Multikinase inhibitors, compositions thereof, 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 inhibition of protein kinases such as, for example, hematopoietic progenitor kinase 1 (HPK1, MAP4K1), human Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase. JPEG2025525278000046.jpg39170

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 inhibition of protein kinases, such as, for example, hematopoietic progenitor kinase 1 (HPK1, MAP4K1), 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. Protein kinases play a crucial role in signal transduction related to numerous cellular functions, such as cell cycle, metabolism, carcinogenesis, differentiation, proliferation, and apoptosis. Furthermore, dysregulated protein kinases have been implicated in numerous pathologies, including immune, neoplastic, metabolic, neurological, and infectious diseases. Many protein kinases are particularly deregulated during tumorigenesis. Therefore, protein kinases are attractive targets for anticancer drugs. 【0003】 Serine / threonine kinases, which are specific for phosphorylating serine and threonine residues, constitute an important group of protein kinases. Another majority of protein kinases are tyrosine kinases, which are specific for phosphorylating tyrosine residues. In addition, there are some dual-specificity kinases that can phosphorylate tyrosine and serine / threonine residues (Expert Rev Anticancer Ther, 2018, 18(12): 1249-1270). 【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 predicted 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 existing intracellular checkpoint molecules. Degraders that target HPK1 for degradation in addition to inhibiting its kinase activity could overcome resistance by eliminating the underlying scaffold HPK1 function. 【0005】 Aurora kinases are a family of highly conserved serine / threonine kinases that are important for accurate transition through mitosis. Aurora kinase A plays a key role in centrosome maturation, spindle assembly, meiotic maturation, and metaphase I spindle orientation, and it has been found to be overexpressed in multiple human cancers (Front Oncol, 2015, 5: 278). A wide range of cancers, including AML, respond therapeutically to Aurora kinase inhibitors due to the overexpression of Aurora kinases in tumors and their association with genetic instability and aneuploidy. Although different Aurora kinase inhibitors have been tested in clinical trials, limited efficacy has been observed. Therefore, novel Aurora kinase inhibitors may be a strategy to achieve significantly improved clinical outcomes and overcome resistance. 【0006】 The human Fms-like tyrosine kinase 3 receptor (FLT3), also known as fetal liver kinase 2 (FLK-2), 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 occur in approximately 25% of patients, and point mutations in the tyrosine kinase domain (TKDs), such as D835 and I836, which occur in approximately 5% of patients. Both FLT3-ITD and FLT3-TKD mutations are constitutively active, leading to ligand-independent FLT3 signaling and cell proliferation (Front Oncol, 2020;10:612880). Current small molecule FLT3 inhibitors have not provided significant clinical benefit as monotherapy. There is a need to provide alternative FLT3 inhibitors that rapidly downmodulate FLT3 and induce downstream kinases in the STAT5 pathway in leukemia. 【0007】 In tumor malignancy, there are always multiple kinase abnormalities and multiple signaling pathways are dysregulated. In addition, a single molecular abnormality can also cause multiple downstream effects. Therefore, multi-targeted therapy using a single molecule (multiple kinase inhibitors or decomposers) to simultaneously target several kinases and several signaling pathways is more desirable than single-targeted therapy. 【0008】 Therefore, the present disclosure aims to provide compounds that simultaneously target several key signaling pathways. 【0009】 Given the aforementioned importance of protein kinases in tumorigenesis, multi-kinase inhibitors 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, multi-kinase inhibitors 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] 【0010】 [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] 【0011】 【Non-Patent Document 1】 Expert Rev Anticancer Ther, 2018, 18(12): 1249 - 1270 【Non-Patent Document 2】 Front Oncol, 2015, 5: 278 【Non-Patent Document 3】 Front Oncol, 2020;10:612880 【Non-Patent Document 4】 S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1 - 19 【Non-Patent Document 5】 Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding 【Non-Patent Document 6】 Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, Edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia 【Non-Patent Document 7】 Encyclopedia of Pharmaceutical Technology, Edited by J. Swarbrick 【Non-Patent Document 8】 J. C. Boylan, 1988 - 1999, Marcel Dekker, New York 【Summary of the Invention】 【Means for Solving the Problems】 【0012】 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 inhibition of protein kinases such as hematopoietic progenitor kinase 1 (HPK1, MAP4K1), human Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase. For example, a compound selected from the compounds of formula I: 【0013】 [ka] 【0014】 a compound of the formula: (i) R 1 and R 2 is a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear alkenyl group, a branched alkenyl group, a cyclic alkenyl group, a linear heteroalkenyl group, a branched heteroalkenyl group, a heteroalkenyl group, a linear alkynyl group, a branched alkynyl group, a 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 are independently selected from; (ii) R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 4is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO2R y , C(O)R w OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , R w N(R x R y )2, R w OR x , R z R', S(O)R y , and SO2R y Selected from; (iv) R x and R y are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; or R x and R y are attached to each other to form an optionally substituted heterocycloalkyl; (v) R w is absent or selected from linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, linear, branched and cyclic alkenyl groups, linear and branched heteroalkenyl groups; (vi) R z is absent or selected from linear, branched and cyclic alkyl groups; (vii) R ' is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; (viii) ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; (ix) Ring B is 【0015】 [ka] 【0016】 Selected from; In formula (x), each R " are independently selected from hydrogen, straight-chain, branched, and cyclic alkyl groups; or two R " combine to form a cycloalkylspirocyclic ring or a heterocycloalkylspirocyclic ring; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl 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; a 3- to 6-membered heterocyclic group, 3- to 6-membered spirocyclic alkyl groups, 3- to 6-membered spiroheterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1, or 2 C1-C6 alkyl groups selected from linear, branched, and cyclic alkyl groups is disclosed herein. 【0017】 In one aspect of the disclosure, the compound of formula I is selected from compounds 1 to 14 shown below, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing. 【0018】 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 comprises a compound selected from Compounds 1 to 14 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. 【0019】 Another aspect of the present disclosure provides methods of treating a disease, disorder, or condition mediated by the inhibition 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 14 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. 【0020】 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 or in separate compositions with 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. In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof a compound selected from Compounds 1 to 14 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 separate compositions. 【0021】 Also disclosed herein are methods of inhibiting 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 of inhibiting protein kinase activity comprises administering to a subject a compound selected from Compounds 1 to 14 shown below, a deuterated derivative of a tautomer thereof, the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of inhibiting protein kinase activity comprises contacting the protein kinase with a compound of Formula I, a deuterated derivative of a tautomer thereof, the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, a method of inhibiting a protein comprises contacting a protein kinase with a compound selected from compounds 1 to 14 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE INVENTION 【0022】 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. 【0023】 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. 【0024】 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. 【0025】 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. 【0026】 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). 【0027】 The compounds disclosed herein can inhibit 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 inhibitors, FLT3 inhibitors, or Aurora A inhibitors, and are useful for treating diseases such as cancer associated with such kinases. 【0028】 The term "inhibitor," as used herein, refers to a molecule that inhibits the activity of kinases such as HPK1, FLT3, and Aurora A. By "inhibit" herein is meant reducing the activity of a target enzyme compared to the activity of that enzyme in the absence of the inhibitor. For example, in some embodiments, the term "inhibit" refers to a decrease in HPK1 activity by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibit refers to a decrease in HPK1 activity by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibit refers to a decrease in HPK1 activity by about 95% to 100%, e.g., a 95%, 96%, 97%, 98%, 99%, or 100% decrease in activity. Such a decrease can be measured using a variety of techniques recognized by those skilled in the art, including in vitro kinase assays. 【0029】 The term "protein kinase inhibitor" or "protein kinase antagonist," as used herein, refers to a molecule that reduces, inhibits, or otherwise alleviates one or more of the biological activities of protein kinases, such as HPK1, FLT3, and Aurora A. Inhibition using a protein kinase inhibitor does not necessarily indicate complete elimination of protein kinase activity. Instead, activity may be reduced by a statistically significant amount, including, for example, at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in protein kinase activity compared to an appropriate control. For example, in some embodiments, the protein kinase inhibitor reduces, inhibits, or otherwise alleviates the serine / threonine kinase activity of HPK1. In some of these embodiments, the protein kinase inhibitor reduces, inhibits, or otherwise attenuates protein kinase-mediated phosphorylation of SLP76 and / or Gad. The presently disclosed compounds can directly bind to and inhibit the kinase activity of a protein kinase. 【0030】 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. 【0031】 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. 【0032】 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. 【0033】 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. 【0034】 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. 【0035】 "Stereoisomers," as used herein, refers to enantiomers and diastereomers. 【0036】 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). 【0037】 The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope. 【0038】 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. 【0039】 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. 【0040】 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. 【0041】 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. 【0042】 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. 【0043】 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). 【0044】 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. 【0045】 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. 【0046】 The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively. 【0047】 As used herein, a "cyano" or "nitrile" group refers to -C≡N. 【0048】 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. 【0049】 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. 【0050】 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. 【0051】 "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, wherein any two rings share only one common atom. 【0052】 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). 【0053】 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). 【0054】 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. 【0055】 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. 【0056】 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. 【0057】 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. 【0058】 The term "subject" refers to an animal, including, but not limited to, a human. 【0059】 The term "therapeutically effective amount" refers to the amount of a compound for which it is administered that produces the desired effect (e.g., improvement in the symptoms of diseases, disorders, and conditions mediated by the inhibition of kinases such as HPK1, reducing the severity of diseases, disorders, and conditions or their symptoms mediated by the inhibition of kinases such as HPK1, and / or reducing the progression of diseases, disorders, and conditions or their symptoms mediated by the inhibition of kinases such as HPK1). The exact amount of a 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). 【0060】 As used herein, the term "treatment" and its cognates refer to slowing or halting disease progression. "Treatment" and its cognates as used herein include, but are not limited to: complete or partial remission of, and lower risk of, diseases, disorders, and conditions mediated by the inhibition of kinases such as HPK1, FLT3, and Aurora A, 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. 【0061】 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. 【0062】 II. Compounds and Compositions In a first embodiment, the compound has the following structural formula I: 【0063】 [ka] 【0064】 a compound of the formula: (i) R 1 and R 2 is a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear alkenyl group, a branched alkenyl group, a cyclic alkenyl group, a linear heteroalkenyl group, a branched heteroalkenyl group, a heteroalkenyl group, a linear alkynyl group, a branched alkynyl group, a cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)Rw N(R x R y )2, OC(O)R w NR x R y , S(O)R y , and SO2R y are independently selected from; (ii) R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO2R y , C(O)R w OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , R w N(R x R y )2, R w OR x , R z R', S(O)R y , and SO2R y Selected from; (iv) R x and R y are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; or R x and R y are attached to each other to form an optionally substituted heterocycloalkyl; (v) R w is absent or selected from linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, linear, branched and cyclic alkenyl groups, linear and branched heteroalkenyl groups; (vi) R zis absent or selected from linear, branched and cyclic alkyl groups; (vii) R ' is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; (viii) ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; (ix) Ring B is 【0065】 [ka] 【0066】 Selected from; In formula (x), each R " are independently selected from hydrogen, straight-chain, branched, and cyclic alkyl groups; or two R " combine to form a cycloalkylspirocyclic ring or a heterocycloalkylspirocyclic ring; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl 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; a 3- to 6-membered heterocyclic group, 3- to 6-membered spirocyclic alkyl groups, 3- to 6-membered spiroheterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1, or 2 C1-C6 alkyl groups selected from linear, branched, and cyclic alkyl groups is disclosed herein. 【0067】 In a second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 and R 2are independently selected from hydrogen, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; R 4 is a halogen group; all other variables not specifically defined herein are as defined in the first embodiment. 【0068】 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 embodiment. 【0069】 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. 【0070】 In a fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is a heterocyclic group; all other variables not specifically defined herein are as defined in the first embodiment. 【0071】 In a sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from straight-chain, branched, and cyclic alkynyl groups; all other variables not specifically defined herein are as defined in the first embodiment. 【0072】 In a seventh embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, straight-chain, branched, and cyclic alkynyl groups are substituted with at least one group selected from C1-C6 straight-chain, branched, and cyclic alkyl groups, C1-C6 straight-chain, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups; all other variables not specifically defined herein are as defined in the sixth embodiment. 【0073】 In an eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is hydrogen; all other variables not specifically defined herein are as defined in any of the preceding embodiments. 【0074】 In a ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any of embodiments 1-7. 【0075】 In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl; all other variables not specifically defined herein are as defined in the ninth embodiment. 【0076】 In an eleventh 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 any of the preceding embodiments. 【0077】 In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is fluoro; all other variables not specifically defined herein are as defined in the eleventh embodiment. 【0078】 In a thirteenth 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 eleventh embodiment. 【0079】 In a fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from an aryl group; all other variables not specifically defined herein are as defined in any of the preceding embodiments. 【0080】 In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is phenyl; all other variables not specifically defined herein are as defined in the fourteenth embodiment. 【0081】 In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from an aryl group, wherein the aryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in the fourteenth embodiment. 【0082】 In a seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is selected from aryl groups, where the aryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the fourteenth embodiment. 【0083】 In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from heteroaryl groups; all other variables not specifically defined herein are as defined in any of embodiments 1-13. 【0084】 In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is selected from a heteroaryl group, wherein the heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in the eighteenth embodiment. 【0085】 In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is selected from heteroaryl groups, where the heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the eighteenth embodiment. 【0086】 In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from a 6-membered heteroaryl group; all other variables not specifically defined herein are as defined in the eighteenth embodiment. 【0087】 In a twenty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in the twenty-first embodiment. 【0088】 In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from 6-membered heteroaryl groups, where the 6-membered heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-first embodiment. 【0089】 In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is a pyridine ring; all other variables not specifically defined herein are as defined in the twenty-third embodiment. 【0090】 In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is a pyrimidine ring; all other variables not specifically defined herein are as defined in the twenty-third embodiment. 【0091】 In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from a five-membered heteroaryl group; all other variables not specifically defined herein are as defined in the eighteenth embodiment. 【0092】 In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from a five-membered heteroaryl group, wherein the five-membered heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in the twenty-sixth embodiment. 【0093】 In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from 5-membered heteroaryl groups, where the 5-membered heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-sixth embodiment. 【0094】 In a 29th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is a thiazole ring; all other variables not specifically defined herein are as defined in the 28th embodiment. 【0095】 In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0096】 [ka] 【0097】 and all other variables not specifically defined herein are as defined in any of the preceding embodiments. 【0098】 In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0099】 [ka] 【0100】 and all other variables not specifically defined herein are as defined in any of embodiments 1-30. 【0101】 In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0102】 [ka] 【0103】 and all other variables not specifically defined herein are as defined in any of embodiments 1-30. 【0104】 In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0105】 [ka] 【0106】 and all other variables not specifically defined herein are as defined in any of embodiments 1-30. 【0107】 In a thirty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is 【0108】 [ka] 【0109】 and all other variables not specifically defined herein are as defined in any of embodiments 1-30. 【0110】 In a thirty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is hydrogen; all other variables not specifically defined herein are as defined in any of the preceding embodiments. 【0111】 In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any of embodiments 1-35. 【0112】 In a thirty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl; all other variables not specifically defined herein are as defined in the thirty-sixth embodiment. 【0113】 In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 14 shown in Table 1 below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing. 【0114】 [Table 1] 【0115】 Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the compounds of formula I, compounds 1 to 14, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharmaceutically acceptable carrier. 【0116】 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. 【0117】 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 14, 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. 【0118】 As discussed above, the pharmaceutical compositions disclosed herein further comprise 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, dispersing aids, suspending 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. 【0119】 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 14, 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 a disease, disorder, or condition mediated by the inhibition of a protein kinase. 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 14, 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 a disease, disorder, or condition mediated by the inhibition of a protein kinase. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by the inhibition 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 14, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. 【0120】 In some embodiments, the protein kinase is selected from hematopoietic progenitor kinase 1 (HPK1), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. 【0121】 In some embodiments, the disease, disorder, or condition is selected from a protein kinase-associated disease, hi some embodiments, the disease, disorder, or condition is selected from a FLT3-associated disease, hi some embodiments, the disease, disorder, or condition is selected from an Aurora A-associated disease. 【0122】 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 (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). 【0123】 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. 【0124】 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 14, 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 14, 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 1-14, 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 1-14, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. 【0125】 The compounds of Formula I, compounds 1 to 14, 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 inhibition of protein kinases. 【0126】 In some embodiments, 2 mg to 1500 mg of a compound of Formula I, compounds 1-14, 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. For example, in some embodiments, 5 mg to 1000 mg, 10 mg to 500 mg, 20 mg to 300 mg, 20 mg to 200 mg, 30 mg to 150 mg, 50 mg to 150 mg, 60 mg to 125 mg, or 70 mg to 120 mg, 80 mg to 115 mg, 90 mg to 110 mg, 95 mg to 110 mg, or 100 mg to 105 mg of at least one compound of Formula I, Compounds 1-14, a tautomer thereof, a deuterated derivative of a compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is administered once daily, twice daily, or three times daily. 【0127】 The compounds of Formula I, compounds 1 to 14, 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. 【0128】 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. 【0129】 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. 【0130】 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). 【0131】 Non-limiting illustrative embodiments 1. Formula (I): 【0132】 [ka] 【0133】 a compound of the formula: (i) R 1 and R 2 is a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear alkenyl group, a branched alkenyl group, a cyclic alkenyl group, a linear heteroalkenyl group, a branched heteroalkenyl group, a heteroalkenyl group, a linear alkynyl group, a branched alkynyl group, a 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 are independently selected from; (ii) R 3 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO2R y , C(O)R w OR y , C(O)R w N(R x R y )2, OC(O)R w NR x R y , R w N(R x R y )2, R w OR x , R z R', S(O)R y , and SO2R y Selected from; (iv) R x and R y are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; or R x and R y are attached to each other to form an optionally substituted heterocycloalkyl; (v) R w is absent or selected from linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, linear, branched and cyclic alkenyl groups, linear and branched heteroalkenyl groups; (vi) R z is absent or selected from linear, branched and cyclic alkyl groups; (vii) R ' is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; (viii) ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; (ix) Ring B is 【0134】 [ka] 【0135】 Selected from; In formula (x), each R " are independently selected from hydrogen, straight-chain, branched, and cyclic alkyl groups; or two R " combine to form a cycloalkylspirocyclic ring or a heterocycloalkylspirocyclic ring; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl 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; a 3- to 6-membered heterocyclic group, 3- to 6-membered spirocyclic alkyl groups, 3- to 6-membered spiroheterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1, or 2 C1-C6 alkyl groups selected from straight-chain, branched, and cyclic alkyl groups). 2.R 1 and R 2 are independently selected from hydrogen, linear alkyl groups, branched alkyl groups, and cyclic alkyl groups; R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein is a halogen group. 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 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein is a heterocyclic group. 6.R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein is selected from linear, branched, and cyclic alkynyl groups. 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 6, wherein the straight-chained, branched, and cyclic alkynyl group is substituted with at least one group selected from C1-C6 straight-chained, branched, and cyclic alkyl groups, C1-C6 straight-chained, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. 8.R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-7, wherein is hydrogen. 9.R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-7, wherein is selected from linear, branched, and cyclic alkyl groups. 10.R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 9, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 11.R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-3, wherein is a halogen group. 12.R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 11, wherein is fluoro. 13.R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 11, wherein is chloro. 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-13, wherein Ring A is selected from aryl groups. 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring A is phenyl. 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring A is selected from an aryl group, wherein the aryl group is substituted with a halogen group. 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring A is selected from aryl groups, where the aryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups. 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-13, wherein Ring A is selected from heteroaryl groups. 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 18, wherein Ring A is selected from a heteroaryl group, wherein the heteroaryl group is substituted with a halogen group. 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 18, wherein Ring A is selected from heteroaryl groups, where the heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups. 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 18, wherein Ring A is selected from a 6-membered heteroaryl group. 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 21, wherein ring A is selected from a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is substituted with a halogen group. 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 21, wherein ring A is selected from 6-membered heteroaryl groups, where the 6-membered heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups. 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein ring A is a pyridine ring. 25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein ring A is a pyrimidine ring. 26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 18, wherein Ring A is selected from a 5-membered heteroaryl group. 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 26, wherein ring A is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is substituted with a halogen group. 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 26, wherein Ring A is selected from 5-membered heteroaryl groups, where the 5-membered heteroaryl groups are substituted with C1-C6 straight, branched, and cyclic alkyl groups. 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 28, wherein ring A is a thiazole ring. 30. Ring B is 【0136】 [ka] 【0137】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 31. Ring B is 【0138】 [ka] 【0139】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 32. Ring B is 【0140】 [ka] 【0141】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 33. Ring B is 【0142】 [ka] 【0143】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 34. Ring B is 【0144】 [ka] 【0145】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 35.R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-34, wherein is hydrogen. 36.R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-34, wherein is selected from linear, branched, and cyclic alkyl groups. 37.R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiments 1-34, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 38. 【0146】 [Table 2] 【0147】 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. 39. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 38, or at least one pharmaceutically acceptable carrier. 40. A method for treating or alleviating a disease, disorder, or condition mediated by inhibition of protein kinases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 38, or a pharmaceutical composition according to embodiment 39. 41. The method of embodiment 40, wherein the protein kinase is selected from hematopoietic progenitor kinase 1 (HPK1), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. 42. 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 38, or a pharmaceutical composition according to embodiment 39. 43. The method of embodiment 40 or 42, wherein the disease, disorder, or condition is selected from protein kinase-associated diseases. 44. The method of embodiment 43, wherein the protein kinase-associated disease is cancer. 45. The method of embodiment 44, wherein the cancer is a solid tumor. 46. The method of embodiment 45, 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. 47. The method of embodiment 44, wherein the cancer is a blood cancer. 48. The method of embodiment 47, 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 (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). 49. 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 45. The method of embodiment 44, 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. 50. The method of embodiment 40 or 42, further comprising administering to the subject an existing standard of care or FDA-approved therapy. 51. The method of embodiment 40 or 42, further comprising administering one or more separate pharmaceutical agents to the subject. 52. The method of embodiment 51, wherein the separate pharmaceutical agents are selected from chemotherapeutic agents, immunotherapeutic agents, and adjunctive therapeutic agents. [Example] 【0148】 Example 1 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. 【0149】 All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of this disclosure. 【0150】 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, as well as in the descriptions for preparing the compounds of Formula I, compounds 1 through 14, 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 【0151】 Preparation of intermediates: Intermediate A1: 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine 【0152】 [ka] 【0153】 Step 1. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: 【0154】 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] + . 【0155】 Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 【0156】 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] + . 【0157】 Step 3. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: 【0158】 To a solution of A1-3 (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), and 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] + . 【0159】 Step 4. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 【0160】 To a solution of A1-4 (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] + . 【0161】 Intermediate A2: 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine 【0162】 [ka] 【0163】 Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine: 【0164】 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). 【0165】 Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine: 【0166】 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 several portions. The reaction mixture was stirred at 80 °C for 6 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). 【0167】 Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine: 【0168】 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] + . 【0169】 Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine: 【0170】 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). 【0171】 General synthesis procedure I: 【0172】 [ka] 【0173】 Step 1. Preparation G-2: To a mixture of G-1 (1.24 mmol) in dioxane (5 mL), KOAc (3.73 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (379 mg, 1.49 mmol), and Pd(dppf)Cl (54 mg, 0.074 mmol) were added. The reaction mixture was degassed with N three times and stirred at 110 °C under N for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 0-40%) to give product G-2. 【0174】 Step 2. Preparation of G-3: To a mixture of G-2 (0.764 mmol) in dioxane / HO (10:1, 5.00 mL) was added KCO (317 mg, 2.29 mmol), Intermediate A1 or A2 (0.764 mmol), and Pd(dppf)Cl (55 mg, 0.0763 mmol). The reaction 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 water (20 mL), then extracted with EA (20 mL × 3), washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 40–60] to give the product. 【0175】 Compound 1: 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 【0176】 [ka] 【0177】 Step 1. 4-(3-Bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one: A mixture of 3-bromoaniline (6.01 g, 34.9 mmol), methyl hydrazinocarboxylate (3 g, 33.3 mmol), triethyl orthoformate (4.94 g, 33.3 mmol), and TsOH (0.13 g, 0.6 mmol) in MeOH (80 mL) was stirred at 65 °C under N for 3 h. After cooling to room temperature, NaOMe (5.4 g, 99.9 mmol) was added, and the mixture was stirred at room temperature for 18 h. After concentration in vacuo, EA (80 mL) and HO (80 mL) were added to the residue, which was then acidified to pH 5–6 with 1 N aqueous HCl. The aqueous phase was extracted with EA (80 mL × 3). The combined organic layers were washed with HO (100 mL) and then twice with 1N aqueous NaOH. The combined NaOH extracts were acidified with concentrated HCl, and the resulting solid was collected by filtration, washed with HO, and dried to give the target product (2 g, 25%) as a white solid. Mass (m / z): 239.9 [M+H] + . 【0178】 Step 2. According to the general synthetic procedure I, the compound 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6 mg, 4%) was obtained from 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one and intermediate A1 as a white solid. Mass (m / z): 453.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.84 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.86 - 7.71 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.41 (d, J = 2.4 Hz, 1H), 2.93 (d, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H). 【0179】 Compound 2: 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 【0180】 [ka] 【0181】 According to Step 2 of General Synthetic Procedure I, the compound 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (23 mg, 18%) was obtained as a white solid from 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,4-triazol-3-one and Intermediate A2. Mass (m / z): 351.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.81 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.83 (t, J = 1.8 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 1.4 Hz, 1H), 2.27 - 2.16 (m, 1H), 0.90 - 0.79 (m, 2H), 0.69 - 0.58 (m, 2H). 【0182】 Example 3 1-(3-{4-chloro-3-ethyl-1H-pyrrole[2,3-b]pyridin-3-yl}phenyl)imidazolidin-2-one 【0183】 [ka] 【0184】 According to the general synthetic procedure I, the compound 1-(3-{4-chloro-3-ethyl-1H-pyrrole[2,3-b]pyridin-3-yl}phenyl)imidazolidin-2-one (90 mg, 34%) was obtained from 1-(3-bromophenyl)imidazolidin-2-one and intermediate A1 as a white solid. Mass (m / z): 341.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 13.26 (s, 1H), 8.11 (s, 1H), 7.73 (s, 1H), 7.50 (dd, J = 19.2, 7.8 Hz, 2H), 7.34 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 4.01 (s, 2H), 3.67 (S, 2H), 3.03 (q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.4 Hz, 3H). 【0185】 Compound 4: 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)imidazolidin-2-one 【0186】 [ka] 【0187】 According to Step 2 of General Synthetic Procedure I, the compound 1-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)imidazolidin-2-one (23 mg, 11%) was obtained as a white solid from 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazolidin-2-one and Intermediate A2. Mass (m / z): 352.9 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 13.14 (s, 1H), 8.09 (s, 1H), 7.76 (s, 1H), 7.48 (s, 2H), 7.18 (d, J = 28.0 Hz, 2H), 4.01 (s, 2H), 3.66 (s, 2H), 2.22 (s, 1H), 1.00 (d, J = 7.6 Hz, 2H), 0.70 (d, J = 4.2 Hz, 2H). 【0188】 Compound 5: 1-(4-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-1,3-thiazol-2-yl)-1,3-diazinan-2-one 【0189】 [ka] 【0190】 Step 1. Preparation of 1-(4-bromo-1,3-thiazol-2-yl)-1,3-diazinan-2-one: To a solution of 4-bromo-1,3-thiazol-2-amine (2 g, 11.2 mmol) in DMF (30 mL) was added 1-chloro-3-isocyanatopropane (2.68 g, 22.4 mmol) and DIEA (4.34 g, 33.6 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EtOAc = 1:1) to give the product as a yellow solid (1.4 g, 44%). Mass (m / z): 262.0 [M+H] + . 【0191】 Step 2. According to the general synthesis procedure I, the compound 1-(4-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-1,3-thiazol-2-yl)-1,3-diazinan-2-one was obtained from 1-(4-bromo-1,3-thiazol-2-yl)-1,3-diazinan-2-one and intermediate A2 as a yellow solid (16 mg, 4.7%). Mass (m / z): 374.1 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.56 (s, 1H), 7.45 (d, J = 6.9 Hz, 2H), 7.26 (s, 1H), 4.11 (t, J = 5.8 Hz, 2H), 3.25 (s, 2H), 2.22 (s, 1H), 2.00 (s, 2H), 0.90 - 0.80 (m, 2H), 0.64 (t, J = 4.6 Hz, 2H). 【0192】 Compound 6: 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)imidazolidin-2-one 【0193】 [ka] 【0194】 Step 1. Preparation of 1-(6-bromopyridin-2-yl)-3-(2-chloroethyl)urea: To a solution of 6-bromopyridin-2-amine (3 g, 0.017 mol) in THF (60 mL) was added 1-chloro-2-isocyanatoethane (2.19 g, 0.02 mol). The reaction mixture was stirred at 75° C. under N2 for 18 hours. The reaction mixture was filtered. The cake was dried to give the product 1-(6-bromopyridin-2-yl)-3-(2-chloroethyl)urea (3.87 g, 80%) as a white solid. Mass (m / z): 279.8 [M+H] + . 【0195】 Step 2. Preparation of 1-(6-bromopyridin-2-yl)imidazolidin-2-one: To a solution of 1-(6-bromopyridin-2-yl)-3-(2-chloroethyl)urea (3.87 g, 0.014 mol) in THF (60 mL) was added NaH (60% in oil, 0.83 g, 0.021 mol) at 0 °C. The reaction mixture was stirred at room temperature under N for 1 hour. After the reaction was completed, the reaction mixture was added to ice water (100 mL) and then extracted with EA (150 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and then dried over anhydrous Na SO . The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the product 1-(6-bromopyridin-2-yl)imidazolidin-2-one as a white solid (3.47 g, 82%). Mass (m / z): 243.8 [M+H] + . 【0196】 Step 3. According to the general synthetic procedure I, the compound 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)imidazolidin-2-one was obtained from 1-(6-bromopyridin-2-yl)imidazolidin-2-one and intermediate A2 as a white solid (11 mg, 8%). Mass (m / z): 354.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.32 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.24 (s, 1H), 4.09 - 4.00 (m, 2H), 3.45 - 3.38 (m, 2H), 2.22 (d, J = 4.8 Hz, 1H), 0.86 (dt, J = 5.8, 4.2 Hz, 2H), 0.65 (q, J = 5.8 Hz, 2H). 【0197】 Compound 7: 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one 【0198】 [ka] 【0199】 Step 1. 1-(4-Bromo-5-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one: To a solution of 4-bromo-5-methyl-1,3-thiazol-2-amine (1 g, 5.18 mmol) and DIEA (2 g, 15.53 mmol) in DMF (2 mL) was added 1-chloro-3-isocyanatopropane (681 mg, 5.69 mmol). The reaction mixture was stirred at 120 °C under N for 18 h. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 1:3) to give the desired product (600 mg, yield: 39%) as a brown solid. Mass (m / z): 276.0 [M+H] + . 【0200】 Step 2. According to the general synthetic procedure I, the compound 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (15 mg, 5%) was obtained from 1-(4-bromo-5-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one and intermediate A2 as a yellow solid. Mass (m / z): 388.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 1.8 Hz, 1H), 3.96 (t, J = 5.8 Hz, 2H), 3.23 (s, 2H), 2.26 - 2.11 (m, 4H), 1.96 (d, J = 5.8 Hz, 2H), 0.89 - 0.80 (m, 2H), 0.68 - 0.58 (m, 2H). 【0201】 Compound 8: 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)tetrahydropyrimidin-2(1H)-one 【0202】 [ka] 【0203】 Step 1. Preparation of 1-(6-bromopyridin-2-yl)-3-(4-chlorobutyl)urea: To a solution of 6-bromopyridin-2-amine (3 g, 0.017 mol) in THF (60 mL) was added 1-chloro-3-isocyanatopropane (2.48 g, 0.02 mol) and TEA (3.49 g, 0.035 mmol). The reaction mixture was stirred at 75 °C under N for 18 hours. The reaction mixture was filtered. The cake was dried to give the product 1-(6-bromopyridin-2-yl)-3-(4-chlorobutyl)urea (3.4 g, 70%) as a white solid. Mass (m / z): 293.8 [M+H] + . 【0204】 Step 2. Preparation of 1-(6-bromopyridin-2-yl)tetrahydropyrimidin-2(1H)-one: To a solution of 1-(6-bromopyridin-2-yl)-3-(4-chlorobutyl)urea (3.4 g, 0.006 mol) in THF (60 mL) was added NaH (60% in oil, 0.67 g, 0.017 mol) at 0 °C. The reaction mixture was stirred at room temperature under N for 1 hour. After the reaction was completed, the reaction mixture was added to ice water (100 mL) and then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and then dried over anhydrous NaSO. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the product 1-(6-bromopyridin-2-yl)tetrahydropyrimidin-2(1H)-one (3.36 g, 94%) as a white solid. Mass (m / z): 255.9 [M+H] + . 【0205】 Step 3. According to the general synthetic procedure I, the compound 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)tetrahydropyrimidin-2(1H)-one (19 mg, 5%) was obtained from 1-(6-bromopyridin-2-yl)tetrahydropyrimidin-2(1H)-one and intermediate A2 as a white solid. Mass (m / z): 368.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.32 (dd, J = 12.0, 4.4 Hz, 2H), 6.94 (s, 1H), 3.98 - 3.89 (m, 2H), 3.23 (t, J = 4.6 Hz, 2H), 2.26 - 2.18 (m, 1H), 1.95 (dd, J = 11.4, 5.8 Hz, 2H), 0.89 - 0.81 (m, 2H), 0.69 - 0.61 (m, 2H). 【0206】 Compound 9: 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one 【0207】 [ka] 【0208】 Step 1. Preparation of 3-(3-chloropropyl)-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea: To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 9.13 mmol) in DCM (20.0 mL) was added 1-chloro-3-isocyanatopropane (1.31 g, 10.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the product, 3-(3-chloropropyl)-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (3.30 g, 96%) as a white solid. Mass (m / z): 340.9 [M+H] + . 【0209】 Step 2. Preparation of 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one: To a mixture of 3-(3-chloropropyl)-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (3.30 g, 9.74 mmol) in THF (30.0 mL) was added NaH (60% in oil, 702 mg, 29.2 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min and then at 50° C. for 2 h. The reaction mixture was quenched with NH4Cl solution (50 mL) and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to give the product 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one (1.20 g, 36%) as a white solid. Mass (m / z): 303.0 [M+H] + . 【0210】 Step 3. According to Step 2 of General Synthetic Procedure I, the compound 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-diazinan-2-one (30 mg, 16%) was obtained from 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one and Intermediate A1 as a white solid. Mass (m / z): 354.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.16 (s, 1H), 7.46 - 7.40 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H), 5.58 (s, 1H), 3.78 (s, 2H), 3.47 (d, J = 8.2 Hz, 2H), 3.00 (q, J = 7.4 Hz, 2H), 2.13 (d, J = 5.0 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H). 【0211】 Compound 10: 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione 【0212】 [ka] 【0213】 Step 1: Preparation of tert-butyl 3-(3-bromophenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate: To a solution of tert-butyl {2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl}formate (2 g, 7.80 mmol) and (3-bromophenyl)boranediol (2.03 g, 10.14 mmol) in DCM (40 mL) was added Cu(OAc) (1.41 g, 7.80 mmol) and pyridine (1.85 g, 23.41 mmol). The reaction mixture was stirred at room temperature under 1 atm of O for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=20:1) to give the product as a white solid (2 g, 56%). Mass (m / z): 432.0 434.0 [M+Na] + . 【0214】 Step 2: Preparation of tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate: According to the general synthetic procedure I, the compound tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate was obtained from tert-butyl 3-(3-bromophenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate and intermediate A2 as a yellow oil (800 mg, 78%). Mass (m / z): 522.0 [M+H] + . 【0215】 Step 3: Preparation of 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: To a solution of tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate (300 mg, 0.573 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by pre-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm, ACN-H2O (0.1% FA), 20-50] to give the product as a white solid (110 mg, 44%). Mass (m / z): 422.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.37 (s, 1H), 9.04 (s, 1H), 8.12 (s, 1H), 7.73 - 7.41 (m, 4H), 7.33 (d, J = 1.6 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.46 - 3.39 (m, 2H), 2.48 - 2.38 (m, 1H), 2.34 - 2.16 (m, 2H), 1.32 - 1.17 (m, 1H), 0.91 - 0.79 (m, 2H), 0.71 - 0.52 (m, 2H). 【0216】 Compound 11: 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,3,7-triazaspiro[4.4]nonan-2-one 【0217】 [ka] 【0218】 Step 1: Preparation of tert-butyl 2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate: To a solution of tert-butyl {2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl}formate (500 mg, 1.95 mmol) in THF (20 mL) was added BH3-THF (1 M, 10 mL, 9.755 mmol). The reaction mixture was stirred at 65 °C under N2 for 3 hours. The reaction mixture was concentrated. 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 (20 mL × 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo to give the product as a white solid (400 mg, 67%). Mass (m / z): 483.3[2M+H] + . 【0219】 Step 2: Preparation of tert-butyl 3-(3-bromophenyl)-2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate: To a solution of tert-butyl {2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl}formate (250 mg, 0.97 mmol) and (3-bromophenyl)boranediol (588 mg, 2.92 mmol) in DCM (10 mL) was added Cu(OAc) (354 mg, 1.95 mmol) and pyridine (231 mg, 2.92 mmol). The reaction mixture was stirred at 25 °C under 1 atm of O for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give the product as a yellow solid (60 mg, 16%). Mass (m / z): 339.9[M-55] + . 【0220】 Step 3: Preparation of tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate: According to the general synthetic procedure I, the compound tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate was obtained from tert-butyl 3-(3-bromophenyl)-2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate and intermediate A2 as a yellow oil (80 mg, 100%). Mass (m / z): 508.0 [M+H] + . 【0221】 Step 4: Preparation of 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,3,7-triazaspiro[4.4]nonan-2-one: To a solution of tert-butyl 3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate (80 mg, 0.157 mmol) in DCM (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated, and the residue was purified by pre-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-H2O (0.1% FA), 18–30] to give the product as a yellow solid (3.5 mg, 5.5%). Mass (m / z): 204.6 [M / 2+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.10 (s, 1H), 7.68 - 7.55 (m, 3H), 7.46 - 7.40 (m, 1H), 7.31 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 3.97 (dd, J = 18.2, 9.8 Hz, 2H), 3.23 (d, J = 11.3 Hz, 3H), 3.05 (d, J = 11.6 Hz, 1H), 2.25 - 2.17 (m, 1H), 2.11 - 1.98 (m, 2H), 0.90 - 0.81 (m, 2H), 0.69 - 0.60 (m, 2H). 【0222】 Compound 12: 4-chloro-N-ethyl-N-methyl-5-(3-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide 【0223】 [ka] 【0224】 Step 1: Preparation of 1-(3-chloropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea: To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1000 mg, 4.5644 mmol) in DCM (20 mL) was added prop-2-enal (654.81 mg, 5.4772 mmol), and the reaction solution was stirred at room temperature for 18 hours and concentrated under reduced pressure to give the target product (1500 mg, 97.04%) as a white solid. Mass (m / z): 339 [M+H] + . 【0225】 Step 2. Preparation of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-2(1H)-one: To a mixture of 3-(3-chloropropyl)-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (1500 mg, 4.42 mmol) in THF (30 mL) was added NaH (531 mg, 13.28 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and at 50° C. for 2 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE=1:1) to give the product (350 mg, yield: 24.84%) as a white solid. Mass (m / z): 303 [M+H] + . 【0226】 Step 3. Preparation of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid: To a solution of 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) in DCM (10 mL) was added AlCl (719 mg, 5.4 mmol). The reaction solution was stirred at room temperature for 1 hour. Then, 2,2,2-trichloroacetyl chloride (471.31 mg, 2.592 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by column chromatography (DCM / MeOH=10:1) to give the target product (250 mg, 39.91%) as a yellow solid. Mass (m / z): 275 [M+H] + . 【0227】 Step 4. Preparation of 5-bromo-4-chloro-N-ethyl-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide: A solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (200 mg, 0.726 mmol), ethyl(methyl)amine (51 mg, 0.87 mmol), DIEA (281 mg, 2.178 mmol), and T3P (50% in EA, 1385 mg, 2.178 mmol) in EA (2 mL). The reaction mixture was stirred at 75 °C under N for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10:1) to give the desired product (70 mg, yield: 28%) as a white solid. Mass (m / z): 316 [M+H] + . 【0228】 Step 5. Preparation of 4-chloro-N-ethyl-N-methyl-5-(3-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide: To a mixture of 5-bromo-4-chloro-N-ethyl-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (60 mg, 0.189 mmol), 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-2-one (85 mg, 0.284 mmol), and KCO (52 mg, 0.379 mmol) in dioxane / HO (10:1, 1 mL) under N was added Pd(dppf)Cl (15 mg, 0.0189 mmol). The reaction mixture was stirred at 90 °C for 18 hours. The reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 10–40] to give the desired product (2.5 mg, yield: 3%) as a white solid. Mass (m / z): 412 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 2H), 7.58 (s, 1H), 7.49 (dd, J = 21.8, 14.2 Hz, 4H), 7.17 (s, 1H), 3.78 (s, 2H), 3.64 (d, J = 7.0 Hz, 1H), 3.51 (s, 2H), 3.31 (s, 1H), 3.12 (s, 1H), 2.92 (s, 1H), 2.16 (s, 2H), 1.25 (s, 2H), 1.10 (s, 2H). 【0229】 Compound 13: 3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(2-oxotetrahydropyrimidin-1(2H)-yl)benzonitrile 【0230】 [ka] 【0231】 Step 1: Preparation of 3-bromo-5-isocyanatobenzonitrile: To a solution of 3-amino-5-bromobenzonitrile (1 g, 5.08 mmol) in DCE (20 mL) was added TEA (0.5 g, 5.08 mmol) and BTC (1.51 g, 5.08 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solution was concentrated under reduced pressure to give the product, 3-bromo-5-isocyanatobenzonitrile, as a yellow solid (1.5 g, 80%). 【0232】 Step 2. Preparation of 1-(3-bromo-5-cyanophenyl)-3-(3-chloropropyl)urea: To a solution of 3-bromo-5-isocyanatobenzonitrile (1.5 g, 6.76 mmol) in DCM (30 mL), 3-chloropropan-1-amine hydrochloride (580 mg, 5.63 mmol) and DIEA (1.15 g, 11.26 mmol) were added. The reaction mixture was stirred at room temperature under N for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EtOAc = 1:1) to give the product 1-(3-bromo-5-cyanophenyl)-3-(3-chloropropyl)urea as a yellow oil (1.39 g, 98%). Mass (m / z): 317.9 [M+H] + . 【0233】 Step 3. Preparation of 3-bromo-5-(2-oxotetrahydropyrimidin-1(2H)-yl)benzonitrile: To a solution of 1-(3-bromo-5-cyanophenyl)-3-(3-chloropropyl)urea (150 mg, 0.48 mmol) in DCM (10 mL) was added TEA (144 mg, 1.44 mmol) and BTC (65 mg, 0.24 mmol). The reaction mixture was stirred at room temperature under N for 3 hours. After the reaction was complete, HO (50 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum. The residue was purified by flash chromatography (PE / EtOAc=1:1) to give the product 3-bromo-5-(2-oxotetrahydropyrimidin-1(2H)-yl)benzonitrile as a yellow solid (60 mg, 48%). Mass (m / z): 282.0 [M+H] + . 【0234】 Step 4. Preparation of 3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(2-oxotetrahydropyrimidin-1(2H)-yl)benzonitrile: According to General Synthetic Procedure I, the product was obtained from 3-bromo-5-(2-oxotetrahydropyrimidin-1(2H)-yl)benzonitrile and Intermediate A2 as a white solid (5 mg, 6.4%). Mass (m / z): 392.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.77 (dd, J = 7.8, 1.6 Hz, 2H), 7.67 (s, 1H), 7.18 (s, 1H), 3.82 (s, 2H), 3.40 (t, J = 5.8 Hz, 2H), 2.25 (t, 1H), 2.17 - 2.09 (m, 2H), 0.91 (dd, J = 8.2, 1.8 Hz, 2H), 0.65 (dd, J = 5.2, 1.6 Hz, 2H). 【0235】 Compound 14: 1-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)phenyl)tetrahydropyrimidin-2(1H)-one 【0236】 [ka] 【0237】 Step 1. N 1Preparation of -(5-bromo-2-(methylsulfonyl)phenyl)propane-1,3-diamine: To a mixture of 4-bromo-2-fluoro-1-methanesulfonylbenzene (1000 mg, 3.95 mmol), 1,3-diaminopropane-1,2,3-tris(ylium) (577 mg, 7.90 mmol), and K2CO3 (1092 mg, 7.90 mmol) in DMSO (10 mL) was added. The reaction mixture was stirred at 80 °C for 18 h. The reaction was filtered and concentrated. The residue was purified by Combiflash using MeOH:DCM (1:10) to give the product (600 mg, 46% yield) as a brown solid. Mass (m / z): 307 [M+H] + . 【0238】 Step 2. Preparation of 1-(5-bromo-2-(methylsulfonyl)phenyl)tetrahydropyrimidin-2(1H)-one: To a solution of N-(3-aminopropyl)-5-bromo-2-methanesulfonylaniline (600 mg, 1.30 mmol), DIEA (503 mg, 3.90 mmol) in DCM (20 mL) was added a solution of BTC (405 mg, 1.36 mmol) in DCM (5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature under N for 18 hours. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE=1:1) to give the desired product (500 mg, yield: 72%) as a brown solid. Mass (m / z): 333 [M+H] + . 【0239】 Step 3. Preparation of 1-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)phenyl)tetrahydropyrimidin-2(1H)-one: Following General Synthetic Procedure I, the desired product (10 mg, yield: 5.8%) was obtained from 1-(5-bromo-2-(methylsulfonyl)phenyl)tetrahydropyrimidin-2(1H)-one and Intermediate A2 as a white solid. Mass (m / z): 445.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.2, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.77 (s, 1H), 3.62 - 3.53 (m, 1H), 3.48 (dd, J = 10.8, 5.2 Hz, 1H), 3.25 - 3.16 (m, 5H), 2.21 - 2.12 (m, 1H), 2.01 - 1.87 (m, 2H), 0.85 - 0.75 (m, 2H), 0.65 - 0.55 (m, 2H). 【0240】 Example 2 Biological Data HPK1 enzyme 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. 【0241】 FLT3-ITD enzyme 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. 【0242】 Aurora A enzyme 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. 【0243】 [Table 3] 【0244】 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 and R 2 are independently selected from a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear alkenyl group, a branched alkenyl group, a cyclic alkenyl group, a linear heteroalkenyl group, a branched heteroalkenyl group, a heteroalkenyl group, a linear alkynyl group, a branched alkynyl group, a cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 , OC(O)R w NR x R y , S(O)R y , and SO 2 R y ; and are independently selected from (ii) R 3 is hydrogen, halogen group, OR x , SR x NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (iii) R 4 These include hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, and C(O)R y CO 2 R y , C(O)R w Ure y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , R w N(R x R y ) 2 , R w Ure x , R z R', S(O)R y , and SO 2 R y Selected from; (iv) R x and R y is independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; or R x and R y They adhere to each other, forming a heterocycloalkyl group which is optionally substituted; (v) R w It is either absent, or selected from linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, linear, branched and cyclic alkenyl groups, and linear and branched heteroalkenyl groups; (compared to) R z It is either absent or selected from linear, branched, and cyclic alkyl groups; (vii) R ' This is selected from optionally substituted heteroaryls and optionally substituted heterocycloalkyls; (viii) Ring A is selected from an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; (ix) Ring B is, 【Chemistry 2】 Selected from; In formula (x), each R " is independently selected from hydrogen, linear, branched, and cyclic alkyl groups; or two R " These combine to form a cycloalkylspirocyclic ring or a heterocycloalkylspirocyclic ring; Here, linear, branched, and cyclic alkyl groups, linear, branched, and cyclic alkenyl 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 to 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, 3-membered to 6-membered spirocyclic alkyl groups, Spiroheterocyclic groups with 3 to 6 members, and 0, 1, or 2 C atoms selected from linear, branched, and cyclic alkyl groups. 1 ~C 6 (Five-membered and six-membered heteroaryl groups optionally substituted with alkyl groups). [Claim 2] R 1 and R 2 is independently selected from hydrogen, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, and R 4 is a halogen group, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1. [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 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein is a heterocyclic group. [Claim 6] R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from linear, branched, and cyclic alkynyl groups. [Claim 7] Linear, branched, and cyclic alkynyl groups are C 1 ~C 6 Linear, branched and cyclic alkyl groups, C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 6, substituted with at least one group selected from linear, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. [Claim 8] R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein is hydrogen. [Claim 9] R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from linear, branched, and cyclic alkyl groups. [Claim 10] R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 9, selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. [Claim 11] R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the halogen group is a halogen group. [Claim 12] R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 11, wherein is fluoro. [Claim 13] R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 11, wherein is chloro. [Claim 14] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from aryl groups. [Claim 15] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 14, wherein ring A is phenyl. [Claim 16] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 14, wherein ring A is selected from an aryl group, where the aryl group is substituted with a halogen group. [Claim 17] Ring A is selected from aryl groups, where the aryl group is C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 14, substituted with linear, branched, or cyclic alkyl groups. [Claim 18] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from heteroaryl groups. [Claim 19] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein ring A is selected from a heteroaryl group, wherein the heteroaryl group is substituted with a halogen group. [Claim 20] Ring A is selected from a heteroaryl group, where the heteroaryl group is C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, substituted with linear, branched, or cyclic alkyl groups. [Claim 21] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein ring A is selected from a 6-membered heteroaryl group. [Claim 22] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 21, wherein ring A is selected from a six-membered heteroaryl group, wherein the six-membered heteroaryl group is substituted with a halogen group. [Claim 23] Ring A is selected from a 6-membered heteroaryl group, where the 6-membered heteroaryl group is C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 21, substituted with linear, branched, or cyclic alkyl groups. [Claim 24] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 23, wherein ring A is a pyridine ring. [Claim 25] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 23, wherein ring A is a pyrimidine ring. [Claim 26] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein ring A is selected from a five-membered heteroaryl group. [Claim 27] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 26, wherein ring A is selected from a five-membered heteroaryl group, wherein the five-membered heteroaryl group is substituted with a halogen group. [Claim 28] Ring A is selected from a 5-membered heteroaryl group, where the 5-membered heteroaryl group is C 1 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 26, substituted with linear, branched, or cyclic alkyl groups. [Claim 29] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 28, wherein ring A is a thiazole ring. [Claim 30] Ring B is 【Transformation 3】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 31] Ring B is 【Chemistry 4】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 32] Ring B is 【Transformation 5】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 33] Ring B is 【Transformation 6】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 34] Ring B is 【Transformation 7】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1. [Claim 35] R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein is hydrogen. [Claim 36] R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from linear, branched, and cyclic alkyl groups. [Claim 37] R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 【Request Item 38】 【Table 1】 Compounds selected from the above, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof. [Claim 39] A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 38, and at least one pharmaceutically acceptable carrier. [Claim 40] The pharmaceutical composition according to claim 39 for treating or alleviating a disease, disorder or condition mediated by inhibition of protein kinase. [Claim 41] The pharmaceutical composition according to claim 40, wherein the protein kinase is selected from hematopoietic precursor kinase 1 (HPK1), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora A. [Claim 42] The pharmaceutical composition according to claim 39 for reducing protein kinase activity in a disease, disorder, or condition. [Claim 43] The pharmaceutical composition according to claim 42, wherein the disease, disorder, or condition is selected from protein kinase-related diseases. [Claim 44] The pharmaceutical composition according to claim 43, wherein the protein kinase-related disease is cancer. [Claim 45] The pharmaceutical composition according to claim 44, wherein the cancer is a solid tumor. [Claim 46] The pharmaceutical composition according to claim 45, 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 47] The pharmaceutical composition according to claim 44, wherein the cancer is a blood cancer. [Claim 48] The pharmaceutical composition according to claim 47, 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 (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 49] 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 44, 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 50] The pharmaceutical composition according to claim 42, to be used in combination with an existing standard treatment or an FDA-approved therapy. [Claim 51] The pharmaceutical composition according to claim 42, which is used in combination with one or more separate pharmaceutical agents. [Claim 52] The pharmaceutical composition according to claim 51, wherein separate pharmaceutical agents are selected from chemotherapeutic agents, immunotherapy agents, and adjunctive therapeutic agents.

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