Multi-kinase degraders, compositions containing the degraders, and methods of using same

Abstract

Provided are compounds of formula (I), tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing, compositions comprising compounds of formula (I), tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, 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, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase. JPEG2025525279000066.jpg25170

Description

[Technical Field] 【0001】 This disclosure provides compounds of Formula I, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing, compositions comprising compounds of Formula I, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, 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, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase. [Background technology] 【0002】 Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. Serine / threonine kinases, which are specific for phosphorylating serine and threonine residues, constitute an important family of protein kinases. Another major family of protein kinases is tyrosine kinases, which are specific for phosphorylating tyrosine residues. In addition, there are dual-specificity kinases that phosphorylate both tyrosine and serine / threonine residues. 【0003】 Protein kinases play critical roles in many cellular functions, such as proliferation, survival, metabolism, and differentiation. Furthermore, dysregulated protein kinases are disease drivers in many pathologies, including immune, neoplastic, metabolic, neurological, and infectious diseases. Protein kinases involved in cell proliferation and survival are frequently mutated or overexpressed in cancer. They are attractive targets for anticancer drugs. 【0004】 Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of the MAP4K family. HPK1 is predominantly expressed in hematopoietic cell lineages and acts as a negative regulator of T lymphocyte and dendritic cell activation. Therefore, HPK1 inhibition is expected to prolong T cell activation and enhance APC function via dendritic cells. HPK1 is therefore identified as a novel anticancer immunotherapy and a potential combination therapy with new and current intracellular checkpoint molecules. Small molecule degraders targeting HPK1 may achieve better efficacy and / or overcome resistance to inhibitors by eliminating its scaffolding function. 【0005】 Mitogen-activated protein kinase 1 / 2 (MEK1 / 2) is a dual-specificity (threonine and tyrosine) protein kinase that functions downstream of RAS in the MAP kinase (MAPK) signaling pathway. They are involved in transmitting growth signals from various extracellular stimuli to the downstream effector ERK1 / 2. When RAS binds to RAF, it phosphorylates and activates MEK1 / 2. Upon phosphorylation, MEK1 / 2 further activates its sole downstream substrate, ERK1 / 2. The MAPK pathway is a critical pathway controlling cell proliferation, survival, and differentiation. MEK1 / 2 inhibitors have been used to treat cancers with an overactivated MAPK pathway. Four MEK inhibitors (MEKi) have been approved by the FDA to date; however, their application is limited by acquired resistance and side effects during long-term treatment. Small molecule degraders that can effectively eliminate MEK protein are expected to address the limitations of current anti-MEK therapies and bring about new breakthroughs in cancer treatment. 【0006】 The human Fms-like tyrosine kinase 3 receptor (FLT3), also known as fetal liver kinase 2 (FLK-2) or CD135, is a member of the receptor tyrosine kinase class III. FLT3 is overexpressed in approximately 90% of acute myeloid leukemia (AML), most acute lymphocytic leukemia (ALL), and blastic phase chronic myeloid leukemia (BC-CML). FLT3 is one of the most frequently mutated genes in hematological malignancies. FLT3 mutations have been found in 1-3% of patients with ALL, 5-10% of patients with myelodysplasia, and 15-35% of patients with AML. FLT3 mutations can be subdivided into internal tandem duplications (ITDs), which are present in approximately 25% of patients, and point mutations in the tyrosine kinase domain (TKDs), such as D835 and I836, which are present in approximately 5% of patients. Both FLT3-ITD and FLT3-TKD mutations are constitutively active, leading to ligand-independent FLT3 signaling and cell proliferation. Current small-molecule FLT3 inhibitors have not provided significant clinical benefit as monotherapy. There is a need for FLT3 degraders that induce rapid degradation of FLT3 and thereby effectively downregulate the downstream STAT5 pathway. Such FLT3 degraders would offer a new option for patients who have failed all currently available drug therapies and stem cell transplantation. 【0007】 Aurora kinases are key cell cycle regulators implicated in the pathogenesis of several tumor types. In humans, there are three isoforms of Aurora kinase: Aurora A, Aurora B, and Aurora C. Aurora A and Aurora B play critical roles in mitosis, whereas Aurora C activity is largely restricted to meiotic cells. Aurora A and Aurora B are closely related structurally but have distinct roles in mitosis. The Aurora A gene (AURKA) is located on chromosome 20ql3.2 and is frequently amplified or overexpressed in a wide range of cancers. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. Aurora A kinase interacts with and phosphorylates a diverse set of proteins that function collectively in regulating mitotic progression and cell division. Aurora A is functionally associated with several tumor suppressors and oncogenes. It promotes the transcription of the c-Myc oncogene and protects the N-Myc protein from ubiquitination and subsequent degradation. It also downregulates p53 and suppresses the function of the BRCA1 / 2 tumor suppressor. Overexpression of Aurora A kinase can result in a stoichiometric imbalance between Aurora A and its interacting partners, leading to oncogenic transformation. The potential role of Aurora A in oncogenesis has led to considerable interest in targeting this kinase for the treatment of cancers with genetic instability, aneuploidy, or genetic mutations in oncogenes (e.g., Myc, RAS, PKA) or tumor suppressors (e.g., TP53, BRCA1 / 2). Although different Aurora A inhibitors have been tested in clinical trials, limited efficacy and significant toxicity have been observed. Novel Aurora A degraders have the potential to improve clinical outcomes. 【0008】 Given the aforementioned importance of protein kinases in tumorigenesis, small molecule degraders can be used as single agents or in combination to treat solid tumors, including, but not limited to, brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, and parathyroid cancer. For example, small molecule degraders can be used as single agents or in combination to treat hematological cancers, including, but not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and myelodysplastic syndromes (MDS). [Prior art documents] [Patent documents] 【0009】 [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] 【0010】 [Non-Patent Document 1] Testa, Bernard and Mayer, Joachim M., Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology, Wiley-VHCA, Zurich, Switzerland 2003 [Non-patent document 2] SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19. [Non-patent document 3] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-patent document 4] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia [Non-patent document 5] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick [Non-patent document 6] J.C. Boylan, 1988–1999, Marcel Dekker, New York Summary of the Invention [Means for solving the problem] 【0011】 One aspect of the present disclosure provides a compound selected from the compounds 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 protein kinases such as hematopoietic progenitor kinase 1 (HPK1, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase. For example, a compound selected from the compounds of the following structural formula I: 【0012】 [ka] 【0013】 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) 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 ) independently selected from 2; (iii) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (iv) m and n are independently selected from 0, 1, and 2; (v) X is absent or selected from a linear, branched, or cyclic alkylene group, a linear, branched, or cyclic heteroalkylene group; (vi) Y and Z are independently absent, -O-, -C(O)-, or -C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S(O)2-, -S(O)2R x -, NR x - and -NR x and C(O)—, where p is selected from 1, 2, 3, 4, 5, and 6; and if X is absent, Y is selected from —O—, —S(O)—, —S(O)R x -, NR x - or -NR x Not C(O)-; (vii) R x , R y and R w are each 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 optionally substituted aryl and heteroaryl groups; (ix) Ring B is absent or selected from cycloalkyl groups and heterocycloalkyl groups; (x) Ring C is 【0014】 [ka] 【0015】 (In the formula, R c is hydrogen; R" is 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 5- and 6-membered heteroaryl groups] is disclosed herein. 【0016】 In one aspect of the disclosure, the compound of formula I is selected from compounds 1 to 18 shown below, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing. 【0017】 In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / 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 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing. These compositions can further comprise an additional active pharmaceutical agent. 【0018】 Another aspect of the present disclosure provides methods of treating a disease, disorder, or condition mediated by the degradation of protein kinases in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / 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 therapeutically effective amount of a compound selected from compounds 1 to 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. 【0019】 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, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / 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 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, together with the additional active pharmaceutical agent, either in the same composition or in a separate composition. 【0020】 Also disclosed herein are methods for reducing protein kinase activity, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / 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 protein kinases comprises administering to a subject a compound selected from compounds 1 to 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. 【0021】 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] 【0022】 [Figure 1]FIG. 1 shows a Western blot of HPK1, FLT3, and MEK1 / 2 degradation according to Example 2 of the present disclosure. [Figure 2] FIG. 1 shows plot data of the degradation of HPK1, FLT3, and MEK1 / 2 according to Example 2 of the present disclosure. [Figure 3] FIG. 1 shows a Western blot of HPK1, FLT3, Aurora A, and MEK1 / 2 degradation according to Example 8 of the present disclosure. [Figure 4] FIG. 10 shows plot data of HPK1 and FLT3 degradation according to Example 8 of the present disclosure. [Figure 5] FIG. 10 shows plot data of Aurora A and MEK1 / 2 degradation according to Example 8 of the present disclosure. [Figure 6] FIG. 1 shows a Western blot of FLT3 and Aurora A degradation according to Example 14 of the present disclosure. [Figure 7] FIG. 10 shows plot data of the degradation of FLT3 and Aurora A according to Example 14 of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION 【0023】 I. Definition The terms "a" or "an" when used herein in reference 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. 【0024】 The term "protein kinase" refers to an enzyme that catalyzes the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. Serine / threonine kinases, which are specific for phosphorylating serine and threonine residues, constitute an important family of protein kinases. Another major family of protein kinases is the tyrosine kinases, which are specific for phosphorylating tyrosine residues. In addition, there are dual specificity kinases that phosphorylate both tyrosine and serine / threonine residues. Examples of protein kinases include, but are not limited to, hematopoietic precursor kinase, mitogen-activated protein kinase 1 / 2, human Fms-like tyrosine kinase 3, and Aurora kinase. 【0025】 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. 【0026】 The term "MEK1 / 2" or "mitogen-activated protein kinase 1 / 2," as used herein, refers to dual-specificity (threonine and tyrosine) protein kinases that function downstream of RAS in the MAP kinase (MAPK) signaling pathway. They are involved in transmitting growth signals from various extracellular stimuli to the downstream effector ERK1 / 2. When RAS binds to RAF, it phosphorylates and activates MEK1 / 2. Upon phosphorylation, MEK1 / 2 further activates its only downstream substrate, ERK1 / 2. The MAPK pathway is an important pathway that controls cell proliferation, survival, and differentiation. MEK1 / 2 inhibitors have been used to treat cancers with an overactivated MAPK pathway. 【0027】 As used herein, the term "FLT3" or "human Fms-like tyrosine kinase 3 receptor," also known as fetal liver kinase 2 (FLK-2) or CD135, refers to a member of receptor tyrosine kinase class III. FLT3 is overexpressed in approximately 90% of acute myeloid leukemia (AML), most acute lymphocytic leukemia (ALL), and blastic phase chronic myeloid leukemia (BC-CML). FLT3 is one of the most frequently mutated genes in hematological malignancies. FLT3 mutations have been found in 1-3% of patients with ALL, 5-10% of patients with myelodysplasia, and 15-35% of patients with AML. FLT3 mutations can be subdivided into internal tandem duplications (ITDs), present in approximately 25% of patients, and point mutations in the tyrosine kinase domain (TKD) (e.g., D835 and I836), present in approximately 5%. Both FLT3-ITD and FLT3-TKD mutations are constitutively active, leading to ligand-independent FLT3 signaling and cell proliferation. 【0028】 The term "Aurora kinase" as used herein refers to a key cell cycle regulator implicated in the pathogenesis of several tumor types. In humans, there are three isoforms of Aurora kinase: Aurora A, Aurora B, and Aurora C. Aurora A and Aurora B play crucial roles in mitosis, whereas Aurora C activity is largely restricted to meiotic cells. Aurora A and Aurora B are closely related structurally but have distinct roles in mitosis. The Aurora A gene (AURKA) is located on chromosome 20ql3.2 and is frequently amplified or overexpressed in a wide range of cancers. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. Aurora A kinase interacts with and phosphorylates a diverse set of proteins that function collectively to regulate mitotic progression and cell division. Aurora A is functionally associated with several tumor suppressors and oncogenes. It promotes the transcription of the c-Myc oncogene and protects the N-Myc protein from ubiquitination and subsequent degradation. It also downregulates p53 and suppresses the function of the BRCA1 / 2 tumor suppressor. Overexpression of Aurora A kinase can result in a stoichiometric imbalance between Aurora A and its interacting partners, leading to oncogenic transformation. The potential role of Aurora A in oncogenesis has led to considerable interest in targeting this kinase for the treatment of cancers with genetic instability, aneuploidy, or genetic mutations of oncogenes (e.g., Myc, RAS, PKA) or tumor suppressors (e.g., TP53, BRCA1 / 2). 【0029】 The compounds disclosed herein can degrade protein kinases.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, MEK1 / 2 degraders, FLT3 degraders, or Aurora A degraders, and are useful for treating diseases such as cancer associated with such kinases. 【0030】 The term "degrading agent," as used herein, refers to a molecular agent that binds to a protein kinase, such as hematopoietic precursor kinase 1, and subsequently reduces the steady-state protein levels of the kinase. In some embodiments, a degrading agent as disclosed herein reduces steady-state protein kinase 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 protein kinase levels by at least 65%. In some embodiments, a degrading agent as disclosed herein reduces steady-state protein kinase levels by at least 85%. 【0031】 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. 【0032】 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. 【0033】 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. 【0034】 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. 【0035】 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. 【0036】 "Stereoisomers," as used herein, refers to enantiomers and diastereomers. 【0037】 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). 【0038】 The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope. 【0039】 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. 【0040】 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. 【0041】 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. 【0042】 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. 【0043】 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. 【0044】 The term "alkynyl" as used herein includes 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. 【0045】 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. 【0046】 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). 【0047】 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. 【0048】 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. 【0049】 The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively. 【0050】 As used herein, a "cyano" or "nitrile" group refers to -C≡N. 【0051】 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. 【0052】 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. 【0053】 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 heteroaryls 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- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like. 【0054】 "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, wherein any two rings share only one common atom. 【0055】 The term "prodrug group" refers to a group that is covalently attached to a compound and results in a compound with improved oral bioavailability and / or tumor targeting, and / or is more active in vivo. Certain compounds of Formula I may contain a prodrug group as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (see Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be more convenient to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug group is, without limitation, a moiety in a compound, such as an ester, which is subsequently metabolically hydrolyzed to the carboxylic acid to release the active entity. Additional examples of prodrug groups include peptidyl derivatives of a compound. 【0056】 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). 【0057】 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). 【0058】 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. 【0059】 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. 【0060】 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. 【0061】 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. 【0062】 The term "subject" refers to an animal, including, but not limited to, a human. 【0063】 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). 【0064】 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. 【0065】 The term "cancer" includes, but is not limited to, cancers of the epidermoid oral cavity, e.g., buccal cavity, lip, tongue, mouth, pharynx; cardiac cancers, e.g., sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers, e.g., bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; gastrointestinal cancers, e.g., esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small bowel or small intestine intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Genitourinary cancers, including intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancer, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including those of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), and breast; blood cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders Lymphatic system disorders; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; thyroid cancers, e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, and paraganglioma; and adrenal gland cancers, such as neuroblastoma. 【0066】 The compounds and compositions of the present application can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, such as antiproliferative agents, anticancer agents, immunomodulatory agents, or anti-inflammatory agents, and / or non-drug therapies. For example, synergistic effects may occur with antiproliferative agents, anticancer agents, immunomodulatory agents, or anti-inflammatory agents. When the compounds of the present application are administered in conjunction with other therapies, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the specific drug used, the condition being treated, and so forth. Combination therapy includes administration of the subject compounds in further combination with one or more other biologically active components (e.g., but not limited to, a second kinase inhibitor, a second and different anti-neoplastic agent), and non-drug therapies (e.g., but not limited to, surgery or radiation treatment). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of treatment. In another aspect of the present application, the compounds can be administered in combination with one or more separate pharmaceutical agents, e.g., chemotherapeutic agents, immunotherapeutic agents, or adjunctive therapeutic agents. In certain embodiments, the separate pharmaceutical agents are anti-PD1 antibodies (e.g., pembrolizumab), HDAC inhibitors (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib or acalabrutinib), mTOR inhibitors (e.g., everolimus), PI3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., rituximab), or rituximab. , enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZF12 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, Ell,UNC1999, or sinefungin), BET inhibitors (e.g., virabresib), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOTlL inhibitors (e.g., pinometostat), FIAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMTl inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420FU / F12 inhibitors (e.g., A-196), CARMl inhibitors (e.g., EZM2302), PLKl inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JF1295), MEK inhibitors (e.g., trametinib, binimetinib, cobimetinib, selmetinib, tinib), PF1F19 inhibitors, PIM inhibitors (e.g., LGF1-447), IGF-IR inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), PARP inhibitors (e.g., olaparib), EGFR inhibitors (e.g., osimertinib), HER2 / NEU inhibitors (i.e., tucatinib), SRC inhibitors (i.e., dasatinib), AKT inhibitors (i.e., , ipatasertib), KRAS(G12C) inhibitors (i.e., sotorasib), KRAS(G12D) inhibitors (i.e., MRTX1133), platinum, or chemotherapy (e.g., bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxane, or dexamethasone). 【0067】 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. 【0068】 II. Compounds and Compositions In a first embodiment, the compounds of the present disclosure have the following structural formula I: 【0069】 [ka] 【0070】 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) 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 ) independently selected from 2; (iii) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (iv) m and n are independently selected from 0, 1, and 2; (v) X is absent or selected from linear, branched, and cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups; (vi) Y and Z are independently absent, -O-, -C(O)-, or -C(O)R x -, -C(S)-, -C(S)Rx -, -[C(R x R y )] p -, -S(O)2-, -S(O)2R x -, NR x - and -NR x and C(O)—, where p is selected from 1, 2, 3, 4, 5, and 6; and if X is absent, Y is selected from —O—, —S(O)—, —S(O)R x -, NR x - or -NR x Not C(O)-; (vii) R x , R y and R w are each 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 optionally substituted aryl and heteroaryl groups; (ix) Ring B is absent or selected from cycloalkyl groups and heterocycloalkyl groups; (x) Ring C is 【0071】 [ka] 【0072】 (In the formula, R c is hydrogen; R" is 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 5- and 6-membered heteroaryl groups]. 【0073】 In a second 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 embodiment. 【0074】 In a third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from C1 to C6 straight chain, branched and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the first or second embodiment. 【0075】 In a fourth 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 third embodiment. 【0076】 In a fifth 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. 【0077】 In a sixth 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 herein are as defined in the fifth embodiment. 【0078】 In a seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2is hydrogen; all other variables not specifically defined herein are as defined in any one of the first through fourth embodiments. 【0079】 In an eighth 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. 【0080】 In a ninth 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 herein are as defined in the eighth embodiment. 【0081】 In a tenth 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 seventh embodiments. 【0082】 In an eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 1 and n is 1; all other variables not specifically defined herein are as defined in the previous embodiments. 【0083】 In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R' is hydrogen; all other variables not specifically defined herein are as defined in the eleventh embodiment. 【0084】 In a thirteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 2 and n is 1; all other variables not specifically defined herein are as defined in the previous embodiments. 【0085】 In a fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R' is hydrogen; all other variables not specifically defined herein are as defined in the thirteenth embodiment. 【0086】 In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is absent; all other variables not specifically defined herein are as defined in the previous embodiments. 【0087】 In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a linear alkylene group; all other variables not specifically defined herein are as defined in the previous embodiments. 【0088】 In a seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a methylene group; all other variables not specifically defined herein are as defined in the sixteenth embodiment. 【0089】 In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is an ethylene group; all other variables not specifically defined herein are as defined in the sixteenth embodiment. 【0090】 In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is absent; all other variables not specifically defined herein are as defined in the previous embodiments. 【0091】 In a twentieth 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 previous embodiments. 【0092】 In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0093】 [ka] 【0094】 all other variables not specifically defined herein are as defined in the twentieth embodiment. 【0095】 In a twenty-second 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. 【0096】 In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0097】 [ka] 【0098】 and all other variables not specifically defined herein are as defined in the previous embodiments. 【0099】 In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R cis hydrogen; all other variables not specifically defined herein are as defined in the twenty-third embodiment. 【0100】 In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-third embodiment. 【0101】 In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the twenty-third embodiment. 【0102】 In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0103】 [ka] 【0104】 and all other variables not specifically defined herein are as defined in any of embodiments 1-22. 【0105】 In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment. 【0106】 In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R cis selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment. 【0107】 In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment. 【0108】 In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0109】 [ka] 【0110】 and all other variables not specifically defined herein are as defined in any of embodiments 1-22. 【0111】 In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R C is hydrogen; all other variables not specifically defined herein are as defined in the thirty-first embodiment. 【0112】 In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-first embodiment. 【0113】 In a thirty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R cis a prodrug group; all other variables not specifically defined herein are as defined in the thirty-first embodiment. 【0114】 In a thirty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0115】 [ka] 【0116】 and all other variables not specifically defined herein are as defined in any of embodiments 1-22. 【0117】 In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment. 【0118】 In a thirty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment. 【0119】 In a thirty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment. 【0120】 In a thirty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0121】 [ka] 【0122】 and all other variables not specifically defined herein are as defined in any of embodiments 1-22. 【0123】 In a fortieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment. 【0124】 In a forty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment. 【0125】 In a forty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment. 【0126】 In a forty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is 【0127】 [ka] 【0128】 and all other variables not specifically defined herein are as defined in any of embodiments 1-22. 【0129】 In a forty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the 43rd embodiment. 【0130】 In a forty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the forty-third embodiment. 【0131】 In a forty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the 43rd embodiment. 【0132】 In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 18 shown in Table 1 below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing. 【0133】 [Table 1A] 【0134】 [Table 1B] 【0135】 Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of Formula I, compounds 1 to 18, 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. 【0136】 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. 【0137】 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 a compound of Formula I, compounds 1 to 18, 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, can be administered as a separate composition simultaneously with, before, or after a composition comprising an additional active pharmaceutical agent. 【0138】 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. 【0139】 III. Methods of Treatment and Use In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof as disclosed herein, including compounds of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating diseases, disorders, or conditions mediated by the degradation of protein kinases. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof as disclosed herein, including compounds of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for the manufacture of a medicament for treating diseases, disorders, or conditions mediated by the degradation of protein kinases. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by the degradation of protein kinases in a subject comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. 【0140】 In some embodiments, the protein kinase is selected from hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. 【0141】 In some embodiments, the disease, disorder, or condition is selected from a protein kinase-associated disease. In some embodiments, the disease, disorder, or condition is selected from a MEK1 / 2-associated disease. In some embodiments, the disease, disorder, or condition is selected from a FLT3-associated disease. In some embodiments, the disease, disorder, or condition is selected from an Aurora A-associated disease. 【0142】 In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor 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, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, and parathyroid cancer. In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and myelodysplastic syndrome (MDS). 【0143】 In some embodiments, the cancer is epidermoid oral cavity, e.g., buccal cavity, lip, tongue, mouth, or pharynx cancer; cardiac cancer, e.g., sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, e.g., bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; gastrointestinal cancer, e.g., esophageal (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small bowel or small intestine cancer. intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Genitourinary cancers, including intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancer, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including those of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), and breast; blood cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, and polyposis lymphatic system disorders; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; cancers of the thyroid gland, e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, and paraganglioma; and cancers of the adrenal gland, such as neuroblastoma. 【0144】 In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts as disclosed herein, including compounds of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in reducing protein kinase activity. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts as disclosed herein, including compounds of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for the manufacture of a medicament for reducing protein kinase activity. In yet another aspect, disclosed herein is a method of decreasing protein kinase activity comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of decreasing protein kinase activity comprising contacting said protein kinase with a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 18, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. 【0145】 The compounds of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / 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 protein kinases. 【0146】 In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, compounds 1 to 18, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / 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. 【0147】 The compounds of Formula I, compounds 1 to 18, their tautomers, deuterated derivatives of the compounds or tautomers, and / 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, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can, for example, 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. 【0148】 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. 【0149】 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, tautomers, pharmaceutically acceptable salts, 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 compound of Formula I and its pharmaceutically acceptable salts" includes 1000 mg of the compound of Formula I and a concentration of the pharmaceutically acceptable salt of the compound of Formula I equivalent to 1000 mg of the compound of Formula I. 【0150】 In another aspect of the present disclosure, the compounds and compositions disclosed herein can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, such as antiproliferative agents, anticancer agents, immunomodulatory agents, or anti-inflammatory agents, and / or non-drug therapies. For example, synergistic effects may occur with antiproliferative, anticancer, immunomodulatory, or anti-inflammatory agents. When the compounds disclosed herein are administered in conjunction with other therapies, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the specific drug used, the condition being treated, and so forth. Combination therapy includes administration of the subject compounds in further combination with one or more other biologically active components (e.g., a second kinase inhibitor, a second and different anti-neoplastic agent), and non-drug therapies (e.g., surgery or radiation treatment). For example, the compounds disclosed herein can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds disclosed herein. The compounds disclosed herein can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug treatments or treatment modalities.Combined treatment generally refers to the administration of two or more drugs in a single cycle or course of treatment.In another aspect of the present disclosure, the compounds can be administered in combination with one or more separate pharmaceutical agents, such as chemotherapeutic agents, immunotherapeutic agents, or adjunctive therapeutic agents. In some embodiments, the separate pharmaceutical agents are an anti-PD1 antibody (e.g., pembrolizumab), an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL-2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., fostamatinib), a JAK2 inhibitor (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), an Aurora kinase inhibitor (e.g., alisertib), an EZF12 inhibitor (e.g., tazemetostat, GSK126,CPI-1205, 3-deazaneplanocin A, EPZ005687, Ell, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOTlL inhibitors (e.g., pinometostat), FIAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMTl inhibitors (e.g., GSK3484862), LS D-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420FU / F12 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JF1295), MEK inhibitors (e.g., tramethicone, nib, binimetinib, cobimetinib, selumetinib), PF1F19 inhibitors, PIM inhibitors (e.g., LGF1-447), IGF-IR inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), PARP inhibitors (e.g., olaparib), EGFR inhibitors (e.g., osimertinib), HER2 / NEU inhibitors (i.e., tucatinib), SRC inhibitors (i.e., dasati nib), AKT inhibitors (i.e., ipatasertib), KRAS(G12C) inhibitors (i.e., sotorasib), KRAS(G12D) inhibitors (i.e., MRTX1133), platinum, or chemotherapy (e.g., bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxane, or dexamethasone). 【0151】 Non-limiting illustrative embodiments 1. Formula (I): 【0152】 [ka] 【0153】 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) 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 ) independently selected from 2; (iii) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (iv) m and n are independently selected from 0, 1, and 2; (v) X is absent or selected from linear, branched, and cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups; (vi) Y and Z are independently absent, -O-, -C(O)-, or -C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S(O)2-, -S(O)2R x -, NR x - and -NR xand C(O)—, where p is selected from 1, 2, 3, 4, 5, and 6; and if X is absent, Y is selected from —O—, —S(O)—, —S(O)R x -, NR x - or -NR x Not C(O)-; (vii) R x , R y , and R w are each 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 optionally substituted aryl and heteroaryl groups; (ix) Ring B is absent or selected from cycloalkyl groups and heterocycloalkyl groups; (x) Ring C is 【0154】 [ka] 【0155】 (In the formula, R c is selected from hydrogen, linear, branched and cyclic alkyl groups, and prodrug groups; R" is 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 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 3The 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 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-7, wherein is hydrogen. 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-10, wherein m is 1 and n is 1. 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 11, wherein each R' is hydrogen. 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-10, wherein m is 2 and n is 1. 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 11, wherein each R' is hydrogen. 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-14, wherein X is absent. 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-14, wherein X is a linear alkylene group. 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 16, wherein X is a methylene group. 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 16, wherein X is an ethylene group. 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-18, wherein Y is absent. 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-19, wherein Ring B is selected from optionally substituted heterocycloalkyl. 21. Ring B is 【0156】 [ka] 【0157】 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 20, selected from: 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-21, wherein Z is absent. 23. Ring C is 【0158】 [ka] 【0159】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 24. R c24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 25. Ring C is 【0160】 [ka] 【0161】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 26. R c 26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 25, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 27. Ring C is 【0162】 [ka] 【0163】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 28. R c 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 27, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 29. Ring C is 【0164】 [ka] 【0165】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 30. R c30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 29, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 31. Ring C is 【0166】 [ka] 【0167】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 32. R c The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 31, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 33. Ring C is 【0168】 [ka] 【0169】 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-22, wherein: 34. R c The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 33, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 35. 【0170】 [Table 2A] 【0171】 [Table 2B] 【0172】 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. 36. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 35, or at least one pharmaceutically acceptable carrier. 37. A method for treating or alleviating a disease, disorder, or condition mediated by degradation of a protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 35, or a pharmaceutical composition according to embodiment 36. 38. The method of embodiment 37, wherein the protein kinase is selected from hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. 39. A method for reducing protein kinase 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, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 35, or a pharmaceutical composition according to embodiment 36. 40. The method of embodiment 39, wherein the disease, disorder, or condition is selected from a protein kinase-associated disease. 41. The method of embodiment 40, wherein the protein kinase-associated disease is cancer. 42. The method of embodiment 41, wherein the cancer is a solid tumor. 43. The method of embodiment 42, wherein the solid tumor 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, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, and parathyroid cancer. 44. The method of embodiment 41, wherein the cancer is a blood cancer. 45. The method of embodiment 44, wherein the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and myelodysplastic syndrome (MDS). 46. Cancers include epidermoid oral cavity, e.g., buccal cavity, lip, tongue, mouth, pharynx; cardiac cancer, e.g., sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, e.g., bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; gastrointestinal cancer, e.g., esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small bowel or small intestine intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Genitourinary cancers, including intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancer, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including those of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), and breast; blood cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, and multiple myeloma 42. The method of embodiment 41, wherein the cancer is selected from: myelodysplastic syndromes (MDS), Hodgkin's disease, non-Hodgkin's hairy cell lymphoma; lymphatic system disorders; skin cancer, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; cancer of the thyroid gland, e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and cancer of the adrenal gland, such as neuroblastoma. 47. The method of embodiment 39, further comprising administering to the subject an existing standard of care or FDA-approved therapy. 48. The method of embodiment 39, further comprising administering to the subject one or more separate pharmaceutical agents. 49. The method of embodiment 48, wherein the separate pharmaceutical agents are selected from chemotherapeutic agents, immunotherapeutic agents, and adjunctive therapeutic agents. [Example] 【0173】 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. 【0174】 All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of this disclosure. 【0175】 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 Formula I, compounds 1 through 18, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing: Abbreviation Å = angstrom Ac = acetyl Ac2O = acetic anhydride Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = ethyl acetate EtOH = ethanol HOAc = acetic acid KOAc = potassium acetate LiHMDS = lithium bis(trimethylsilyl)amide MeMgBr = methylmagnesium bromide MeOH = methanol NaOAc = sodium acetate NBS = N-bromosuccinimide Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PTSA = p-toluenesulfonic acid monohydrate rt = room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TsCl = p-toluenesulfonyl chloride UV=ultraviolet light X-Phos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 【0176】 Synthesis of intermediate compounds: Intermediate A1: 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine 【0177】 [ka] 【0178】 Step 1. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: 【0179】 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 layer was 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] + . 【0180】 Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 【0181】 To a solution of AlCl3 (27.8 g, 0.20 mol) in DME (200 mL) was added LiAlH4 (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 N2 for 3 h. After the reaction was completed, H2O (500 mL) was added to the reaction mixture, which was then extracted with EA (200 mL x 3). The combined organic layer was washed with brine (100 mL x 2) and then dried over anhydrous Na2SO4. 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] + . 【0182】 Step 3. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: 【0183】 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] + . 【0184】 Step 4. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 【0185】 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] + . 【0186】 Intermediate A2: 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine 【0187】 [ka] 【0188】 Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine: 【0189】 To a solution of compound 4-chloropyridin-2-amine (300 g, 2.34 mol, 1.0 equivalent) in acetonitrile (3000 mL), NBS (458 g, 2.57 mol, 1.1 equivalent) was added in 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)δ8.10 (s, 1H), 6.67 (s, 1H), 6.45 (s, 2H). 【0190】 Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine: 【0191】 To a solution of compound 5-bromo-4-chloropyridin-2-amine (407 g, 1.97 mol, 1.0 equivalent) in AcOH (2000 mL) was added NIS (666 g, 2.96 mol, 1.5 equivalent) in portions. The reaction mixture was stirred at 80 °C for 4 hours. 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 a solution of NaSO (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)δ8.10 (s, 1H), 6.62 (s, 2H). 【0192】 Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine: 【0193】 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 × 3), washed with brine (2000 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel with 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] + . 【0194】 Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine: 【0195】 To a mixture of the 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 hour. The reaction mixture was quenched with water (1000 mL), extracted with EA (1000 mL x 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)δ11.92 (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). 【0196】 Intermediate A3: 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine 【0197】 [ka] 【0198】 Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone: 【0199】 To a solution of 3-bromo-4-chloro-1H-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, 11.7%). Mass (m / z): 308.7[M+H]+. 【0200】 Step 2. Preparation of 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine: 【0201】 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 completed, 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, 13.1%) as a brown solid compound. Mass (m / z): 295.0 [M+H]+. 【0202】 Intermediate A4: 2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)acetaldehyde 【0203】 [ka] 【0204】 Step 1. Preparation of {3-[(3-bromophenyl)amino]propyl}(2,2-dimethoxyethyl)amine: 【0205】 A solution of N-(3-aminopropyl)-3-bromoaniline (5.8 g, 25.3 mmol) and 2,2-dimethoxyacetaldehyde (2.9 g, 27.8 mmol) in MeOH (100 mL) and AcOH (1 mL) was stirred under nitrogen at 25° C. for 0.5 h. Then, NaBH3CN (4.8 g, 75.9 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solution was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=30:1) to give the product as a pale yellow oil (4.2 g, 47%). Mass (m / z): 317.2 [M+H] + . 【0206】 Step 2. Preparation of 1-(3-bromophenyl)-3-(2,2-dimethoxyethyl)-1,3-diazinan-2-one: 【0207】 A solution of triphosgene (1.53 g, 5.16 mmol, triphosgene) in DCM (20 mL) was added dropwise over 30 min to a stirred solution of {3-[(3-bromophenyl)amino]propyl}(2,2-dimethoxyethyl)amine (4.1 g, 12.9 mmol) and DIEA (3.33 g, 25.8 mmol) in DCM (40 mL) at 0 °C. The solution was stirred at 25 °C for 2 h. The solution was concentrated under reduced pressure. The residue was purified by flash column (PE / EA = 1:1) to give the product as a pale yellow oil (1.8 g, 36%). Mass (m / z): 343.1 [M+H] + . 【0208】 Step 3. Preparation of 1-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one: 【0209】 To a solution of 1-(3-bromophenyl)-3-(2,2-dimethoxyethyl)-1,3-diazinan-2-one (1.5 g, 4.4 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.13 g, 12.3 mmol), and KOAc (1.3 g, 13.2 mmol) in 1,4-dioxane (50 mL) was added Pd(dppf)Cl (320 mg, 0.44 mmol). The mixture was stirred under nitrogen at 90 °C for 5 h. Water (100 mL) was added, and the mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and dried over Na SO . The mixture was then filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE / EA=1:1) to give the product as a brown oil (1.1 g, 57%). Mass (m / z): 391.3 [M+H] + . 【0210】 Step 4. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(2,2-dimethoxyethyl)-1,3-diazinan-2-one: 【0211】 To a solution of 1-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one (200 mg, 0.51 mmol), 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (146 mg, 0.56 mmol), and KCO (212 mg, 1.53 mmol) in 1,4-dioxane / HO (10:1, 10 mL) was added Pd(dppf)Cl (37 mg, 0.051 mmol). The solution was stirred under nitrogen at 90 °C for 6 h. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over NaSO. Then it was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE / EA=1:1) to obtain the product as a yellow solid compound (200 mg, 79% yield). Mass (m / z): 443.2 [M+H]+. 【0212】 Step 5. Preparation of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]acetaldehyde: 【0213】 To a solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(2,2-dimethoxyethyl)-1,3-diazinan-2-one (180 mg, 0.41 mmol) in DCM (20 mL) was added TFA (1 mL) and HO (1 mL). The reaction mixture was stirred at 25° C. for 16 hours. Water (15 mL) was added, and the mixture was extracted with DCM (20 mL×2). The combined DCM layers were washed with saturated NaHCO (15 mL×2) and brine (20 mL), dried over NaSO, and concentrated to give the product as a brown oil (220 mg, 82%). Mass (m / z): 397.2 [M+H] + . 【0214】 Intermediate A5: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate 【0215】 [ka] 【0216】 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). The reaction mixture was stirred at 90 °C under N for 18 h. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over NaSO, and concentrated. The residue was purified by Combiflash (DCM / MeOH=10:1) to give the product (1 g, 73%) as a brown solid. Mass (m / z): 462.1 [M+Na] + . 【0217】 Intermediate A6: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)naphthalen-2-yl)piperazine-1-carboxylate 【0218】 [ka] 【0219】 Step 1. Preparation of 6-bromonaphthalen-1-amine: 【0220】 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] + . 【0221】 Step 2. Preparation of 3-[(6-bromonaphthalen-1-yl)amino]propanoic acid: 【0222】 To a mixture of 6-bromonaphthalen-1-amine (3.87 g, 0.0174 mol) in toluene (40.0 mL, Toluene) was added propa-enoic acid (7.52 g, 0.104 mol). The reaction mixture was degassed with N2 and stirred at 110 °C for 21 hours. 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] + . 【0223】 Step 3. Preparation of 1-(6-bromonaphthalen-1-yl)-1,3-diazinan-2,4-dione: 【0224】 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 hours. 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] + . 【0225】 Step 4. Preparation of tert-butyl {4-[5-(2,4-dioxo-1,3-diazinan-1-yl)naphthalen-2-yl]piperazin-1-yl}formate: 【0226】 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) was added 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). 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] + . 【0227】 Intermediates A7 and A8: 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 【0228】 [ka] 【0229】 Step 1. Preparation of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: 【0230】 To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.3 g, 2.8 mmol) in DCM (40 mL) was added TFA (2 mL) and HO (2 mL). The reaction mixture was stirred at 25 °C for 16 h. Water (30 mL) was added, and the mixture was extracted with DCM (40 mL × 2). The combined DCM layers were washed with saturated NaHCO (30 mL × 2) and brine (40 mL), dried over NaSO, and concentrated to give the crude product. A solution of this crude product, 1-(3-bromophenyl)-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (1 g, 2.8 mmol) and DIEA (1.09 g, 8.4 mmol) in DMSO (20 mL) was stirred under nitrogen at 120° C. for 2 hours. Water (50 mL) was added, and the mixture was extracted with EA (30 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 residue was purified by flash chromatography (PE / EA=1:1) to give the product as a brown solid (1.1 g, 57%). Mass (m / z): 607.7 [M+H] + . 【0231】 Step 2. Preparation of 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione and 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 【0232】 To a solution of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1.4 g, 2.3 mmol) in AcOH (20 mL) was added Zn powder (1.5 g, 2.3 mmol), and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine (20 mL×2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC [Gemini-C18, 150×21.2 mm, 5 μm; ACN—H2O (0.1% TFA), 55-60] to give the product: 【0233】 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 27%). Mass (m / z): 680.3 [M+H] + . 【0234】 3-(5-(4-((3-(3-Bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 11%). Mass (m / z): 680.3 [M+H] + . 【0235】 Step 3. Preparation of 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione: 【0236】 To a solution of 3-[6-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 0.72 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (275 mg, 1.08 mmol), and KOAc (213 mg, 2.17 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl (53 mg, 0.072 mmol). The mixture was stirred under nitrogen at 110 °C for 2 hours. Water (15 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (DCM / MeOH = 20:1) to give the product A7 as a brown solid (300 mg, 58%). Mass (m / z): 642.4 [M+H] + . 【0237】 Following the same procedure, 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione gave the product A8 as a brown solid (140 mg, 64%). Mass (m / z): 642.3 [M+H] +. 【0238】 General synthesis procedure I: 【0239】 [ka] 【0240】 Step 1. Preparation G1-2: 【0241】 To a solution of G1-1 (0.25 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 3 hours. Methyl tert-butyl ether (50 mL) was added, and the mixture was filtered. The cake was dried to give product G1-2, which was used directly in the next step. 【0242】 Step 2. Preparation of G1-3: 【0243】 To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]acetaldehyde (110 mg, 0.28 mmol) in THF (3 mL) was added G1-2 (0.26 mmol), silatrane (146 mg, 0.83 mmol), and AcOH (1 drop). The reaction mixture was stirred at 70 °C for 16 h. The solution was concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 30–40] to give the product. 【0244】 General Synthetic Procedure II: 【0245】 [ka] 【0246】 Step 1. Preparation of G2-2: 【0247】 A solution of 1,3-dibromobenzene (18 g, 63.63 mmol), propane-1,3-diamine (14.1 g, 190.87 mmol), KOH (7.14 g, 127.25 mmol), and CuCl (630 mg, 6.36 mmol) was added to the resulting mixture and stirred at 0 °C under N for 16 h. After the reaction was complete, HO (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (300 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash [DCM / MeOH (10% NH) = 0-10%] to give the product as a brown oil (10.7 g, 73%). Mass (m / z): 231.1 [M+H] + . 【0248】 Step 2. Preparation of G2-4: 【0249】 N 1 To a solution of -(3-bromophenyl)propane-1,3-diamine (10.7 g, 46.96 mmol) in MeOH (200 mL) was added G2-3 (46.96 mmol), AcOH (0.5 mL), and NaCNBH (8.85 g, 140.88 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was purified by CombiFlash column [DCM / MeOH (10% NH) = 0-10%] to give the product. 【0250】 Step 3. Preparation of G2-5: 【0251】 To a solution of G2-4 (42.19 mmol) in DCM (200 mL) was added TEA (8.5 g, 84.37 mmol) and triphosgene (6.25 g, 21.09 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, HO (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 3). The combined organic layer was washed with brine (300 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product. 【0252】 Example 1 3-[6-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 【0253】 [ka] 【0254】 Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidine-1-carboxylate: 【0255】 A solution of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (626 mg, 2 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (400 mL, 2.4 mmol), TTMSS (750 mL, 2.4 mmol), NiCl-glyme (22 mg, 0.1 mmol), dtbpy (27 mg, 0.1 mmol), Ir[dF(CF)ppy](dtbpy)PF (23 mg, 0.02 mmol), and NaCO (424 mg, 4 mmol) in DME (10 mL) was stirred under nitrogen at 25 °C and irradiated with a blue LED for 16 h. The solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product as a light purple solid (466 mg, 58%). Mass (m / z): 400.2 [M+H] + . 【0256】 Step 2. According to the general synthetic procedure I, tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidine-1-carboxylate gave the product 3-[6-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a yellow solid (17 mg, 8.6%). Mass (m / z): 680.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.01 (d, J = 4.6 Hz, 1H), 9.80-9.53 (m, 1H), 8.11 (d, J = 5.8 Hz, 1H), 7.94 (d, J = 22.2 Hz, 1H), 7.62 (dd, J = 21.4, 7.6 Hz, 2H), 7.42 (dd, J = 14.0, 7.2 Hz, 4H), 7.23 (t, J = 6.8 Hz, 1H), 5.13 (dd, J = 13.2, 4.8 Hz, 1H), 4.48 (d, J = 8.6 Hz, 2H), 4.43 (s, 1H), 4.34 - 4.22 (m, 4H), 3.55 (s, 4H), 3.48 (s, 2H), 3.42 (d, J = 5.6 Hz, 2H), 2.96 - 2.85 (m, 4H), 2.02-1.99 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H). 【0257】 Example 2 3-[5-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 【0258】 [ka] 【0259】 Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate: 【0260】 A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (517 mg, 1.6 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (315 mL, 1.9 mmol), TTMSS (600 mL, 1.9 mmol), NiCl-glyme (18 mg, 0.08 mmol), dtbpy (22 mg, 0.08 mmol), Ir[dF(CF)ppy](dtbpy)PF (18 mg, 0.016 mmol), and NaCO (339 mg, 3.2 mmol) in DME (8 mL) was stirred under nitrogen at 25 °C and irradiated with a blue LED for 16 h. The solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product as a pale pink solid (458 mg, 71%). Mass (m / z): 400.2 [M+H] + . 【0261】 Step 2. According to the general synthetic procedure I, tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate gave the product 3-[5-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a yellow solid (13 mg, 6.6%). Mass (m / z): 680.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.00 (s, 1H), 9.83-9.55 (m, 1H), 8.11 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 15.8, 9.0 Hz, 4H), 7.24 (d, J = 6.6 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.51 (d, J = 5.2 Hz, 2H), 4.41 (d, J = 5.8 Hz, 1H), 4.28 (dd, J = 29.2, 10.6 Hz, 4H), 3.56 (s, 4H), 3.45 (d, J = 17.2 Hz, 2H), 3.42 - 3.36 (m, 2H), 2.91 (td, J = 12.4, 5.4 Hz, 4H), 2.19 - 1.88 (m, 4H), 1.26 (dd, J = 14.4, 7.2 Hz, 3H). 【0262】 Example 3 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 【0263】 [ka] 【0264】 Step 1. Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate: 【0265】 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, 1.13 mmol) in MeOH (10 mL) and THF (10 mL) was added 10% Pd / C (50 mg, 10% wt / wt). The reaction was then stirred for 18 hours at 40° C. under 1 atm of H2. The mixture was filtered, and the filtrate was concentrated to give the target product (400 mg, 75%) as a gray solid. Mass (m / z): 464.0 [M+Na] + . 【0266】 Step 2. Following general synthetic procedure I, tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate gave the desired product, 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16 mg, 9%) as a white solid. Mass (m / z): 722.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.09 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.80 - 7.74 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.37 - 7.32 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 6.4 Hz, 1H), 5.19 - 5.04 (m, 1H), 3.69 (d, J = 4.8 Hz, 2H), 3.41 (dd, J = 14.0, 8.4 Hz, 8H), 2.88 - 2.82 (m, 3H), 2.56 (d, J = 17.8 Hz, 4H), 2.02 (d, J = 4.6 Hz, 4H), 1.81 (s, 2H), 1.73 (s, 2H), 1.21 (t, J = 7.4 Hz, 3H). 【0267】 Example 4 1-(6-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione 【0268】 [ka] 【0269】 Following general synthetic procedure I, tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)naphthalen-2-yl)piperazine-1-carboxylate gave the desired product 1-(6-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione (12 mg, 8%) as a white solid. Mass (m / z): 704.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.43 (s, 1H), 8.13 (d, J = 15.2 Hz, 2H), 7.72 (dd, J = 18.8, 8.8 Hz, 2H), 7.41 (dd, J = 14.6, 7.2 Hz, 4H), 7.33 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 14.6, 7.8 Hz, 3H), 3.85 (d, J = 4.8 Hz, 1H), 3.76 - 3.68 (m, 2H), 3.67 - 3.54 (m, 2H), 3.46 (d, J = 5.2 Hz, 4H), 3.26 (s, 3H), 2.91 (dd, J = 15.0, 7.6 Hz, 3H), 2.77 - 2.52 (m, 7H), 2.05 (s, 2H), 1.26 (t, J = 7.4 Hz, 3H). 【0270】 Example 5 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 【0271】 [ka] 【0272】 Following general synthetic procedure I, tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate gave the desired product 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (31 mg, 17%) as a white solid. Mass (m / z): 720.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (d, J = 2.2 Hz, 1H), 11.15 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.89 (dd, J = 18.0, 7.8 Hz, 2H), 7.38 (tt, J = 16.0, 8.0 Hz, 4H), 7.22 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 5.16 (dd, J = 12.8, 5.2 Hz, 1H), 3.73 (s, 4H), 3.58 (s, 2H), 3.45 (t, J = 5.8 Hz, 4H), 2.97 - 2.82 (m, 4H), 2.80 - 2.52 (m, 5H), 2.13 - 1.95 (m, 3H), 1.26 (t, J = 7.4 Hz, 3H). 【0273】 Example 6 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 【0274】 [ka] 【0275】 Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-1-carboxylate: 【0276】 A solution of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (337 mg, 1 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (246 mL, 1.5 mmol), TTMSS (466 mL, 1.5 mmol), NiCl-glyme (11 mg, 0.05 mmol), dtbpy (14 mg, 0.05 mmol), Ir[dF(CF)ppy](dtbpy)PF (11 mg, 0.01 mmol), and 2,6-dimethylpyridine (580 mL, 5 mmol) in DME (5 mL) was stirred under nitrogen at 25 °C and irradiated with a blue LED for 16 h. The solution was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product as a pale yellow solid (220 mg, 53%). Mass (m / z): 414.2 [M+H] + . 【0277】 Step 2. According to the general synthetic procedure I, the product 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (7 mg, yield: 4%) was obtained from tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-1-carboxylate as a white solid. Mass (m / z): 694.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.77 (d, J = 2.4 Hz, 1H), 11.14 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.85 (s, 2H), 7.43 - 7.29 (m, 4H), 7.20 (d, J = 7.4 Hz, 1H), 5.14 (dd, J = 12.8, 5.4 Hz, 1H), 3.80 (d, J = 6.8 Hz, 1H), 3.70 (dt, J = 13.8, 5.8 Hz, 4H), 3.44 (t, J = 5.8 Hz, 2H), 3.28 (dd, J = 15.2, 8.8 Hz, 5H), 2.97 - 2.80 (m, 3H), 2.59 (dd, J = 31.8, 13.6 Hz, 3H), 2.06 (s, 3H), 1.26 (dd, J = 13.8, 6.2 Hz, 3H). 【0278】 Example 7 3-(5-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 【0279】 [ka] 【0280】 Step 1. Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate: 【0281】 A solution of 3-(5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (171 mg, 0.5 mmol), tert-butyl piperazine-1-carboxylate (186 mg, 1 mmol), Ruphos-Pd-GII (77 mg, 0.1 mmol), Ruphos (47 mg, 0.1 mmol), CsCO (489 mg, 1.5 mmol), and 4A MS (100 mg) in dioxane (10 mL) was stirred at 100 °C under nitrogen for 24 hours. The solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH = 40:1) to give the product as a white solid (70 mg, 31%). Mass (m / z): 447.2 [M+H] + . 【0282】 Step 2. According to general synthetic procedure I, tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate gave the product 3-(5-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 11%) as a white solid. Mass (m / z): 727.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 10.99 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 11.2 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.24 (d, J = 7.4 Hz, 1H), 5.09 (dd, J = 13.2, 4.8 Hz, 1H), 4.36 (d, J = 17.2 Hz, 2H), 4.25 (d, J = 17.4 Hz, 2H), 3.77 (d, J = 5.8 Hz, 3H), 3.71 (s, 2H), 3.45 (dd, J = 14.8, 9.4 Hz, 4H), 3.30 (d, J = 10.8 Hz, 2H), 3.16 (d, J = 11.8 Hz, 2H), 2.96 - 2.82 (m, 3H), 2.67 - 2.55 (m, 2H), 2.40 - 2.35 (m, 1H), 2.10 (s, 2H), 2.03 - 1.94 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H). 【0283】 Example 8 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 【0284】 [ka] 【0285】 Step 1. Following general synthetic procedure II, the product tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate was obtained as a yellow oil (11.1 g, 58%) from tert-butyl 4-formylpiperidine-1-carboxylate. Mass (m / z): 473.9 [M+H] + . 【0286】 Step 2. Preparation of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: 【0287】 To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (11.1 g, 24.48 mmol) in dioxane (200 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (9.3 g, 36.72 mmol), KOAc (7.2 g, 73.45 mmol), and Pd(dppf)Cl (1.79 g, 2.45 mmol). The reaction mixture was stirred at 90 °C under N for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a brown oil (12.3 g, 80%). Mass (m / z): 522.0 [M+H] + . 【0288】 Step 3. Preparation of tert-butyl 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: 【0289】 To a solution of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (12.3 g, 24.58 mmol) in dioxane / HO (10:1, 200 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.37 g, 24.58 mmol), KCO (10.19 g, 73.73 mmol), and Pd(dppf)Cl (1.79 g, 2.46 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was completed, HO (300 mL) was added to the reaction mixture, which was then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product as a brown solid (5.83 g, 39%). Mass (m / z): 552.0 [M+H] + . 【0290】 Step 4. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: 【0291】 To a solution of tert-butyl 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (5.83 g, 12.9 mmol) in DCM / TFA (3:1, 50 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product as a brown oil (9.58 g, purity: 60%). Mass (m / z): 451.9 [M+H] + . 【0292】 Step 5. Preparation of 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: 【0293】 To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (4.23 g, 9.36 mmol) in DMSO (100 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.585 g, 9.36 mmol) and DIEA (3.63 g, 20.08 mmol). The reaction mixture was stirred at 120 °C under N for 2 hours. After the reaction was completed, HO (300 mL) was added to the reaction mixture, which was then extracted with EA (200 mL × 3). The combined organic layer was washed with brine (300 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 as a yellow solid (1.45 g, 21%). Mass (m / z): 707.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.08 (s, 1H), 8.11 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.37 (ddd, J = 25.2, 13.8, 8.2 Hz, 5H), 7.22 (t, J = 9.8 Hz, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.39 (t, J = 5.8 Hz, 2H), 3.20 (d, J = 7.2 Hz, 2H), 3.02 - 2.82 (m, 5H), 2.62 - 2.53 (m, 2H), 2.03 (dd, J = 12.8, 7.2 Hz, 4H), 1.71 (d, J = 11.8 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H). 【0294】 Example 9 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione 【0295】 [ka] 【0296】 Step 1. Following general synthetic procedure II, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate gave the product tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 56%) as a yellow oil. Mass (m / z): 488.2 [M+H] + . 【0297】 Step 2. Preparation of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: 【0298】 To a solution of tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 1.41 mmol) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (538 mg, 2.12 mmol), KOAc (416 mg, 4.24 mmol), and Pd(dppf)Cl (103 mg, 0.14 mmol). The reaction mixture was stirred at 90 °C under N for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product (650 mg, 89%) as a brown oil. Mass (m / z): 536.0 [M+H] + . 【0299】 Step 3. Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: 【0300】 To a solution of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (650 mg, 1.26 mmol) in dioxane / HO (10:1, 15 mL) was added 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (343 mg, 1.26 mmol), KCO (523 mg, 3.79 mmol), and Pd(dppf)Cl (92 mg, 0.13 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was complete, HO (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product (250 mg, 34%) as a yellow oil. Mass (m / z): 578.3 [M+H] + . 【0301】 Step 4. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one: 【0302】 To a solution of tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (250 mg, 0.43 mmol) in TFA / DCM (3:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product (230 mg, purity: 89%) as a brown oil. Mass (m / z): 477.9 [M+H] + . 【0303】 Step 5. Preparation of 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: 【0304】 To a solution of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one (230 mg, 0.48 mmol) in DMSO (10 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (142 mg, 0.48 mmol) and DIEA (187 mg, 1.44 mmol). The reaction mixture was stirred at 120° C. under N for 2 hours. After the reaction was completed, HO (20 mL) was added to the reaction mixture, which was then extracted with EA (20 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 in vacuo and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a yellow solid (85 mg, 23%). Mass (m / z): 751.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (d, J = 2.4 Hz, 1H), 11.11 (s, 1H), 8.11 (s, 1H), 7.69 (d, J = 11.6 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.34 - 7.28 (m, 2H), 7.23 - 7.19 (m, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.75 - 3.69 (m, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.36 (d, J = 10.2 Hz, 4H), 2.90 - 2.82 (m, 3H), 2.56 (dd, J = 19.8, 10.6 Hz, 2H), 2.23 - 2.15 (m, 1H), 2.04 (dd, J = 14.6, 9.2 Hz, 3H), 1.84 (d, J = 11.8 Hz, 2H), 1.50 (d, J = 6.8 Hz, 3H), 1.37 - 1.28 (m, 2H), 0.83 (ddd, J = 8.2, 6.0, 4.0 Hz, 2H), 0.66 - 0.60 (m, 2H). 【0305】 Example 10 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 【0306】 [ka] 【0307】 Step 1. Preparation of 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: 【0308】 To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.3 g, 4.7 mmol) in DMF (20 mL) was added NaH (60% in oil, 226 mg, 9.41 mmol) at 0 °C. The mixture was stirred at 0 °C under N for 0.5 h. Then, CHCl (1002 mg, 7.06 mmol) was added. The reaction mixture was stirred at room temperature under N for 2.5 h. The reaction mixture was poured into ice water (50 mL) and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL × 3) and dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by CombiFlash column (DCM / MeOH = 0-10%) to give the product (375 mg, 27%) as a yellow solid. Mass (m / z): 291.0 [M+H] + . 【0309】 Step 2. Preparation of 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: 【0310】 To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (400 mg, 0.89 mmol) in DMSO (5 mL) was added 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (257 mg, 0.89 mmol) and DIEA (343 mg, 2.66 mmol). The reaction mixture was stirred at 120° C. under N for 2 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL) and then extracted with EA (15 mL×3). The combined organic layer was washed with brine (20 mL×3) and then dried over anhydrous NaSO. It was then filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 um; ACN-HO (0.1% FA) 30-50] to give the product 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (59 mg, 9%). Mass (m / z): 722.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.36 (ddd, J = 19.0, 7.8, 2.3 Hz, 5H), 7.26 - 7.18 (m, 2H), 5.13 (dd, J = 13.0, 5.4 Hz, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.39 (t, J = 5.8 Hz, 2H), 3.20 (d, J = 7.2 Hz, 2H), 3.01 (s, 3H), 2.99 - 2.87 (m, 5H), 2.55 (d, J = 5.0 Hz, 1H), 2.05 (d, J = 5.2 Hz, 4H), 1.70 (s, 2H), 1.28 (t, J = 7.4 Hz, 3H). 【0311】 Example 11 3-[6-(4-{[3-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 【0312】 [ka] 【0313】 To a solution of 33-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (100 mg, 0.15 mmol), 3-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (50.8 mg, 0.18 mmol), and KPO (99 mg, 0.46 mmol) in 1,4-dioxane / HO (10:1, 3 mL) was added Pd(dppf)Cl (11 mg, 0.015 mmol). The solution was stirred under nitrogen at 85 °C for 16 h. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. It was then filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN--H2O (0.1% TFA), 30-50] to give the product as a yellow solid (2.3 mg, 2%). Mass (m / z): 706.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.97 (s, 1H), 8.11 (s, 1H), 7.54 (s, 2H), 7.45 - 7.36 (m, 2H), 7.31 (dd, J = 22.0, 12.8 Hz, 2H), 7.25 - 7.19 (m, 1H), 7.15 (s, 1H), 5.20 - 4.96 (m, 1H), 4.32 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.75 (dd, J = 14.0, 9.0 Hz, 4H), 3.40 (s, 2H), 3.22 (d, J = 7.2 Hz, 2H), 3.00 - 2.88 (m, 2H), 2.77 - 2.64 (m, 2H), 2.24 (dd, J = 28.6, 23.6 Hz, 2H), 2.12 - 2.00 (m, 2H), 1.91 (d, J = 39.8 Hz, 2H), 1.72 (d, J = 11.2 Hz, 2H), 1.32 - 1.21 (m, 2H), 0.90 - 0.79 (m, 2H), 0.73 - 0.59 (m, 2H). 【0314】 Example 12 3-[5-(4-{[3-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 【0315】 [ka] 【0316】 To a solution of 3-{1-oxo-5-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (70 mg, 0.11 mmol), 3-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.11 mmol), and KPO (69 mg, 0.33 mmol) in 1,4-dioxane / HO (10:1, 3 mL) was added Pd(dppf)Cl (8 mg, 0.011 mmol). The solution was stirred under nitrogen at 85 °C for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN--H2O (0.1% TFA), 35-50] to give the product as a yellow solid (1.3 mg, 1.5%). Mass (m / z): 706.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.94 (s, 1H), 8.10 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.37 (s, 2H), 7.35 - 7.28 (m, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.05 (s, 1H), 5.03 (dd, J = 13.4, 5.2 Hz, 1H), 4.31 (d, J = 16.8 Hz, 2H), 4.18 (d, J = 16.6 Hz, 2H), 3.89 (d, J = 11.6 Hz, 2H), 3.74 (s, 2H), 3.21 (d, J = 6.8 Hz, 2H), 2.85 (d, J = 10.6 Hz, 2H), 2.20 (d, J = 4.6 Hz, 2H), 2.06 (s, 2H), 1.94 (s, 2H), 1.70 (d, J = 10.8 Hz, 2H), 1.23 (s, 4H), 0.88 - 0.80 (m, 2H), 0.64 (d, J = 3.4 Hz, 2H). 【0317】 Example 13 3-(6-{4-[(3-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione 【0318】 [ka] 【0319】 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (100 mg, 0.15 mmol), 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.18 mmol), and KPO (99 mg, 0.4 mmol). To a solution of Pd(dppf)Cl (6 mmol) in 1,4-dioxane / HO (5 mL) was added Pd(dppf)Cl (11 mg, 0.015 mmol). The solution was stirred under nitrogen at 85 °C for 16 h. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over NaSO. It was then filtered, and the filtrate was concentrated. The crude product was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 30-50] to give the product as a yellow solid (6 mg, 5.1%). Mass (m / z): 730.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.10 (d, J = 1.8 Hz, 1H), 10.97 (s, 1H), 8.15 (d, J = 12.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.38 (td, J = 15.2, 7.8 Hz, 4H), 7.23 (dd, J = 16.4, 8.0 Hz, 2H), 7.15 (s, 1H), 6.48 - 6.12 (m, 1H), 5.09 (dd, J = 13.2, 5.0 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.86 - 3.66 (m, 4H), 3.52 (td, J = 17.2, 4.2 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.71 (t, J = 11.5 Hz, 2H), 2.58 (d, J = 17.0 Hz, 1H), 2.42 - 2.29 (m, 1H), 2.10 - 2.00 (m, 2H), 1.98-1.85 (m, 2H), 1.71 (d, J = 11.2 Hz, 2H), 1.32-1.23 (m, 2H). 【0320】 Example 14 3-(5-{4-[(3-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione 【0321】 [ka] 【0322】 To a solution of 3-{1-oxo-5-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (70 mg, 0.11 mmol), 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 0.11 mmol), and KPO (69 mg, 0.33 mmol) in 1,4-dioxane / HO (10:1, 3 mL) was added Pd(dppf)Cl (8 mg, 0.011 mmol). The solution was stirred under nitrogen at 85 °C for 16 h. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. It was then filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN--H2O (0.1% FA), 35-50] to give the product as a yellow solid (2 mg, 2.5%). Mass (m / z): 730.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.93 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.43 - 7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.03 (d, J = 12.6 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.18 (d, J = 17.2 Hz, 1H), 3.89 (d, J = 11.4 Hz, 2H), 3.74 (s, 2H), 3.54 (d, J = 16.6 Hz, 2H), 3.40 (s, 2H), 3.20 (s, 2H), 2.85 (dd, J = 25.6, 13.0 Hz, 2H), 2.63 (d, J = 28.0 Hz, 2H), 2.33 (s, 1H), 2.06 (s, 2H), 1.93 (s, 2H), 1.70 (d, J = 11.0 Hz, 2H), 1.24 (s, 2H). 【0323】 Example 15 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 【0324】 [ka] 【0325】 Step 1. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-diazinan-2-one: To a solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (700 mg, 1.55 mmol) in DMSO (20 mL) was added 1,2-difluoro-4-nitrobenzene (246 mg, 1.55 mmol) and DIEA (1001 mg, 7.75 mmol). The reaction mixture was stirred at 120 °C under N for 1 h. After the reaction was completed, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-diazinan-2-one as a yellow solid (660 mg, 72%). Mass (m / z): 590.9 [M+H] + . 【0326】 Step 2. Preparation of 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one: A solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-diazinan-2-one (650 mg, 1.1 mmol) in EA (10 mL) was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash [DCM / MeOH (10% NH .HO) = 0-10%] to give the product 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one as a brown solid (450 mg, 72%). Mass (m / z): 561.0 [M+H] + . 【0327】 Step 3. Preparation of 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione: To a solution of 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one (200 mg, 0.36 mmol) in DMF (10 mL) was added 3-bromopiperidine-2,6-dione (342 mg, 1.8 mmol) and NaHCO (90 mg, 1.07 mmol). The reaction mixture was stirred at 80 °C under N for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione as a white solid (4 mg, 1%). Mass (m / z): 672.0 [M+H] + . 1H NMR (400 MHz, MeOD) δ 8.11 (s, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.26 (s, 1H), 6.99 (s, 1H), 6.54 (d, J = 17.8 Hz, 2H), 4.24 (s, 1H), 3.84 - 3.75 (m, 2H), 3.52 (t, J = 5.8 Hz, 2H), 3.34 (d, J = 7.2 Hz, 4H), 3.01 (q, J = 7.4 Hz, 2H), 2.86 - 2.68 (m, 4H), 2.28 (s, 1H), 2.18 (dd, J = 13.4, 7.4 Hz, 2H), 1.88 (d, J = 20.2 Hz, 4H), 1.53 (s, 2H), 1.33 (t, J = 7.4 Hz, 4H). 【0328】 Example 16 3-((4-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 【0329】 [ka] 【0330】 Step 1. Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (1200 mg, 2.33 mmol) in dioxane / HO (10:1, 30 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (605 mg, 2.33 mmol), NaCO (742 mg, 7.0 mmol), and Pd(dppf)Cl (170 mg, 0.23 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was complete, HO (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product (600 mg, 45%) as a yellow oil. Mass (m / z): 566.3 [M+H] + . 【0331】 Step 2. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (600 mg, 1.06 mmol) in TFA / DCM (3:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product (560 mg, purity: 89%) as a brown oil. Mass (m / z): 466.2 [M+H] + . 【0332】 Step 3. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-diazinan-2-one: To a solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-[2-(piperidin-4-yl)ethyl]-1,3-diazinan-2-one (500 mg, 1.72 mmol) in DMSO (10 mL) was added 1,2-difluoro-4-nitrobenzene (474 mg, 1.72 mmol) and DIEA (692 mg, 5.36 mmol). The reaction mixture was stirred at 80 °C under N for 1 h. After the reaction was completed, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-diazinan-2-one as a yellow solid (436 mg, 67%). Mass (m / z): 605.1 [M+H] + . 【0333】 Step 4. Preparation of 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one: A solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-diazinan-2-one (436 mg, 0.72 mmol) in EA (10 mL) was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash [DCM / MeOH (10% NH .HO) = 0-10%] to give the product 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one as a brown solid (300 mg, 72%). Mass (m / z): 575.2 [M+H] + . 【0334】 Step 5. Preparation of 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}piperidin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione: To a solution of 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one (250 mg, 0.43 mmol) in DMF (10 mL) was added 3-bromopiperidine-2,6-dione (415 mg, 2.15 mmol) and NaHCO (110 mg, 1.30 mmol). The reaction mixture was stirred at 80 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}piperidin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione as a white solid (30 mg, 10%). Mass (m / z): 686.0 [M+H] + . 1H NMR (400 MHz, MeOD) δ 8.10 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.32 (t, J = 7.4 Hz, 2H), 7.25 (s, 1H), 6.88 (s, 1H), 6.56 - 6.42 (m, 2H), 4.61 (s, 1H), 4.23 (d, J = 8.2 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.47 (t, J = 7.6 Hz, 4H), 3.22 (d, J = 10.8 Hz, 2H), 3.00 (q, J = 7.4 Hz, 2H), 2.85 - 2.72 (m, 2H), 2.62 (s, 2H), 2.29 (s, 1H), 2.20 - 2.12 (m, 2H), 1.86 (s, 2H), 1.59 (s, 2H), 1.44 (s, 2H), 1.32 (s, 4H). 【0335】 Example 17 3-[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}piperazin-1-yl)phenyl]piperidine-2,6-dione 【0336】 [ka] 【0337】 To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]acetaldehyde (200 mg, 0.50 mmol) in THF (5 mL) was added 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride (156 mg, 0.50 mmol), silatrane (265 mg, 1.5 mmol), and AcOH (1 drop). The reaction mixture was stirred at 70° C. under N for 18 hours. The solution was concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 20–50] to give the desired product (20 mg, 6%) as a white solid. Mass (m / z): 654.1 [M+H] + . 1 HNMR (400 MHz, MeOD) δ 8.00 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.16 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.71 - 3.65 (m, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.44 (t, J = 5.8 Hz, 2H), 3.14 - 3.07 (m, 4H), 2.89 (q, J = 7.4 Hz, 2H), 2.72 (s, 4H), 2.65 (t, J = 6.6 Hz, 2H), 2.58 - 2.46 (m, 2H), 2.11 - 2.04 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H). 【0338】 Example 18 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}piperazin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione 【0339】 [ka] 【0340】 To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]acetaldehyde (200 mg, 0.50 mmol) in THF (5 mL) was added 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione hydrochloride (173 mg, 0.50 mmol), silatrane (265 mg, 1.5 mmol), and AcOH (1 drop). The reaction mixture was stirred at 70 °C under N for 18 hours. The solution was concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 20–50] to give the desired product (8 mg, 2%) as a white solid. Mass (m / z): 687.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.79 (s, 1H), 8.11 (s, 1H), 7.37 (dd, J = 14.6, 8.4 Hz, 4H), 7.20 (d, J = 7.4 Hz, 1H), 6.79 (s, 1H), 6.50 (d, J = 14.8 Hz, 1H), 6.39 (d, J = 8.6 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.29 - 4.21 (m, 1H), 3.73 - 3.69 (m, 2H), 3.42 (d, J = 6.0 Hz, 4H), 2.92 (q, J = 7.4 Hz, 2H), 2.84 (s, 4H), 2.69 (d, J = 11.2 Hz, 1H), 2.54 (s, 6H), 2.13 - 1.96 (m, 4H), 1.84 (dd, J = 12.2, 4.4 Hz, 1H), 1.26 (t, J = 7.4 Hz, 3H). 【0341】 General assay procedure: PK1 enzyme inhibition assay Compounds were dissolved in 100% DMSO at a concentration of 10 mM. HPK1 protein was purchased from Signal Chem (M23-11G-10). 2.5 μL of 2X HPK1 protein was added per well to assay plates containing test compounds, centrifuged at 1500 rpm for 1 minute, and then incubated at 25°C for 60 minutes. MBP protein was purchased from Signal Chem (M42-51N), and ATP was purchased from Promega (V9102). 2.5 μL of 2X MBP (0.2 μg / ul) and ATP (20 μM) were added per well, centrifuged at 1500 rpm for 1 minute, and then incubated at 25°C for 60 minutes. 5 μL of ADP-Glo (Promega (V9102)) was then added to the assay plate, and unconsumed ATP was depleted for 60 minutes. Then, it was centrifuged at 1500 rpm for 1 minute and incubated at 25°C for 60 minutes. Finally, ADP was converted to ATP by adding 10 μL of kinase assay reagent from Promega (V9102) to the assay plate, which was centrifuged at 1500 rpm for 1 minute and incubated at 25°C for 40 minutes. After 40 minutes of incubation, fluorescence was determined. Based on the results, IC values of the compounds were calculated. 50 The IC value was calculated. 50 The results are shown in Table 2 below. 【0342】 FLT3-ITD enzyme inhibition assay Compounds were dissolved in 100% DMSO at a concentration of 10 mM. FLT3-ITD protein was purchased from Invitrogen (PV6191). 10 μL of 2.5× FLT3-ITD protein was added per well to the assay plate containing the test compound, centrifuged at 1000 rpm for 1 minute, and then incubated at 25° C. for 10 minutes. Peptide 2 was purchased from GL Biochem (112394), and ATP was purchased from Promega (V9102). 15 μL of a mixture of 1.67× Peptide 2 (final concentration: 3 μM) and ATP (final concentration: 97.2 μM) was added per well, centrifuged at 1000 rpm for 1 minute, and then incubated at 25° C. for 40 minutes. Then, 30 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent 3, 50 mM EDTA) was added to the assay plate and centrifuged at 1000 rpm for 1 minute. The product was determined. Based on the results, the IC of the compound was calculated. 50 The IC value was calculated. 50 The results are shown in Table 2 below. 【0343】 Aurora A enzyme inhibition assay Compounds were dissolved in 100% DMSO at a concentration of 10 mM. Aurora A protein was purchased from Carna (05-101). 10 μL of 2.5X Aurora A protein was added per well to the assay plate containing the test compound, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 10 minutes. Peptide 21 was purchased from GL Biochem (116370), and ATP was purchased from Promega (V9102). 15 μL of a mixture of 1.67X Peptide 21 (final concentration 3 μM) and ATP (final concentration 14.58 μM) was added per well, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 40 minutes. Then, 30 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent 3, 50 mM EDTA) was added to the assay plate and centrifuged at 1000 rpm for 1 minute. The product was determined. Based on the results, the IC of the compound was calculated. 50 The IC value was calculated. 50 The results are shown in Table 2 below. 【0344】 [Table 3] 【0345】 HPK1 degradation assay Frozen human PBMCs were purchased from Shanghai OribioTech and recovered in culture medium (RMPI1640) before use. Cells were then incubated with various concentrations of compounds. After 18 hours of incubation, cells were harvested and lysed. Protein concentrations were determined using a BCA protein assay kit (Thermo, 23227). HPK1 protein levels were determined by Western blot using anti-human HPK1 polyclonal antibody (CST, 4472S). Proteins were loaded into each well of a precast gel and subjected to electrophoretic separation by SDS-PAGE. Proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% nonfat milk, and probed with anti-human HPK1 or β-actin antibodies (CST, 3700S) using standard Western blotting procedures. 【0346】 MEK1 / 2 degradation assay Prior to use, MV-411 cells were cultured in IMDM medium, and IMR32 cells were cultured in MEM medium. The cells were then incubated with various concentrations of compounds. After incubation, the cells were harvested and lysed. Protein concentrations were determined using a BCA protein assay kit (Thermo, 23227). FLT3 protein levels were determined by Western blot using an anti-human MEK1 / 2 polyclonal antibody (CST, 9122S). Proteins were loaded into each well of a precast gel and subjected to electrophoretic separation by SDS-PAGE. Proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% nonfat milk, and probed with anti-human MEK1 / 2 or β-actin antibodies (CST, 3700S) and COX IV antibodies (CST, 4850S) using standard Western blotting procedures. 【0347】 FLT3 degradation assay Before use, MV-411 cells were cultured in medium (IMDM). The cells were then incubated with various concentrations of compounds. After incubation, the cells were harvested and lysed. Protein concentrations were determined using a BCA protein assay kit (Thermo, 23227). FLT3 protein levels were determined by Western blot using an anti-human FLT3 monoclonal antibody (CST, 3462S). Proteins were loaded into each well of a precast gel and subjected to electrophoretic separation by SDS-PAGE. Proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% nonfat milk, and probed with anti-human FLT3 or β-actin antibodies (CST, 3700S) using standard Western blotting procedures. 【0348】 Aurora A degradation assay Prior to use, IMR32 cells were cultured in MEM medium, Huh7 cells in DMEM medium, and HL-60 cells in IMDM medium. The cells were then incubated with various concentrations of compounds. After incubation, the cells were harvested and lysed. Protein concentrations were determined using a BCA protein assay kit (Thermo, 23227). AURKA protein levels were determined by Western blot using an anti-human AURKA monoclonal antibody (CST, 14475S). Proteins were loaded into each well of a precast gel and subjected to electrophoretic separation by SDS-PAGE. Proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% nonfat milk, and probed with anti-human AURKA or β-actin antibodies (CST, 3700S) or COX IV antibodies (CST, 4850S) using standard Western blotting procedures. 【0349】 The results for HPK1, FLT3, Aurora, and MEK are shown in Table 3. 【0350】 [Table 4] 【0351】 Other embodiments The present disclosure provides merely illustrative embodiments. Those skilled in the art will readily recognize from the present disclosure and the claims that various changes, modifications, and variations can be made without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

[Claim 1] Equation (I): 【Chemistry 1】 Compounds thereof, tautomers thereof, deuterated derivatives of the compound or tautomer, or pharmaceutically acceptable salts thereof [in the formula, (i) R 1 is selected from linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, linear, branched and cyclic alkenyl groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, 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 ; and is selected from (ii) R 2 and R 3 is hydrogen, halogen group, OR x , SR x NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected independently of; (iii) Each R' is independently selected from hydrogen, halogen groups, linear, branched, and cyclic alkyl groups; (iv) m and n are independently selected from 0, 1, and 2; (v) X is absent, or selected from linear, branched, or cyclic alkylene groups, or linear, branched, and cyclic heteroalkylene groups; (vi) Y and Z are independent, nonexistent, or -O-, -C(O)-, -C(O)R x -, -C(S)-, -C(S)R x -,-[C(R x R y )] p -, -S(O) 2 -, -S(O) 2 R x -, NR x -, and -NR x C(O)- is selected, where p is selected from 1, 2, 3, 4, 5, and 6; where if X does not exist, Y is -O-, -S(O) 2 -, -S(O) 2 R x -, NR x -, or -NR x Not C(O)-; (vii) R x , R y and R w These 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 substituted aryl and heteroaryl groups by optional choice, (ix) Ring B is absent or selected from cycloalkyl groups and heterocycloalkyl groups; (x) Ring C is, 【Chemistry 2】 (In the formula, R c R'' is selected from hydrogen, linear, branched and cyclic alkyl groups, and prodrug groups; R'' is hydrogen, halogen groups, OR x (Selected from linear, branched, and cyclic alkyl groups) Selected from; Here, 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: halogen group, Hydroxy, Thiol, 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, -NHaryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NH aryl 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 group, benzylamino group, and benzylthio group, 3- to 6-membered heterocycloalkenyl groups, Heterocyclic groups with 3 to 6 members, and Five-membered and six-membered heteroaryl groups. [Claim 2] R 1 However, 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 according to claim 1, selected from hydrogen, linear, branched, and cyclic alkyl groups. [Claim 3] R 1 However, C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from linear, branched, and cyclic alkyl groups. [Claim 4] R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 3, selected from methyl, ethyl, cyclopropyl, and cyclobutyl. [Claim 5] R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R and R 3 are each independently selected from hydrogen and halogen groups. [Claim 6] R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 5, wherein is chloro. [Claim 7] R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein is hydrogen. [Claim 8] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein m is 1 and n is 1. [Claim 9] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 8, wherein each R' is hydrogen. [Claim 10] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein m is 2 and n is 1. [Claim 11] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is absent. [Claim 12] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is a linear alkylene group. [Claim 13] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 12, wherein X is a methylene group. [Claim 14] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 12, wherein X is an ethylene group. [Claim 15] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein Y is absent. [Claim 16] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein ring B is selected from heterocycloalkyl groups that are optionally substituted. [Claim 17] Ring B is 【Transformation 3】 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the compound, tautomer, deuterated derivative, or salt of the compound, tautomer, or deuterated derivative [Claim 18] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein Z is absent. [Claim 19] Ring C is 【Chemistry 4】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 20] Ring C is 【Transformation 5】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 21] Ring C is 【Transformation 6】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 22] Ring C is 【Transformation 7】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 23] Ring C is 【Transformation 8】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 24] Ring C is 【Chemistry 9】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. 【Request Item 25】 【Table 1A】 Table 1B Compounds selected from the above, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof. [Claim 26] A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of claims 1 to 25, and at least one pharmaceutically acceptable carrier. [Claim 27] ​​The pharmaceutical composition according to claim 26 for treating or alleviating a disease, disorder or condition mediated by the degradation of protein kinases. [Claim 28] The pharmaceutical composition according to claim 27, wherein the protein kinase is selected from hematopoietic precursor kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. [Claim 29] The pharmaceutical composition according to claim 26 for reducing protein activity in a disease, disorder, or condition. [Claim 30] The pharmaceutical composition according to claim 29, wherein the disease, disorder, or condition is selected from protein kinase-related diseases. [Claim 31] The pharmaceutical composition according to claim 30, wherein the protein kinase-related disease is cancer. [Claim 32] The pharmaceutical composition according to claim 31, wherein the cancer is a solid tumor. [Claim 33] The pharmaceutical composition according to claim 32, wherein the solid tumor is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive organ cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, and parathyroid cancer. [Claim 34] The pharmaceutical composition according to claim 31, wherein the cancer is a blood cancer. [Claim 35] The pharmaceutical composition according to claim 34, wherein the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and myelodysplastic syndrome (MDS). [Claim 36] Cancers of the epidermal oral cavity, e.g., buccal oral cavity, lips, tongue, mouth, pharynx; cardiac cancers, e.g., sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers, e.g., bronchogenic lung carcinomas (squamous or epidermal, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinomas, bronchial adenomas, sarcomas, lymphomas, chondromatous hamartomas, mesotheliomas; gastrointestinal cancers, e.g., esophageal (squamous cell carcinoma, laryngosal, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small bowel or small intestine intestines) (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Urogenital cancers, including intestines (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), colon, colorectal, colon-rectum, rectum; kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancers, e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancers, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcomas, fibrosarcomas, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrosis exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; cancers of the nervous system, including the skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, gliomas), and brain (astrocytoma, medulloblastoma, glioma, ependymocyteoma, germ cell tumor (pineal glandoma), glioblastoma pleomorphoma, oligodendroglioma, Schwannoma, retinoblastoma, congenital tumors, spinal nerve fibroma, meningioma, glioma, sarcoma);Gynecological cancers, including the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-enveloplastic cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), and breast; hematological cancers, such as blood cancers, including blood (myelocytic leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, bone marrow) A pharmaceutical composition according to claim 31, selected from cancers of the adrenal gland such as dysplasia, Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma) hairy cell; lymphatic system disorders; skin cancers including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacinthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; thyroid cancers, such as papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal cancers such as neuroblastoma. [Claim 37] The pharmaceutical composition according to claim 29, to be used in combination with an existing standard treatment or an FDA-approved therapy. [Claim 38] The pharmaceutical composition according to claim 29, which is used in combination with one or more separate pharmaceutical agents. [Claim 39] The pharmaceutical composition according to claim 38, wherein separate pharmaceutical agents are selected from chemotherapeutic agents, immunotherapy agents, and adjunctive therapeutic agents.

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