Kinase modulators, compositions comprising kinase modulators, and methods of using same - Patents.com

Abstract

The present disclosure provides compounds of formula I', compositions comprising compounds of formula I', and methods of using same in treating diseases, disorders, or conditions mediated by inhibition of certain kinases, e.g., hematopoietic progenitor kinase 1 (HPK1) and / or Fms-related receptor tyrosine kinases (FLTs), e.g., FLT3. JPEG2024531438000096.jpg37170

Description

[Technical field]

[0001] This disclosure relates to novel compounds that are useful for treating certain diseases. In particular, this disclosure relates to compounds that inhibit the activity of certain kinases, such as hematopoietic progenitor kinases (HPKs) such as HPK1, which enhance immune responses, and / or Fms-related receptor tyrosine kinases (FLTs) such as FLT3, and treat certain kinase-dependent disorders, such as HPK1-dependent and / or FLT3-dependent disorders. [Background technology]

[0002] Hematopoietic precursor kinase 1 (HPK1), also known as MAP4K1, is a serine / threonine kinase that is predominantly expressed in hematopoietic cells such as T cells, B cells, and dendritic cells (DCs). Structurally, HPK1 contains an N-terminal kinase domain, a proline-rich domain, and a C-terminal citron homology domain. Traditionally, HPK1 activity can be modulated by the kinase domain. HPK1 binds to many adaptor proteins, including Grb2, Nck, Crk, SLP-76, and the actin-binding adaptor HIP-55. The proline-rich domain can bind to proteins containing SH3 domains. HPK1 can prevent the complex formation of ADAP and SLP76 by interacting with IKK-α / β. HPK1 kinase activity can be induced by various receptor stimuli, including, for example, TCR, BCR, EP2 / 4, and CD95 (Sawasdikosol & Burakoff, 2020). After TCR engagement, HPK1 is phosphorylated by ZAP70 at tyrosine 379, allowing binding to the SH2 domain of SLP76. HPK1 subsequently phosphorylates serine 376 of SLP76 and threonine 262 of Gad (DiBartolo et al., 2007; Lasserre et al., 2011), creating binding sites for SLP76 and 14-3-3 disruption of the LAT complex (diBartolo et al., 2007; Lasserre et al., 2011). This acts as a negative feedback signaling to TCR activation. The function of HPK1 has been validated by various genetic evidences, either due to HPK1 deficiency or kinase dead. HPK1- / - T cells have a lower activation threshold with increased proinflammatory cytokine and hyperproliferative responses (Liu et al., 2019). HPK1- / - T cells also exhibit resistance to PGE2-mediated suppression (Alzabin et al., 2009). HPK1- / - dendritic cells have demonstrated superior antigen-presenting capacity in vitro, leading to antitumor responses in vivo. In addition, HPK1- / - mice showed better antitumor activity than wild-type mice in several tumor models (Liu et al., 2019).These highlight the importance of HPK1 kinase activity in enhancing immune cell function and preventing tumor progression. In addition to autoimmune diseases, MAP4K1 expression has also been reported to be a novel resistance mechanism and independent prognostic marker in AML (Knight et al., 2021; Ling et al., 2021). Thus, targeting HPK1 has the potential to become a novel treatment for cancer and other HPK1-related disorders.

[0003] Human FMS-like tyrosine kinase 3 (FLT3), or fetal liver kinase 2 (FLK-2), CD135, is a member of receptor tyrosine kinase class III. FLT3 is overexpressed in approximately 90% of acute myeloid leukemias (AML), B-precursor cell acute lymphocytic leukemias (ALL), a fraction of T-cell ALL, and blast crisis phase of chronic myeloid leukemia (BC-CML). FLT3 is one of the most frequently mutated genes in AML. FLT3 mutations can be subdivided into internal tandem duplications (ITDs), which are found in approximately 25% of patients, and point mutations in the tyrosine kinase domain (TKD), such as D835 and I836, which are found in approximately 5% of patients. D835Y substitutions constitute approximately 50% of FLT3-TKD mutations. Both FLT3-ITD and FLT3-TKD mutations are constitutively active through autophosphorylation, 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 induce rapid down-modulation of FLT3 and downstream kinases of the STAT5 pathway in leukemia.

[0004] In summary, an HPK1 inhibitor, a FLT3 inhibitor, a dual HPK1-FLT3 inhibitor, or a fixed dose combination of an HPK1 inhibitor and an FLT3 inhibitor may provide a more effective treatment option for certain cancer patients. [Prior art documents] [Patent documents]

[0005]

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Non-licensed literature

[0006] [Non-licensed document 1] SM Berge, J. Pharmaceutical Sciences, 1977, 66, 1 page 19 [Non-licensed document 2] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-licensed document 3] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia

Non-licensed Document 4

Non-licensed Document 5

[0007] One aspect of the present disclosure provides a compound selected from the compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, which can be used in the treatment of diseases mediated by inhibition of hematopoietic progenitor kinase 1 (HPK1) and / or inhibition of human FMS-like tyrosine kinase 3 (FLT3). For example, a compound of the following structural formula I: [ka] Disclosed herein is a compound of the formula: (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 3is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each 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; (vii) 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; (viii) Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups.

[0008] In one aspect of the disclosure, the compound of formula I is selected from compounds 1 to 62 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0009] In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a compound selected from compounds 1 to 62 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. These compositions may further comprise an additional active pharmaceutical agent.

[0010] Another aspect of the disclosure provides a method of treating a disease, disorder, or condition mediated by inhibition of hematopoietic progenitor kinase 1 (HPK1) and / or inhibition of human FMS-like tyrosine kinase 3 in a subject comprising administering a therapeutically effective amount of a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a compound selected from compounds 1 to 62 shown below, a deuterated derivative of a tautomer thereof, a compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0011] In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof a compound selected from compounds 1 to 62 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, either in the same composition or in a separate composition, with the additional active pharmaceutical agent.

[0012] Additionally, disclosed herein are methods of inhibiting HPK1 activity and / or methods of inhibiting human FMS-like tyrosine kinase 3 activity comprising administering to a subject a therapeutically effective amount of a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the methods of inhibiting HPK1 and / or inhibiting human FMS-like tyrosine kinase 3 activity comprise administering to a subject a compound selected from compounds 1 to 62 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of inhibiting HPK1 activity and / or the method of inhibiting human FMS-like tyrosine kinase 3 comprises contacting said HPK1 and / or human FMS-like tyrosine kinase 3 with a compound of formula I, I', IIA, IIa', IIIA, IIIA', IIIB, and IIIB', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method of inhibiting HPK1 and / or the method of inhibiting human FMS-like tyrosine kinase 3 comprises contacting HPK1 and / or human FMS-like tyrosine kinase 3 with a compound selected from compounds 1 to 62 shown below, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] I. Definition The terms "a" or "an" when used herein in reference to a noun include the phrase "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 more than one additional pharmaceutical agent.

[0014] 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 the modulation of 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.

[0015] The term "FLT3" or "human FMS-like tyrosine kinase 3" as used herein is a member of the receptor tyrosine kinase class III. FLT3 is overexpressed in approximately 90% of acute myeloid leukemias (AML), B-precursor cell acute lymphocytic leukemias (ALL), a fraction of T-cell ALL, and blast crisis phase of chronic myeloid leukemia (BC-CML). FLT3 is one of the most frequently mutated genes in AML.

[0016] The compounds disclosed herein can inhibit HPK1 and / or FLT3.Therefore, the compounds disclosed herein are generally useful in treating diseases or conditions associated with these kinases.In one embodiment, the compounds disclosed herein are inhibitors and are useful in treating diseases such as cancer associated with these kinases.

[0017] The term "inhibitor" as used herein refers to a molecule that inhibits the activity of HPK1 and / or FLT3. By "inhibit" herein is meant to decrease the activity of the target enzyme as compared to the activity of the target enzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" refers to a decrease in HPK1 and / or FLT3 activity of 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 and / or FLT3 activity of 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 and / or FLT3 activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such a decrease can be measured using a variety of techniques recognizable by those of skill in the art, including in vitro kinase assays.

[0018] The term "HPK1 and / or FLT3 inhibitor" as used herein refers to a molecule that reduces, inhibits, or otherwise alleviates one or more of the biological activities of HPK1 and / or FLT3. Inhibition using HPK1 and / or FLT3 inhibitors does not necessarily indicate complete elimination of HPK1 and / or FLT3 activity. Instead, activity can be reduced in a statistically significant amount, including at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% reduction in HPK1 and / or FLT3 activity, for example, compared to a suitable control. In some embodiments, HPK1 and / or FLT3 inhibitors reduce, inhibit, or otherwise alleviate the serine / threonine kinase activity of HPK1 and / or FLT3. In some of these embodiments, the HPK1 and / or FLT3 inhibitor reduces, inhibits, or otherwise alleviates HPK1-mediated phosphorylation of SLP76 and / or Gads. The presently disclosed compounds can directly bind to and inhibit the kinase activity of HPK1 and / or FLT3.

[0019] 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 between the constituent atoms of the molecule. Thus, it is clear to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains a smaller amount of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopic substitutions in the compounds of the present disclosure depends on a number of 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 in total is less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions 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 compounds.

[0020] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted". In general, the term "substituted" refers to the replacement of a hydrogen group in a given structure with a group of specified substituents. 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 a specified group, the substituents may be either the same or different at every position. Combinations of substituents contemplated by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0021] 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 with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon with C, are within the scope of this disclosure.

[0022] Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds are within the scope of the present disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0023] 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.

[0024] "Stereoisomers", as used herein, refer to enantiomers and diastereomers.

[0025] 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 " 2H"). It is recognized that some variation in natural isotopic abundance occurs in synthetic compounds depending on the origin of the chemical materials used in the 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 a "deuterated derivative" of a compound of the present disclosure is referenced, at least one hydrogen is 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).

[0026] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0027] The term "alkyl" as used herein means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1 to 30 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1 to 3 alkyl carbon atoms. And in still other embodiments, an alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, an alkyl group is substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is straight or linear or unbranched. In some embodiments, an alkyl group is branched.

[0028] The term "cycloalkyl" refers to a fully saturated, monocyclic C 3~8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8~14 In some embodiments, the cycloalkyl group is a C to C alkyl group, and in some embodiments, the cycloalkyl group is a C to C 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, cyclohexyl, and adamantyl.

[0029] 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 refers to a hydrocarbon, where any individual ring in said bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes, for example, a combination of monocyclic carbocyclic rings 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 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.

[0030] The term "alkenyl" as used herein means 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 chain, linear, or unbranched. In some embodiments, an alkenyl group is branched.

[0031] The term "heterocyclyl," as used herein, means a non-aromatic (i.e., fully saturated, or partially saturated since 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: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members, where 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.

[0032] 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 means one or more of oxygen, sulfur, and nitrogen, including (as in N-substituted pyrrolidinyl).

[0033] 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 satisfied by substituents, thus causing the compound to contain double or triple bonds.

[0034] 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.

[0035] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0036] As used herein, a "cyano" or a "nitrile" group refers to --C.ident.N.

[0037] As used herein, a "carboxylate" group refers to --COOH.

[0038] As used herein, the term "aminoalkylcarboxylate" group refers to a fully saturated, straight or branched hydrocarbon chain substituted with amino and carboxylate groups. In some embodiments, the amino and carboxylate groups are substituents on the same carbon atom of the alkyl group. In some embodiments, the amino and carboxylate groups are substituents on different carbon atoms of the alkyl group.

[0039] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having 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 aromatic rings and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows.

[0040] 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 all rings in the system are aromatic rings 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 are phenyl (C6) rings and naphthyl (C 10 ) ring. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0041] The term "heteroaryl" refers to a monocyclic, or spirocyclic, fused, or bridged, bicyclic or tricyclic ring system having a total of 5 to 14 ring members, where 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 a phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, 2-amino-4-hydroxy-1H-pteridine, and the like.

[0042] "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, where any two rings share only one common atom.

[0043] The term "glycosidic" refers to a carbohydrate group, such as a mono-, di-, tri-, tetra- or polysaccharide group, which can exist in various isomeric forms, e.g., α-D, α-L, β-D or β-L forms. The carbohydrate group may be optionally substituted with other types of substituents or even additional glycosidic groups. In some embodiments, the glycoside group is selected from an α-D-glucopyranoside group, an α-D-galactopyranoside group, an α-D-mannopyranoside group, an α-L-fucopyranoside group, an α-L-arabinopyranoside group, a β-D-glucopyranoside group, a β-D-galactopyranoside group, a β-D-glucuronide group, a β-D-lactopyranoside group, a β-D-xylopyranoside group, a β-D-glucosaminide group, a β-D-galactosaminide group, a β-D-aloside group, a β-D-lyxoside group, a β-D-taloside group, a β-D-threoside group, a β-D-riboside group, a β-D-fructoside group, a β-D-rhamnoside group, and a β-L-glucoside group.

[0044] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0045] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

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

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

[0048] Acids commonly used to form pharma-ceutically 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 pharma- ceutically 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, hexyne-2,4-diol ... Included are oates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, as well as those formed with organic acids, such as maleic acid.

[0049] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4Suitable non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0050] The term "subject" refers to animals, including, but not limited to, humans.

[0051] The term "therapeutically effective amount" refers to the amount of a compound for which it is administered to produce the desired effect (e.g., amelioration in symptoms of diseases, disorders, and conditions mediated by inhibition of HPK1 and / or FLT3, reducing the severity of diseases, disorders, and conditions mediated by inhibition of HPK1 and / or FLT3 or symptoms thereof, and / or reducing the progression of diseases, disorders, and conditions mediated by inhibition of HPK1 and / or FLT3 or symptoms thereof). The exact amount of a therapeutically effective amount depends on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0052] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. As used herein, "treatment" and its cognates include, but are not limited to: complete or partial remission, lower risk of diseases, disorders, and conditions mediated by the inhibition of HPK1 and / or FLT3, and disease-related complications. Improvement in or reduction in the severity of any of these symptoms can be easily determined according to methods and techniques known or subsequently developed in the art.

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

[0054] II. Compounds and Compositions In a first embodiment, the compound of the present disclosure has the following structural formula I: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2Ry Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each 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; (vii) 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; (viii) Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and Five- and six-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups.

[0055] In a second embodiment, the compound of the present disclosure has the following structural formula I': [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein (ix) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (x) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (xi) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xii) R 5 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 NC(O)R x , C(O)R w NC(O)R x NHR y , C(O)R w NR x R y , O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (xiii) each R' and R" is independently selected from hydrogen, linear, branched, and cyclic alkyl groups, linear, branched, and cyclic aminoalkyl groups, carbocyclic groups, and heterocyclic groups; (xiv) X is N and CR x Selected from; (xv) each R X and R y are independently selected from hydrogen, linear, branched and cyclic alkyl groups, linear, branched and cyclic aminoalkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, heteroaryl groups, and glycosidic groups; (xvi) 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; (xvii) Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, carbocyclic groups, linear, branched and cyclic aminoalkyl 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, Carboxylate groups; Hydroxy, Thiol, amino, Cyano, [ka] -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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, 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 aminoalkyl carboxylate groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups optionally substituted with 0, 1 or 2 C1-C6 linear, branched and cyclic alkyl groups or halogen groups; and Five- and six-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups.

[0056] In a second embodiment, the compound of the present disclosure has the following structural formula IIA: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 , Z 2 , Z 3 , and Z 4 CR z and N, where R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0057] In a third embodiment, the compound of the present disclosure has the following structural formula IIA': [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 , Z 2 , Z 3 , and Z 4 CR z and N, where R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; all other variables not specifically defined herein are as defined in the second embodiment in formula (I').

[0058] In a fourth embodiment, the compound of the present disclosure has the following structural formula IIIA: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 and Z 2 CR z and N are independently selected from Z 3 is O, S, and NR z Selected from R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups, and all other variables not specifically defined herein are as defined in the first embodiment.

[0059] In a fifth embodiment, the compound of the present disclosure has the following structural formula IIIA': [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 and Z 2 CR z and N are independently selected from Z 3 is O, S, and NRz where R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups, and all other variables not specifically defined herein are as defined in the second embodiment in formula (I').

[0060] In a sixth embodiment, the compound of the present disclosure has the following structural formula IIIB: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 and Z 3 CR z and N are independently selected from Z 2 is O, S, and NR z where R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups, and all other variables not specifically defined herein are as defined in the first embodiment.

[0061] In a seventh embodiment, the compound of the present disclosure has the following structural formula IIIB': [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein each Z 1 and Z 3 CR z and N are independently selected from Z 2 is O, S, and NR z where R zare independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups, and all other variables not specifically defined herein are as defined in the second embodiment in formula (I').

[0062] In a fifth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen radical; R 3 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0063] In a sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third and fourth embodiments.

[0064] In a seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third and fourth embodiments.

[0065] In an eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from heterocyclic groups; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0066] In a ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from linear, branched, and cyclic alkynyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0067] In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from linear, branched and cyclic alkynyl groups substituted with at least one group selected from C1-C6 linear, branched and cyclic alkyl groups, C1-C6 linear, 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 any one of the first, second, third and fourth embodiments.

[0068] In an eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 is a halogen group; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0069] In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 is fluoro; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0070] In a thirteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2is chloro; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0071] In a fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 is hydrogen; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0072] In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 one of the first, second, third, and fourth embodiments.

[0073] In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third and fourth embodiments.

[0074] In a seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4 is hydrogen; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0075] In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4 CO2R ywhere R y is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0076] In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4 is C(O)R y where R y is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0077] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R y is selected from a C1 to C6 straight chain alkyl group; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0078] In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R y is selected from C1-C6 straight chain alkyl groups substituted with -N(C1-C6 straight chain, branched and cyclic alkyl groups)2; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0079] In a twenty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R y is selected from C1-C6 straight chain alkyl groups substituted with C1-C6 straight chain, branched and cyclic hydroxyalkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0080] In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R y is selected from C1-C6 straight chain alkyl groups substituted with C1-C6 straight chain, branched and cyclic aminoalkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0081] In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R y is selected from C1-C6 straight chain alkyl groups substituted with C1-C6 straight chain, branched and cyclic alkoxy groups; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0082] In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4 is SO2R y where R y is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0083] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure; R 4 is SO2R y where R y is selected from a C1 to C6 straight chain alkyl group; all other variables not specifically defined herein are as defined in any one of the first, second, third and fourth embodiments.

[0084] In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 one of the first, second, third, and fourth embodiments.

[0085] In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, ring A is phenyl; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0086] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Ring A is selected from an aryl group, where the aryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0087] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third, and fourth embodiments.

[0088] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Ring A is selected from a heteroaryl group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0089] In a thirty-second embodiment, in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Ring A is selected from a heteroaryl group, where the heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0090] In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third, and fourth embodiments.

[0091] In a thirty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third, and fourth embodiments.

[0092] In a thirty-fifth embodiment, in the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of the present disclosure, ring A is selected from a six-membered heteroaryl group, where the six-membered heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0093] In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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 any one of the first, second, third, and fourth embodiments.

[0094] In a thirty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, ring A is a pyridine ring; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0095] In a thirty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, ring A is a pyrimidine ring; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0096] In a thirty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, ring A is selected from a 5-membered heteroaryl group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0097] In a fortieth embodiment, in the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of the present disclosure, Ring A is selected from a 5-membered heteroaryl group, where the 5-membered heteroaryl group is substituted with a halogen group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0098] In a forty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma-ceutically acceptable salt of the present disclosure, Ring A is selected from a 5-membered heteroaryl group, where the 5-membered heteroaryl group is substituted with a C1-C6 straight, branched, and cyclic alkyl group; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0099] In a forty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, ring A is a thiazole ring; all other variables not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0100] In a forty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is CR z and Z 3 is CR z and Z 4 is CR z and all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0101] In a forty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is N and Z 3 is CR z and Z 4 is CR z and all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0102] In a forty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is CR z and Z 3 is N and Z 4 is CR z and all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0103] In a forty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is CR z and Z 3 is CR z and Z 4 is N; all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0104] In a forty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is N and Z 3 is CR z and Z 4 is CR z and all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0105] In a forty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is CR z and Z 3 is N and Z 4 is CR z and all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0106] In a forty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is CR z and Z 3 is CR z and Z 4is N; all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0107] In a fiftieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is CR z and Z 3 is CR z and Z 4 is N; all other variables not specifically defined herein are as defined in any one of the first and second embodiments.

[0108] In a fifty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is CR z and Z 3 is O; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0109] In a fifty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is CR z and Z 3 is S; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0110] In a fifty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is CR z and Z 3is O; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0111] In a fifty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is CR z and Z 3 is S; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0112] In a fifty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is N and Z 3 is O; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0113] In a fifty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is N and Z 3 is S; all other variables not specifically defined herein are as defined in any one of the first and third embodiments.

[0114] In a fifty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is O and Z 3 is CR z and all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0115] In a fifty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is S and Z 3 is CR z and all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0116] In a fifty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is O and Z 3 is CR z and all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0117] In a sixtieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is N and Z 2 is S and Z 3 is CR z and all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0118] In a sixty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2 is O and Z 3 is N; all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0119] In a sixty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Z 1 is CR z and Z 2is S and Z 3 is N; all other variables not specifically defined herein are as defined in any one of the first and fourth embodiments.

[0120] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 62 shown in Table 1 below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0121] [Table 1A]

[0122] [Table 1B]

[0123] [Table 1C]

[0124] [Table 1D]

[0125] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0126] In some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant, hi some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0127] It will also be appreciated that the pharmaceutical compositions of the present disclosure can be used in combination therapy; that is, the pharmaceutical compositions disclosed herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered as a separate composition, either simultaneously with, prior to, or after a composition comprising an additional active pharmaceutical agent.

[0128] As discussed above, the pharmaceutical compositions disclosed herein further comprise a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier can be selected from adjuvants and vehicles. The pharma- ceutically acceptable carrier, as used herein, can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersing aids, suspension aids, surface active agents, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants that are suitable 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 undesirable 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 pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, 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, ... 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, releasing agents, coating agents, sweetening agents, flavoring agents, perfumes, preservatives, and antioxidants.

[0129] III. Methods of Treatment and Use In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts as disclosed herein, including compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating a disease, disorder, or condition mediated by inhibition of HPK1. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as disclosed herein, including compounds of formulas I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease, disorder, or condition mediated by inhibition of HPK1 and / or FLT3. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by inhibition of HPK1 and / or FLT3 in a subject comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as disclosed herein, including a compound of Formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof.

[0130] In some embodiments, the disease, disorder, or condition is selected from HPK1 and / or FLT3 associated diseases. In some embodiments, the disease, disorder, or condition is selected from cancer, dysregulated immune response, or disease involving aberrant HPK1 and / or FLT3 expression, activity, and / or signaling. In some embodiments, the cancer is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, kidney cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, parathyroid cancer, lymphoma, sarcoma, and leukemia.

[0131] In some embodiments, the brain cancer is selected from brainstem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma multiforme, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor. In some embodiments, the liver cancer is selected from hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), bile duct adenocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma. In some embodiments, the respiratory cancer and / or lung cancer is selected from small cell lung cancer, non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma. In some embodiments, the gastrointestinal cancer is selected from anal cancer, colon cancer, rectal cancer, gallbladder cancer, gastric cancer, esophageal cancer, stomach cancer, pancreatic cancer, salivary gland cancer, small intestine cancer, and colorectal cancer. In some embodiments, the kidney cancer is selected from renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini ductal carcinoma, clear cell sarcoma of the kidney, mesodermal nephroma, and Wilms' tumor. In some embodiments, the skin cancer is selected from malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer. In some embodiments, the head and neck cancer is selected from squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell. In some embodiments, the reproductive cancer is selected from prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma. In some embodiments, the ovarian cancer is selected from serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenic tumors. In some embodiments, the cervical cancer is selected from squamous cell carcinomas, adenocarcinomas, adenosquamous carcinomas, small cell carcinomas, neuroendocrine tumors, vitreous cell carcinomas, and choriocarcinomas. In some embodiments, the bone cancer is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumors. In some embodiments, the breast cancer is selected from triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.In some embodiments, the sarcoma is selected from soft tissue sarcoma, chondrosarcoma, Ewing's sarcoma, angiosarcoma, fibrosarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, teratoma, osteosarcoma, malignant fibrous histiocytoma, liposarcoma, lymphosarcoma, and rhabdomyosarcoma. In some embodiments, the eye cancer is selected from intraocular melanoma and retinoblastoma. In some embodiments, the hematological cancer is selected from lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), acute promyelocytic leukemia (APL), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALC), and / or rhabdomyosarcoma. L), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), mantle cell lymphoma, non-Hodgkin's lymphoma (NHL, including relapsed or refractory NHL), Hodgkin's lymphoma, multiple myeloma, and combinations of the above cancers. In some embodiments, the nervous system cancer is selected from cancer of the skull, cancer of the meninges, brain cancer, glioblastoma, spinal cancer, neuroblastoma, and Lhermitte-Duclos disease.

[0132] In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts as disclosed herein, including compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in inhibiting HPK1 and / or FLT3 activity. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts as disclosed herein, including compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for the manufacture of a medicament for inhibiting HPK1 and / or FLT3 activity. In yet another aspect, disclosed herein is a method of inhibiting HPK1 and / or FLT3 activity comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as disclosed herein, including a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of inhibiting HPK1 activity and / or FLT3 comprising contacting said HPK1 and / or FLT3 with a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as disclosed herein, including a compound of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof.

[0133] The compounds of Formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically 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 a disease, disorder, or condition mediated by inhibition of HPK1 and / or FLT3.

[0134] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, is administered once daily, twice daily, or three times daily.

[0135] The compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', any of compounds 1 to 62, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, buccally, intravaginally, transdermally, by patch, pump administration, or via an implanted reservoir, the pharmaceutical composition being appropriately formulated. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are as described in International Patent Application Nos. WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0136] The useful dosage or therapeutically effective amount of the compound or its pharma- ceutically acceptable salt as disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0137] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of the pharma- ceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. The amount of the compounds, pharma- ceutically acceptable salts, solvates, and deuterated derivatives disclosed herein is 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 pharma- ceutically acceptable salts" includes 1000 mg of the compound of formula I and the concentration of the pharma- ceutically acceptable salt of the compound of formula I equivalent to 1000 mg of the compound of formula I.

[0138] Non-Limiting Illustrative Embodiments 1. Formula (I): [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R ySelected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each 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; (vii) 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; (viii) Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups. 2.R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 3.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1 or 2, wherein is selected from C1-C6 straight chain, branched and cyclic alkyl groups. 4.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 3, wherein is selected from methyl, ethyl, cyclopropyl, and cyclobutyl. 5.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1, wherein is a heterocyclic group. 6.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1, wherein is selected from linear, branched, and cyclic alkynyl groups. 7. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 6, wherein the linear, branched, and cyclic alkynyl groups are substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, C1-C6 linear, 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 pharma- ceutically acceptable salt of any of embodiments 1-7, wherein is a halogen group. 9.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein is fluoro. 10.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein is chloro. 11.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-7, wherein is hydrogen. 12.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-7, wherein is selected from linear, branched, and cyclic alkyl groups. 13.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 12, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 14.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-13, wherein is hydrogen. 15.R 4 But CO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-13, wherein is selected from linear, branched, and cyclic alkyl groups. 16.R 4 But, C(O)R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-13, wherein is selected from linear, branched, and cyclic alkyl groups. 17.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 15 or 16, wherein is selected from C1 to C6 straight chain alkyl groups. 18. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 17, wherein the C1-C6 straight chain alkyl group is substituted with -N(C1-C6 straight chain, branched and cyclic alkyl group)2. 19. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 17, wherein the C1-C6 straight chain alkyl group is replaced with a C1-C6 straight chain, branched and cyclic hydroxyalkyl group. 20. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 17, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic aminoalkyl group. 21. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 17, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic alkoxy group. 22.R 4 But SO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-13, wherein is selected from linear, branched, and cyclic alkyl groups. 23.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 22, wherein is selected from C1-C6 straight chain alkyl groups. 24. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-23, wherein Ring A is selected from aryl groups. 25. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 24, wherein Ring A is phenyl. 26. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-23, wherein Ring A is selected from an aryl group, wherein the aryl group is substituted with a halogen group. 27. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-23, wherein Ring A is selected from aryl groups, where the aryl groups are substituted with C1-C6 straight chain, branched and cyclic alkyl groups. 28. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-23, wherein Ring A is selected from heteroaryl groups. 29. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 28, wherein Ring A is selected from a heteroaryl group, wherein the heteroaryl group is substituted with a halogen group. 30. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 28, wherein Ring A is selected from heteroaryl groups, where the heteroaryl groups are substituted with C1-C6 straight chain, branched and cyclic alkyl groups. 31. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 28, wherein Ring A is selected from a 6-membered heteroaryl group. 32. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 31, wherein ring A is selected from a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is substituted with a halogen group. 33. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 31, 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. 34. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 31-33, wherein Ring A is a pyridine ring. 35. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 31-33, wherein Ring A is a pyrimidine ring. 36. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 28, wherein Ring A is selected from a 5-membered heteroaryl group. 37. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 36, wherein Ring A is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is substituted with a halogen group. 38. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 36, 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. 39. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 36-38, wherein Ring A is a thiazole ring. 40.Formula (IIA): [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, (i) R 1 is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; and heteroaryl groups; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each Z 1 , Z 2 , Z 3 , and Z 4 CR z or N; (vii) 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; (viii) Each R X , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups. 41.R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 40, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 42.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 40 or 41, wherein is selected from C1 to C6 straight chain, branched and cyclic alkyl groups. 43.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 42, wherein is selected from methyl, ethyl, cyclopropyl, and cyclobutyl. 44.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 40, wherein is a heterocyclic group. 45.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 42, wherein is selected from linear, branched, and cyclic alkynyl groups. 46. ​​The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 45, wherein the linear, branched, and cyclic alkynyl group is substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, C1-C6 linear, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. 47.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-46, wherein is a halogen group. 48.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 47, wherein is fluoro. 49.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 49, wherein is chloro. 50.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-46, wherein is hydrogen. 51.R 2The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-46, wherein is selected from linear, branched, and cyclic alkyl groups. 52.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 51, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 53.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-52, wherein is hydrogen. 54.R 4 But CO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-52, wherein is selected from linear, branched, and cyclic alkyl groups. 55.R 4 But, C(O)R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 1-13, wherein is selected from linear, branched, and cyclic alkyl groups. 56.R y 56. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 54 or 55, wherein is selected from C1 to C6 straight chain alkyl groups. 57. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein the C1-C6 straight chain alkyl group is substituted with -N(C1-C6 straight chain, branched and cyclic alkyl group)2. 58. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein the C1-C6 straight chain alkyl group is replaced with a C1-C6 straight chain, branched and cyclic hydroxyalkyl group. 59. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic aminoalkyl group. 60. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic alkoxy group. 61.R 4 But SO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-52, wherein is selected from linear, branched, and cyclic alkyl groups. 62.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 61, wherein is selected from C1-C6 straight chain alkyl groups. 63.Z 1 is N and Z 2 CR z and Z 3 CR z and Z 4 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein: 64.Z 1 CR z and Z 2 is N and Z 3 CR z and Z 4 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein: 65.Z 1 CR z and Z 2 CR z and Z 3 is N and Z 4 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein: 66.Z 1 CR z and Z 2 CR z and Z 3 CR z and Z 4The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein 67.Z 1 is N and Z 2 is N and Z 3 CR z and Z 4 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein: 68.Z 1 is N and Z 2 CR z and Z 3 is N and Z 4 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein: 69.Z 1 CR z and Z 2 CR z and Z 3 CR z and Z 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein is N. 70.Z 1 is N and Z 2 CR z and Z 3 CR z and Z 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 40-62, wherein is N. 71.Formula (IIIA): [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, (i) R 1is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each Z 1 and Z 2 CR z or N; (vii) Z 3 is O, S, and NRz Selected from; (viii) 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; (ix) Each R X , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups. 72.R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen radical; R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 71, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 73.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 71 or 72, wherein is selected from C1 to C6 straight chain, branched and cyclic alkyl groups. 74.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73, wherein is selected from methyl, ethyl, cyclopropyl, and cyclobutyl. 75.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 71, wherein is a heterocyclic group. 76.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 71, wherein is selected from linear, branched, and cyclic alkynyl groups. 77. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 76, wherein the linear, branched, and cyclic alkynyl group is substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, C1-C6 linear, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. 78.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-77, wherein is a halogen group. 79.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 78, wherein is fluoro. 80.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 78, wherein is chloro. 81.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-77, wherein is hydrogen. 82.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-77, wherein is selected from linear, branched, and cyclic alkyl groups. 83.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 82, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 84.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-83, wherein is hydrogen. 85.R 4 But CO2R y where R yThe compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-83, wherein is selected from linear, branched, and cyclic alkyl groups. 86.R 4 But, C(O)R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-83, wherein is selected from linear, branched, and cyclic alkyl groups. 87.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 85 or 86, wherein is selected from C1 to C6 straight chain alkyl groups. 88. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 87, wherein the C1-C6 straight chain alkyl group is substituted with -N(C1-C6 straight chain, branched and cyclic alkyl group)2. 89. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 87, wherein the C1-C6 straight chain alkyl group is replaced with a C1-C6 straight chain, branched and cyclic hydroxyalkyl group. 90. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 87, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic aminoalkyl group. 91. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 87, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic alkoxy group. 92.R 4 But SO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-83, wherein is selected from linear, branched, and cyclic alkyl groups. 93.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 92, wherein is selected from C1-C6 straight chain alkyl groups. 94.Z 1 CR z and Z2 CR z and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein 95.Z 1 CR z and Z 2 CR z and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein is S. 96.Z 1 is N and Z 2 CR z and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein 97.Z 1 is N and Z 2 CR z and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein is S. 98.Z 1 CR z and Z 2 is N and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein 99.Z 1 CR z and Z 2 is N and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein is S. 100.Formula (IIIB): [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, (i) R 1is a linear, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a linear, branched and cyclic alkenyl group, a linear and branched heteroalkenyl group, a linear, branched and cyclic alkynyl group, COR x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , N.H.R. x , N(R x )2, CHR x , and C(R x )2 is selected; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) 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, O.C.(O)R w NR x R y , S(O)R y , and SO2R y Selected from; (v) X is N and CR x Selected from; (vi) Each Z 1 and Z 3 CR z or N; (vii) Z 2 is O, S, and NRz Selected from; (viii) 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; (ix) Each R X , R y , and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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, Thiol, 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 groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups optionally substituted with 0, 1 or 2 C1-C6 straight chain, branched and cyclic alkyl groups. 101.R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups. 102.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100 or 101, wherein is selected from C1-C6 straight chain, branched, and cyclic alkyl groups. 103.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 102, wherein is selected from methyl, ethyl, cyclopropyl, and cyclobutyl. 104.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100, wherein is a heterocyclic group. 105.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100, wherein is selected from linear, branched, and cyclic alkynyl groups. 106. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 105, wherein the linear, branched, and cyclic alkynyl group is substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, C1-C6 linear, branched, and cyclic aminoalkyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. 107.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-106, wherein is a halogen group. 108.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 107, wherein is fluoro. 109.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 107, wherein is chloro. 110.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-106, wherein is hydrogen. 111.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-106, wherein is selected from linear, branched, and cyclic alkyl groups. 112.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 111, wherein is selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 113.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-112, wherein is hydrogen. 114.R 4 But CO2R y where R yThe compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-112, wherein is selected from linear, branched, and cyclic alkyl groups. 115.R 4 But, C(O)R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-112, wherein is selected from linear, branched, and cyclic alkyl groups. 116.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 114 or 115, wherein is selected from C1 to C6 straight chain alkyl groups. 117. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 116, wherein the C1-C6 straight chain alkyl group is substituted with -N(C1-C6 straight chain, branched and cyclic alkyl group)2. 118. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 116, wherein the C1-C6 straight chain alkyl group is replaced with a C1-C6 straight chain, branched and cyclic hydroxyalkyl group. 119. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 116, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic aminoalkyl group. 120. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 116, wherein the C1-C6 straight chain alkyl group is substituted with a C1-C6 straight chain, branched and cyclic alkoxy group. 121.R 4 But SO2R y where R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 100-112, wherein is selected from linear, branched, and cyclic alkyl groups. 122.R y The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121, wherein is selected from C1-C6 straight chain alkyl groups. 123.Z 1CR z and Z 2 is O and Z 3 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein: 124.Z 1 CR z and Z 2 is S and Z 3 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein: 125.Z 1 is N and Z 2 is O and Z 3 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein: 126.Z 1 is N and Z 2 is S and Z 3 CR z The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein: 127.Z 1 CR z and Z 2 is O and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein is N. 128.Z 1 CR z and Z 2 is S and Z 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of embodiments 71-93, wherein is N. 129. A compound selected from the compounds of Table 1, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing. 130. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt according to any one of embodiments 1 to 129, and at least one pharma- ceutically acceptable carrier. 131. A method for treating or alleviating a disease, disorder or condition mediated by inhibition of hematopoietic progenitor kinase 1 (HPK1) and / or human FMS-like tyrosine kinase 3 (FLT3), comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt according to any one of embodiments 1 to 129, or a pharmaceutical composition according to embodiment 130. 132. A method for reducing HPK1 and / or FLT3 activity in a disease, disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 129, or a pharmaceutical composition according to embodiment 130. 133. The method of embodiment 132, wherein the disease, disorder, or condition is selected from HPK1 and / or FLT3 associated diseases. 134. The method of embodiment 132, wherein the HPK1 and / or FLT3 associated disease is selected from cancer, a dysregulated immune response, or a disease involving aberrant HPK1 and / or FLT3 expression, activity, and / or signaling. 135. The method of embodiment 132, wherein the cancer is selected from brain cancer, breast cancer, respiratory and / or lung cancer, reproductive cancer, bone cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, kidney cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer, parathyroid cancer, lymphoma, sarcoma, and leukemia. 136. The method of embodiment 135, wherein the brain cancer is selected from brain stem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastoma multiforme, medulloblastomas, ependymoma, neuroectodermal tumors, and pineal tumors. 137. The method of embodiment 135, wherein the liver cancer is selected from hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), biliary adenocarcinoma (intrahepatic cholangiocarcinoma) and mixed hepatocellular-biliary adenocarcinoma. 138. The method of embodiment 135, wherein the respiratory and / or lung cancer is selected from small cell lung cancer, non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma. 139. The method of embodiment 135, wherein the gastrointestinal cancer is selected from anal cancer, colon cancer, rectal cancer, gallbladder cancer, gastric cancer, esophageal cancer, stomach cancer, pancreatic cancer, salivary gland cancer, small intestine cancer, and colorectal cancer. 140. The method of embodiment 135, wherein the renal cancer is selected from renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini ductal carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor. 141. The method of embodiment 135, wherein the skin cancer is selected from malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer and non-melanoma skin cancer. The method of embodiment 127, wherein the head and neck cancer is selected from squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell. 142. The method of embodiment 135, wherein the reproductive cancer is selected from prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma. 143. The method of embodiment 135, wherein the ovarian cancer is selected from serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenic tumors. 144. The method of embodiment 135, wherein the cervical cancer is selected from squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, hyaloid cell carcinoma, and choriocarcinoma. 145. The method of embodiment 135, wherein the bone cancer is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor. 146. The method of embodiment 135, wherein the breast cancer is selected from triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. 147. The method of embodiment 135, wherein the sarcoma is selected from sarcoma of the soft tissue, chondrosarcoma, Ewing's sarcoma, angiosarcoma, fibrosarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, teratoma, osteosarcoma, malignant fibrous histiocytoma, liposarcoma, lymphosarcoma, and rhabdomyosarcoma. 148. The method of embodiment 135, wherein the eye cancer is selected from intraocular melanoma and retinoblastoma. 149. Hematological cancers include lymphomas, leukemias, e.g. acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CHL), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), acute promyelocytic leukemia (APL), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic 136. The method of embodiment 135, wherein the cancer is selected from primary myeloma (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), mantle cell lymphoma, non-Hodgkin's lymphoma (including NHL, relapsed or refractory NHL), Hodgkin's lymphoma, multiple myeloma, and combinations of said cancers. 150. The method of embodiment 135, wherein the nervous system cancer is selected from skull cancer, meningeal cancer, brain cancer, glioblastoma, spinal cancer, neuroblastoma, and Lhermitte-Duclos disease. 151. The method of embodiment 135, further comprising administering to the subject an existing standard of care or FDA approved therapy. EXAMPLES

[0139] Compound synthesis In order to provide a complete understanding of the present disclosure, the following examples are disclosed. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present disclosure in any manner.

[0140] All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of this disclosure.

[0141] The compounds of the present disclosure can be made according to standard chemical practices or as disclosed herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing the compounds of formula I, I', IIA, IIA', IIIA, IIIA', IIIB, and IIIB', compounds 1 through 62, pharma- ceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing: Abbreviation ACN = acetonitrile Boc2O = di-tert-butyl dicarbonate DCE = 1,2-dichloroethane DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DME = dimethoxyethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = ethyl acetate EtOH = ethanol HOAc = acetic acid KOAc = Potassium Acetate MeOH = methanol NaOAc = Sodium Acetate NBS = N-bromosuccinimide NIS = N-iodosuccinimide NMP = N-methyl-2-pyrrolidone PE=petroleum ether 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 TLC = Thin Layer Chromatography TsCl = p-toluenesulfonyl chloride

[0142] Example 1 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0143] [ka]

[0144] Step 1. (General Step H) Preparation of tert-butyl 4-(3-bromophenyl)-3-oxopiperazine-1-carboxylate: To a solution of compound 1 (77.33 g, 0.273 mol), compound 2 (50 g, 0.248 mol), 3,4,7,8-tetramethyl-1,10-phenanthroline (17.62 g, 0.074 mol) in dioxane (1000 mL) under N2, Cu(OAc)2 (9 g, 0.05 mol) and Cs2CO3 (162 g, 0.5 mol) were added. The reaction mixture was stirred at 100 °C for 16 h. The reaction was filtered and concentrated. The residue was slurried with EA / PE (1:10, 550 mL) for 2 h. The solid was filtered to give compound 3 (70 g, 79% yield) as a yellow solid. Mass (m / z): 376.7 [M+Na] + .

[0145] Step 2. (General Step I) Preparation of tert-butyl 3-oxo-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate: To a solution of compound 3 (107 g, 0.3 mol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (91.5 g, 0.36 mol) and KOAc (88.45 g, 0.9 mol) in dioxane (1500 mL) was added Pd(dppf)2Cl2 (14.9 g, 0.018 mol) under N2. The reaction mixture was stirred at 110 °C for 16 h. The reaction was filtered and concentrated. Water (500 mL) was added to the reaction and extracted with EA (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by CombiFlash using EA / PE (1:2) to give compound 4 (92 g, 75.9% yield) as a white solid. Mass (m / z): 402.6 [M+H] + .

[0146] Step 3. (General Step L) Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.25 mol) in DCM (550 mL) was added AlCl3 (101.27 g, 0.76 mol) and acetyl chloride (21.92 g, 0.28 mol) at 0 °C under N2. The reaction mixture was stirred at room temperature under N2 for 7 h. 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 NaOH aqueous solution and extracted with EA (500 mL × 3). The combined organic layers were washed with brine (300 mL × 3) and then dried over anhydrous Na2SO4. 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] + .

[0147] Step 4. (General Step M) Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: 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 under vacuum 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] + .

[0148] Step 5. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: To a solution of 7 (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 h. The solution was washed with saturated Na2CO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4. The reaction mixture was filtered and the filtrate was concentrated to dryness to give the desired product 8 as a white solid (17.4 g, yield: 64.6%). Mass (m / z): 240.7 [M+H] + .

[0149] Step 6. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 8 (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 h. 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 9 as a white solid (4.1 g, yield: 22%). Mass (m / z): 258.7 [M+H] + .

[0150] Step 7. (General Step A) Preparation of tert-butyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a mixture of compound 9 (4.1 g, 15.8 mmol), compound 4 (7.01 g, 17.38 mmol) and K2CO3 (6.55 g, 4.74 mmol) in dioxane / H2O (10:1, 50 mL) was added Pd(dppf)Cl2 (1.16 g, 1.58 mmol) under N2. The reaction mixture was stirred at 90 °C for 4 h. The reaction was filtered and concentrated. The residue was purified by CombiFlash with DCM / PE (1:2) to give compound 10 (5.8 g, yield: 80%) as a yellow solid. Mass (m / z): 455.2 [M+H] + .

[0151] Step 8. (General Step B1) Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: To a mixture of compound 10 (5.8 g, 12.7 mmol) in DCM (20 mL) was added HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was slurried in DCM (10 mL) for 1 h. The solid was filtered to give Example 1 HCl salt (4.1 g, yield: 91%) as a yellow solid. Mass (m / z): 354.7 [M+H] + . 1 H NMR (400 MHz, DMSO)δ12.02 (s, 1H), 10.25 (s, 2H), 8.17 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 19.0, 10.0 Hz, 4H), 4.00 (t, J = 5.0 Hz, 2H), 3.87 (s, 2H), 3.55 (s, 2H), 2.97 - 2.90 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H).

[0152] Example 2 Methyl 4-chloro-5-(3-(2-oxopiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0153] [ka]

[0154] Step 1. Preparation of methyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate: Following general step A, methyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate was prepared as a brown solid (140 mg, 41%). Mass (m / z): 484.8 [M+H] + .

[0155] Step 2. Preparation of methyl 4-chloro-5-(3-(2-oxopiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate: Following general step B1, methyl 4-chloro-5-(3-(2-oxopiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate was prepared as a brown solid (64 mg, 57%). Mass (m / z): 385.0 [M+H] + .

[0156] Example 3 1-(3-(4-chloro-3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0157] [ka]

[0158] Step 1. tert-Butyl 4-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a brown solid (15 g, 77% yield). MS: m / z=426.9 (M+1, ESI+).

[0159] Step 2. (General Step F) tert-Butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a solution of tert-butyl [4-(3-{4-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-oxopiperazin-1-yl]formate (15 g, 35.1 mmol) in acetone (300 mL) was added NIS (8.69 g, 38.6 mmol). The resulting mixture was stirred at 25° C. for 4 h and then concentrated. The residue was diluted with EA (200 mL), washed with water (100 mL×2), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (EA:PE=1:1) to give tert-butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (8 g, 39% yield) as a yellow solid. MS: m / z=552.7.(M+1, ESI+).

[0160] Step 3. 1-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B1, 1-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a white solid (3 g, 70% yield). MS: m / z=452.6 (M+1, ESI+).

[0161] Step 4. (General Step G) 1-(3-(4-chloro-3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: A mixture of 1-(3-{4-chloro-5-iodo-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)piperazin-2-one (200 mg, 0.4418 mmol), 3,3-dimethylbut-1-yne (181.46 mg, 2.209 mmol), bis(triphenylphosphine)palladium(II) chloride (31.01 mg, 0.0441 mmol) and copper(I) iodide (16.83 mg, 0.0883 mmol) in TEA (2 mL) and DMF (2 mL) was stirred at room temperature under nitrogen for 18 hours. Methyl tert-butyl ether was added. A white solid precipitated and was filtered. The residue was purified by column chromatography (MeOH:DCM=1:10) to give the crude product, which was further purified by preparative HPLC (xbridge-c18 150×19 mm, 5 um, mobile phase: ACN-HO (0.1% FA), gradient: 20-40) to give 1-(3-(4-chloro-3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (3 mg, 1.58% yield) as a yellow solid. MS: m / z=407 (M+1, ESI+).

[0162] Example 4 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0163] [ka]

[0164] Step 1. (General Step J) tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: A mixture of tert-butyl 4-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (5 g, 9 mmol), 4-DMAP (0.11 g, 0.9 mmol), (Boc)2O (2.95 g, 13.5 mmol) and TEA (01.82 g, 18 mmol) in DCM (50 mL) was stirred at room temperature under nitrogen overnight. The mixture was concentrated, and the residue was purified by column chromatography (eluted with EA:PE=1:1) to give tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.5 g, 40%) as a yellow solid. MS: m / z=652.7 (M+1, ESI+).

[0165] Step 2. (General Step K) tert-Butyl 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a solution of tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, 0.763 mmol), palladium diacetate (17.14 mg, 0.076 mmol), [(t-Bu)3Ph]BF4 (22.15 mg, 0.076 mmol) and zinc bromide (171.92 mg, 0.763 mmol) in THF (5 mL) was added bromo(cyclopropyl)magnesium (1.5 mL, 1.53 mmol) dropwise over 30 min at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 18 h. Quenched with water, extracted with EA (20 mL×3), dried over Na2SO4, filtered, evaporated, and the residue was purified by column chromatography (EA:PE=1:1) to give tert-butyl 4-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (250 mg, 21%) as a black oil. MS: m / z=466.9 (M+1, ESI+).

[0166] Step 3. (General Step B2) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: A solution of tert-butyl [4-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)-3-oxopiperazin-1-yl]formate (250 mg, 0.5342 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 18 h. After concentration, the residue was purified by preparative HPLC (xbridge-c18 150×19 mm, 5 um, mobile phase: ACN-H2O (0.1% TA), gradient: 10-40) to give 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (14 mg, 6.42% yield) as a yellow solid. MS: m / z=367 (M+1, ESI+).

[0167] Example 5 1-(3-(4-chloro-3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0168] [ka]

[0169] Step 1. tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following the general step G, tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a yellow solid (80 mg, 83%). MS: (m / z)=590.9 (M+1, ESI+).

[0170] Step 2. 1-(3-(4-chloro-3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (Example 10): Following the general step B2, 1-(3-(4-chloro-3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (3 mg, 6%). MS: m / z=390.9 (M+1, ESI+).

[0171] Example 6 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0172] [ka]

[0173] Step 1. tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following the general step G, tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a grey solid (300 mg, 74%). MS: (m / z)=627.8 (M+1, ESI+).

[0174] Step 2. 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following the general step B2, 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (example 11) was prepared as a grey solid (120 mg, 72%). MS (m / z)=427.8 (M+1, ESI+).

[0175] Example 7 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0176] [ka]

[0177] Step 1. tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following the general step G, tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a grey solid (150 mg, 74%). MS: m / z=627.8 (M+1, ESI+).

[0178] Step 2. 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (Example 12): Following the general step B2, 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a grey solid (80 mg, 71%). MS: m / z=427.8 (M+1, ESI+).

[0179] Example 8 1-(3-(4-chloro-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0180] [ka]

[0181] Step 1. tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following general step G, tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a yellow solid (80 mg, 83%). MS: (m / z)=607.8 (M+1, ESI+).

[0182] Step 2. 1-(3-(4-chloro-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (Example 13): Following the general step B2, 1-(3-(4-chloro-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (3 mg, 7%). MS: (m / z)=407.9 (M+1, ESI+).

[0183] Example 9 1-(6-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one

[0184] [ka]

[0185] Step 1. Preparation of [4-(6-bromopyridin-2-yl)-3-oxopiperazin-1-yl]tert-butyl formate Following general step H, [4-(6-bromopyridin-2-yl)-3-oxopiperazin-1-yl]tert-butyl formate was prepared as a brown solid (1.02 g, 26.8% yield). Mass (m / z): 355.8 [M+H] + .

[0186] Step 2. Preparation of tert-butyl 3-oxo-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate Following general step I, tert-butyl 3-oxo-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate was prepared as a crude product which was used in the next step without further purification.

[0187] Step 3. Preparation of tert-butyl 4-(6-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(6-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a brown solid (170 mg, 26% yield). Mass (m / z): 455.8 [M+H] + .

[0188] Step 4. Preparation of 1-(6-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one Following general step B2, 1-(6-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one was prepared as a yellow solid (26 mg, 19%). Mass (m / z): 355.9 [M+H] + .

[0189] Example 10 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one

[0190] [ka]

[0191] Step 1. Preparation of tert-butyl 4-(4-bromothiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step H, tert-butyl 4-(4-bromothiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a white solid (9 g, 54%). Mass (m / z): 383.7 [M+Na] + .

[0192] Step 2. Preparation of (2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)thiazol-4-yl)boronic acid: Following general step I, (2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)thiazol-4-yl)boronic acid was prepared as a crude oil which was used in the next step without further purification.

[0193] Step 3. Preparation of tert-butyl 4-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a white solid (200 mg, 28%). Mass (m / z): 461.7 [M+H] + .

[0194] Step 4. Preparation of 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one: Following general step B2, 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one was prepared as a white solid (85 mg, 52%). Mass (m / z): 361.9 [M+H] + .

[0195] Example 11 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one

[0196] [ka]

[0197] Step 1. Preparation of tert-butyl 4-(4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a white solid (400 mg, 60%). Mass (m / z): 433.8 [M+H] + .

[0198] Step 2. Preparation of tert-butyl 4-(4-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step F, tert-butyl 4-(4-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow oil (400 mg, 62%). Mass (m / z): 559.6 [M+H] + .

[0199] Step 3. Preparation of tert-butyl 5-(2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)thiazol-4-yl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following general step J, tert-butyl 5-(2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)thiazol-4-yl)-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a colorless oil (200 mg, 38%). Mass (m / z): 603.5 [M-55] + .

[0200] Step 4. Preparation of tert-butyl 4-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step K, tert-butyl 4-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow oil (40 mg, 17%). Mass (m / z): 473.9 [M+H] + .

[0201] Step 5. Preparation of 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one: Following general step B2, 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)piperazin-2-one was prepared as a white solid (8.2 mg, 25%). Mass (m / z): 373.8 [M+H] + .

[0202] Example 12 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0203] [ka]

[0204] Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone Following general step L, 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone was prepared as a yellow solid (200 mg, 12%). Mass (m / z): 308.7 [M+H] + .

[0205] Step 2. Preparation of 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine: Following general step M, 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine was prepared as a brown solid (50 mg, 13%). Mass (m / z): 295.0 [M+H] + .

[0206] Step 3. Preparation of tert-butyl 4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a brown solid (70 mg, yield: 33%). Mass (m / z): 491.1 [M+H] + .

[0207] Step 4. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one Following general step B2, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (5 mg, 8%). Mass (m / z): 391.0 [M+H] + .

[0208] (Example 13) 1-(3-(4-chloro-3-((6-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0209] [ka]

[0210] Step 1. tert-Butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-((6-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate: Following general step G, tert-butyl 5-(3-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)phenyl)-4-chloro-3-((6-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared as a yellow solid (100 mg, 48%). Mass (m / z): 641.8 [M+H] + .

[0211] Step 2. 1-(3-(4-chloro-3-((6-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B2, 1-(3-(4-chloro-3-((6-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (50 mg, 69%). Mass (m / z): 442.1 [M+H] + .

[0212] Example 14 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0213] [ka]

[0214] Step 1. 1-Methyl-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole: Following general step G, 1-methyl-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole was prepared as a black oil (1.6 g, 69%). Mass (m / z): 180.0 [M+H] + .

[0215] Step 2. 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one Following general step G, 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (11 mg, 11%). Mass (m / z): 431.7 [M+H] + .

[0216] Example 15 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one

[0217] [ka]

[0218] Step 1. Preparation of tert-butyl 4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow oil (800 mg, 34% yield). Mass (m / z): 468.1 [M+H] + .

[0219] Step 2. Preparation of 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one: Following general step B1, 1-(6-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one was prepared as a yellow semi-solid (4.70 g, 67% yield). Mass (m / z): 368.1 [M+H] + .

[0220] (Example 16) 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one

[0221] [ka]

[0222] Step 1. Preparation of tert-butyl 4-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (100 mg, 12%). Mass (m / z): 492.1 [M+H] + .

[0223] Step 2. Preparation of 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one: Following general step B2, 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one was prepared as a pale yellow solid (18 mg, 21%). Mass (m / z): 392.1 [M+H] + .

[0224] (Example 17) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)piperazin-2-one

[0225] [ka]

[0226] Step 1. Preparation of [4-(3-bromo-4-fluorophenyl)-3-oxopiperazin-1-yl]tert-butyl formate: Following general step H, [4-(3-bromo-4-fluorophenyl)-3-oxopiperazin-1-yl]tert-butyl formate was prepared as a yellow oil (3.6 g, 51%). Mass (m / z): 394.9 [M+Na] + .

[0227] Steps 2 and 3. Preparation of tert-butyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate: Following general steps I and A, tert-butyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (60 mg, 38%). Mass (m / z): 473.2 [M+H] + .

[0228] Step 4. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)piperazin-2-one: Following general step B1, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)piperazin-2-one was prepared as a white solid (10 mg, 30%). Mass (m / z): 373.1 [M+H] + .

[0229] (Example 18) 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one

[0230] [ka]

[0231] Step 1. Preparation of tert-butyl 4-(4-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step H, tert-butyl 4-(4-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (2.0 g, 71%). Mass (m / z): 356.0, 358.1 [M+H] + .

[0232] Step 2. Preparation of (2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-4-yl)boronic acid: Following general step I, (2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-4-yl)boronic acid was prepared as a yellow solid (1.3 g, 64%). Mass (m / z): 322.0 [M+H] + .

[0233] Step 3. Preparation of tert-butyl 4-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow oil (300 mg, 78%). Mass (m / z): 467.9 [M+H] + .

[0234] Step 4. Preparation of 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one: Following general step B1, 1-(4-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-2-one was prepared as a yellow solid (268 mg, 96%). Mass (m / z): 367.9 [M+H] + .

[0235] (Example 19) 1-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazin-2-one

[0236] [ka]

[0237] Step 1. Preparation of tert-butyl 4-(5-bromopyridin-3-yl)-3-oxopiperazine-1-carboxylate: Following general step H, tert-butyl 4-(5-bromopyridin-3-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (2.8 g, 30%). Mass (m / z): 356.0, 358.1 [M+H] + .

[0238] Step 2. Preparation of (5-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-3-yl)boronic acid: Following general step I, (5-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-3-yl)boronic acid was prepared as a yellow solid (850 mg, 30%). Mass (m / z): 321.9 [M+H] + .

[0239] Step 3. Preparation of tert-butyl 4-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)-3-oxopiperazine-1-carboxylate: Following general step A, tert-butyl 4-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (200 mg, 52%). Mass (m / z): 468.0 [M+H] + .

[0240] Step 4. Preparation of 1-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazin-2-one: Following general step B1, 1-(5-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazin-2-one was prepared as a yellow solid (200 mg, 14%). Mass (m / z): 368.0 [M+H] + .

[0241] (Example 20) 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)piperazin-2-one

[0242] [ka]

[0243] Step 1. Preparation of tert-butyl 4-(4-bromo-5-methylthiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general step H, tert-butyl 4-(4-bromo-5-methylthiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (800 mg, 49%). Mass (m / z): 376.1, 378.0 [M+H] + .

[0244] Steps 2 and 3. Preparation of tert-butyl 4-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)-3-oxopiperazine-1-carboxylate: Following general steps I and A, tert-butyl 4-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (1.0 g, 69%). Mass (m / z): 476.1 [M+H] + .

[0245] Step 4. Preparation of 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)piperazin-2-one: Following general step B2, 1-(4-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylthiazol-2-yl)piperazin-2-one was prepared as a white solid (68 mg, 8%). Mass (m / z): 376.1 [M+H] + .

[0246] Example 21 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(hydroxymethyl)phenyl)piperazin-2-one

[0247] [ka]

[0248] Step 1. Preparation of [4-(3-bromo-4-formylphenyl)-3-oxopiperazin-1-yl]tert-butyl formate: Following general step H, [4-(3-bromo-4-formylphenyl)-3-oxopiperazin-1-yl]tert-butyl formate was prepared as a yellow oil (1.2 g, 16%). Mass (m / z): 405.1 [M+Na] + .

[0249] Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: Following general step M, 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine was prepared as a brown solid (4.0 g, 85%). Mass (m / z): 224.9 [M+H] + .

[0250] Steps 3 and 4. Preparation of tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-formylphenyl)-3-oxopiperazine-1-carboxylate: Following general steps I and A, tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-formylphenyl)-3-oxopiperazine-1-carboxylate was prepared as a yellow solid (300 mg, 24%). Mass (m / z): 449.2 [M+H] + .

[0251] Step 5. (General Step R) Preparation of tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(hydroxymethyl)phenyl)-3-oxopiperazine-1-carboxylate: To a solution of tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-formylphenyl)-3-oxopiperazine-1-carboxylate (210 mg, 0.47 mmol) in MeOH (10 mL) was added NaBH4 (35 mg, 0.92 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 2 h and then concentrated in vacuo. The crude residue was purified by CombiFlash (PE / EA=4:1) to give tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(hydroxymethyl)phenyl)-3-oxopiperazine-1-carboxylate (140 mg, 66%) as a yellow solid. Mass (m / z): 451.2 [M+H] + .

[0252] Step 6. Preparation of 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(hydroxymethyl)phenyl)piperazin-2-one: Following general step B2, 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(hydroxymethyl)phenyl)piperazin-2-one was prepared as a pale yellow solid (25 mg, 22%). Mass (m / z): 351.2 [M+H] + .

[0253] Example 22 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one

[0254] Example 23 (R)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one

[0255] Example 24 (S)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one

[0256] [ka]

[0257] Step 1. Preparation of ethyl 1-(3-bromophenyl)-2-oxopiperidine-3-carboxylate: Following general step H, ethyl 1-(3-bromophenyl)-2-oxopiperidine-3-carboxylate was prepared as a yellow oil (5.34 g, 56%). Mass (m / z): 325.8 [M+H] + .

[0258] Step 2. Preparation of 1-(3-bromophenyl)-3-(hydroxymethyl)piperidin-2-one: Following general step R, 1-(3-bromophenyl)-3-(hydroxymethyl)piperidin-2-one was prepared as a yellow oil (3.9 g, 83%). Mass (m / z): 284.1 [M+H] + .

[0259] Step 3. Preparation of 3-(hydroxymethyl)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-2-one: Following general step I, 3-(hydroxymethyl)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-2-one was prepared as a yellow oil (5.07 g, 93%). Mass (m / z): 332.1 [M+H] + .

[0260] Step 4. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one, (R)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one and (S)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one Following general step A, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one was prepared as a white solid (200 mg, 5.8%). Mass (m / z): 384.2 [M+H] + .

[0261] Racemic 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one was further separated by chiral SFC [SP-120-10-C18-BIO-C18, 250×50 mm, 20% IPA (DEA) in CO2] to give (R)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one as a white solid (35 mg) and (S)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(hydroxymethyl)piperidin-2-one as a white solid (34 mg).

[0262] (Example 25) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0263] [ka]

[0264] Step 1. (General Step C) Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one: To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (150 mg, 0.422 mmol) in DMF (5.0 mL) was added methoxyacetic acid (57 mg, 0.634 mmol), DIEA (164 mg, 1.26 mmol) and T3P (538 mg, 0.854 mmol, 50% in EtOAc). The resulting solution was stirred at room temperature for 16 h and then diluted with H2O. The aqueous medium was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH=15:1) to give 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one as a white solid (66.8 mg, 36%). Mass (m / z): 426.9[M+H] + .

[0265] (Example 26) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-morpholinoacetyl)piperazin-2-one

[0266] [ka]

[0267] Step 1. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-morpholinoacetyl)piperazin-2-one Following general step C, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-morpholinoacetyl)piperazin-2-one was prepared as a white solid (78.5 mg, 37%). Mass (m / z): 481.9 [M+H] + .

[0268] Example 27 Methyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate

[0269] [ka]

[0270] Step 1. (General Step D) Preparation of methyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (150 mg, 0.42 mmol) in DCM (5 mL) was added TEA (86 mg, 0.84 mmol) and methyl carbonochloridate (44 mg, 0.46 mmol) at 0° C. The reaction mixture was stirred at room temperature under N for 16 h. After the reaction was completed, H2O (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL×3). The combined organic layer was washed with brine (20 mL×2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum and the crude product was purified by CombiFlash (DCM / MeOH=0-2.5%) to give the product methyl 4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate (Example 5) as a white solid (26 mg, 15%). Mass (m / z): 412.8[M+H] + .

[0271] (Example 28) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one

[0272] [ka]

[0273] Step 1 and Step 2. (General Step E) Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one: A solution of 1,1,2-trimethoxyethane (338 mg, 2.818 mmol) in 1N HCl solution (5 mL) was stirred at 50° C. for 3 h. The solution was cooled to room temperature and extracted with DCE (5 mL×2). The combined organic layers were washed with brine (20 mL×2) and dried over Na2SO4. The solution was added to a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (50 mg, 0.14 mmol) in DCE (5 mL), followed by AcOH (2 drops) and sodium triacetoxyborohydride (89 mg, 0.422 mmol). The reaction mixture was stirred at room temperature under N2 for 3 h and then concentrated. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one as a yellow solid (66.8 mg, 36%). Mass (m / z): 412.9[M+H] + .

[0274] (Example 29) 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0275] [ka]

[0276] Step 1. Preparation of 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one: Following general step C, 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a white solid (15 mg, 42%). Mass (m / z): 500.1 [M+H] + .

[0277] (Example 30) 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one

[0278] [ka]

[0279] Step 1. Preparation of 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one Following general step C, 1-(3-(4-chloro-3-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one was prepared as a white solid (10 mg, 27%). Mass (m / z): 513.2 [M+H] + .

[0280] (Example 31) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one

[0281] [ka]

[0282] Step 1. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one: Following general step C, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylglycyl)piperazin-2-one was prepared as a white solid (15 mg, 18%). Mass (m / z): 440.2 [M+H] +.

[0283] Example 32 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0284] [ka]

[0285] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one: Following the general step C, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a white solid (25 mg, 7%). MS: (m / z)=438.9 (M+1, ESI+).

[0286] (Example 33) 4-(2-((1s,3s)-adamantan-1-yl)acetyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0287] [ka]

[0288] Step 1. Preparation of 4-(2-((1s,3s)-adamantan-1-yl)acetyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step C, 4-(2-((1s,3s)-adamantan-1-yl)acetyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a white solid (4.0 mg, 6.6%). Mass (m / z): 530.8 [M+H] + .

[0289] (Example 34) 2-((3r,5r,7r)-adamantan-1-yl)-N-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)acetamide

[0290] [ka]

[0291] Step 1. Preparation of ethyl 4-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)butanoate: Following general step C, ethyl 4-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)butanoate was prepared as a colorless oil (240 mg, 60%). Mass (m / z): 308.0 [M+H] + .

[0292] Step 2. (General Step N) Preparation of 4-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)butanoic acid: To a solution of ethyl 4-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)butanoate (240 mg, 0.78 mmol) in a mixed solvent of MeOH (4 mL) and HO (1 mL) was added NaOH (312 mg, 7.8 mmol). The resulting solution was stirred at ambient temperature for 16 h and then diluted with water (10 mL). The aqueous solution was acidified to pH 3-4 with aqueous HCl (2 M) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 4-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)butanoic acid as a white solid (210 mg, 77%). Mass (m / z): 280.1 [M+H] + .

[0293] Step 3. Preparation of 2-((3r,5r,7r)-adamantan-1-yl)-N-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)acetamide: Following general step C, 2-((3r,5r,7r)-adamantan-1-yl)-N-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutyl)acetamide was prepared as a white solid (15 mg, 10%). Mass (m / z): 615.8 [M+H] + .

[0294] Example 35 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0295] [ka]

[0296] Step 1. 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one Following general step C, 1-(3-(4-chloro-3-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a white solid (2.3 mg, 3.8%). Mass (m / z): 500.1 [M+H] + .

[0297] (Example 36) 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0298] [ka]

[0299] Step 1. 1-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one: Following general step C, 1-(3-(4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a yellow solid (110 mg, 90%). Mass (m / z): 524.7 [M+H] + .

[0300] Step 2. 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one: Following general step G, 1-(3-(4-chloro-3-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a yellow solid (4 mg, 24%). Mass (m / z): 504.0 [M+H] + .

[0301] (Example 37) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one

[0302] [ka]

[0303] Step 1. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one Following general step E, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one was prepared as a white solid (120 mg, 25%). Mass (m / z): 449.1 [M+H] + .

[0304] (Example 38) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one

[0305] [ka]

[0306] Step 1. 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one Following general step C, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyacetyl)piperazin-2-one was prepared as a pale yellow solid (11 mg, 18%). Mass (m / z): 463.1 [M+H] + .

[0307] (Example 39) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one

[0308] [ka]

[0309] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one Following general step E, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-methoxyethyl)piperazin-2-one was prepared as a white solid (8 mg, 2%). Mass (m / z): 425.0 [M+H] + .

[0310] (Example 40) 1-(4-((dimethylamino)methyl)-3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0311] [ka]

[0312] Step 1. Preparation of tert-butyl 4-(4-((dimethylamino)methyl)-3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step E, tert-butyl 4-(4-((dimethylamino)methyl)-3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a pale yellow solid (130 mg, 55%). Mass (m / z): 478.3 [M+H] + . Step 2. Preparation of 1-(4-((dimethylamino)methyl)-3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one:

[0313] Following general step B2, 1-(4-((dimethylamino)methyl)-3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a pale yellow solid (20 mg, 19%). Mass (m / z): 378.2 [M+H] + .

[0314] (Example 41) 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((methylamino)methyl)phenyl)piperazin-2-one

[0315] [ka]

[0316] Step 1. Preparation of tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((methylamino)methyl)phenyl)-3-oxopiperazine-1-carboxylate: Following general step E, tert-butyl 4-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((methylamino)methyl)phenyl)-3-oxopiperazine-1-carboxylate was prepared as a pale yellow solid (120 mg, 52%). Mass (m / z): 464.3 [M+H] + .

[0317] Step 2. Preparation of 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((methylamino)methyl)phenyl)piperazin-2-one: Following general step B2, 1-(3-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((methylamino)methyl)phenyl)piperazin-2-one was prepared as a pale yellow solid (2.6 mg, 2.7%). Mass (m / z): 364.3 [M+H] + .

[0318] (Example 42) 4-(L-valyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0319] [ka]

[0320] Step 1. tert-Butyl (S)-(1-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate: Following general step C, tert-butyl (S)-(1-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate was prepared as a yellow oil (68 mg, 85%). Mass (m / z): 554.3 [M+H] + .

[0321] Step 2. 4-(L-valyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one Following general step B2, 4-(L-valyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a white solid (35 mg, 71%). Mass (m / z): 454.2 [M+H] + .

[0322] (Example 43) 4-(L-phenylalanyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one

[0323] [ka]

[0324] Step 1. Preparation of tert-butyl (S)-(1-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamate: Following general step C, tert-butyl (S)-(1-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamate was prepared as a yellow solid (50 mg, 56%). Mass (m / z): 602.3 [M+H] + .

[0325] Step 2. Preparation of 4-(L-phenylalanyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one: Following general step B2, 4-(L-phenylalanyl)-1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one was prepared as a yellow solid (37 mg, 85%). Mass (m / z): 502.2 [M+H] + .

[0326] (Example 44) (S)-2-Amino-N-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)-3-methylbutanamide

[0327] [ka]

[0328] Step 1. Preparation of methyl (tert-butoxycarbonyl)-L-valyl glycinate: Following general step C, methyl (tert-butoxycarbonyl)-L-valylglycinate was prepared as a white solid (800 mg, 99%). Mass (m / z): 233.1 [M+H-56] + .

[0329] Step 2. Preparation of (tert-butoxycarbonyl)-L-valylglycine: Following general step N, (tert-butoxycarbonyl)-L-valylglycine was prepared as a colorless oil (700 mg, 81%). Mass (m / z): 547.4 [2M-H] - .

[0330] Step 3. Preparation of tert-butyl (S)-(1-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate: Following general step C, tert-butyl (S)-(1-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate was prepared as a yellow solid (36 mg, 32%). Mass (m / z): 611.4 [M+H] + .

[0331] Step 4. Preparation of (S)-2-amino-N-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)-3-methylbutanamide: Following general step B2, (S)-2-amino-N-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)-3-methylbutanamide was prepared as a white solid (6.5 mg, 25%). Mass (m / z): 511.2 [M+H] + .

[0332] (Example 45) (R)-2-amino-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)phenyl)propanoic acid

[0333] [ka]

[0334] Step 1. Preparation of tert-Butyl (tert-butoxycarbonyl)-D-tyrosinate: Following general step J, tert-butyl (tert-butoxycarbonyl)-D-tyrosinate was prepared as a yellow solid (1 g, 71%). Mass (m / z): 338.2 [M+H] + .

[0335] Step 2. (General Step Q) Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-ethoxy-2-oxoethoxy)phenyl)propanoate: To a solution of tert-butyl(tert-butoxycarbonyl)-D-tyrosinate (1.0 g, 3.0 mmol) in DMF (10 mL) was added NaH (60% in oil, 144 mg, 3.6 mmol) and ethyl 2-bromoacetate (500 mg, 3.0 mmol) successively at 0° C. The resulting mixture was stirred under N2 at 0° C. for 2 h and then diluted with H2O (20 mL). The aqueous solution was extracted with EA (30 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated in vacuo. The crude residue was purified by Combiflash (PE / EA=0-12%) to give the product tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-ethoxy-2-oxoethoxy)phenyl)propanoate as a yellow solid (758 mg, 60%). Mass (m / z): 424.2 [M+H] + .

[0336] Step 3. Preparation of (R)-2-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenoxy)acetic acid: Following general step N, (R)-2-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenoxy)acetic acid was prepared as a yellow solid (20 mg, 66%). Mass (m / z): 396.2 [M+H] + .

[0337] Step 4. Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)phenyl)propanoate: Following general step C, tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)phenyl)propanoate was prepared as a yellow solid (20 mg, 50%). Mass (m / z): 732.4 [M+H] + .

[0338] Step 5. Preparation of (R)-2-amino-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)phenyl)propanoic acid: Following general step B2, (R)-2-amino-3-(4-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)phenyl)propanoic acid was prepared as a yellow solid (6 mg, 36%). Mass (m / z): 576.3 [M+H] + .

[0339] (Example 46) (R)-2-amino-3-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)phenyl)propanoic acid

[0340] [ka]

[0341] Step 1. Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)propanoate: To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)propanoic acid (1.56 g, 5.01 mmol) in toluene (20 mL), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (1.52 g, 7.48 mmol) was added. The reaction mixture was stirred at 110 °C under N2 for 8 h. After the reaction was completed, the solvent was removed under reduced pressure and the residue was purified by Combiflash (PE / EA=0-10%) to give the product tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)propanoate as a yellow solid (0.56 g, 30%).

[0342] Step 2. Preparation of tert-butyl (R)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate: To a solution of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)propanoate (560 mg, 1.52 mmol) in EtOH (16 mL) and HO (4 mL) was added Fe (514 mg, 9.15 mmol) and NH4Cl (1.62 g, 30.48 mmol). The reaction mixture was stirred at 80 °C under N2 for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by CombiFlash (DCM / MeOH=0-10%) to give the product tert-butyl (R)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a brown oil (477 mg, 92%). Mass (m / z): 237.1 [M+H-100] + .

[0343] Step 3. Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-((2-ethoxy-2-oxoethyl)amino)phenyl)propanoate: To a solution of tert-butyl (R)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (477 g, 1.41 mmol) in CH3CN (10 mL) was added ethyl 2-bromoacetate (260 mg, 1.55 mmol) and DIPEA (548 mg, 4.24 mmol). The reaction mixture was stirred at 60 °C under N2 for 6 h. The solvent was removed under reduced pressure and the residue was purified by CombiFlash (PE / EA = 0-30%) to give the product tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-((2-ethoxy-2-oxoethyl)amino)phenyl)propanoate as a brown oil (467 mg, 80%). Mass (m / z): 845.5 [2M+H] + .

[0344] Step 4. Preparation of (R)-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)glycine: Following general step N, (R)-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)glycine was prepared as a brown oil (379 mg, 88%). Mass (m / z): 787.4 [2M-H] - .

[0345] Step 5. Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)phenyl)propanoate: Following general step C, tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)phenyl)propanoate was prepared as a yellow oil (100 mg, 47%). Mass (m / z): 731.4 [M+H]+ .

[0346] Step 6. Preparation of (R)-2-amino-3-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)phenyl)propanoic acid: Following general step B2, (R)-2-amino-3-(4-((2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethyl)amino)phenyl)propanoic acid was prepared as a white solid (5.2 mg, 6.6%). Mass (m / z): 575.3 [M+H] + .

[0347] (Example 47) (S)-2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-5-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-5-oxopentanoic acid

[0348] [ka]

[0349] Step 1. Preparation of (S)-2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-5-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-5-oxopentanoic acid Following general step C, (S)-2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-5-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-5-oxopentanoic acid was prepared as a white solid (5 mg, 3.1%). Mass (m / z): 777.8[M+H] + .

[0350] (Example 48) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butanoyl)piperazin-2-one

[0351] [ka]

[0352] Step 1. (General Step S) Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(pent-4-en-1-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: To a solution of [(2R,3R,4S,5R,6S)-3,4,5,6-tetrakis(acetyloxy)oxan-2-yl]methyl acetate (5.00 g, 12.8 mmol) in DCM (50 mL) was added boron trifluoride etherate (2.91 g, 20.5 mmol) at 0° C. The resulting solution was stirred at 0° C. for 0.5 h, followed by the addition of pent-4-en-1-ol (1.43 g, 16.7 mmol) at 0° C. The mixture was further stirred at 25° C. for 16 h, then diluted with saturated aqueous NaHCO3 (25 mL). The aqueous medium was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (PE / EA=3:1) to give the product (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(pent-4-en-1-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate as a colorless oil (1.50 g, 28%). Mass (m / z): 438.8 [M+Na] + .

[0353] Step 2. (General Step T) Preparation of 4-(((2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butanoic acid: To a solution of [(2R,3R,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-(pent-4-en-1-yloxy)oxan-2-yl]methyl acetate (1.36 g, 3.25 mmol) in a mixed solvent of DCM (5.2 mL), MeCN (5.2 mL) and H2O (7.8 mL) was added NaIO4 (4.64 g, 13.0 mmol) and RuCl3-3H2O (15 mg, 0.065 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, and then another batch of NaIO4 (4.64 g, 13.0 mmol) was added. The resulting mixture was further stirred at 25 °C for 2 h and then diluted with water (20 mL). The aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (PE / EA / MeOH=1:1:0.1) to give the product 4-(((2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butanoic acid as a colorless oil (1.00 g, 71%). Mass (m / z): 457.1 [M+Na] + .

[0354] Step 3. Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Following general step C, (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate was prepared as a colorless oil (380 mg, 76%). Mass (m / z): 770.7 [M+H] + .

[0355] Step 4. (General Step U) Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butanoyl)piperazin-2-one: To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-4-oxobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (380 mg, 0.49 mmol) in a mixture of THF (3 mL) and MeOH (3 mL) was added K2CO3 (136 mg, 0.99 mmol). The resulting mixture was stirred at 25 °C under N2 for 2 h and then concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM / MeOH=20:1) to give the product 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butanoyl)piperazin-2-one as a white solid (119 mg, 40%). Mass (m / z): 602.8[M+H] + .

[0356] (Example 49) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)piperazin-2-one

[0357] [ka]

[0358] Step 1. Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(allyloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Following general step S, (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(allyloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate was prepared as a colorless oil (2.80 g, 45%). Mass (m / z): 410.8 [M+Na] + .

[0359] Step 2. Preparation of 2-(((2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetic acid: Following general step T, 2-(((2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetic acid was prepared as a colorless oil (700 mg, 50%). Mass (m / z): 428.8 [M+Na] + .

[0360] Step 3. Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Following general step C, (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate was prepared as a colorless oil (120 mg, 71%). Mass (m / z): 742.7 [M+H] + .

[0361] Step 4. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)piperazin-2-one: Following general step U, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)piperazin-2-one was prepared as a white solid (22 mg, 21%). Mass (m / z): 574.7 [M+H] + .

[0362] (Example 50) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(3-((3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenoxy)acetyl)piperazin-2-one

[0363] [ka]

[0364] Step 1. Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(benzyloxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate: To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (2 g, 4.86 mmol) in THF (30 mL) was added cobalt(II) acetylacetonate (87 mg, 0.24 mmol) and TMEDA (28 mg, 0.24 mmol) at 0 °C under N2. It was then added dropwise at a very slow rate onto a cooled (0-5 °C) suspension of (3-(benzyloxy)phenyl)magnesium bromide (0.5 M, 14.6 mL, 7.3 mmol). The reaction mixture was stirred at 0 °C under N2 for 1 h. After the reaction was complete, H2O (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum and the crude product was purified by CombiFlash (PE / EA=0-50%) to give the product (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(benzyloxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate as a yellow solid (2.2 g, 87%). Mass (m / z): 536.7 [M+Na] + .

[0365] Step 2. Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-hydroxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate: To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(benzyloxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.1 g, 2.13 mmol) in THF (20 mL) was added 10% Pd / C (220 mg, 20 wt / wt%). The reaction mixture was stirred at room temperature under H2 in a balloon for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude product, which was purified by CombiFlash (PE / EA=0-30%) to give the product (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-hydroxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate as a white solid (841 mg, 92%). Mass (m / z): 446.7 [M+Na] + .

[0366] Step 3. Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(2-(tert-butoxy)-2-oxoethoxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate: To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-hydroxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (840 mg, 1.97 mmol) in MeCO (10 mL) was added tert-butyl 2-bromoacetate (579 mg, 2.96 mmol) and KCO (410 mg, 2.96 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude product, which was purified by Combiflash (PE / EA=0-30%) to give the product (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(2-(tert-butoxy)-2-oxoethoxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate as a yellow oil (690 mg, 64%). Mass (m / z): 560.8[M+Na] + .

[0367] Step 4. Preparation of 2-(3-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenoxy)acetic acid: Following general step B2, 2-(3-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenoxy)acetic acid was prepared as a brown oil (550 mg, 88%). Mass (m / z): 504.8 [M+Na] + .

[0368] Step 5. Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2oxoethoxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Following general step C, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(2-(4-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-oxopiperazin-1-yl)-2oxoethoxy)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate was prepared as a yellow solid (840 mg, 90%). Mass (m / z): 818.7 [M+H] + .

[0369] Step 6. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(3-((3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenoxy)acetyl)piperazin-2-one: Following general step U, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(2-(3-((3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenoxy)acetyl)piperazin-2-one was prepared as a white solid (345 mg, 51%). Mass (m / z): 650.6 [M+H] + .

[0370] (Example 51) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one

[0371] [ka]

[0372] Step 1. (General Step O) Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one: To a solution of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-2-one (70 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) in DCM (5 mL) was added MsCl (23 mg, 0.20 mmol) at 0° C. The resulting solution was stirred at ambient temperature under N2 for 16 h and then concentrated under reduced pressure. The crude residue was purified by CombiFlash (MeOH / DCM=0-2%) to give 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one as a white solid (10 mg, 11%). Mass (m / z): 468.9[M+H] + .

[0373] (Example 52) 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one

[0374] [ka]

[0375] Step 1. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one: Following the general step O, 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one was prepared as a yellow solid (80 mg, 43%). Mass (m / z): 432.8 [M+H] + .

[0376] (Example 53) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one

[0377] [ka]

[0378] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one: Following general step O, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(methylsulfonyl)piperazin-2-one was prepared as a white solid (16 mg, 6%). Mass (m / z): 444.8 [M+H] + .

[0379] (Example 54) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one

[0380] [ka]

[0381] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one: Following the general step O, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one was prepared as a brown solid (25 mg, 9%). Mass (m / z): 488.8 [M+H] + .

[0382] (Example 55) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one

[0383] [ka]

[0384] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazin-2-one: Following general step O, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazin-2-one was prepared as a white solid (316 mg, 75%). Mass (m / z): 507.0 [M+H]+ .

[0385] Step 2. (General Step P) Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one: To a solution of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazin-2-one (300 mg, 0.59 mmol) in DMF (10 mL) was added morpholine (77 mg, 0.89 mmol), K2CO3 (163 mg, 1.18 mmol) and NaI (177 mg, 1.18 mmol). The resulting mixture was stirred at 70 °C under N2 for 3 h and then diluted with H2O (50 mL). The aqueous medium was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC [Gemini-C18, 150×21.2 mm, 5 um, ACN-H2O (0.1% TFA), 10-40%] to give 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one as a white solid (75 mg, 22%). Mass (m / z): 558.0 [M+H] + .

[0386] (Example 56) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one

[0387] [ka]

[0388] Step 1. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one: Following general step P, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one was prepared as a yellow solid (400 mg, 29%). Mass (m / z): 516.1 [M+H] + .

[0389] (Example 57) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-methylazetidin-1-yl)propyl)sulfonyl)piperazin-2-one

[0390] [ka]

[0391] Step 1. 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-methylazetidin-1-yl)propyl)sulfonyl)piperazin-2-one Following general step P, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-methylazetidin-1-yl)propyl)sulfonyl)piperazin-2-one was prepared as a yellow solid (20 mg, 12%). Mass (m / z): 542.2 [M+H] + .

[0392] (Example 58) 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-fluoroazetidin-1-yl)propyl)sulfonyl)piperazin-2-one

[0393] [ka]

[0394] Step 1. 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-fluoroazetidin-1-yl)propyl)sulfonyl)piperazin-2-one Following general step P, 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(3-fluoroazetidin-1-yl)propyl)sulfonyl)piperazin-2-one was prepared as a pale yellow solid (15 mg, 9.0%). Mass (m / z): 546.2 [M+H] + .

[0395] (Example 59) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one

[0396] [ka]

[0397] Step 1. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazin-2-one: Following general step O, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazin-2-one was prepared as a yellow solid (130 mg, 55%). Mass (m / z): 531.1 [M+H] + .

[0398] Step 2. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one Following general step P, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-morpholinopropyl)sulfonyl)piperazin-2-one was prepared as a pale yellow solid (55 mg, 13%). Mass (m / z): 581.8 [M+H] + .

[0399] (Example 60) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one

[0400] [ka]

[0401] Step 1. 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one Following general step P, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((3-(dimethylamino)propyl)sulfonyl)piperazin-2-one was prepared as a white solid (1.2 g, 65%). Mass (m / z): 540.2 [M+H] + .

[0402] (Example 61) 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-4-(methylsulfonyl)piperazin-2-one

[0403] [ka]

[0404] Step 1. Preparation of 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-4-(methylsulfonyl)piperazin-2-one: Following the general step O, 1-(6-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-4-(methylsulfonyl)piperazin-2-one was prepared as a pale yellow solid (3 mg, 7.4%). Mass (m / z): 470.1 [M+H] + .

[0405] (Example 62) 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one

[0406] [ka]

[0407] Step 1. Preparation of 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one Following the general step O, 1-(3-(4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-((2-methoxyethyl)sulfonyl)piperazin-2-one was prepared as a yellow solid (15 mg, 7.3%). Mass (m / z): 513.1 [M+H] + .

[0408] General assay procedure: HPK1 enzyme inhibition assay Compounds were dissolved in 100% DMSO at a concentration of 10 mM. HPK1 protein was purchased from Signal Chem (M23-11G-10). 2.5 μL of 2X HPK1 protein was added per well to the assay plate containing the test compound, 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). The two were added to a mixture of 2.5 μL per well of 2X MBP (0.2ug / ul) and ATP (20 μM), centrifuged at 1500 rpm for 1 minute, and then incubated at 25° C. for 60 minutes. 5 μL of ADP-Glo ​​from Promega (V9102) was then added to the assay plate to deplete unconsumed ATP for 60 minutes. Then, it was centrifuged at 1500 rpm for 1 min and incubated at 25° C. for 60 min. Finally, ADP was converted to ATP by adding 10 μL of kinase assay reagent from Promega (V9102) to the assay plate, centrifuged at 1500 rpm for 1 min and incubated at 25° C. for 40 min. After 40 min of incubation, the fluorescence was determined. Based on the results, the IC 50 The IC value was calculated. 50 The results are shown in Table 2 below.

[0409] +++: IC 50 <=10nM;++: 10nM <IC 50 <=100nM;+: 100nM <IC 50 <=1 μM; NA: not active, IC 50 >1 μM

[0410] [Table 2A]

[0411] [Table 2B]

[0412] HPK1 p-SLP-76 inhibition assay Prior to compound treatment, Jurkat cells were starved overnight in RPMI-1640 medium supplemented with 0.5% FBS. Cell density was adjusted to 1:1 in assay medium (RPMI-1640, no phenol red, with 0.5% FBS). * The cells were adjusted to 10^7 cells / mL and 16uL of cell suspension was transferred per well to a 384-well plate (Corning #3765). A 6X solution of test compound was prepared in assay medium and 4uL was added per well to the 384-well plate. The plate was then incubated at 37°C, 5% CO2 for 4 hours. Jurkat cells in 384-well plates were stimulated with anti-CD3 (BD ​​Biosciences #555329, final concentration is 10ug / mL) for 20 minutes at 37°C, 5% CO2 by adding 4uL of 6X antibody solution per well. Phospho-SLP76 HTRF kit was purchased from Cisbio (63ADK076PEH). After anti-CD3 stimulation, 8uL of 4X lysis buffer was added to the 384-well plate. The plate was centrifuged at 1,000 rpm for 1 min, shaken at 250 rpm for 60 min, and centrifuged again at 1,000 rpm for 5 min. The cell lysate was then transferred to an assay plate (Greiner #784075) at 16 uL per well. 4 uL per well of detection antibody mix prepared in detection buffer was added to the assay plate, followed by centrifugation at 1,000 rpm for 1 min and incubation at 25°C overnight. Fluorescence emission at two different wavelengths (665 nm and 620 nm) was read by an HTRF compatible microplate reader to determine the IC of the compounds. 50 The value was calculated.

[0413] A: IC 50 <=300nM; B: 300nM <IC 50 <=3μM; C: 3μM <IC 50 <=10 μM; NA: not active, IC 50 >10 μM

[0414] [Table 3A]

[0415] [Table 3B]

[0416] [Table 3C]

[0417] FLT3-ITD enzyme inhibition assay Compounds were dissolved in 100% DMSO at a concentration of 10 mM. FLT3-ITD protein was purchased from Invitrogen (PV6190). 5 μL of 2X 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 15 minutes. HTRF KinEASE-TK kit was purchased from Cisbio (62TK0PEC), and ATP was purchased from Thermo Fisher Scientific (R0441). TK-substrate-biotin and ATP were added to a mixture of 2X TK-substrate-biotin (final concentration is 2 μM) and ATP (final concentration is 15 μM) at 5 μL per well, centrifuged at 1000 rpm for 1 minute, and then incubated at 25° C. for 60 minutes. Then, 10 μL of detection buffer (0.25x TK-antibody Eu3+-cryptate, 0.125 μM streptavidin-XL 665) was added to the assay plate, centrifuged at 1000 rpm for 1 minute, and then incubated at 25° C. for 60 minutes and at 4° C. overnight to determine the product. Based on the results, the IC of the compound was calculated. 50 The IC value was calculated. 50 The results are shown in Table 3.

[0418] +++:IC 50 <=10nM;++: 10nM <IC 50 <=100nM;+: 100nM <IC50 <=1 μM; NA: not active, IC 50 >1 μM

[0419] [Table 4]

[0420] Other embodiments The present disclosure provides merely illustrative embodiments. Those skilled in the art will readily recognize from the present disclosure and 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

1. Formula (I): 【Chemical 1】 a compound of the formula: (i) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO 2 R 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 , S(O)R y , and SO 2 R y Selected from; (v) X is N and CR x Selected from; (vi) Each 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; (vii) 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; (viii) ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; 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)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups; C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 0, 1 or 2 C 1 ~C 6 5- and 6-membered heteroaryl groups optionally substituted with straight-chain, branched, and cyclic alkyl groups.

2. Formula (I'): 【Chemistry 2】 a compound of the formula: (i) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO 2 R y , C(O)R w OR y , C(O)R w NC(O)R x , C(O)R w NC(O)R x NHR y , C(O)R w NR x R y ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (v) each R' and R" is independently selected from hydrogen, linear, branched, and cyclic alkyl groups, linear, branched, and cyclic aminoalkyl groups, carbocyclic groups, and heterocyclic groups; (vi) X is N and CR x Selected from; (vii) Each R X and R y are independently selected from hydrogen, linear, branched and cyclic alkyl groups, linear, branched and cyclic aminoalkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, heteroaryl groups, and glycoside groups; (viii) 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; (ix) Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, carbocyclic groups, linear, branched and cyclic aminoalkyl 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, carboxylate groups; Hydroxy, thiols, amino, Cyano, 【Chemistry 3】 -OC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups; C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkylcarboxylate groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 0, 1 or 2 C 1 ~C 6 3- to 6-membered heterocyclic groups optionally substituted with linear, branched, and cyclic alkyl groups or halogen groups, and 0, 1 or 2 C 1 ~C 6 5- and 6-membered heteroaryl groups optionally substituted with straight-chain, branched, and cyclic alkyl groups.

3. Formula (IIA): 【Chemistry 4】 a compound of the formula: (i) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (ii) R 2 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (iii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO 2 R 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 , S(O)R y , and SO 2 R y Selected from; (v) X is N and CR x Selected from; (vi) Each Z 1 , Z 2 , Z 3 and Z 4 is CR z or N independently selected; (vii) 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; (viii) Each R X , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups; C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 0, 1 or 2 C 1 ~C 6 5- and 6-membered heteroaryl groups optionally substituted with straight-chain, branched, and cyclic alkyl groups.

4. Formula (IIIA): 【Chemistry 5】 a compound of the formula: (x) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (xi) R 2 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (xii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xiii) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO 2 R 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 , S(O)R y , and SO 2 R y Selected from; (xiv) X is N and CR x Selected from; (xv) each Z 1 and Z 2 is CR z or N independently selected; (xvi) Z 3 are O, S, and NR z Selected from; (xvii) 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; (xviii) each R X , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups, C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 0, 1 or 2 C 1 ~C 6 5- and 6-membered heteroaryl groups optionally substituted with straight-chain, branched, and cyclic alkyl groups.

5. Formula (IIIB): 【Chemistry 6】 a compound of the formula: (x) R 1 is a straight-chain, branched and cyclic alkyl group, a carbocyclic group, a heterocyclic group, a straight-chain, branched and cyclic alkenyl group, a straight-chain and branched heteroalkenyl group, a straight-chain, branched and cyclic alkynyl group, CO 2 R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y ) 2 ,OC(O)R w NR x R y , S(O)R y , and SO 2 R y Selected from; (xi) R 2 is hydrogen, halogen, OR x , S.R. x , NHR x , N(R x ) 2 , CHR x , and C(R x ) 2 Selected from; (xii) R 3 is selected from hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xiii) R 4 is hydrogen, linear, branched and cyclic alkyl groups, heterocyclic groups, C(O)R y , CO 2 R 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 , S(O)R y , and SO 2 R y Selected from; (xiv) X is N and CR x Selected from; (xv) each Z 1 and Z 3 is CR z or N independently selected; (xvi) Z 2 are O, S, and NR z Selected from; (xvii) 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; (xviii) each R X , R y and R z are independently selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; 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)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups; C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 0, 1 or 2 C 1 ~C 6 5- and 6-membered heteroaryl groups optionally substituted with straight-chain, branched, and cyclic alkyl groups.

6. 【Table 1A】 Table 1B Table 1C Table 1D 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.

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

8. 10. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6 for use in a method for treating or alleviating a disease, disorder, or condition mediated by inhibition of hematopoietic progenitor kinase 1 (HPK1) and / or human FMS-like tyrosine kinase 3 (FLT3), said method comprising administering to a subject in need thereof a therapeutically effective amount of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6.

9. 10. A pharmaceutical composition for use in a method for decreasing HPK1 and / or FLT3 activity in a disease, disorder, or condition, comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6, said method comprising administering to a subject in need thereof a therapeutically effective amount of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6.

10. 10. The pharmaceutical composition of claim 9, wherein the disease, disorder, or condition is selected from HPK1 and / or FLT3-associated diseases, including cancer, a dysregulated immune response, or a disease involving aberrant HPK1 and / or FLT3 expression, activity, and / or signaling.

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

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