] Example 45 3-Cyclopropyl-1H-pyrrolo5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0512] [ka]

[0513] Step 1. Preparation of tert-butyl (4-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}piperidin-1-yl)formate: To a mixture of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (250 mg, 0.682 mmol) in MeOH (10 mL) and HOAc (0.05 mL) was added tert-butyl [4-(2-oxoethyl)piperidin-1-yl]formate (156 mg, 0.682 mmol) and NaBHCN (128 mg, 2.04 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=0-2.5%) to give the product tert-butyl (4-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}piperidin-1-yl)formate (370 mg, 89%) as a white solid. Mass (m / z): 577.9 [M+H] + .

[0514] Step 2. Preparation of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-4-[2-(piperidin-4-yl)ethyl]piperazin-2-one: Following general step B2, the product (900 mg, 88%) was obtained as a brown oil. Mass (m / z): 477.9 [M+H] + .

[0515] Step 3. Preparation of 5-(4-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step L was followed to give the desired product (188 mg, 15%) as a yellow solid. Mass (m / z): 751.7 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.2 Hz, 1H), 11.12 (s, 1H), 8.13 (d, J = 4.4 Hz, 1H), 7.71 (d, J = 11.4 Hz, 1H), 7.51 - 7.38 (m, 5H), 7.31 (d, J = 1.8 Hz, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.74 (s, 2H), 3.60 (d, J = 12.0 Hz, 2H), 3.20 (s, 2H), 2.86 (dd, J = 28.4, 15.2 Hz, 5H), 2.59 (dd, J = 36.8, 17.8 Hz, 3H), 2.22-2.18 (m, 1H), 2.09 - 2.01 (m, 2H), 1.82 (d, J = 12.2 Hz, 2H), 1.50 (s, 2H), 1.37 - 1.31 (m, 2H), 1.23 (s, 1H), 0.87 - 0.83 (m, 2H), 0.66 - 0.62 (m, 2H).

[0516] Example 46 3-Cyclopropyl-1H-pyrrolo 3-(6-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0517] [ka]

[0518] Step 1. Preparation of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]piperidin-4-yl}oxy)acetate and tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}oxy)acetate: To a mixture of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)acetate (500 mg, 1.06 mmol) in HOAc (10 mL) was added zinc (694 mg, 10.6 mmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a mixture of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]piperidin-4-yl}oxy)acetate and tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}oxy)acetate as a yellow oil (1.0 g, 99%). Mass (m / z): 401.9 [M-55] + .

[0519] Step 2. Preparation of ({1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidin-4-yl}oxy)acetic acid and ({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}oxy)acetic acid: To a mixture of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]piperidin-4-yl}oxy)acetate and tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}oxy)acetate (1.0 g, 2.11 mmol) in HOAc (10 mL) was added TFA (16.6 g, 146 mmol) and EtSiH (5.79 g, 50 mmol). The reaction mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Combiflash [Gemini-C18 150 × 21.2 mm, 5 um; mobile phase: MeCN / HO (0.5% FA); ratio: 10–20] to give ({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}oxy)acetic acid (100 mg, 11%), 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 10.5, 1.6 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.33 (dd, J = 17.2, 6.2 Hz, 1H), 4.21 - 4.17 (m, 1H), 4.07 (s, 2H), 3.68 - 3.55 (m, 3H), 3.03 - 3.09 (m, 2H), 2.95 - 2.85 (m, 1H), 2.58 (dd, J = 14.2, 2.4 Hz, 1H), 2.42 - 2.30 (m, 1H), 1.99 - 1.91 (m, 3H), 1.57 - 1.48 (m, 2H) and ({1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidin-4-yl}oxy)acetic acid (100 mg, 11%) was obtained. Mass (m / z): 401.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.98 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.5, 2.3 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 5.09 (dd, J = 13.3, 4.9 Hz, 1H), 4.26 (dd, J = 52.1, 16.7 Hz, 2H), 4.07 (s, 2H), 3.58 - 3.55 (m, 3H), 3.97 - 2.86 (m, 3H), 2.59 (d, J = 18.0 Hz, 1H), 2.37 (dt, J = 14.0, 9.1 Hz, 1H), 2.00 - 1.91 (m, 3H), 1.59 - 1.53 (m, 2H).

[0520] Step 3. Preparation of 3-[6-(4-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione: Followed general step F to obtain the desired product as a white solid (34 mg, 45%). Mass (m / z): 749.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 13.06 (s, 1H), 8.25 (d, J = 13.0 Hz, 1H), 8.12 (s, 1H), 7.96 - 7.83 (m, 2H), 7.61 - 7.57 (m, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 5.19 (dd, J = 12.8, 4.2 Hz, 1H), 4.53 - 4.41 (m, 4H), 4.33 (s, 2H), 4.04 (s, 1H), 3.95 - 3.85 (m, 4H), 3.77 - 3.72 (m, 2H), 3.39 (s, 2H), 2.96 - 2.81 (m, 2H), 2.43 - 2.37 (m, 3H), 2.24 - 2.19 (m, 2H), 2.13 (d, J = 12.2 Hz, 2H), 1.00 (q, J = 6.0 Hz, 2H), 0.69 (q, J = 5.4 Hz, 2H).

[0521] Example 47 3-Cyclopropyl-1H-pyrrolo 3-(5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0522] [ka]

[0523] Step 1. Preparation of 3-[5-(4-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione: Followed general step F to obtain the product as a white solid (27 mg, 28%). Mass (m / z): 749.7 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.65 (dd, J = 13.6, 8.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.16 - 7.21 (m, 3H), 5.11 (dd, J = 13.2, 5.2 Hz, 1H), 4.45 (s, 1H), 4.39 (dd, J = 10.8, 4.2 Hz, 4H), 4.05 - 3.98 (m, 2H), 3.95 (s, 1H), 3.87 (t, J = 5.2 Hz, 1H), 3.75 (dd, J = 6.6, 3.4 Hz, 3H), 3.24 (d, J = 6.8 Hz, 3H), 2.94 - 2.85 (m, 1H), 2.79 - 2.74 (m, 1H), 2.45 (m, 1H), 2.24 - 2.19 (m, 1H), 2.17 - 2.08 (m, 3H), 1.84 (s, 2H), 0.91 (d, J = 7.8 Hz, 2H), 0.65 (d, J = 5.2 Hz, 2H).

[0524] Example 48 3-Cyclopropyl-1H-pyrrolo5-(4-((1-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-1-oxopropan-2-yl)oxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0525] [ka]

[0526] Step 1. Preparation of benzyl 4-4-{[1-(tert-butoxy)-1-oxopropan-2-yl]oxy}piperidine-1-carboxylate: To a solution of benzyl 4-4-hydroxypiperidine-1-carboxylate (10.2 g, 43.4 mmol) in DMF (100 mL) was added NaH (2.26 g, 56.42 mmol) at 0 °C. The mixture was stirred at 25 °C under nitrogen for 1 hour. Then tert-butyl 2-bromopropanoate (13.61 g, 65.1 mmol) was added. The mixture was stirred at 110 °C under nitrogen for 16 hours, cooled to room temperature, quenched with aqueous NH Cl, diluted with HO (500 mL), extracted with EA (500 mL × 2), and washed with water (50 mL × 2) and saturated brine. The organic layer was concentrated in vacuo, and the residue was purified by Combiflash (PE / EA=4:1) to give the product (5 g, 31.8%) as a yellowish oil. Mass (m / z): 386.2 [M+Na]+.

[0527] Step 2. Preparation of tert-butyl 2-(piperidin-4-yloxy)propanoate: Followed general step K to obtain the desired product (500 mg, 71.43%) as a pale oil. Mass (m / z): 230.2 [M+H]+.

[0528] Step 3. Preparation of tert-butyl 2-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)propanoate: General step L was followed to give the product (1 g, 71%) as a yellow solid. Mass (m / z): 504.2 [M+H]+.

[0529] Step 4. Preparation of 2-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl}oxy)propanoic acid: Following general step B2, the desired product (800 mg, 80%) was obtained as a yellow solid. Mass (m / z): 447.8 [M+H]+.

[0530] Step 5. Preparation of 5-[4-({1-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-1-oxopropan-2-yl}oxy)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: Followed general step F to obtain the desired product as a yellow solid (60 mg, 39.58%). Mass (m / z): 796.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (d, J = 9.9 Hz, 1H), 11.11 (s, 1H), 8.12 (d, J = 4.3 Hz, 1H), 7.64 (dd, J = 36.6, 11.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.42 (dd, J = 18.9, 7.2 Hz, 3H), 7.29 (d, J = 9.8 Hz, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 4.56 (m, 2H), 4.21 (d, J = 5.9 Hz, 1H), 3.80 (s, 2H), 3.61 (s, 1H), 3.47 (s, 2H), 3.04 (t, J = 9.7 Hz, 2H), 2.88 (m, 1H), 2.57 (m, 4H), 2.14 (m, 2H), 2.00 (d, J = 8.6 Hz, 2H), 1.62 (d, J = 9.2 Hz, 2H), 1.31 (d, J = 6.1 Hz, 3H), 0.83 (s, 2H), 0.63 (d, J = 4.5 Hz, 2H).

[0531] Example 49 5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0532] [ka]

[0533] Step 1. Preparation of tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethoxy)piperidine-1-carboxylate: To a solution of {[1-(tert-butyl-$l^{3}-oxy)piperidin-4-yl]oxy}acetic acid (500 mg, 1.9208 mmol) and methoxy(methyl)amine hydrochloride (281 mg, 2.88 mmol) in DCM (10 mL) was added DIEA (993 mg, 7.68 mmol) and T3P (2445 mg, 3.84 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with water (20 mL) and extracted with EA (20 mL). The organic phase was collected and evaporated to give the product as a colorless oil (600 mg, 92%). Mass (m / z): 247.1 [M-55] + .

[0534] Step 2. Preparation of tert-butyl 4-(2-oxopropoxy)piperidine-1-carboxylate: To a solution of tert-butyl (4-{[methoxy(methyl)carbamoyl]methoxy}piperidin-1-yl)formate (600 mg, 1.9778 mmol) in THF (5 mL) was added methylmagnesium bromide (0.8 mL, 2.37 mmol) at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h and at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution. The reaction mixture was washed with water (10 mL) and extracted with EA (10 mL). The organic phase was collected and evaporated to give the product as a colorless oil (300 mg, 52%). Mass (m / z): 202.1 [M-55] + .

[0535] Step 3. Preparation of tert-butyl 4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidine-1-carboxylate: Following general step M1, the product was obtained as a colorless oil (170 mg, 46%). Mass (m / z): 607.9 [M+H] + .

[0536] Step 4. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(1-(piperidin-4-yloxy)propan-2-yl)piperazin-2-one: Following general step B2, the product was obtained as a yellow oil (200 mg, 98%). Mass (m / z): 508.0 [M+H] + .

[0537] Step 5. Preparation of 5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to give the product as a yellow solid (40 mg, 12%). Mass (m / z): 782.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.2 Hz, 1H), 11.08 (s, 1H), 8.09 (s, 1H), 7.69 (d, J = 11.4 Hz, 1H), 7.54 (s, 1H), 7.49 - 7.35 (m, 4H), 7.29 (d, J = 1.7 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.01 - 3.92 (m, 3H), 3.73 - 3.58 (m, 8H), 3.50 - 3.44 (m, 2H), 3.05 (t, J = 9.6 Hz, 2H), 2.91 - 2.78 (m, 1H), 2.61 - 2.50 (m, 1H), 2.22 - 2.09 (m, 1H), 2.04 - 1.93 (m, 3H), 1.72 - 1.56 (m, 2H), 1.31 (d, J = 5.9 Hz, 3H), 0.84 - 0.78 (m, 2H), 0.64 - 0.57 (m, 2H).

[0538] Example 50 1-(5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazine-1-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0539] [ka]

[0540] Step 1. Preparation of 3-((2-carboxyethyl)amino)-4-methylbenzoic acid: To a solution of 3-amino-4-methylbenzoic acid (1.1 g, 7.28 mmol) in toluene (20 mL) was added acrylic acid (2.09 g, 29.11 mmol). The reaction mixture was stirred at 100° C. under N2 for 3 hours. The reaction mixture was filtered and the filter cake was concentrated under vacuum to give the product 3-((2-carboxyethyl)amino)-4-methylbenzoic acid as a white solid (1.5 g, 92%). Mass (m / z): 224.1 [M+Na] + .

[0541] Step 2. Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid: To a solution of 3-((2-carboxyethyl)amino)-4-methylbenzoic acid (1.5 g, 6.72 mmol) in AcOH (30 mL) was added urea (1 g, 16.80 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The solvent was removed under reduced pressure to give the product 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid as a brown oil (4.1 g, 73%). Mass (m / z): 249.0 [M+H] + .

[0542] Step 3. Preparation of tert-butyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperazin-1-yl)propanoate: From 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid (700 mg, 2.82 mmol), following general step F, the product tert-butyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperazin-1-yl)propanoate was obtained as a yellow solid (1.2 g, 95%). Mass (m / z): 445.2 [M+Na] + .

[0543] Step 4. Preparation of 3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperazin-1-yl)propanoic acid: Following general step B2, the product was obtained as a yellow oil (1 g, 76%). Mass (m / z): 389.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.40 (dd, J = 4.8, 3.2 Hz, 2H), 7.36 (d, J = 1.6 Hz, 1H), 3.82 - 3.78 (m, 4H), 3.54 (dd, J = 8.4, 5.2 Hz, 4H), 3.36 - 3.31 (m, 4H), 2.76 (t, J = 7.4 Hz, 4H), 2.24 (s, 3H).

[0544] Step 5. Preparation of 1-(5-(4-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-oxopropyl)piperazine-1-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione: Followed general step F to obtain the product as a white solid (32 mg, 30%). Mass (m / z): 724.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.39 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.45 - 7.32 (m, 5H), 7.28 (s, 1H), 4.33 (s, 1H), 4.20 (s, 1H), 3.93 - 3.74 (m, 6H), 3.63 - 3.33 (m, 7H), 2.92 (q, J = 7.4 Hz, 2H), 2.85 - 2.56 (m, 7H), 2.22 (s, 3H), 1.27 (t, J = 7.4 Hz, 3H).

[0545] Example 51 5-(4-(3-((4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)cyclobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0546] [ka]

[0547] Step 1. Preparation of tert-butyl 4-(3-(methoxycarbonyl)cyclobutyl)piperazine-1-carboxylate: To a solution of tert-butyl piperazine-1-carboxylate (5 g, 26.8 mmol), methoxyacetic acid (3.43 g, 26.8 mmol) in 1,2-dichloroethane (50 mL) was added AcOH (1 mL). The reaction solution was stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (17.04 g, 80.4 mmol) was added. The reaction solution was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=10:1) to give the target product (2.5 g, 29.85%) as a colorless oil. Mass (m / z): 299.1 [M+H]+.

[0548] Step 2. Preparation of tert-butyl 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylate: To a solution of tert-butyl 4-[3-(methoxycarbonyl)cyclobutyl]piperazine-1-carboxylate (2.5 g, 0.0084 mol) in THF (50 mL) was added LiAlH (1.28 g, 0.0336 mol) at 0 °C. The reaction mixture was stirred at room temperature under N for 3 h. After the reaction was complete, HO (1.3 mL), NaOH (15%, 1 mL), HO (10 mL) were added to the reaction mixture, and MgSO (10 g) was added to the reaction mixture. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the target product (1 g, 41.67%) as a colorless oil. Mass (m / z): 271 [M+H] + .

[0549] Step 3. Preparation of tert-butyl 4-(3-((tosyloxy)methyl)cyclobutyl)piperazine-1-carboxylate: To a solution of tert-butyl {4-[3-(hydroxymethyl)cyclobutyl]piperazin-1-yl}formate (1 g, 0.0037 mol) and 4-DMAP (0.5 g, 0.0040 mol) in DCM (20 mL) was added TsCl (0.71 g, 0.0037 mol) at 0° C. under N2, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (PE / EA=5:1) to give the desired product (0.7 g, yield: 43.24%) as a white solid. Mass (m / z): 425.0 [M+H] + .

[0550] Step 4. Preparation of tert-butyl 4-(3-((4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)cyclobutyl)piperazine-1-carboxylate: A mixture of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (300 mg, 0.8178 mmol), tert-butyl {4-[3-({[(4-methylbenzene)sulfonyl]oxy}methyl)cyclobutyl]piperazin-1-yl}formate (452.43 mg, 1.0631 mmol), NaI (122.67 mg, 0.8178 mmol), and KCO (339.08 mg, 2.4534 mmol) in DMA (3 mL) was stirred at 120° C. for 18 h. The residue was then diluted with EA (20 mL), washed with water (20 mL × 4), dried over NaSO, filtered, and evaporated. The residue was purified by column chromatography to give the target product (200 mg, 56.02%) as a yellow solid. Mass (m / z): 619 [M+H] + .

[0551] Step 5. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(piperazin-1-yl)cyclobutyl)methyl)piperazin-2-one): Following general step B2, the desired product (150 mg, yield: 85.12%) was obtained as a black oil. Mass (m / z): 519 [M+H] + .

[0552] Step 6. Preparation of 5-(4-(3-((4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)methyl)cyclobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to give the product (40 mg, yield: 17.8%) as a yellow solid. Mass (m / z): 793 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 11.77 (d, J = 2.4 Hz, 1H), 11.12 (s, 1H), 8.13 (d, J = 5.8 Hz, 1H), 7.77 (d, J = 10.7 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.44 - 7.36 (m, 2H), 7.31 (d, J = 1.6 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.05 (s, 1H), 3.73 (s, 3H), 3.20 (s, 4H), 2.85 (dd, J = 19.2, 14.0 Hz, 5H), 2.60 (dd, J = 35.0, 16.8 Hz, 6H), 2.24 (ddd, J = 22.1, 13.4, 10.7 Hz, 4H), 2.14 - 1.98 (m, 2H), 1.92 (s, 1H), 1.68 (s, 2H), 0.85 (ddd, J = 8.2, 6.0, 4.0 Hz, 2H), 0.68 - 0.60 (m, 2H).

[0553] Example 52 3-Cyclopropyl-1H-pyrrolo5-(2-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0554] [ka]

[0555] Step 1. Preparation of methyl 2-[7-(tert-butyl-$l^{3}-oxy)-2,7-diazaspiro[3.5]nonan-2-yl]acetate: To a solution of tert-butyl {2,7-diazaspiro[3.5]nonan-7-yl}formate (200 mg, 0.88 mmol) in MeCN (10 mL) was added methyl 2-bromoacetate (161.5 mg, 1.056 mmol) and K2CO3 (973 mg, 7.04 mmol) at 25 °C. The mixture was stirred at 85 °C under nitrogen for 1 h. The mixture was concentrated, and the residue was purified by Combiflash (PE / EA = 1:1) to give the product (180 mg, 61.5%) as a colorless oil. Mass (m / z): 299.0 [M+Na]+

[0556] Step 2. Preparation of tert-butyl [2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]formate: To a solution of methyl 2-[7-(tert-butyl-$l^{3}-oxy)-2,7-diazaspiro[3.5]nonan-2-yl]acetate (180 mg, 0.60 mmol) in THF (5 mL) was added LiAlH4 (36 mg, 0.90 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with 15% aqueous NaOH at 0 °C, filtered, and the filtrate was concentrated to give the product (90 mg, 52.41%) as a yellowish oil. Mass (m / z): 271.2 [M+H]+.

[0557] Step 3. Preparation of tert-butyl [2-(2-{[(4-methylbenzene)sulfonyl]oxy}ethyl)-2,7-diazaspiro[3.5]nonan-7-yl]formate: To a solution of tert-butyl [2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]formate (90 mg, 0.33 mmol) in DCM (5 mL) was added TsCl (94 mg, 0.50 mmol), TEA (67 mg, 0.66 mmol), and 4-DMAP (8 mg, 0.066 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 5 h. The solvent was removed under vacuum, and the residue was purified by Combiflash (PE / EA = 1:1) to give the product (76 mg, 32.33%) as a yellowish oil. Mass (m / z): 425.2[M+H]+.

[0558] Step 4. Preparation of tert-butyl (2-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}-2,7-diazaspiro[3.5]nonan-7-yl)formate: General step G2 was followed to give the product (30 mg, 5.43%) as a brown solid. Mass (m / z): 619.1 [M+H]+.

[0559] Step 5. Preparation of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-4-(2-{2,7-diazaspiro[3.5]nonan-2-yl}ethyl)piperazin-2-one: Following general step B2, the desired product (20 mg, 71%) was obtained as a brown solid. Mass (m / z): 518.9 [M+H]+.

[0560] Step 6. Preparation of 5-(2-{2-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]ethyl}-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: Followed general step L to obtain the desired product as a yellow solid (2 mg, 6.5%). Mass (m / z): 792.8 [M+H]+. 1 HNMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.10 (d, J = 9.4 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 7.73 (d, J = 11.3 Hz, 1H), 7.63 (d, J = 12.4 Hz, 1H), 7.52 (m, 1H), 7.47 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J = 7.3 Hz, 1H), 5.09 (m, 1H), 3.95 (s, 2H), 3.78 (s, 2H), 3.65 (s, 2H), 3.21 (s, 2H), 2.88 (s, 2H), 2.67 (s, 2H), 2.57 (d, J = 31.3 Hz, 4H), 2.33 (s, 1H), 2.16 (d, J = 28.2 Hz, 2H), 2.07 (s, 6H), 1.21 (d, J = 17.3 Hz, 2H), 0.84 (d, J = 7.6 Hz, 2H), 0.65 (m, 2H).

[0561] Example 53 5-(4-(3-(4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0562] [ka]

[0563] Step 1. Preparation of tert-butyl 4-(3-(4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazin-1-yl)propyl)piperazine-1-carboxylate: Following general step G2, the product was obtained as a yellow oil (500 mg, 82%). Mass (m / z): 594.3 [M+H] + .

[0564] Step 2. Preparation of 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-4-(3-(piperazin-1-yl)propyl)piperazin-2-one: Following general step B2, the product 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-4-(3-(piperazin-1-yl)propyl)piperazin-2-one was obtained as a yellow oil (600 mg, purity: 60%). Mass (m / z): 494.0 [M+H] + .

[0565] Step 3. Preparation of 5-(4-(3-(4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: General step L was followed to provide the product 5-(4-(3-(4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione as a yellow solid (90 mg, 15%). Mass (m / z): 767.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 11.14 (s, 1H), 8.33 (s, 1H), 7.96 (t, J = 9.6 Hz, 2H), 7.84 (d, J = 11.0 Hz, 1H), 7.63 (d, J = 7.4 Hz, 2H), 7.35 (s, 1H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 4.16 (s, 4H), 3.50 (d, J = 35.4 Hz, 10H), 3.25 (s, 3H), 2.88 (d, J = 11.6 Hz, 2H), 2.70 - 2.56 (m, 2H), 2.22 (s, 1H), 2.08 (s, 3H), 0.86 (dt, J = 5.7, 3.8 Hz, 2H), 0.66 (q, J = 5.8 Hz, 2H).

[0566] Example 54 3-(5-(1-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0567] [ka]

[0568] Step 1. 3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanal: To a solution of 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (1000 mg, 2.7260 mmol) in DCM (10 mL) was added prop-2-enal (916.97 mg, 16.356 mmol). The reaction solution was stirred at room temperature for 18 hours and concentrated under reduced pressure to give the target product (1 g, 78.06%) as a yellow solid. Mass (m / z): 423 [M+H] +.

[0569] Step 2. Preparation of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Following general step B2, the product 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (150 mg, yield: 93.27%) was obtained as a brown solid. Mass (m / z): 328 [M+H] + .

[0570] Step 3. (General Step M2) Preparation of 3-(5-(1-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (120 mg, 0.3665 mmol), 3-[4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]propanal (155 mg, 0.3665 mmol) and SILATRANE (192.7 mg, 1.0995 mmol) in THF (2 mL) and AcOH (2 drops) was stirred at 75 °C under N for 18 h, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=10:1) to give the crude product, which was further purified by preparative HPLC (Gemini-C18 150×21.2 mm, 5 μm; ACN-HO (0.1% FA) 10-30) to give the desired product (2.5 mg, yield: 0.87%) as a white solid. Mass (m / z): 734 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.57 (dd, J = 17.3, 9.7 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H), 7.19 (s, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 (q, J = 17.3 Hz, 2H), 3.95 - 3.81 (m, 2H), 3.70 (d, J = 12.0 Hz, 2H), 3.39 (s, 2H), 3.29 - 3.19 (m, 2H), 3.17 - 3.02 (m, 3H), 3.02 - 2.87 (m, 3H), 2.84 - 2.76 (m, 1H), 2.69 (t, J = 6.5 Hz, 2H), 2.50 (dd, J = 13.3, 4.6 Hz, 1H), 2.34 - 2.12 (m, 4H), 2.04 (d, J = 10.4 Hz, 4H), 1.00 - 0.87 (m, 2H), 0.72 - 0.57 (m, 2H).

[0571] Example 55 3-(2,2-Difluoroethyl)-1H-pyrrolo 3-(5-(1-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0572] [ka]

[0573] Step 1. Preparation of tert-butyl {4-[2-(4-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)ethyl]piperidin-1-yl}formate: General step M1 was followed to obtain the product as a brown solid (130 mg, 42.13%). Mass (m / z): 603.3 [M+H]+.

[0574] Step 2. Preparation of 1-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-4-[2-(piperidin-4-yl)ethyl]piperazin-2-one: Following general step B2, the product (70 mg, 80.76%) was obtained as a pale yellow solid. Mass (m / z): 502.9 [M+H]+.

[0575] Step 3. Preparation of 5-{4-[2-(4-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-3-oxopiperazin-1-yl)ethyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step L was followed to obtain the product (5 mg, 4.4%) as a yellow solid. Mass (m / z): 775.7 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 12.12 (d, J = 2.5 Hz, 1H), 11.09 (s, 1H), 8.15 (s, 1H), 7.70 (d, J = 11.4 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 1.8 Hz, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.40 (m, 1H), 6.40 - 6.12 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.99 (t, J = 20.0 Hz, 4H), 3.29 (s, 4H), 2.85 (m, 4H), 2.54 (m, 2H), 2.00 (m, 2H), 1.79 (d, J = 11.8 Hz, 2H), 1.69 (d, J = 7.1 Hz, 2H), 1.55 (s, 1H), 1.26 (m, 4H).

[0576] Example 56 3-(5-(1-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0577] [ka]

[0578] Step 1. Preparation of 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Following general step B2, the desired product (1 g, yield: 96.67%) was obtained as a brown solid. Mass (m / z): 326 [M+H] + .

[0579] Step 2. Preparation of 3-(5-(1-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: General step M2 was followed to give the desired product (400 mg, yield: 6%) as a white solid. Mass (m / z): 732 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (d, J = 2.4 Hz, 1H), 10.98 (s, 1H), 8.14 - 8.12 (m, 1H), 7.75 - 7.65 (m, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.40 (dd, J = 11.4, 4.8 Hz, 2H), 7.31 (d, J = 1.7 Hz, 1H), 6.34 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.79 - 3.69 (m, 2H), 3.36 (s, 3H), 3.22 (s, 3H), 2.97 - 2.76 (m, 5H), 2.62 (s, 5H), 2.44 - 2.30 (m, 1H), 2.21 (s, 1H), 2.06 - 1.94 (m, 1H), 1.77 (s, 2H), 0.90 - 0.79 (m, 2H), 0.69 - 0.60 (m, 2H).

[0580] Example 57 3-(5-(4-(2-(4-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0581] [ka]

[0582] Step 1. Preparation of 3-(5-(4-(2-(4-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Followed general step F to obtain the target product (6 mg, 9.77%) as a yellow solid. Mass (m / z): 810.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 10.91 (s, 1H), 8.54 (d, J = 4.5 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.77 (td, J = 7.8, 1.6 Hz, 1H), 7.50 (dd, J = 7.8, 5.4 Hz, 3H), 7.48 - 7.37 (m, 3H), 7.31 (dd, J = 7.0, 5.2 Hz, 1H), 7.02 (d, J = 10.0 Hz, 2H), 5.00 (dd, J = 13.3, 5.0 Hz, 1H), 4.27 (dd, J = 11.4, 4.3 Hz, 4H), 4.15 (d, J = 16.6 Hz, 2H), 3.81 (d, J = 22.6 Hz, 4H), 3.63 (d, J = 13.4 Hz, 3H), 3.04 (t, J = 10.7 Hz, 2H), 2.94 - 2.79 (m, 1H), 2.54 (d, J = 16.1 Hz, 1H), 2.39 - 2.25 (m, 1H), 1.92 (d, J = 5.1 Hz, 3H), 1.59 - 1.45 (m, 2H).

[0583] Example 58 1-(6-(1-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperidin-4-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0584] [ka]

[0585] Step 1. Preparation of 3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanal: To a solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (100 mg, 0.2818 mmol) in DCM (1 mL) was added prop-2-enal (94.79 mg, 1.6908 mmol). The reaction solution was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give 3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propanal (100 mg, 77.71%) as a yellow solid. Mass (m / z): 411 [M+H] + .

[0586] Step 2. Preparation of 1-(6-(1-(3-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperidin-4-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione: General step M2 was followed to give the product (9 mg, yield: 8.1%) as a white solid. Mass (m / z): 718 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.07 (d, J = 3.5 Hz, 1H), 7.99 - 7.84 (m, 3H), 7.82 - 7.72 (m, 1H), 7.58 - 7.38 (m, 6H), 7.32 (dd, J = 20.9, 8.0 Hz, 1H), 7.24 (s, 1H), 3.94 (m, 1H), 3.87 - 3.70 (m, 4H), 3.65 (d, J = 12.1 Hz, 1H), 3.35 (s, 2H), 3.23 - 3.07 (m, 3H), 3.07 - 2.79 (m, 9H), 2.64 (t, J = 6.4 Hz, 2H), 2.26 - 1.82 (m, 5H), 1.31 (t, J = 7.4 Hz, 3H).

[0587] Example 59 3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one

[0588] [ka]

[0589] Step 1. Preparation of tert-butyl N-{4-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]butyl}carbamate: To a mixture of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (300 mg, 0.846 mmol) in MeCN (10 mL) was added KCO (234 mg, 1.69 mmol), NaI (127 mg, 0.846 mmol), and tert-butyl N-(4-bromobutyl)carbamate (320 mg, 1.29 mmol). The reaction mixture was stirred at 60 °C under N for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and then extracted with EA (20 mL × 3). The EA layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA = 0-40%) to give the product tert-butyl N-{4-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]butyl}carbamate (380 mg, 77%) as a yellow solid. Mass (m / z): 526.2 [M+H] + .

[0590] Step 2. Preparation of 4-(4-aminobutyl)-1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one: From tert-butyl N-{4-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]butyl}carbamate (380 mg, 0.722 mmol), the product 4-(4-aminobutyl)-1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (380 mg, 99%) was obtained as a yellow solid from general step B2. Mass (m / z): 425.9 [M+H] + .

[0591] Step 3. Preparation of 5-({4-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]butyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: From 4-(4-aminobutyl)-1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (330 mg, 0.774 mmol), following general step L, the product 5-({4-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]butyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (70.0 mg, 12%) was obtained as a yellow solid. Mass (m / z): 681.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (d, J = 2.4 Hz, 1H), 11.07 (s, 1H), 8.13 (s, 1H), 7.60-7.55 (m, 2H), 7.49-7.45 (m, 2H), 7.42-7.40 (m, 2H), 6.98 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.4, 2.0 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.10-4.00 (m, 4H), 3.69 (s, 2H), 3.27 (dt, J = 13.4, 7.2 Hz, 4H), 2.95-2.83 (m, 3H), 2.60-2.52 (m, 2H), 2.46 (d, J = 4.4 Hz, 1H), 2.01-1.98 (m, 1H), 1.81 (d, J = 7.4 Hz, 2H), 1.66-1.63 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H).

[0592] Example 60 5-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0593] [ka]

[0594] Step 1. Preparation of tert-butyl (2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)carbamate: General step M1 was followed to give the product as a white solid (550 mg, 83%). Mass (m / z): 498.1 [M+H] + .

[0595] Step 2. Preparation of 4-(2-aminoethyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B2, the product was obtained as a yellow oil (1.2 g, purity: 60%). Mass (m / z): 398.1 [M+H] + .

[0596] Step 3. Preparation of 5-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following general step L, the product 5-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid (70 mg, 8%). Mass (m / z): 654.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 11.08 (s, 1H), 8.13 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.57 - 7.36 (m, 5H), 7.13 (s, 1H), 7.07 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.81 (s, 2H), 3.37 (s, 4H), 2.92 (dd, J = 14.8, 7.6 Hz, 3H), 2.88 (s, 1H), 2.69 - 2.51 (m, 5H), 2.05 - 1.95 (m, 1H), 1.28 (t, J = 7.4 Hz, 3H).

[0597] Example 61 3-(6-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0598] Example 62 3-(5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0599] [ka]

[0600] Step 1. Preparation of 1-(3-bromophenyl)-4-[2-(piperidin-4-yl)ethyl]piperazin-2-one: Following general step B2, the product (2.0 g, 95%) was obtained as a yellow solid. Mass (m / z): 366.1 [M+H] + .

[0601] Step 2. Preparation of 5-(4-{2-[4-(3-bromophenyl)-3-oxopiperazin-1-yl]ethyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione: General step L was followed to give the product (1.8 g, 62%) as a white solid. Mass (m / z): 340.9 [M+H] + .

[0602] Step 3. Preparation of 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-3-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-hydroxy-3-oxoisoindolin-2-yl)piperidine-2,6-dione: To a mixture of 5-(4-{2-[4-(3-bromophenyl)-3-oxopiperazin-1-yl]ethyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione (1.75 g, 2.73 mmol) in HOAc (20 mL) was added zinc (1.78 g, 27.32 mmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired product mixture (2.2 g, 96%) as a brown oil. Mass (m / z): 641.7 [M+H] + .

[0603] Step 4. Preparation of 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(6-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a mixture of 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-3-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-hydroxy-3-oxoisoindolin-2-yl)piperidine-2,6-dione (2.2 g, 3.4 mmol) in HOAc (20 mL) was added EtSiH (9.33 g, 0.080 mol) and TFA (26.8 g, 0.235 mol). The reaction mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=0-4%) to give the desired product mixture (1.2 g, 50%) as a white solid. Mass (m / z): 625.8 [M+H] + .

[0604] Step 5. Preparation of 3-(5-fluoro-1-oxo-6-(4-(2-(3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and 3-(6-fluoro-1-oxo-5-(4-(2-(3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione: 3-(5-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(6-(4-(2-(4-(3-bromophenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl) To a mixture of piperidine-2,6-dione (1.2 g, 1.9 mmol) in dioxane (20 mL) was added KOAc (0.56 g, 5.7 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (580 mg, 2.2 mmol), and Pd(dppf)Cl (140 mg, 0.02 mmol). The reaction mixture was stirred at 110 °C under N for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (30 mL), then extracted with EA (30 mL × 3), washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=0-4%) to give the desired product mixture (700 mg, 37%) as a yellow solid. Mass (m / z): 673.9 [M+H] + .

[0605] Step 6. Preparation of 3-(6-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step A, a mixture of the two desired products (85 mg, 15%) was obtained as a white solid from 3-(5-fluoro-1-oxo-6-(4-(2-(3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and 3-(6-fluoro-1-oxo-5-(4-(2-(3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (250 mg, 0.371 mmol). Mass (m / z): 737.8[M+H] + The mixture (85 mg, 0.115 mmol) was separated by SFC [column: chiralpak-OJ; 250 mm × 20 mm, 5 μm; mobile phase: CO2-EtOH] to give the following:

[0606] 3-(6-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: (8 mg, white solid, RT=5.38 min), mass (m / z): 737.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.78 (d, J = 2.2 Hz, 1H), 10.99 (s, 1H), 8.13 (s, 1H), 7.49 (s, 2H), 7.44 - 7.41 (m, 3H), 7.33 - 7.29 (M, 2H), 5.08 (dd, J = 13.2, 5.0 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.23 (d, J = 17.2 Hz, 1H), 3.75 (s, 2H), 3.20 (s, 2H), 2.95 - 2.86 (m, 2H), 2.72 - 2.66 (m, 2H), 2.61 - 2.57 (m, 1H), 2.40 - 2.32 (m, 2H), 2.24 - 2.17 (m, 1H), 2.02 - 1.95 (m, 2H), 1.82 (d, J = 11.4 Hz, 2H), 1.51 (s, 2H), 1.36 (d, J = 12.4 Hz, 2H), 1.23 (s, 4H), 0.86 - 0.84 (m, 3H), 0.65 - 0.64 (m, 2H).

[0607] 3-(5-(4-(2-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: (6 mg, white solid, RT=5.41 min), mass (m / z): 737.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.00 (s, 1H), 8.13 (s, 1H), 7.70 - 7.73 (m, 3H), 7.67 - 7.65 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 2.94 - 2.86 (m, 1H), 2.76 - 2.67 (m, 2H), 2.59 (d, J = 16.7 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.22 - 2.14 (m, 2H), 1.98 (dd, J = 10.2, 5.1 Hz, 1H), 1.82 (d, J = 11.5 Hz, 2H), 1.67 - 1.60 (m, 7H), 1.42 - 1.32 (m, 9H), 0.86 - 0.84 (m, 3H), 0.66 - 0.62 (m, 2H).

[0608] Example 63 3-(5-(4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0609] [ka]

[0610] Step 1. Preparation of 3-(5-(4-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: General step M2 was followed to give the desired product (31 mg, yield: 13.17%) as a white solid. Mass (m / z): 735 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.2 Hz, 1H), 10.96 (s, 1H), 8.13 (d, J = 5.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 16.4, 8.6 Hz, 2H), 7.44 - 7.36 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.16 (s, 2H), 5.06 (dd, J = 13.3, 5.0 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 3.76 (d, J = 5.4 Hz, 2H), 3.43 (d, J = 80.0 Hz, 11H), 2.98 - 2.79 (m, 3H), 2.70 - 2.52 (m, 3H), 2.47 - 2.29 (m, 2H), 2.20 (m, 1H), 2.02 - 1.72 (m, 3H), 1.24 (s, 1H), 0.85 (ddd, J = 8.2, 6.0, 4.0 Hz, 2H), 0.70 - 0.59 (m, 2H).

[0611] Example 64 3-(5-(8-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0612] [ka]

[0613] Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate: To a mixture of compound 1 (500 mg, 1.5473 mmol), compound 2 (622.47 g, 1.8567 mmol), and KPO (394.13 g, 1.8567 mmol) in dioxane / HO (10:1, 100 mL) was added Pd(dppf)Cl (56.61 mg, 0.0773 mmol) under N. The reaction mixture was stirred at 90 °C for 18 h, 5% aqueous citric acid (20 mL) was added, and the mixture was extracted with DCM (20 mL × 2). The organic layer was washed with brine (20 mL x 2), dried over Na2SO4, concentrated, and the residue was purified by Combiflash with MeOH / DCM (1:10) to give the target compound (500 mg, yield: 67.99%) as a brown solid. Mass (m / z): 452 [M+H] + .

[0614] Step 2. Preparation of 3-(5-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step B2, the desired product (350 mg, yield: 85.44%) was obtained as a brown solid. Mass (m / z): 352 [M+H] + .

[0615] Step 3. Preparation of 3-(5-(8-(3-(4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)propyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: General step M2 was followed to give the desired product (32 mg, yield: 7.04%) as a white solid. Mass (m / z): 758 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.75 (d, J = 2.2 Hz, 1H), 10.98 (s, 1H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.71 - 7.60 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.43 - 7.35 (m, 2H), 7.30 (d, J = 1.7 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.4 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.56 (s, 1H), 3.51 (s, 1H), 3.18 (s, 2H), 2.97 - 2.83 (m, 2H), 2.82 - 2.76 (m, 3H), 2.65 - 2.52 (m, 3H), 2.48 - 2.32 (m, 3H), 2.25 - 2.15 (m, 1H), 2.08 (d, J = 16.8 Hz, 2H), 2.02 - 1.88 (m, 2H), 1.81 (s, 1H), 1.74 - 1.63 (m, 2H), 1.55 (s, 1H), 0.85 (dq, J = 5.8, 4.0 Hz, 2H), 0.69 - 0.59 (m, 2H).

[0616] Example 65 3-(6-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0617] [ka]

[0618] Step 1. (General Step E2) Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)octanoate: To a solution of 3-(6-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (0.2 g, 768 μmol) in DMF (4 mL) was added dipotassium carbonate (106 mg, 768 μmol) and tert-butyl 2-bromoacetate (107 mg, 384 μmol). The mixture was stirred at 25° C. for 12 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica column chromatography (PE:THF=1:1) to give 0.065 g of crude product. The crude product was then triturated with MTBE (5 mL). The filtrate was collected by filtration, washed with MTBE (3 mL), and evaporated to dryness under reduced pressure to give the product (50 mg, 15.11%). Mass (m / z): 459.3 [M+H] + .

[0619] Step 2. Preparation of 8-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)octanoic acid: Following general step B2, the product 8-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)octanoic acid was obtained as a yellow oil (50 mg, purity: 60%). Mass (m / z): 403.0 [M+H] + .

[0620] Step 3. Preparation of 3-(6-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Following general step F, the product 3-(6-((8-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-8-oxooctyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was obtained as a white solid (30 mg, 40%). Mass (m / z): 738.7 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.35 - 7.28 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.2, 2.4 Hz, 1H), 5.11 - 5.02 (m, 1H), 4.39 - 4.28 (m, 4H), 3.95 - 3.90 (m, 2H), 3.88 - 3.84 (m, 1H), 3.78 (s, 1H), 3.71 (dd, J = 7.4, 5.8 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 2.85 (dd, J = 5.0, 2.4 Hz, 2H), 2.42 (dd, J = 9.8, 7.2 Hz, 3H), 2.13 - 2.04 (m, 1H), 1.64 - 1.56 (m, 2H), 1.54 - 1.46 (m, 2H), 1.31 (t, J = 7.4 Hz, 9H).

[0621] Example 66 3-Ethyl-1H-pyrrolo-3-(6-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0622] [ka]

[0623] Step 1. Preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)acetate: Following general step E2, the desired product was obtained as a white solid (50 mg, 23%). Mass (m / z): 375.2 [M+H] + .

[0624] Step 2. Preparation of {[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]oxy}acetic acid: Following general step B2, the product {[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]oxy}acetic acid was obtained as a colorless oil (42 mg, 94%). Mass (m / z): 318.9 [M+H] + .

[0625] Step 3. Preparation of 3-(6-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione: General Step F was followed to give the product 3-(6-{2-[4-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]-2-oxoethoxy}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (45 mg, 52%) as a white solid. Mass (m / z): 655.0 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.50 - 7.30 (m, 6H), 7.27 (s, 1H), 5.13 (dd, J = 13.2, 5.2 Hz, 1H), 5.02 (d, J = 3.0 Hz, 2H), 4.48-4.34 (m, 4H), 4.05 - 3.94 (m, 4H), 3.97-4.04 (m, 3H), 3.85 (t, J = 8.0 Hz, 1H), 3.00 (q, J = 7.4, 0.8 Hz, 3H), 2.89 - 2.85 (m, 1H), 2.79-2.74 (m, 1H), 2.51-2.43 (m, 1H), 2.19-2.13 (m, 1H), 1....

Claims

1. Formula (I): 【Chemical 1】 a compound of the formula: (i) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (ii) Each R 2 , R 3 and R 4 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 are independently selected from; (iii) R 5 is hydrogen, R x , -CH 2 OC(O)R x - and -CH 2 OC(O)C(R x R y )NH 2 Selected from; (iv) Each W 1 , W 2 , W 3 and W 4 is C(R w ) 2 and C(O); (v) V is N and CR x Selected from; (vi) When V is N, X is absent, or -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -, -S(O) 2 - and -S(O) 2 R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (vii) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (viii) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (ix) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (x) Ring A is selected from aryl groups and heteroaryl groups; (xi) Ring B is absent or selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups, C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups).

2. Formula (I'): 【Chemistry 2】 a compound of the formula: (i) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (ii) Each R 2 and R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 are independently selected from; (iii) V is N and CR x Selected from; (iv) When V is N, X is absent, or -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -, -S(O) 2 - and -S(O) 2 R x or V is selected from CR x When X is absent, or -O-, -S-, or -NR x -, -C(O)-, -C(S)-, and -C(R x R y )-selected from (v) Y is absent or selected from linear, branched, and cyclic alkylene groups and PEG groups; (vi) Z is absent, -O-, or -NR z -, -NR y selected from —C(O)—, —C(O)—, —C(S)—, and —C(O)O—; (vii) Each R w , R x , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (viii) Ring A is selected from aryl and heteroaryl groups; (ix) Ring B is absent or selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group; (x) Ring C is 【Chemistry 3】 (In the formula, R c is selected from hydrogen, linear, branched, and cyclic alkyl groups; each R' and R" is selected from hydrogen, a halogen group, OR x , linear, branched and cyclic alkyl groups) Selected from; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups, C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups].

3. 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 2, wherein Y is selected from a PEG group.

4. Ring B is 【Chemistry 4】 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or 2, selected from:

5. 【Table 1A】 Table 1B Table 1C Table 1D 【Table 1E】 【Table 1F】 Table 1G 【Table 1H】 【Table 1I】 Table 1J a compound selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

6. 10. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5, and at least one pharmaceutically acceptable carrier.

7. A pharmaceutical composition for use in a method for treating or alleviating a disease, disorder or condition mediated by degradation of hematopoietic precursor kinase 1 (HPK1), said pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 2 and 5, said method comprising administering a therapeutically effective amount of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 2 and 5 to a subject in need thereof.

8. A pharmaceutical composition for use in a method for reducing HPK1 activity in a disease, disorder or condition, said pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5, said method comprising administering to a subject in need thereof a therapeutically effective amount of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5.

9. 9. The pharmaceutical composition of claim 8, wherein the disease, disorder, or condition is selected from HPK1-associated diseases.

10. The pharmaceutical composition of claim 9, wherein the HPK1-associated disease is selected from cancer, a dysregulated immune response, or a disease involving aberrant HPK1 expression, activity, and / or signaling.

11. 11. The pharmaceutical composition of claim 10, wherein the cancer is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, kidney cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, parathyroid cancer, lymphoma, sarcoma, and leukemia.

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