INHIBITORS OF EGFR OR HER2 AND METHODS OF USE CROSS-REFERENCE This application claims priority to and the benefit of U.S. Provisional Patent Application No.63/411960, filed September 30, 2022, the content of which is incorporated herein by reference in its entirety. BACKGROUND EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have been shown to be effective therapeutic agents for patients with non-small cell lung cancer (NSCLC) that harbors somatic activating mutations in EGFR. However, responders typically relapse 6-19 months after taking EGFR TKIs as a consequence of becoming resistant to the inhibitors. The most common resistance mutation occurs at the gatekeeper T790M position. Another mechanism of resistance involves upregulation of alternative signal transduction pathways. Several EGFR gene mutations (e.g., G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR TKIs in advanced NSCLC. In addition, the acquired gefitinib resistant mutation, T790M, is treatable with a third generation EGFR inhibitor, osimertinib. However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, afatinib, and osimertinib). One exception is the EGFR-A763_Y764insFQEA insertion which is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Human epidermal growth factor receptor 2 (HER2) is another member of the human epidermal growth factor receptor family. HER2 mutations, which mainly consist of exon 20 insertion mutations, have been reported in approximately 1-4% of NSCLC patients. Phase I and II clinical data demonstrated that patients harboring HER2 mutations partially responded to treatment with afatinib, neratinib, or dacomitinib. Although patients with HER2 insYVMA have reported durable responses to afatinib as a single agent, a recent phase II trial of dacomitinib showed no response in all 13 patients with HER2 insYVMA (A775_G776insYVMA), which represents up to 80% of HER2 mutations in lung cancers. Thus, novel therapies for patients with EGFR mutations (e.g., exon 20 insertion mutations) are desired. Further, compounds possessing activity against HER2 mutations are needed, as they may have extended utility in treating tumors harboring such mutations. SUMMARY The present disclosure features a class of novel small molecule compounds that inhibit epidermal growth factor receptor tyrosine kinase (EGFR) and/or human epidermal growth factor receptor 2 (HER2). In some embodiments, the compounds are capable of modulating (e.g., inhibiting or decreasing) EGFR and/or HER2 that are resistant to other drugs, e.g., EGFR and/or HER2 with exon 20 mutations, exon 19 mutations, gefitinib resistant T790M mutation, and/or exon 20 insertion mutations. In an aspect, the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , X ¹ , X ² , and X ³ are each described herein in detail below. In an aspect, the present disclosure relates to a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , and X ³ are each described herein in detail below. In an aspect, the present disclosure relates to a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , and X ³ are each described herein in detail below. In another aspect, the present disclosure relates to a compound selected from , _{, or a pharmaceutically} acceptable salt thereof. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of any one of the formulae described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure relates to a kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) HER2 or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and HER2 or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of treating or preventing a disease or disorder, such as a kinase mediated disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy, such as a therapy with gefitinib or erlotinib, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of treating or preventing a disease or disorder, such as a kinase mediated disease or disorder, in a subject in need thereof, wherein the subject is identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a compound of the present disclosure for modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and/or HER2 or a mutant thereof; for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder; for treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In another aspect, the present disclosure relates to a compound of the present disclosure for use in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In another aspect, the present disclosure relates to use of a compound of the present disclosure in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In another aspect, the present disclosure relates to a compound of the present disclosure for use in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In another aspect, the present disclosure relates to use of a compound of the present disclosure in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout the disclosure are hereby expressly incorporated herein in their entireties by reference. DETAILED DESCRIPTION Compounds The present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X ¹ is N, CR ³ , or CHR ³ ; X ² is C or N; X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C ₁ -C ₄ alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; each R ^a2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C1-C6 haloalkyl, C1-C6 alkyl, or C1-C6 alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula: (i-40) (i-41) ; L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; R _E5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In another aspect, the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X ¹ is N, CR ³ , or CHR ³ ; X ² is C or N; X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C ₁ -C ₄ alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R ^a2 ; each R ^a2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C3-C8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula: , ) (i-40) (i-41) ; L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; R _E5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In another aspect, the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X ¹ is CR ³ or CHR ³ ; X ² is C or N; X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R ^a1 ; R ² is H; R ³ is H; R ⁵ is C ₆ -C ₁₀ aryl or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C6-C10 aryl, C3-C10 cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; each R ^a2 is independently halo,–NR ⁿ¹ R ⁿ² , or C ₁ -C ₆ alkyl; each R ^b1 is independently W or C ₁ -C ₆ heteroalkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C2-C4 alkenyl; R ⁸ is C ₂ -C ₄ alkenyl; W is NR ⁿ⁵ C(O)R ⁷ or C(O)R ⁸ ; m is 0 or 1; and n is 0 or 1, wherein at least one R ^a1 or R ^b1 is W. In another aspect, the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X ¹ is N, CR ³ , or CHR ³ ; X ² is C or N; X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl or heteroaryl comprising a 5- or 6-membered ring and 1-2 N heteroatoms, wherein the aryl or heteroaryl is optionally substituted with one or more R ^a1 ; R ² is H; R ⁵ is C6-C10 aryl or heterocyclyl comprising a 5-membered ring and 1-2 N heteroatoms wherein the aryl or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₅ cycloalkyl, or heteroaryl comprising a 5- or 6-membered ring and 1- 2 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or heterocyclyl comprising one or two 6-membered rings and 1-2 heteroatoms selected from N or O, wherein the heteroalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; R ^a2 is C ₁ -C ₆ alkyl; each R ^b1 is independently W, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl; each R ^c1 is independently –CN, halogen, C1-C6 alkyl, or C1-C6 alkoxy; each of R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ ; m is 0, 1, or 2; and n is 0 or 1, wherein at least one R ^a1 or R ^b1 is W. In some embodiments, the compound is of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C ₁ -C ₄ alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; R ^a2 is halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula: , L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; R _E5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In some embodiments, the compound is of Formula IIa: (Iia), or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1.In some embodiments, the compound is of Formula Iib: (Iib), or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1 In some embodiments, the compound is of Formula III: or a pharmaceutically acceptable salt thereof, wherein: X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C ₁ -C ₄ alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; R ^a2 is halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula:

L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; RE5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In some embodiments, the compound is of Formula IIIa: (IIIa), or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1. In some embodiments, the compound is of Formula IIIb: or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1. In some embodiments, the compound is of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C1-C4 alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R ^a2 ; R ^a2 is halo hydroxy –NR ⁿ¹ R ⁿ² C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula: , ,

L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; R _E5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In some embodiments, the compound is of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X ³ is –(CH ₂ ) _m –; R ¹ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^a1 ; R ² is H or C ₁ -C ₄ alkyl; R ³ is H or C ₁ -C ₄ alkyl; R ⁵ is C ₆ -C ₁₀ aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ^b1 ; R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, cycloalkyl, or heteroaryl is optionally substituted with one or more R ^c1 ; each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 ; R ^a2 is halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 ; each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl; each R ^c1 is independently –CN, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; each of R ⁿ¹ , R ⁿ² , R ⁿ³ , R ⁿ⁴ , and R ⁿ⁵ is independently H or C ₁ -C ₄ alkyl; R ⁷ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; R ⁸ is C ₂ -C ₄ alkenyl optionally substituted with one or more R ⁹ ; each R ⁹ is independently –NR ⁿ³ R ⁿ⁴ ; W is NR ⁿ⁵ C(O)R ⁷ , C(O)R ⁸ , or is of formula:

L ₃ is a bond or an optionally substituted C ₁ -C ₄ hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with –C=O–, –O–, –S–, –NR _L3a –, –NR _L3a C(=O)–, –C(=O)NR _L3a –, –SC(=O)–, –C(=O)S–, –OC(=O)–, –C(=O)O–, –NR _L3a C(=S)–, –C(=S)NR _L3a –, trans–CR _L3b =CR _L3b –, cis–CR _L3b =CR _L3b –, –C≡C–, –S(=O)–, –S(=O)O–, –OS(=O)–, –S(=O)NR _L3a –, –NR _L3a S(=O)–, –S(=O) ₂ –, –S(=O) ₂ O–, –OS(=O) ₂ –, –S(=O) ₂ NR _L3a –, or –NR _L3a S(=O) ₂ –; R _L3a is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each R _L3b is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _L3b groups are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; L ₄ is a bond or an optionally substituted C ₁ -C ₆ hydrocarbon chain; each of R _E1 , R _E2 , and R _E3 is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH ₂ OR _EE , CH ₂ N(R _EE ) ₂ , CH ₂ SR _EE , OR _EE , N(R _EE ) ₂ , Si(R _EE ) ₃ , or SR _EE , or R _E1 and R _E3 , or R _E2 and R _E3 , or R _E1 and R _E2 are joined to form an optionally substituted C ₃ -C ₈ carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R _EE is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - C ₆ alkoxy, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R _EE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S; RE5 is halogen; R _E6 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; each Y is independently O, S, or NR _E7 ; R _E7 is H, optionally substituted C ₁ -C ₆ alkyl, or a nitrogen protecting group; a is 1 or 2; each z is independently 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3, wherein at least one R ^a1 or R ^b1 is W. In some embodiments, the compound is of Formula Iva: N N HN N N O R ¹ R ⁵ (Iva), or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1. In some embodiments, the compound is of Formula Ivb: or a pharmaceutically acceptable salt thereof, wherein X ³ is –(CH ₂ ) _m – and m is 0 or 1. For any of the Formulae described herein, where applicable: In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, R ² is H or Me. In some embodiments, R ² is H. In some embodiments, R ³ is H or Me. In some embodiments, R ³ is H. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl. In some embodiments, R ⁴ is Me. In some embodiments, R ⁴ is . In some embodiments, X ⁴ is –(CH ₂ )–. In some embodiments, R ¹ is C ₆ -C ₁₀ aryl or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is C ₆ -C ₁₀ aryl or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is C ₆ -C ₁₀ aryl, wherein the aryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is C ₆ aryl optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heteroaryl comprising one 6-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heteroaryl comprising one 6-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heteroaryl comprising one 5-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heteroaryl comprising one 5-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heterocyclyl comprising one 5-membered ring and 1-2 N atoms, wherein the heterocyclyl is optionally substituted with one or more R ^a1 . In some embodiments, R ¹ is heterocyclyl comprising one 5-membered ring and 1 N atoms, wherein the heterocyclyl is optionally substituted with one or more R ^a1 . In some embodiments, each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 . In some embodiments, each R ^a1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R ^a2 . In some embodiments, each R ^a1 is independently W, F, Cl, Me, -OR ⁿ⁶ , – NR ⁿ⁶ -(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –O-(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –NR ⁿ⁶ -(CH ₂ )1-4-OR ⁿ⁷ , –O-(CH ₂ )1-4-OR ⁿ⁷ , , where ^{n6 n7} in each of R , R , and R ⁿ⁸ is independently H or C ₁ -C ₄ alkyl. N H ₃ C H ₃ C N In some embodiments, each R ^a1 is independently W, F, Cl, Me, -OMe, CH ₃ , In some embodiments, each R ^a1 is independently W, F, Cl, Me, -OMe, , In some embodiments, at least one R ^a1 is W. In some embodiments, each R ^a1 is independently –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^a2 . In some embodiments, each R ^a1 is independently –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R ^a2 . In some embodiments, each R ^a1 is independently F, Cl, Me, -OR ⁿ⁶ , –NR ⁿ⁶ -(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –O-(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –NR ⁿ⁶ -(CH ₂ )1-4-OR ⁿ⁷ , –O-(CH ₂ )1-4-OR ⁿ⁷ , independently H or C ₁ -C ₄ alkyl. In some embodiments, each R ^a1 is independently F, Cl, Me, -OR ⁿ⁶ , – NR ⁿ⁶ -(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –O-(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –NR ⁿ⁶ -(CH ₂ )1-4-OR ⁿ⁷ , –O-(CH ₂ )1-4-OR ⁿ⁷ , , wherein each of R ⁿ⁶ , R ⁿ⁷ , and R ⁿ⁸ is independently H or C ₁ -C ₄ alkyl. In some embodiments, each R ^a1 is independently F, Cl, Me, -OMe, In some embodiments, each R ^a1 is independently F, Cl, Me, -OMe, , In some embodiments, each R ^a2 is independently h halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl. In some embodiments, each R ^a2 is independently hydroxy, –NR ⁿ¹ R ⁿ² , or methyl. In some embodiments, R ⁵ is C ₆ -C ₁₀ aryl or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is C ₆ -C ₁₀ aryl or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is C ₆ -C ₁₀ aryl, wherein the aryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is C ₆ aryl optionally substituted with one or more R ^b1 . . In some embodiments, R ⁵ is heteroaryl comprising one 6-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heteroaryl comprising one 6-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heteroaryl comprising one 5- membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heteroaryl comprising one 5-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heterocyclyl comprising one 5-membered ring and 1-2 N atoms, wherein the heterocyclyl is optionally substituted with one or more R ^b1 . In some embodiments, R ⁵ is heterocyclyl comprising one 5-membered ring and 1 N atoms, wherein the heterocyclyl is optionally substituted with one or more R ^b1 . In some embodiments, each R ^b1 is independently W, –CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R ^b2 . In some embodiments, each R ^b1 is independently W, F, Cl, Me, -OR ⁿ⁶ , –NR ⁿ⁶ -(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –O-(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –NR ⁿ⁶ -(CH ₂ )1-4-OR ⁿ⁷ , –O-(CH ₂ )1-4-OR ⁿ⁷ , independently H or C ₁ -C ₄ alkyl. In some embodiments, each R ^b1 is independently W, F, Cl, Me, -OMe, In some embodiments, at least one R ^b1 is W. In some embodiments each R ^b1 is independently F Cl Me -OR ⁿ⁶ –NR ⁿ⁶ -(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –O-(CH ₂ )1-4-NR ⁿ⁷ R ⁿ⁸ , –NR ⁿ⁶ -(CH ₂ )1-4-OR ⁿ⁷ , –O-(CH ₂ )1-4-OR ⁿ⁷ , , where ^{n6 n7 n8} in each of R , R , and R is independently H or C ₁ -C ₄ alkyl. In some embodiments, each R ^b1 is independently F, Cl, Me, -OMe, In some embodiments, each R ^b2 is independently halo, hydroxy, –NR ⁿ¹ R ⁿ² , C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkyl. In some embodiments, each R ^b2 is independently hydroxy, –NR ⁿ¹ R ⁿ² , or methyl. In some embodiments, W is NR ₈ C(O)R ₉ or C(O)R ₉ . In some embodiments, W is selected from formulae (i-1)-(i-5), (i-9)-(i-16), (i-18), (i-19), (i-28), (i-29), and (i-36)-(i-39). In some embodiments, W is selected from formulae (i-1), (i-3), (i-9), (i-13), (i-14), (i-16), (i-18), (i-19), (i-29), and (i-36)-(i-39). In some embodiments, W is selected from formulae (i-2), (i-10), (i-15), (i-28), and (i-34). In some embodiments, W is selected from formulae (i-4), (i-5), and (i-10). In some embodiments, W is selected from formulae (i-11) and (i-12). In some embodiments, W is selected from formulae (i-6)-(i-8), (i-17), (i-20)-(i-27), (i-30)-(i-35), (i-40), and (i-41). In some embodiments, W is selected from formulae (i-6)-(i-8), (i-17), (i-20)-(i-27), (i-30), (i-34), (i-40), and (i-41). In some embodiments, at least one In some embodiments, L ₃ is –NR _L3a –. In some embodiments, R _L3a is H. In some embodiments, R _E1 is H. In some embodiments, R _E2 is H. In some embodiments, R _E3 is H. In some embodiments, R _E1 , R _E2 , and R _E3 are each H. In some embodiments, Y is O. In some embodiments, R ⁶ is phenyl, bicyclo [1,1,1] pentyl, or heteroaryl comprising one 5- or 6-membered rings and 1-3 N atoms, wherein the phenyl or heteroaryl is optionally substituted with one or more R ^c1 . In some embodiments, R ⁶ is phenyl or heteroaryl comprising one 5- or 6-membered rings and 1-3 N atoms, wherein the phenyl or heteroaryl is optionally substituted with one or more R ^c1 . In some embodiments, R ⁶ is phenyl, pyridyl, thiazolyl, or pyrazolyl, optionally substituted with one or more R ^c1 . In some embodiments, each R ^c1 is independently –CN, F, Me, or -OMe. In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 , X ¹ , X ² , X ³ , X ⁴ , and W can each be selected from any of the substituents as described herein, for example, in Formula I’ or Formula I. Any of the substituents described herein for any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 , X ¹ , X ² , X ³ , X ⁴ , and W, for example, in any of Formulae I, II, III, IV, Iia, Iib, IIIa, IIIb, Iva, or Ivb, can be combined with any of the substituents described herein for one or more of the remainder of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 , X ¹ , X ² , X ³ , X ⁴ , and W, for example, in any of Formulae I, II, III, IV, Iia, Iib, IIIa, IIIb, Iva, or Ivb. Non-limiting illustrative compounds of the disclosure are listed in Table 1. In some embodiments, the compound is selected from the compounds discosed in Table 1 (e.g., Compound Nos.1-40). In an aspect, the compound has the structure of any one of the compounds discosed in Table 1 (e.g., Compound Nos.1-40). Table 1

In another aspect, disclosed is a compound selected from , _{, or a pharmaceutically} acceptable salt thereof. In an aspect, disclosed is a compound selected from the group consisting of: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-phenyl-7,8- dihydropteridin-2-yl)amino)phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1-methyl-1H- pyrazol-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)a mino)phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(1H-pyrazol- 3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ac rylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(1H-pyrazol- 4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ac rylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1-methyl-1H- pyrazol-4-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)a mino)phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(4-methoxyphenyl)-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ac rylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(3-methoxyphenyl)-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ac rylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(2-methoxyphenyl)-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ac rylamide; N-(5-((6-(3-cyanophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2, 3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acry lamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(thiazol-4-yl)- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylami de; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(51ntercon-4- yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acry lamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(51ntercon-3- yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acry lamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(51ntercon-2- yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acry lamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-phenyl- 5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl )acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-phenyl-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide; N-(5-((6-(2,4-difluorobenzyl)-8-methyl-7-oxo-5,6,7,8-tetrahy dropyrimido[4,5-d]pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methox yphenyl)acrylamide; N-(5-((6-benzyl-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4, 5-d]pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylami de; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(52ntercon-2- yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)ph enyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(52ntercon-3- yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)ph enyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(52ntercon-4- yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)ph enyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(thiazol-4-yl)- 5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl )acrylamide; N-(5-((6-(3-cyanophenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropy rimido[4,5-d]pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methox yphenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(2-methoxyphenyl)-8-methyl- 7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino) phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(3-methoxyphenyl)-8-methyl- 7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino) phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(4-methoxyphenyl)-8-methyl- 7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino) phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1-methyl-1H- pyrazol-4-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimid in-2-yl)amino)phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(1H-pyrazol- 4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino) phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo-6-(1H-pyrazol- 3-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino) phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1-methyl-1H- pyrazol-3-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimid in-2-yl)amino)phenyl)acrylamide; N-(3-(2-((3-fluoro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-p henylpyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide; N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-p henylpyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide; 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 1-methyl-1H-pyrazol-4-yl)amino)- 6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one; 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one; 1-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-7-(( 3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H) -one; N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenylpyri do[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide; N-(3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-y l)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide; N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-6-(2,4-di fluorophenyl)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide; N-(5-((6-(bicyclo[1.1.1]pentan-1-yl)-8-methyl-7-oxo-5,6,7,8- tetrahydropyrimido[4,5- d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)a mino)-4- methoxyphenyl)acrylamide; 1-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-7-(( 1-methyl-1H-pyrazol-4- yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H) -one; 8-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 6-morpholinopyridin-3-yl)amino)- 6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxy-5-((8 -methyl-7-oxo-6-phenyl- 5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)53nter con-3-yl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-methyl-7- oxo-6-phenyl-5,6,7,8- tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-(2,2,2-trif luoroethoxy)53ntercon-3- yl)acrylamide; N-(3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7-oxopyri do[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide; N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-p henoxypyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide; N-(3-(6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)- 7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide; N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide; N-(5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrim idin-2-yl)amino)-2- morpholinopyridin-3-yl)acrylamide; and N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenoxypyr ido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof. In another aspect, disclosed is a compound selected from N-(3-(2-((3-chloro-1-methyl- 1H-pyrazol-4-yl)amino)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin -8(7H)-yl)phenyl)acrylamide or N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenoxypyr ido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof. The compounds of the disclosure may inhibit one or more receptors of the ErbB receptor tyrosine kinase family. For example, a compound of the present disclosure may inhibit EGFR, HER2, HER3, and/or HER4, and/or any mutant thereof. In some embodiments, a compound of the present disclosure inhibits EGFR. In some embodiments, a compound of the present disclosure inhibits a mutant EGFR. In some embodiments, a compound of the present disclosure inhibits HER2. In some embodiments, a compound of the present disclosure inhibits a mutant HER2. In some embodiments, a compound of the present disclosure inhibits EGFR and HER2 and/or a mutant thereof. The compounds of the disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR or a mutant thereof and/or HER2 or a mutant thereof. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations described herein. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations, but do not affect the activity of a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of HER2 containing one or more mutations. In some embodiments, the mutant HER2 contains one or more mutations described herein. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of HER2 containing one or more mutations, but do not affect the activity of a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations and HER2 containing one or more mutations. In some embodiments, the mutant EGFR or mutant HER2 contains one or more mutations described herein. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations and HER2 containing one or more mutations, but do not affect the activity of a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2. In some embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2. In some embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2. In some embodiments, the compounds of the disclosure exhibit from about 1000- fold to about 10000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2. More potent modulation (e.g., inhibition) of EGFR containing one or more mutations and/or HER2 containing one or more mutations, such as those described herein, relative to a wild-type EGFR or a wild-type HER2, provides a novel approach to the treatment or prevention of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erthematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy. In some embodiments, the inhibition of activity of EGFR or HER2 or a mutant thereof is measured by IC ₅₀ . In some embodiments, the inhibition of activity of EGFR or HER2 or a mutant thereof is measured by EC ₅₀ . In some embodiments, the compounds of the disclosure are potent inhibitor of a drug- resistant EGFR mutant relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure are more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, and TAK-285. In some embodiments, the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., as measured by IC ₅₀ ) than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, and TAK-285. In some embodiments, the compounds of the disclosure are potent inhibitor of a drug- resistant HER2 mutant relative to a wild-type HER2. In some embodiments, the compounds of the disclosure are more potent than one or more known HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib. In some embodiments, the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC ₅₀ ) than one or more known HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib. In some embodiments, the compounds of the disclosure are potent inhibitor of a drug- resistant EGFR mutant and drug-resistant HER2 mutant relative to a wild-type EGFR and a wild- type HER2. In some embodiments, the compounds of the disclosure are more potent than one or more known EGRF and/or HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib. In some embodiments, the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC ₅₀ ) than one or more known EGRF and/or HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib. Potency of a compound can be determined by IC ₅₀ value. A compound with a lower IC ₅₀ value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC ₅₀ value. In some embodiments, the substantially similar conditions comprise determining an EGFR-dependent or a HER2-dependent phosphorylation level in cells expressing a wild-type EGFR, a wild-type HER2, or a mutant thereof, such as those described herein, or a fragment of any thereof. The selectivity between wild-type EGFR and EGFR containing one or more mutations as described herein or between wild-type HER2 and HER2 containing one or more mutations as described herein can be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity. For example, Ba/F3 cells transfected with wild-type EGFR, or Ba/F3 cells transfected with a mutant EGFR can be used. Proliferation assays are performed at a range of inhibitor concentrations (10 µM, 3 µM, 1.1 µM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC ₅₀ is calculated. An alternative method to measure effects on EGFR and/or HER2 activity is to assay phosphorylation of wild-type EGFR, wild-type HER2, and/or a mutant thereof, such as those described herein. Wild-type EGFR, wild-type HER2, or a mutant thereof, such as those described herein, can be transfected into cells which do not normally express endogenous EGFR or HER2. The ability of the inhibitor (using concentrations as above) to inhibit phosphorylation can be assayed. Another aspect of the disclosure is an isotopically labeled compound of any of the compounds disclosed herein. Such compounds have one or more isotope atoms which may or may not be radioactive (e.g., ³ H, ² H, ¹⁴ C, ¹³ C, ¹⁸ F, ³⁵ S, ³² P, ¹²⁵ I, and ¹³¹ I) introduced into the compound. Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications. The disclosure also provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting protein kinase activity of at least one protein kinase selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, optionally in combination with a second agent and instructions for use in treating cancer. In some embodiments, the compound in the kit inhibits more than one protein kinase In another aspect, the disclosure provides a method of synthesizing a compound disclosed herein. The synthesis of the compounds of the disclosure can be found herein and in the Examples below. Other embodiments are a method of making a compound of any of the formulae herein using any one, or combination of, reactions delineated herein. The method can include the use of one or more intermediates or chemical reagents delineated herein. A compound of the disclosure can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the disclosure can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the disclosure can be prepared using salts of the starting materials or intermediates. The free acid or free base forms of the compounds of the disclosure can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of the disclosure in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the disclosure in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.). Prodrugs of the compounds of the disclosure can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the disclosure with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like). Protected derivatives of the compounds of the disclosure can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, “Protecting Groups in Organic Chemistry”, 3 ^rd edition, John Wiley and Sons, Inc., 1999. Compounds of the present disclosure can be conveniently prepared or formed during the process of the disclosure, as solvates (e.g., hydrates). Hydrates of compounds of the present disclosure can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol. Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Combinations of substituents and variables envisioned by the disclosure are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). When any variable (e.g., R ₇ ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R ₇ moieties, then R ₇ at each occurrence is selected independently from the definition of R ₇ . Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds within a designated atom’s normal valency. In addition, some of the compounds of the disclosure have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. All such isomeric forms of such compounds are expressly included in the present disclosure. Optical isomers may be prepared from their respective optically active precursors by the procedures described herein, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Furthermore, the structures and other compounds discussed in the disclosure include all atropic isomers thereof. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine. The compounds of the disclosure may also be represented in multiple tautomeric forms, in such instances, the disclosure expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the disclosure expressly includes all such reaction products). In the present disclosure, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present disclosure. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The compounds of the disclosure may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. The compounds of the disclosure are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of some embodiments for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Definitions Listed below are definitions of various terms used to describe the disclosure. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. The term "cancer" includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above- identified conditions. The terms “disease(s)”, “disorder(s)”, and “condition(s)” are used interchangeably, unless the context clearly dictates otherwise. The term "EGFR" herein refers to epidermal growth factor receptor kinase. The term "HER2", "Her2", "ERBB2", or "Erbb2" herein refers to human epidermal growth factor receptor 2. HER2 is also known as CD340 or Neu. As used herein, the term “mutant EGFR” or “EGFR mutant” refers to EGFR with one or more mutations. In some embodiments, the EGFR mutant has one or more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19 insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21. In some embodiments, the mutant EGFR contains one or more mutations selected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins 20), L718Q, G719S, G719C, G719A, D761Y, T790M, C797S, L844V, T854A, L858R, L861Q, I941R, V948R, D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, H773dupH, D770_N771insNPG, H773_V774insNPH, P772_H773insPNP, N771_P772insH, A775_G776insYVMA, A763_Y764insFQEA, V774_C775insHV, N771_P772insV, D770_N771insGL, N771delinsGY, and H773_V774insAH. In some embodiments, the mutant EGFR contains one or more mutations selected from D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, H773dupH, D770_N771insNPG, H773_V774insNPH, P772_H773insPNP, and N771_P772insH. In some embodiments, the mutant EGFR contains a combination of two or more mutations (such as mutations described herein). In some embodiments, the mutant EGFR contains a combination of two or more mutations selected from Del 19/L718Q, Del 19/T790M, Del 19/L844V, Del 19/T790M/L718Q, Del/T790M/C797S, Del 19/T790M/L844V, L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S, and L858R/T790M/I941R. An EGFR sensitizing mutation comprises without limitation G719S, G719C, G719A, L861Q, L858R, Del 19, and/or Ins 20. A drug-resistant EGFR mutant can have without limitation a drug resistance mutation comprising L718Q, D761Y, T790M, T854A, D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, A775_G776insYVMA, and/or H773dupH. As used herein, the term “mutant HER2” or “HER2 mutant” refers to HER2 with one or more mutations. In some embodiments, the HER2 mutant has one or more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19 insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21. In some embodiments, the mutant HER2 contains one or more mutations selected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins 20), T798M, T798I, L869R, A775_G776insYVMA, A775_G776insSVMA, A775_G776insI, G776delinsVC, G776delinsLC, P780_Y781insGSP, M774delinsWLV, and G778_S779insCPG. In some embodiments, the mutant EGFR contains a combination of two or more mutations (such as mutations described herein). As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the process of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the disclosure, or separately by reacting the free base or acid function with a suitable acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters of the compounds formed by the process of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein, refers to those prodrugs of the compounds formed by the process of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure. "Prodrug", as used herein, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the present disclosure. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002). “Prevent”, “preventing”, and “prevention” describes reducing or eliminating the onset of a disease, condition, or disorder and/or symptoms or complications thereof. The term "subject" as used herein refers to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be referred to herein as a patient. The term "therapeutically effective amount" or “effective amount” of a compound or pharmaceutical composition of the disclosure, as used herein, means a sufficient amount of the compound or pharmaceutical composition so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. "Treat", "treating", and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms. The disclosure also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the disclosure. For example, compounds of the disclosure having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the disclosure. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Chemical Terms The term "alkyl," as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six, or one and eight carbon atoms, respectively. Examples of C ₁ -C ₆ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C ₁ -C ₈ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl, neopentyl, n-hexyl, heptyl, octyl radicals. The term "alkenyl," as used herein, denotes a monovalent group derived from a hydrocarbon moiety containing, In some embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like. The term "alkynyl," as used herein, denotes a monovalent group derived from a hydrocarbon moiety containing, In some embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group. Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl and the like. The term "alkoxy" refers to an -O-alkyl radical. The term "aryl," as used herein, refers to a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The term "heteroaryl," as used herein, refers to a mono- or poly-cyclic (e.g., bi-, or tri- cyclic or more) fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which at least one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. In accordance with the disclosure, any of the heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted. The term "cycloalkyl" or "carbocyclyl" as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. Examples of C ₃ -C ₈ -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C ₃ -C ₁₂ -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Also contemplated is a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon- carbon double bond by the removal of a single hydrogen atom. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. As used herein, “haloalkyl” can include alkyl structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6 alkyl-CF3, -C1-C6 alkyl-C2F). Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluoroisopropyl. As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH ₂ -CH ₂ -O- CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -NHCH ₂ -, - C(O)NH-, -C(O)N(CH3), -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, -CH2-CH2-S(O)2- CH ₃ , -CH=CH-O-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ , -O-CH ₃ , and -O- CH ₂ -CH ₃ . Up to two or three heteroatoms may be consecutive, such as, for example, -CH ₂ -NH- OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ . Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH ₂ O-CH ₃ , –NR ^C R ^D , or the like, it will be understood that the terms heteroalkyl and –CH ₂ O-CH ₃ or –NR ^C R ^D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH ₂ O-CH ₃ , –NR ^C R ^D , or the like. If a count of carbons is included, that refers to the total number of carbons not including heteroatoms. For example, C _1-10 heteroalkyl includes at least 1 and up to 10 total carbons. In some cases the total number of heteroatoms in a heteroalkyl is 1, 1-2, 1-3, or 1-4. If not otherwise defined, heteroalkyl includes 1-10 carbons and 1-4 heteroatoms. The term “heterocyclyl,” as used herein, refers to a non-aromatic 3-, 4-, 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused of non-fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, and (iv) the nitrogen heteroatom may optionally be quaternized. Representative heterocyclyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The term "alkylamino" refers to a group having the structure NH(C ₁ -C ₁₂ alkyl), e.g., NH(C ₁ -C ₆ alkyl), where C ₁ -C ₆ alkyl is as previously defined. The term "dialkylamino" refers to a group having the structure N(C ₁ -C ₁₂ alkyl) ₂ , e.g., N(C1-C6 alkyl)2, where C1-C6 alkyl is as previously defined. The terms "hal," "halo," and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine. As described herein, a compound of the disclosure may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen in a given structure with the radical of a specified substituent. 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, and the substituent may be either the same or different at every position. It is understood that the alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl, or the like can be substituted, by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to: -F, -CI, -Br, - I, -OH, protected hydroxy, -NO ₂ , -CN, -NH ₂ , protected amino, -NH-C ₁ -C ₁₂ -alkyl, -NH-C ₂ -C ₁₂ - alkenyl, -NH-C ₂ -C ₁₂ -alkenyl, -NH -C ₃ -C ₁₂ -cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH - heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C ₁ -C ₁₂ -alkyl, -O-C ₂ -C ₁₂ - alkenyl, -O-C ₂ -C ₁₂ -alkenyl, -O-C3-C ₁₂ -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, - C(O)-C ₁ -C ₁₂ -alkyl, -C(O)- C ₂ -C ₁₂ -alkenyl, -C(O)-C ₂ -C ₁₂ -alkenyl, -C(O)-C ₃ -C ₁₂ -cycloalkyl, - C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH ₂ , -CONH-C ₁ -C ₁₂ -alkyl, -CONH- C ₂ -C ₁₂ -alkenyl, -CONH-C ₂ -C ₁₂ -alkenyl, -CONH-C ₃ -C ₁₂ -cycloalkyl, -CONH-aryl, -CONH- heteroaryl, -CONH-heterocycloalkyl,-OCO ₂ -C ₁ -C ₁₂ -alkyl, -OCO ₂ -C ₂ -C ₁₂ -alkenyl, -OCO ₂ -C ₂ - C ₁₂ -alkenyl, -OCO ₂ -C ₃ -C ₁₂ -cycloalkyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocycloalkyl, -OCONH ₂ , -OCONH-C ₁ -C ₁₂ -alkyl, -OCONH- C ₂ -C ₁₂ -alkenyl, -OCONH- C ₂ -C ₁₂ -alkenyl, - OCONH-C ₃ -C ₁₂ -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, - NHC(O)-C ₁ -C ₁₂ -alkyl, -NHC(O)-C ₂ -C ₁₂ -alkenyl, -NHC(O)-C ₂ -C ₁₂ -alkenyl, -NHC(O)-C ₃ -C ₁₂ - cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO ₂ -C ₁ -C ₁₂ - alkyl, -NHCO ₂ -C ₂ -C ₁₂ -alkenyl, -NHCO ₂ -C ₂ -C ₁₂ -alkenyl, -NHCO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHCO ₂ - aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ - heterocycloalkyl, NHC(O)NH ₂ , -NHC(O)NH-C ₁ -C ₁₂ -alkyl, - NHC(O)NH-C ₂ -C ₁₂ -alkenyl, -NHC(O)NH-C ₂ -C ₁₂ -alkenyl, -NHC(O)NH-C ₃ -C ₁₂ -cycloalkyl, - NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH ₂ , - NHC(S)NH-C ₁ -C ₁₂ -alkyl, -NHC(S)NH-C ₂ -C ₁₂ -alkenyl, -NHC(S)NH-C ₂ -C ₁₂ -alkenyl, - NHC(S)NH-C3-C12-cycloalkyl, -NHC(S)NH-aryl,-NHC(S)NH-heteroaryl, -NHC(S)NH- heterocycloalkyl, -NHC(NH)NH ₂ , -NHC(NH)NH- C ₁ -C ₁₂ -alkyl, -NHC(NH)NH-C ₂ -C ₁₂ -alkenyl, -NHC(NH)NH-C ₂ -C ₁₂ -alkenyl, -NHC(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)NH-aryl, - NHC(NH)NH-heteroaryl, -NHC(nH)NHheterocycloalkyl, -NHC(NH)-C ₁ -C ₁₂ -alkyl, -NHC(NH)- C ₂ -C ₁₂ -alkenyl, -NHC(NH)-C ₂ -C ₁₂ -alkenyl, -NHC(NH)-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)-aryl, - NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C ₁ -C ₁₂ -alkyl, -C(NH)NH-C ₂ - C ₁₂ -alkenyl, -C(NH)NH-C ₂ -C ₁₂ -alkenyl, C(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -C(NH)NH-aryl, - C(NH)NH-heteroaryl, -C(nH)NHheterocycloalkyl, -S(O)-C ₁ -C ₁₂ -alkyl, -S(O)-C ₂ -C ₁₂ -alkenyl,- S(O)-C ₂ -C ₁₂ -alkenyl, -S(O)-C ₃ -C ₁₂ -cycloalkyl,- S(O)-aryl, -S(O)-heteroaryl, -S(O)- heterocycloalkyl -SO ₂ NH ₂ , -SO ₂ NH-C ₁ -C ₁₂ -alkyl, -SO ₂ NH-C ₂ -C ₁₂ -alkenyl, -SO ₂ NH-C ₂ -C ₁₂ - alkenyl, -SO2NH-C3-C12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH- heterocycloalkyl, -NHSO ₂ -C ₁ -C ₁₂ -alkyl, -NHSO ₂ -C ₂ -C ₁₂ -alkenyl,- NHSO ₂ -C ₂ -C ₁₂ -alkenyl, - NHSO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocycloalkyl, - CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C ₃ - C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C ₁ - C ₁₂ -alkyl, -S-C ₂ -C ₁₂ -alkenyl, -S-C ₂ -C ₁₂ -alkenyl, -S-C ₃ -C ₁₂ -cycloalkyl, -S-aryl, -S-heteroaryl, -S- heterocycloalkyl, or methylthiomethyl. In some embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, –OH, –OR, –N(R) ₂ , –C(=O)R, –C(=O)N(R) ₂ , –CO ₂ R, –SO ₂ R, –C(=NR)R, – C(=NR)OR, –C(=NR)N(R) ₂ , –SO ₂ N(R) ₂ , –SO ₂ R, –SO ₂ OR, –SOR, –C(=S)N(R) ₂ , –C(=O)SR, – C(=S)SR, C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. For example, nitrogen protecting groups such as amide groups (e.g., –C(=O)R) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3– pyridylcarboxamide, N–benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o– nitophenylacetamide, o–nitrophenoxyacetamide, acetoacetamide, (N′– dithiobenzyloxyacylamino)acetamide, 3–(p–hydroxyphenyl)propanamide, 3–(o– nitrophenyl)propanamide, 2–methyl–2–(o–nitrophenoxy)propanamide, 2–methyl–2–(o– phenylazophenoxy)propanamide, 4–chlorobutanamide, 3–methyl–3–nitrobutanamide, o– nitrocinnamide, N–acetylmethionine derivative, o–nitrobenzamide, and o– (benzoyloxymethyl)benzamide. Nitrogen protecting groups, such as carbamate groups (e.g., –C(=O)OR), include, but are not limited to, methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc), 9–(2– sulfo)fluorenylmethyl carbamate, 9–(2,7–dibromo)fluoroenylmethyl carbamate, 2,7–di–t–butyl– [9–(10,10–dioxo–10,10,10,10–tetrahydrothioxanthyl)]m ethyl carbamate (DBD–Tmoc), 4– methoxyphenacyl carbamate (Phenoc), 2,2,2–trichloroethyl carbamate (Troc), 2– trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1–(1–adamantyl)–1– methylethyl carbamate (Adpoc), 1,1–dimethyl–2–haloethyl carbamate, 1,1–dimethyl–2,2– dibromoethyl carbamate (DB–t–BOC), 1,1–dimethyl–2,2,2–trichloroethyl carbamate (TCBOC), 1–methyl–1–(4–biphenylyl)ethyl carbamate (Bpoc), 1–(3,5–di–t–butylphenyl)–1–methylethyl carbamate (t–Bumeoc), 2–(2′– and 4′–pyridyl)ethyl carbamate (Pyoc), 2–(N,N– dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (BOC), 1–adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1–isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4–nitrocinnamyl carbamate (Noc), 8–quinolyl carbamate, N– hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p–methoxybenzyl carbamate (Moz), p–nitobenzyl carbamate, p–bromobenzyl carbamate, p–chlorobenzyl carbamate, 2,4–dichlorobenzyl carbamate, 4–methylsulfinylbenzyl carbamate (Msz), 9– anthrylmethyl carbamate, diphenylmethyl carbamate, 2–methylthioethyl carbamate, 2– methylsulfonylethyl carbamate, 2–(p–toluenesulfonyl)ethyl carbamate, [2–(1,3– dithianyl)]methyl carbamate (Dmoc), 4–methylthiophenyl carbamate (Mtpc), 2,4– dimethylthiophenyl carbamate (Bmpc), 2–phosphonioethyl carbamate (Peoc), 2– triphenylphosphonioisopropyl carbamate (Ppoc), 1,1–dimethyl–2–cyanoethyl carbamate, m– chloro–p–acyloxybenzyl carbamate, p–(dihydroxyboryl)benzyl carbamate, 5– benzisoxazolylmethyl carbamate, 2–(trifluoromethyl)–6–chromonylmethyl carbamate (Tcroc), m–nitrophenyl carbamate, 3,5–dimethoxybenzyl carbamate, o–nitrobenzyl carbamate, 3,4– dimethoxy–6–nitrobenzyl carbamate, phenyl(o–nitrophenyl)methyl carbamate, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2,2–dimethoxyacylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3–(N,N–dimethylcarboxamido)propyl carbamate, 1,1– dimethylpropynyl carbamate, di(2–pyridyl)methyl carbamate, 2–furanylmethyl carbamate, 2– iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p–(p′– methoxyphenylazo)benzyl carbamate, 1–methylcyclobutyl carbamate, 1–methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1–methyl–1–(3,5–dimethoxyphenyl)ethyl carbamate, 1–methyl–1–(p–phenylazophenyl)ethyl carbamate, 1–methyl–1–phenylethyl carbamate, 1–methyl–1–(4–pyridyl)ethyl carbamate, phenyl carbamate, p–(phenylazo)benzyl carbamate, 2,4,6–tri–t–butylphenyl carbamate, 4–(trimethylammonium)benzyl carbamate, and 2,4,6–trimethylbenzyl carbamate. Nitrogen protecting groups, such as sulfonamide groups (e.g., –S(=O) ₂ R), include, but are not limited to, p–toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,–trimethyl–4– methoxybenzenesulfonamide (Mtr), 2,4,6–trimethoxybenzenesulfonamide (Mtb), 2,6–dimethyl– 4–methoxybenzenesulfonamide (Pme), 2,3,5,6–tetramethyl–4–methoxybenzenesulfonamide (Mte), 4–methoxybenzenesulfonamide (Mbs), 2,4,6–trimethylbenzenesulfonamide (Mts), 2,6– dimethoxy–4–methylbenzenesulfonamide (iMds), 2,2,5,7,8–pentamethylchroman–6– sulfonamide (Pmc), methanesulfonamide (Ms), β–trimethylsilylethanesulfonamide (SES), 9– anthracenesulfonamide, 4–(4′,8′–dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include, but are not limited to, phenothiazinyl–(10)–acyl derivative, N′–p–toluenesulfonylaminoacyl derivative, N′–phenylaminothioacyl derivative, N– benzoylphenylalanyl derivative, N–acetylmethionine derivative, 4,5–diphenyl–3–oxazolin–2– one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5– dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5– substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl–1,3,5– triazacyclohexan–2–one, 1–substituted 3,5–dinitro–4–pyridone, N–methylamine, N–allylamine, N–[2–(trimethylsilyl)ethoxy]methylamine (SEM), N–3–acetoxypropylamine, N–(1–isopropyl–4– nitro–2–oxo–3–pyroolin–3–yl)amine, quaternary ammonium salts, N–benzylamine, N–di(4– methoxyphenyl)methylamine, N–5–dibenzosuberylamine, N–triphenylmethylamine (Tr), N–[(4– methoxyphenyl)diphenylmethyl]amine (MMTr), N–9–phenylfluorenylamine (PhF), N–2,7– dichloro–9–fluorenylmethyleneamine, N–ferrocenylmethylamino (Fcm), N–2–picolylamino N′– oxide, N–1,1–dimethylthiomethyleneamine, N–benzylideneamine, N–p– methoxybenzylideneamine, N–diphenylmethyleneamine, N–[(2– pyridyl)mesityl]methyleneamine, N–(N′,N′–dimethylaminomethylene)amine, N,N′– isopropylidenediamine, N–p–nitrobenzylideneamine, N–salicylideneamine, N–5– chlorosalicylideneamine, N–(5–chloro–2–hydroxyphenyl)phenylmethyleneamine, N– cyclohexylideneamine, N–(5,5–dimethyl–3–oxo–1–cyclohexenyl)amine, N–borane derivative, N–diphenylborinic acid derivative, N–[phenyl(pentaacylchromium– or tungsten)acyl]amine, N– copper chelate, N–zinc chelate, N–nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4–dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3–nitropyridinesulfenamide (Npys). As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Org ^an ic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., –OC(=O)SR, – OC(=O)R, –OCO ₂ R, –OC(=O)N(R) ₂ , –OC(=NR)R, –OC(=NR)OR, –OC(=NR)N(R) ₂ , – OS(=O)R, –OSO ₂ R, –OP(R) ₂ , –OP(R) ₃ , –OP(=O) ₂ R, –OP(=O)(R) ₂ , –OP(=O)(OR) ₂ , – OP(=O) ₂ N(R) ₂ , and –OP(=O)(NR) ₂ ). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), or trifluoromethanesulfonate (triflate, –OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”. A carbon atom bonded to four non-identical substituents is termed a “chiral center”. “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. “Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H ₂ O. Methods of Synthesizing the Compounds A compound of the present disclosure may be made by a variety of methods, including standard chemistry. The synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof. Suitable synthetic routes are depicted in the schemes below. A compound of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999, incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of a compound of the present disclosure. A compound disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of a compound disclosed herein. Those skilled in the art will recognize if a stereocenter exists in a compound disclosed herein. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- lnterscience, 1994). All the abbreviations used in the disclosure are found in “Protective Groups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCK INDEX by MERCK & Co., Inc, or other chemistry books or chemicals catalogs by chemicals vendor such as Aldrich, or according to usage know in the art. By way of example, a compound of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. In some embodiments, a compound of the present disclosure can be synthesized by following the steps outlined in General Scheme A. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme A In some embodiments, a compound of the present disclosure may also be prepared according to General Scheme B. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme B In some embodiments, a compound of the present disclosure may also be prepared according to General Scheme C. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme C A mixture of enantiomers, diastereomers, and/or cis/trans isomers resulting from the processes described above can be separated into their single components by chiral salt technique, chromatography using normal phase, or reverse phase or chiral column, depending on the nature of the separation. It should be understood that in the description and formulae shown above, the various groups, such as R ¹ -R ⁶ , m, and n, are as defined herein, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds in the Schemes are mere representatives with elected substituents to illustrate the general synthetic methodology of a compound disclosed herein. Starting materials, reagents and solvents were purchased from commercial suppliers and were used without further purification unless otherwise noted. All reactions were monitored using a Waters Acquity UPLC/MS system (Waters PDA eλ Detector, QDa Detector, Sample manager – FL, Binary Solvent Manager) using Acquity UPLC® BEH C18 column (2.1 x 50 mm, 1.7 µm particle size): solvent gradient = 85 % A at 0 min, 1 % A at 1.6 min; solvent A = 0.1 % formic acid in Water; solvent B = 0.1 % formic acid in Acetonitrile; flow rate : 0.6 mL/min. Reaction products were purified by flash column chromatography using CombiFlash ^® Rf with Teledyne Isco RediSep ^® R _f columns (4 g, 12 g, 24 g, 40 g, or 80 g) and Waters HPLC system using SunFire ^TM Prep C18 column (19 x 100 mm, 5 µm particle size): solvent gradient = 80 % A at 0 min, 10 % A at 25 min; solvent A = 0.035 % TFA in Water; solvent B = 0.035 % TFA in MeOH; flow rate : 25 mL/min. NMR spectra were recorded on 500 MHz Bruker Advance III spectrometers. Chemical shifts are reported relative to methanol (δ = 3.30), chloroform (δ = 7.24) or dimethyl sulfoxide (δ = 2.50) for ¹ H NMR and ¹³ C NMR. Data are reported as (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). Biological Assays A compound of the present disclosure can be tested for its activity with various biological assays. Suitable assays include, but are not limited to, western blot analysis, MTS assay, and Cell Titer Glo (CTG) luminescent cell viability assay. CTG assays can be performed on various cells lines, such as A431, wild-type EGFRs, or insertion mutants EGFRs transformed Ba/F3 cells (e.g., L858R, L858R/T790M, L858R/C797S L858R/T790M/C797S, Del19, Del19/T790M, Del19/C797S, Del19/T790M/C797S). Non-limiting, representative assays are described briefly below. Proliferation Inhibition Assay Cell growth inhibition can be assessed by MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®). Cells are seeded and grow in culture plates before they are exposed to representative compounds of the disclosure for various duration. The viability of the cells are then assessed. Data are normalized to untreated cells and displayed graphically using GraphPad Prism (GraphPad Software, Inc.). The growth curves can be fitted using a nonlinear regression model with sigmoidal dose response. Western blot analysis Cells are seeded and grow in culture plates, and then treated with representative compounds of the disclosure the following day for various duration. Cells are washed with PBS and lysed. The lysates are separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the appropriate antibodies, such as phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102), and HSP90 (SC-7947). In addition, various types of cell lines may be used in testing the compound of the present disclosure. Non-limiting illustrative cell lines are listed in the table below. Table 2 Methods of Use Another aspect of the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR and/or HER2, and/or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof. Another aspect of the present disclosure relates to a method of treating or preventing a disease or disorder (e.g., cancer) in which EGFR and/or HER2, and/or a mutant thereof, plays a role, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the disease or disorder is resistant to an EGFR targeted therapy and/or a HER2 targeted therapy. In some embodiments, the EGFR targeted therapy and/or the HER2 targeted therapy is a therapy with an inhibitor of EGFR, HER2, and/or a mutant thereof, such as the inhibitors described herein. In some embodiments, the disease is cancer or a proliferative disease. In some embodiments, the cancer cell comprises a mutant EGFR and/or a mutant HER2. In some embodiments, the cancer is a cancer of B cell origin. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, the cancer is a lineage dependent cancer where EGFR and/or HER2, and/or a mutant thereof, plays a role in the initiation and/or development of the cancer. In some embodiments, the subject is identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In some embodiments, the disclosure provides a method of treating any of the disorders described herein, wherein the subject is a human. In some embodiments, the disclosure provides a method of preventing any of the disorders described herein, wherein the subject is a human. Another aspect of the present disclosure relates to a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, for modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and/or HER2 or a mutant thereof; for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder; for treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. Another aspect of the present disclosure relates to a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, for use in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. Another aspect of the present disclosure relates to use of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. Another aspect of the present disclosure relates to a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, for use in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. Another aspect of the present disclosure relates to use of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder. In some embodiments, the EGFR is a wild-type EGFR. In other embodiments, the EGFR has one or more mutations, such as those described herein. In some embodiments, the HER2 is a wild-type HER2. In other embodiments, the HER2 has one or more mutations, such as those described herein. One aspect of the disclosure provides compounds that are useful for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, a proliferative or hyperproliferative disease. Examples of proliferative and hyperproliferative diseases include, without limitation, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colonrectum, large intestine, rectum, brain and central nervous system; chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary. The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. In one aspect of the disclosure, the present disclosure provides for the use of one or more a compound of the disclosure in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein. The disclosure further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist. The subject compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. Pharmaceutical Compositions In another aspect, the disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier. A compound of the disclosure can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present disclosure in free form or in a pharmaceutically acceptable salt form in association. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present disclosure with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. The pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of a compound of the present disclosure formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of the disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in tum, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Dosage forms for topical or transdermal administration of a compound of the disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the disclosure. The ointments, pastes, creams and gels may contain, in addition to an active compound of the disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound of the disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. According to the methods of treatment of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the disclosure, as used herein, means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts a therapeutically effective amount of a compound of the disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment. In general, a compound of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of the disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of the disclosure and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of the disclosure and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-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 sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase- mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure. In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds of disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and instructions for use in treating cancer. In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting EGFR and/or HER2 activity selected from a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. EXAMPLES Example 1. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-phenyl-7,8-dihydropteridin-2-yl)amino)phenyl) acrylamide (compound 1) Synthesis of 2-chloro-8-methyl-6-phenylpteridin-7(8H)-one (a): prepared according to literature procedure (Bondinell, William E., et al.) Synthesis of compound 1: Prepared according to same procedure used for compound 14. LCMS (m/z): 529.75 [M+H]+. Example 2. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-6-(1-methyl-1H-pyrazol-3-yl)-7-oxo-7,8-dihydropyrido[ 2,3-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 2) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8 mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyri do[2,3-d]pyrimidin-7(8H)- one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (1-methyl-1H-pyrazol-3-yl)boronic acid (75 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 99%) as brown solid. LCMS (m/z): 508.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-3-yl)py rido[2,3-d]pyrimidin- 7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyri do[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.19 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 478.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1- methyl-1H-pyrazol-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (2) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-3-yl)py rido[2,3-d]pyrimidin-7(8H)- one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 2 (45 mg, two step yield 34%) as yellow solid. LCMS (m/z): 532.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.72 (s, 1H), 8.61 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 6.82 (s, 1H), 6.46 – 6.26 (m, 3H), 5.75 – 5.64 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 2.93 – 2.86 (m, 2H), 2.73 (s, 3H), 2.35 – 2.30 (m, 2H), 2.28 (s, 6H). Example 3. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(1H-pyrazol-3-yl)-7,8-dihydropyrido[2,3-d]pyr imidin-2- yl)amino)phenyl)acrylamide (compound 3) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(4 mL/ 1 mL) was added (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (116 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.80 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 16 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 87%) as brown solid. LCMS (m/z): 578.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (200 mg, 0.19 mmol) in EtOAc (10 mL) was added 10% Pd/C (100 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated. The residue was dissovled with DCM (5 mL), and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 4 hours, and then concentrated to give compound (k) (160 mg, crude), which was used directly for the next step. LCMS (m/z): 464.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(1H-pyrazol-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)a mino)phenyl)acrylamide (3) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (160 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (37 mg, 0.41 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 3 (33.6 mg, two step yield 11%) as yellow solid. LCMS (m/z): 518.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.71 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.38 – 7.32 (m, 1H), 6.82 (s, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 16.8, 1.6 Hz, 1H), 6.38 – 6.24 (m, 1H), 5.74 – 5.66 (m, 1H), 4.01 (s, 3H), 3.91 (s, 3H), 2.95 – 2.85 (m, 2H), 2.73 (s, 3H), 2.39 – 2.22 (m, 8H). Example 4. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(1H-pyrazol-4-yl)-7,8-dihydropyrido[2,3-d]pyr imidin-2- yl)amino)phenyl)acrylamide (compound 4) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one(d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d] pyrimidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (1H-pyrazol-4-yl)boronic acid (67 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 100%) as brown solid. LCMS (m/z): 494.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d] pyrimidin-7(8H)-one (200 mg, 0.39 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 464.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(1H-pyrazol-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)a mino)phenyl)acrylamide (compound 4) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 4 (20 mg, two step yield 11%) as yellow solid. LCMS (m/z): 518.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.09 (s, 1H), 9.71 (s, 1H), 8.63 (s, 1H), 8.29 (s, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 6.81 (s, 1H), 6.49 – 6.24 (m, 2H), 5.75 – 5.62 (m, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 2.94 – 2.87 (m, 2H), 2.72 (s, 3H), 2.36 – 2.24 (m, 8H).

Example 5. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-oxo-7,8-dihydropyrido[ 2,3-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 5) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyri do[2,3-d]pyrimidin-7(8H)- one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (1-methyl-1H-pyrazol-4-yl)boronic acid (75 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 99%) as brown solid. LCMS (m/z): 508.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-4-yl)py rido[2,3-d]pyrimidin- 7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyri do[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.39 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (160 mg, crude), which was used directly for the next step. LCMS (m/z): 478.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-6-(1- methyl-1H-pyrazol-4-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 5) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(1-methyl-1H-pyrazol-4-yl)py rido[2,3-d]pyrimidin-7(8H)- one (160 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (36 mg, 0.40 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 5 (40 mg, two step yield 19%) as yellow solid. LCMS (m/z): 532.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.95 (s, 1H), 9.68 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 6.79 (s, 1H), 6.58 – 6.31 (m, 2H), 5.75 – 5.65 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 2.97 (s, 2H), 2.73 (s, 3H), 2.50 – 2.25 (m, 8H). Example 6. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(4- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 6) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(4-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (4-methoxyphenyl)boronic acid (75 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 96%) as brown solid. LCMS (m/z): 534.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(4-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(4-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one (200 mg, 0.37 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 504.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(4- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 6) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(4-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 6 (25 mg, two step yield 19%) as yellow solid. LCMS (m/z): 558.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 9.71 (s, 1H), 8.59 (s, 1H), 7.93 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.43 (dd, J = 16.8, 1.6 Hz, 1H), 6.36 – 6.25 (m, 1H), 5.75 – 5.65 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 2.96 – 2.82 (m, 2H), 2.72 (s, 3H), 2.34 –2.22 (s, 8H). Example 7. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(3- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 7) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one(d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na2CO3 solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(3-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (450 mg, 0.89 mmol) in 1,4- dioxane/ water(10 mL/ 3 mL) was added (3-methoxyphenyl)boronic acid (176.1 mg, 1.16 mmol), Pd(dppf)Cl ₂ (65.23 mg, 0.089 mmol) and K ₂ CO ₃ (246 mg, 1.78 mmol) and the mixture was stirred at 95 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (300 mg, yield 63.2%) as yellow oil. LCMS (m/z): 534.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(3-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(3-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one ( 100 mg, 0.19 mmol) in methanol (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (94 mg, crude), which was used directly for the next step. LCMS (m/z): 504.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(3- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 7) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(3-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (94 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (22 mg, 0.24 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 7 (33.6 mg, two step yield 32.2%) as yellow solid. LCMS (m/z): 558.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.76 (s, 1H), 6.44 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 11.6 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.11 (s, 2H), 2.94 – 2.33 (m, 11H).

Example 8. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(2- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 8) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one(d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(2-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (2-methoxyphenyl)boronic acid (90 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 96%) as brown solid. LCMS (m/z): 534.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(2-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-6-(2-methoxyphenyl)-8-methylpyrido[2,3-d] pyrimidin-7(8H)-one (200 mg, 0.37 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 504.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 -(2- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 8) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-6-(2-methoxyphenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (26 mg, 0.29 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 8 (35 mg, two step yield 26%) as yellow solid. LCMS (m/z): 558.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.07 (s, 1H), 9.72 (s, 1H), 8.56 (s, 1H), 7.92 (s, 1H), 7.58 (s, 1H), 7.40 – 7.33 (m, 2H), 7.07 – 6.95 (m, 2H), 6.81 (s, 1H), 6.49 – 6.13 (m, 2H), 5.73 – 5.64 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.82 (s, 3H), 2.90 (brs, 2H), 2.72 (s, 3H), 2.28 (brs, 8H). Example 9. Synthesis of N-(5-((6-(3-cyanophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2, 3- d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)a mino)-4- methoxyphenyl)acrylamide (compound 9) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5 - nitrophenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]py rimidin-6-yl)benzonitrile (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added (3-cyanophenyl)boronic acid (87 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 96%) as brown solid. LCMS (m/z): 529.2 [M+H] ⁺ . Synthesis of 3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-6- yl)benzonitrile (k) To a solution of 3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5 - nitrophenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]py rimidin-6-yl)benzonitrile (200 mg, 0.38 mmol) in EtOAc (10 mL) was added 10% Pd/C (100 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 499.2 [M+H] ⁺ . Synthesis of N-(5-((6-(3-cyanophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2, 3-d]pyrimidin- 2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-meth oxyphenyl)acrylamide (compound 9) To a solution of 3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-6-yl)benzonitrile (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (26 mg, 0.28 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 9 (20 mg, two step yield 15%) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.06 (s, 1H), 9.70 (s, 1H), 8.64 (s, 1H), 8.04 – 7.98 (m, 2H), 7.98 – 7.90 (m, 1H), 7.69 (s, 1H), 7.64 (dt, J = 7.6, 1.2 Hz, 1H), 7.58 – 7.49 (m, 1H), 6.80 (s, 1H), 6.43 (d, J = 16.4 Hz, 1H), 5.76 – 5.67 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.96 (brs, 2H), 2.73 (s, 3H), 2.33 (brs, 8H). LCMS (m/z): 553.2 [M+H] ⁺ . Example 10. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(thiazol-4-yl)-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 10) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na2CO3 solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(thiazol-4-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added thiazol-4-ylboronic acid (77 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (120 mg, yield 59%) as brown solid. LCMS (m/z): 511.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(thiazol-4-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(thiazol-4-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (120 mg, 0.24 mmol) in EtOAc (10 mL) was added 10% Pd/C (60 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (80 mg, crude), which was used directly for the next step. LCMS (m/z): 481.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(thiazol-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amin o)phenyl)acrylamide (compound 10) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(thiazol-4-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (80 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (18 mg, 0.20 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep-HPLC to give compound 10 (25 mg, two step yield 28%) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.07 (s, 1H), 9.72 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 7.2 Hz, 2H), 8.64 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 6.81 (s, 1H), 6.50 – 6.25 (m, 2H), 5.72 – 5.68 (m, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 3.00 – 2.84 (m, 2H), 2.72 (s, 3H), 2.40 – 2.21 (m, 8H).LCMS (m/z): 535.2 [M+H] ⁺ . Example 11. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(pyridin-4-yl)-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 11) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-4-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(5 mL/ 1 mL) was added pyridin-4-ylboronic acid (73 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 100%) as brown solid. LCMS (m/z): 505.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-4-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-4-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (200 mg, 0.19 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 475.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(pyridin-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amin o)phenyl)acrylamide (compound 11) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-4-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep-HPLC to give compound 11 (55 mg, two step yield 41%) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.71 (s, 1H), 8.68 – 8.64 (m, 3H), 8.01 (s, 1H), 7.77 (s, 1H), 7.68 – 7.64 (m, 2H), 6.82 (s, 1H), 6.43 (dd, J = 16.8, 1.6 Hz, 1H), 6.36 – 6.26 (m, 1H), 5.70 (dd, J = 10.0, 1.6 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 2.90 (t, J = 5.2 Hz, 2H), 2.73 (s, 3H), 2.32 (t, J = 5.2 Hz, 2H), 2.28 (s, 6H). LCMS (m/z): 529.2 [M+H] ⁺ .

Example 12. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(pyridin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 12) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K2CO3 (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-3-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane /H2O (8 mL/2 mL) was added pyridin-3-ylboronic acid (53 mg, 0.43 mmol) and Pd(dppf)Cl ₂ (30 mg, 0.04 mmol) K ₂ CO ₃ (110 mg, 0.80 mmol) at room temperature. The resulting mixture was stirred at 80 ^o C overnight under nitrogen atmosphere, and the mixture was diluted with EtOAc (50 mL). The organic phase was washed with water (30 mL), brine (30 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound j as brown solid (200 mg, 99% isolated yield). LCMS (m/z): 505.1 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-3-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-3-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (200 mg, 0.40 mmol) in EtOAc (20 mL) was added Pd/C (20 mg, 0.20 mmol). The mixture was stirred at room temperature overnight under hydrogen atmosphere, and filtered through the celite. The filtrate was concentrated to compound (k) as light brown solid (160 mg, crude), which used directly for the next step. LCMS (m/z): 475.1 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(pyridin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amin o)phenyl)acrylamide (compound 12) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-3-yl)pyrido[2,3-d]p yrimidin-7(8H)-one in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (10 mg, 0.11 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated, the residue was purified by Prep-HPLC to afford compound 12 as yellow solid (15 mg, 8.4 % isolated yield for two steps). (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 9.71 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.65 (s, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 – 8.11 (m, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 6.82 (s, 1H), 6.45 – 6,30 (m, 2H), 5.70 (d, J = 12.0 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 2.92 (s, 2H), 2.73 (s, 3H), 2.30 (s, 8H). LCMS (m/z): 529.2 [M+H] ⁺ . Example 13. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(pyridin-2-yl)-7,8-dihydropyrido[2,3-d]pyrimi din-2- yl)amino)phenyl)acrylamide (compound 13) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 mL). The aqueous phase was extracted with EtOAc (80 mL × 3), and the combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 20/1-10/1) to afford compound (b) as white solid (5 g, 70% isolated yield). LCMS (m/z): 272.1 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (c) To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.3 mmol) in DMF (60 mL) was added K ₂ CO ₃ (4.8 g, 34.8 mmol) and MeI (4.8 g, 33.8 mmol) at room temperature. The reaction mixture was stirred at 100 ^o C for 16 hours. The resulting mixture was diluted with water (100 mL), the precipitate was formed and filtered. The filter cake was washed with water (80 mL × 2), dried to afford crude compound (c) as yellow solid (4.1 g, crude), which was used directly for the next step. LCMS (m/z): 286.0 [M+H] ⁺ . Synthesis of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (d) To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (3 g, 10.4 mmol) in DCM (40 mL) was added m-CPBA (5.4 g, 31.4 mmol) at room temperature, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous Na ₂ CO ₃ solution (50 mL× 2), concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/10) to afford compound (d) as light yellow solid (2.8 g, 82% isolated yield). LCMS (m/z): 318.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl pyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7( 8H)-one (2.8 g, 8.8 mmol) in DMSO (30 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (1.9 g, 10.6 mmol) and TFA (30 mL) at 0 ^o C. The resulting mixture was stirred at 100 ^o C for 16 hours, and then diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), brine (80 mL) dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/20-1/5) to afford compound (f) as brown solid (1.7 g, 46% isolated yield). LCMS (m/z): 424.0 [M+H] ⁺ . Synthesis of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of 6-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.7 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (816 mg, 8.0 mmol) and K ₂ CO ₃ (1.6 g, 12.0 mmol). The resulting mixture was stirred at 100 ^o C for 2 hours, and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (40 mL × 3), the combined organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (h) as brown solid (1.17 g, 58% isolated yield). LCMS (m/z): 506.0 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-2-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (j) To a solution of 6-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-meth oxy-5- nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.40 mmol) in 1,4- dioxane/ water(4 mL/ 1 mL) was added pyridin-2-ylboronic acid (73 mg, 0.59 mmol), Pd(dppf)Cl ₂ (29 mg, 0.04 mmol) and K ₂ CO ₃ (110 mg, 0.79 mmol) and the mixture was stirred at 80 ^o C under nitrogen atmosphere for 4 hours and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-5/1) to give compound (j) (200 mg, yield 100%) as brown solid. LCMS (m/z): 505.2 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-2-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (k) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-(pyridin-2-yl)pyrido[2,3-d]pyr imidin-7(8H)-one (200 mg, 0.19 mmol) in EtOAc (10 mL) was added 10% Pd/C (94 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through the celite, and the filtration was concentrated to give compound (k) (120 mg, crude), which was used directly for the next step. LCMS (m/z): 475.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-(pyridin-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amin o)phenyl)acrylamide (compound 13) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-(pyridin-2-yl)pyrido[2,3-d]p yrimidin-7(8H)-one (120 mg, crude) and 5% NaHCO ₃ (1.0 mL) in DCM (4 mL) at 0 ^o C was a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep-HPLC to give compound 13 (25 mg, two step yield 19%) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 9.72 (s, 1H), 8.78 – 8.63 (m, 2H), 8.53 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.60 – 7.40 (m, 1H), 6.82 (s, 1H), 6.47 – 6.25 (m, 2H), 5.70 (d, J = 10.8 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 2.90 (t, J = 5.2 Hz, 2H), 2.72 (s, 3H), 2.35 – 2.28 (m, 8H). LCMS (m/z): 529.2 [M+H] ⁺ . Example 14. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrim idin-2- yl)amino)phenyl)acrylamide (compound 14) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (c) To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride (2.17 g, 32.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours, and then concentrated. The residue was added water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 5/1-2/1) to afford compound (c) as light yellow solid (4.7 g, 96% isolated yield). LCMS (m/z): 228.1 [M+H] ⁺ . Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (d) To a solution LAH (2.36 g, 62.1 mmol) in THF (50 mL) was added a solution of ethyl 4- (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.7 g, 20.7 mmol) in THF (30 mL) at 0 ^o C. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and then quenched with water (3 mL) drop-wisely at 0 ^o C. The mixture was stirred at room temperature for 1 hour, and then filtered through the celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-1/1) to afford to give compound (d) as light yellow solid (3.0 g, 78% isolated yield). LCMS (m/z): 186.1 [M+H] ⁺ . Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (e) To a solution (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (1.0 g, 5.41 mmol) in THF/DCM (20 mL) was added MnO2 (2.35 g, 27.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered through the celite. The filtrate was concentrated to give compound (e) as light yellow solid (1.0 g, crude), which was used directly for the next step. LCMS (m/z): 183.9 [M+H] ⁺ . Synthesis of N-methyl-2-(methylthio)-5-((phenylamino)methyl)pyrimidin-4-a mine (g) A solution 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (10 g, 54.6 mmol) and aniline (7.63 g, 82.0 mmol) in toluene (120 mL) was refluxed for 16 hours using a Dean- Stark apparatus to remove the water as it is formed. The reaction mixture was concentrated, and the residue was dissolved with MeOH (50 mL). The resulting mixture was added NaBH ₄ (4.15 g, 109 mmol) portion-wisely, and then stirred at 50 ^o C for 5 hours. The solution was quenched by aq. sat. NH ₄ Cl (6 mL) at 0 ^o C, and then diluted with brine (100 mL), the aqueous phase was extracted with EtOAc (50 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/1-1/4) to afford compound (g) as white solid (8 g, 56% isolated yield). LCMS (m/z): 261.1 [M+H] ⁺ . Synthesis of 1-methyl-7-(methylthio)-3-phenyl-3,4-dihydropyrimido[4,5-d]p yrimidin-2(1H)- one (i) To a solution N-methyl-2-(methylthio)-5-((phenylamino)methyl)pyrimidin-4-a mine (8.0 g, 30.8 mmol) and DIPEA (11.9 g, 92.3 mmol) in acetonitrile (100 mL) was added protion- wisely triphosgene (3.08 mg, 10.5 mmol) at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 1 hour, and then warmed to room temperature for 4 hours. The reaction mixture was diluted with water (100 mL), the aqueous phase was extracted with EtOAc (80 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (i) as white solid (8.0 g, 91% isolated yield). LCMS (m/z): 287.0 [M+H] ⁺ . Synthesis of 1-methyl-7-(methylsulfonyl)-3-phenyl-3,4-dihydropyrimido[4,5 -d]pyrimidin- 2(1H)-one (j) To a solution of 1-methyl-7-(methylthio)-3-phenyl-3,4-dihydropyrimido[4,5-d]p yrimidin- 2(1H)-one (8.0 g, 30.0 mmol) in DCM (100 mL) was added m-CPBA (16.98 g, 83.9 mmol, 85% ) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then filtered. The filtrate was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (j) as white solid (8.0 g, 90% isolated yield). LCMS (m/z): 319.0 [M+H] ⁺ . Synthesis of 7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-1-methyl-3-pheny l-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (l) To a solution of 1-methyl-7-(methylsulfonyl)-3-phenyl-3,4-dihydropyrimido[4,5 - d]pyrimidin-2(1H)-one (8.0 g, 25.2 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (9.36 g, 50.4 mmol) in DMSO (50 mL) was added TFA (50 mL). The reaction mixture was stirred at 100 ^o C for 16 hours, and cooled to room temperature, diluted with water (250 mL). The precipitation was formed, filtered and washed with water. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/4) to afford compound (l) as yellow solid (3.6 g, 34% isolated yield). LCMS (m/z): 425.1 [M+H] ⁺ . Synthesis of 7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimido[4,5 -d]pyrimidin-2(1H)-one (n) The mixture of 7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-1-methyl-3-pheny l-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (3.6 g, 8.49 mmol), N ¹ ,N ¹ ,N ² -trimethylethane-1,2- diamine (1.30 g, 13.0 mmol) and K ₂ CO ₃ (2.34 g, 17.0 mmol) in 1,4-dioxane (50 mL) was stirred at 100 ^o C for 16 hours. After cooled to room temperature, the mixture was diluted with brine (100 mL), the aqueous phase was extracted with EtOAc (80 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (n) as white solid (3.0 g, 70% isolated yield). LCMS (m/z): 507.2 [M+H] ⁺ . Synthesis of 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (o) To a solution of 7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimido[4,5 -d]pyrimidin-2(1H)-one (3.0 g, 0.36 mmol) in EtOAc (100 mL) was added Pd/C (300 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reacition mixture was filtered through the celite, the filtrate was concentrated under reduced pressure to give white solid (2.0 g, 71% yield), which was used directly for the next step. LCMS (m/z): 477.1 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)ami no)phenyl)acrylamide (compound 14) To a solution of 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (2.0 g, 4.20 mmol) in DCM (50 mL) was added NaHCO ₃ solution (5%, 30 mL), the mixture was cooled down to 0 ^o C and then the acryloyl chloride solution (1 M in DCM, 5.0 mL) was added drop-wisely. The reaction mixture was stirred at room temperature for 1 hour, diluted with brine (100 mL) and extracted with DCM (80 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) and pulped with (DCM/ petroleum ether = 1/5) to afford compound 14 as an off-white solid (1.25 g, 56 % isolated yield). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.03 (s, 1H), 8.04 (s, 1H), 7.47 – 7.26 (m, 5H), 6.95 (s, 1H), 6.52 (dd, J = 16.8, 10.0 Hz, 1H), 6.36 (dd, J = 16.8, 1.6 Hz, 1H), 5.78 (dd, J = 10.0, 1.6 Hz, 1H), 4.72 (s, 2H), 3.94 (s, 3H), 3.46 (s, 3H), 3.12 (t, J = 5.3 Hz, 2H), 2.68 (s, 3H), 2.60 (brs, 2H), 2.40 (s, 6H). LCMS (m/z): 531.3 [M+H] ⁺ . Example 15. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)phenyl)acrylamide (compound 15) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (c) To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride (2.17 g, 32.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours, and then concentrated. The residue was added water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 5/1-2/1) to afford compound (c) as light yellow solid (4.7 g, 96% isolated yield). LCMS (m/z): 228.1 [M+H] ⁺ . Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (d) To a solution LAH (2.36 g, 62.1 mmol) in THF (50 mL) was added a solution of ethyl 4- (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.7 g, 20.7 mmol) in THF (30 mL) at 0 ^o C. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and then quenched with water (3 mL) drop-wisely at 0 ^o C. The mixture was stirred at room temperature for 1 hour, and then filtered through the celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-1/1) to afford to give compound (d) as light yellow solid (3.0 g, 78% isolated yield). LCMS (m/z): 186.1 [M+H] ⁺ . Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (e) To a solution (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (1.0 g, 5.41 mmol) in THF/DCM (20 mL) was added MnO2 (2.35 g, 27.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered through the celite. The filtrate was concentrated to give compound (e) as light yellow solid (1.0 g, crude), which was used directly for the next step. LCMS (m/z): 183.9 [M+H] ⁺ . Synthesis of 8-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H) -one (g) To a solution of 4-(methylamino)-2-(methylthio) pyrimidine-5-carbaldehyde (2.2 g, 12.0 mmol) in NMP (30 mL) was added K ₂ CO ₃ (3.32 g, 24.0 mmol) and ethyl 2-phenylacetate (2.96 g, 18.0 mmol). The reaction mixture was stirred at 110 ^o C for 16 hours. After cooled down to room temperature the mixture was diluted with brine (60 mL), and the aqueous phase was extracted with EtOAc (50 mL × 3), the combined organic phase was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-2/1) to afford compound (g) as light yellow solid (2.6 g, 76% isolated yield). LCMS (m/z): 284.0 [M+H] ⁺ . Synthesis of 8-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7 (8H)-one (h) To a solution of 8-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H) -one (1.6 g, 5.65 mmol) in DCM (30 mL) was added m-CPBA (3.43 g, 17.0 mmol, 85% ) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (h) as light yellow solid (1.6 g, 90% isolated yield). LCMS (m/z): 316.0 [M+H] ⁺ . Synthesis of 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl-6-pheny lpyrido[2,3- d]pyrimidin-7(8H)-one (j) To a solution of 8-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7 (8H)-one (500 mg, 1.59 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (590 mg, 3.17 mmol) in DMSO (8 mL) was added TFA (8 mL). The reaction mixture was stirred at 100 ^o C for 16 hours, and cooled to room temperature, diluted with water (100 mL). The precipitation was formed, filtered and washed with water. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/4) to afford compound (j) as pale solid (150 mg, 23% isolated yield). LCMS (m/z): 421.8 [M+H] ⁺ . Synthesis of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-phenylpyrido[2,3-d]pyrimidin-7 (8H)-one (l) The mixture of 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.36 mmol), N ¹ ,N ¹ ,N ² -trimethylethane-1,2- diamine (54 mg, 0.53 mmol) and K ₂ CO ₃ (98 mg, 0.71 mmol) in 1,4-dioxane (10 mL) was stirred at 100 ^o C for 4 hours. After cooled to room temperature, the mixture was diluted with brine (30 mL), the aqueous phase was extracted with EtOAc (50 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (l) as pale solid (130 mg, 73% isolated yield). LCMS (m/z): 503.9 [M+H] ⁺ . Synthesis of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-phenylpyrido[2,3-d]pyrimidin -7(8H)-one (m) To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-8-methyl-6-phenylpyrido[2,3-d]pyrimidin-7 (8H)-one (130 mg, 0.26 mmol) in EtOH (10 mL) was added Raney Ni (50 mg), the mixture was heated to reflux, and then hydrazine monohydrate (0.5 mL) was added dropwise, the mixture was stirred under reflux for 2 hours and filtered through the celite, the filtrate was concentrated under reduced pressure to give the crude compound (m) as brown solid (100 mg, crude). LCMS (m/z): 474.3 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 -methyl-7-oxo- 6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl )acrylamide (compound 15) To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-8-methyl-6-phenylpyrido[2,3-d]pyrimidin -7(8H)-one (100 mg, 0.26 mmol) in DCM (5 mL) was added NaHCO ₃ solution (5%, 3 mL), the mixture was cooled down to 0 ^o C and then the acryloyl chloride solution (1 M in DCM, 0.30 mL) was added drop-wisely. The reaction mixture was stirred at room temperature for 1 hour, diluted with brine (10 mL) and extracted with DCM (30 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 15 as an orange solid (40 mg, 29 % isolated yield of 2 steps). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 9.72 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.71 – 7.66 (m, 2H), 7.65 (s, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 6.82 (s, 1H), 6.43 (dd, J = 16.8, 1.6 Hz, 1H), 6.37 – 6.24 (m, 1H), 5.69 (dd, J = 10.0, 1.6 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.72 (s, 3H), 2.35 – 2.25 (m, 8H). LCMS (m/z): 528.2 [M+H] ⁺ . Example 16. Synthesis of N-(5-((6-(2,4-difluorobenzyl)-8-methyl-7-oxo-5,6,7,8- tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylami de (compound 16) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (c) To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride (2.17 g, 32.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours, and then concentrated. The residue was added water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 5/1-2/1) to afford compound (c) as light yellow solid (4.7 g, 96% isolated yield). LCMS (m/z): 228.1 [M+H] ⁺ . Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (d) To a solution LAH (2.36 g, 62.1 mmol) in THF (50 mL) was added a solution of ethyl 4- (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.7 g, 20.7 mmol) in THF (30 mL) at 0 ^o C. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and then quenched with water (3 mL) drop-wisely at 0 ^o C. The mixture was stirred at room temperature for 1 hour, and then filtered through the celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-1/1) to afford to give compound (d) as light yellow solid (3.0 g, 78% isolated yield). LCMS (m/z): 186.1 [M+H] ⁺ . Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (e) To a solution (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (1.0 g, 5.41 mmol) in THF/DCM (20 mL) was added MnO2 (2.35 g, 27.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered through the celite. The filtrate was concentrated to give compound (e) as light yellow solid (1.0 g, crude), which was used directly for the next step. LCMS (m/z): 183.9 [M+H] ⁺ . Synthesis of 5-(((2,4-difluorobenzyl)amino)methyl)-N-methyl-2-(methylthio )pyrimidin-4- amine (g) To a solution 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.0 g, 10.9 mmol) in DCM (50 mL) was added (2,4-difluorophenyl)methanamine (1.87 g, 13.1 mmol) and AcOH (2 drops). The reaction mixture was stirred at room temperature for 1 hour, and then added NaBH(OAc)3 (9.27 g, 43.7 mmol). The reaction mixture was stirred at room temperature for 16 hour, and then diluted with water (50 mL), the organic phase was separated, and the aqueous phase was extracted with DCM (50 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/1-1/8) to afford compound (g) as light yellow oil (1.66 g, 45% isolated yield). LCMS (m/z): 311.1 [M+H] ⁺ . Synthesis of 3-(2,4-difluorobenzyl)-1-methyl-7-(methylthio)-3,4-dihydropy rimido[4,5- d]pyrimidin-2(1H)-one (i) To a solution 5-(((2,4-difluorobenzyl)amino)methyl)-N-methyl-2-(methylthio )pyrimidin- 4-amine (1.60 g, 5.16 mmol) and DIPEA (2.00 g, 15.5 mmol) in acetonitrile (20 mL) was added protion-wisely triphosgene (531 mg, 1.81 mmol) at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 1 hour, and then warmed to room temperature for 4 hours. The reaction mixture was diluted with water (30 mL), the aqueous phase was extracted with EtOAc (30 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (i) as white solid (1.5 g, 87% isolated yield). LCMS (m/z): 337.0 [M+H] ⁺ . Synthesis of 3-(2,4-difluorobenzyl)-1-methyl-7-(methylsulfonyl)-3,4-dihyd ropyrimido[4,5- d]pyrimidin-2(1H)-one (j) To a solution of 3-(2,4-difluorobenzyl)-1-methyl-7-(methylthio)-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.5 g, 4.46 mmol) in DCM (30 mL) was added m- CPBA (2.71 g, 13.4 mmol, 85% ) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (j) as light yellow solid (1.5 g, 91% isolated yield). LCMS (m/z): 369.1 [M+H] ⁺ . Synthesis of 3-(2,4-difluorobenzyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl) amino)-1-methyl- 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (l) To a solution of 3-(2,4-difluorobenzyl)-1-methyl-7-(methylsulfonyl)-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (900 mg, 2.45 mmol) and 4-fluoro-2-methoxy-5- nitroaniline (910 mg, 4.89 mmol) in DMSO (8 mL) was added TFA (8 mL). The reaction mixture was stirred at 100 ^o C for 16 hours, and cooled to room temperature, diluted with water (100 mL). The precipitation was formed, filtered and washed with water. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/4) to afford compound (l) as yellow solid (183 mg, 16% isolated yield). LCMS (m/z): 475.1 [M+H] ⁺ . Synthesis of 3-(2,4-difluorobenzyl)-7-((4-((2-(dimethylamino)ethyl)(methy l)amino)-2- methoxy-5-nitrophenyl)amino)-1-methyl-3,4-dihydropyrimido[4, 5-d]pyrimidin-2(1H)-one (n) The mixture of 3-(2,4-difluorobenzyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl) amino)-1- methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (183 mg, 0.39 mmol), N ¹ ,N ¹ ,N ² - trimethylethane-1,2-diamine (60 mg, 0.58 mmol) and K ₂ CO ₃ (107 mg, 0.77 mmol) in 1,4- dioxane (10 mL) was stirred at 100 ^o C for 4 hours. After cooled to room temperature, the mixture was diluted with brine (30 mL), the aqueous phase was extracted with EtOAc (50 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (n) as brown oil (200 mg, 93% isolated yield). LCMS (m/z): 557.2 [M+H] ⁺ . Synthesis of 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-3-(2,4-difluorobenzyl)-1-methyl-3,4-dih ydropyrimido[4,5- d]pyrimidin-2(1H)-one (o) To a solution of 3-(2,4-difluorobenzyl)-7-((4-((2-(dimethylamino)ethyl)(methy l)amino)- 2-methoxy-5-nitrophenyl)amino)-1-methyl-3,4-dihydropyrimido[ 4,5-d]pyrimidin-2(1H)-one (200 mg, 0.36 mmol) in EtOAc (10 mL) was added Pd/C (50 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reacition mixture was filtered through the celite, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give a colorless oil (58 mg g, 31% isolated yield). LCMS (m/z): 527.3 [M+H] ⁺ . Synthesis of N-(5-((6-(2,4-difluorobenzyl)-8-methyl-7-oxo-5,6,7,8-tetrahy dropyrimido[4,5- d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)a mino)-4- methoxyphenyl)acrylamide (compound 16) To a solution of 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-3-(2,4-difluorobenzyl)-1-methyl-3,4-dih ydropyrimido[4,5-d]pyrimidin- 2(1H)-one (58 mg, 0.11 mmol) in DCM (5 mL) was added NaHCO ₃ solution (5%, 3 mL), the mixture was cooled down to 0 ^o C and then the acryloyl chloride solution (1 M in DCM, 0.12 mL) was added drop-wisely. The reaction mixture was stirred at room temperature for 1 hour, diluted with brine (10 mL) and extracted with DCM (30 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 16 as a white solid (25 mg, 39 % isolated yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.05 (s, 1H), 9.53 (s, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 7.45 (dd, J = 15.2, 8.4 Hz, 1H), 6.91 – 6.79 (m, 2H), 6.77 (s, 1H), 6.46 – 6.34 (m, 1H), 6.33 – 6.21 (m, 1H), 5.70 – 5.61 (m, 1H), 4.68 (s, 2H), 4.27 (s, 2H), 3.87 (s, 3H), 3.54 (s, 3H), 2.87 (t, J = 5.6 Hz, 2H), 2.69 (s, 3H), 2.32 – 2.22 (m, 8H). LCMS (m/z): 581.2 [M+H] ⁺ . Example 17. Synthesis of N-(5-((6-benzyl-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4, 5- d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)a mino)-4- methoxyphenyl)acrylamide (compound 17) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (c) To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride (2.17 g, 32.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours, and then concentrated. The residue was added water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 5/1-2/1) to afford compound (c) as light yellow solid (4.7 g, 96% isolated yield). LCMS (m/z): 228.1 [M+H] ⁺ . Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (d) To a solution LAH (2.36 g, 62.1 mmol) in THF (50 mL) was added a solution of ethyl 4- (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.7 g, 20.7 mmol) in THF (30 mL) at 0 ^o C. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and then quenched with water (3 mL) drop-wisely at 0 ^o C. The mixture was stirred at room temperature for 1 hour, and then filtered through the celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-1/1) to afford to give compound (d) as light yellow solid (3.0 g, 78% isolated yield). LCMS (m/z): 186.1 [M+H] ⁺ . Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (e) To a solution (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (1.0 g, 5.41 mmol) in THF/DCM (20 mL) was added MnO2 (2.35 g, 27.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered through the celite. The filtrate was concentrated to give compound (e) as light yellow solid (1.0 g, crude), which was used directly for the next step. LCMS (m/z): 183.9 [M+H] ⁺ . Synthesis of 5-((benzylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-a mine (g) To a solution 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.0 g, 10.9 mmol) in DCM (50 mL) was added phenylmethanamine (1.40 g, 13.1 mmol) and AcOH (2 drops). The reaction mixture was stirred at room temperature for 1 hour, and then added NaBH(OAc)3 (9.27 g, 43.7 mmol). The reaction mixture was stirred at room temperature for 16 hour, and then diluted with water (50 mL), the organic phase was separated, and the aqueous phase was extracted with DCM (50 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/1-1/8) to afford compound (g) as light yellow oil (1.4 g, 47% isolated yield). LCMS (m/z): 275.1 [M+H] ⁺ . Synthesis of 3-benzyl-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]p yrimidin-2(1H)- one (i) To a solution 5-((benzylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-a mine (1.40 g, 5.11 mmol) and DIPEA (1.98 g, 15.3 mmol) in acetonitrile (20 mL) was added protion-wisely triphosgene (526 mg, 1.79 mmol) at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 1 hour, and then warmed to room temperature for 4 hours. The reaction mixture was diluted with water (30 mL), the aqueous phase was extracted with EtOAc (30 mL× 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (i) as white solid (1.13 g, 74% isolated yield). LCMS (m/z): 301.0 [M+H] ⁺ . Synthesis of 3-benzyl-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5 -d]pyrimidin- 2(1H)-one (j) To a solution of 3-benzyl-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]p yrimidin- 2(1H)-one (1.13 g, 3.77 mmol) in DCM (30 mL) was added m-CPBA (2.28 g, 11.3 mmol, 85% ) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford compound (j) as light yellow solid (1.1 g, 85% isolated yield). LCMS (m/z): 333.1 [M+H] ⁺ . Synthesis of 3-benzyl-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-1-methy l-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (l) To a solution of 3-benzyl-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5 - d]pyrimidin-2(1H)-one (500 mg, 1.51 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (560 mg, 3.01 mmol) in DMSO (8 mL) was added TFA (8 mL). The reaction mixture was stirred at 100 ^o C for 16 hours, and cooled to room temperature, diluted with water (100 mL). The precipitation was formed, filtered and washed with water. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/4) to afford compound (l) as yellow solid (220 mg, 33% isolated yield). LCMS (m/z): 439.1 [M+H] ⁺ . Synthesis of 3-benzyl-7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-met hoxy-5- nitrophenyl)amino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimi din-2(1H)-one (n) The mixture of 3-benzyl-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-1-methy l-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (220 mg, 0.50 mmol), N ¹ ,N ¹ ,N ² -trimethylethane- 1,2-diamine (76 mg, 0.75 mmol) and K ₂ CO ₃ (208 mg, 1.51 mmol) in 1,4-dioxane (10 mL) was stirred at 100 ^o C for 4 hours. After cooled to room temperature, the mixture was diluted with brine (30 mL), the aqueous phase was extracted with EtOAc (50 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (n) as brown oil (200 mg, 77% isolated yield). LCMS (m/z): 521.2 [M+H] ⁺ . Synthesis of 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-3-benzyl-1-methyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (o) To a solution of 3-benzyl-7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-met hoxy-5- nitrophenyl)amino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimi din-2(1H)-one (200 mg, 0.38 mmol) in EtOAc (10 mL) was added Pd/C (50 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reacition mixture was filtered through the celite, the filtrate was concentrated under reduced pressure to give the crude compound o as brown solid (4.0 g, crude), which was used directly for the next step. LCMS (m/z): 491.3 [M+H] ⁺ . Synthesis of N-(5-((6-benzyl-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4, 5-d]pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methox yphenyl)acrylamide (compound 17) To a solution of crude 7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-3-benzyl-1-methyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (200 mg, 0.38 mmol) in DCM (5 mL) was added NaHCO ₃ solution (5%, 3 mL), the mixture was cooled down to 0 ^o C and then the acryloyl chloride solution (1 M in DCM, 0.5 mL) was added drop-wisely. The reaction mixture was stirred at room temperature for 1 hour, diluted with brine (10 mL) and extracted with DCM (30 mL × 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by Prep- HPLC to afford compound 17 as an off-white solid (50 mg, 24 % isolated yield for two steps).1H NMR (400 MHz, CDCl ₃ ) δ 10.03 (s, 1H), 9.53 (s, 1H), 7.90 (s, 1H), 7.53 (s, 1H), 7.41 – 7.28 (m, 5H), 6.76 (s, 1H), 6.45 – 6.20 (m, 2H), 5.66 (d, J = 12.0 Hz, 1H), 4.68 (s, 2H), 4.18 (s, 2H), 3.87 (s, 3H), 3.56 (s, 3H), 2.88 (brs, 2H), 2.69 (s, 3H), 2.27 (brs, 8H).. LCMS (m/z): 545.3 [M+H] ⁺ . Example 18. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-( ntercon-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 18) Prepared according to the procedure for compound 14. Example 19. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-( ntercon-3-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 19) Prepared according to the procedure for compound 14. Example 20. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-( ntercon-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 20) Prepared according to the procedure for compound 14. Example 21. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(thiazol-4-yl)-5,6,7,8-tetrahydropyrimido[4,5 -d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 21) Prepared according to the procedure for compound 14. Example 22. Synthesis of N-(5-((6-(3-cyanophenyl)-8-methyl-7-oxo-5,6,7,8- tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylami de (compound 22) Prepared according to the procedure for compound 14. Example 23. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 - (2-methoxyphenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[ 4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 23) Prepared according to the procedure for compound 14. Example 24. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 - (3-methoxyphenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[ 4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 24) Prepared according to the procedure for compound 14. Example 25. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6 - (4-methoxyphenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[ 4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 25) Prepared according to the procedure for compound 14. Example 26. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-oxo-5,6,7,8-tetrahydro pyrimido[4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 26) Prepared according to the procedure for compound 14. Example 27. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrimido[ 4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 27) Prepared according to the procedure for compound 14. Example 28. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-7-oxo-6-(1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrimido[ 4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 28) Prepared according to the procedure for compound 14. Example 29. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8 - methyl-6-(1-methyl-1H-pyrazol-3-yl)-7-oxo-5,6,7,8-tetrahydro pyrimido[4,5-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 29) Prepared according to the procedure for compound 14. Example 30. Synthesis of N-(3-(2-((3-fluoro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 30) Prepared according to the procedure for compound 31. Example 31. Synthesis of N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 31) Synthesis of 3-chloro-1-methyl-1H-pyrazole (b) To a solution of 1-methyl-1H-pyrazol-3-amine (7.5 g, 77.3 mmol) in concentrated HCl (30 mL) was added a solution of sodium nitrite (5.87 g, 85.1 mmol) in H ₂ O (10.0 mL) over a 10 min period at 0 °C. The reaction solution was stirred for 0.5 hour at 0 °C, and then added a solution of copper(I) chloride (7.58 g, 77.3 mmol) in concentrated HCl (10 mL) drop-wisely. The mixture was stirred at room temperature overnight, and extracted with DCM (80 mL × 3), and the combined organic phase was washed with aq. sat. NaHCO ₃ (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 100/1- 50/1) to afford compound (b) as a white solid (5.7 g, 64% isolated yield). LCMS (m/z): 117.2 [M+H] ⁺ . Synthesis of 3-chloro-1-methyl-4-nitro-1H-pyrazole (c). To a solution of 3-chloro-1-methyl-1H-pyrazole (7.7 g, 66.4 mmol) in concentrated sulfuric acid (30 mL) was added fuming nitric acid (10 mL, 240 mmol) over 30 min 0 °C. The reaction mixture was stirred at room temperature for 2 hours, and then poured in ice/water, the precipitate was formed and filtered. The filtered cake was dried under reduced pressure to give compound (c) as a yellow solid (6 g, 56% yield), which was used directly for the next step. LCMS (m/z): 162.1 [M+H] ⁺ . Synthesis of 3-chloro-1-methyl-1H-pyrazol-4-amine (d) To a solution of 3-Chloro-1-methyl-4-nitro-1H-pyrazole (5.0 g, 31 mmol) in EtOH (50 mL) was added Raney Ni (1 g), the mixture was heated to reflux, and then hydrazine monohydrate (6.5 mL, 130 mmol) was added dropwise, the mixture was stirred under reflux for 2 hours and filtered through celite, the filtrate was concentrated under reduced pressure to give the crude compound (d) as an light yellow oil (1.8 g, 44% yield). LCMS (m/z): 132.1[M+H] ⁺ . Synthesis of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (e) To a solution of 3-chloro-1-methyl-1H-pyrazol-4-amine (1.4 g, 8.70 mmol) and Et ₃ N (1.76 g, 17.4 mmol) in DCM (20 mL) was added a solution of AcCl (0.82 g, 10.4 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (e) as brown oil (1.4 g, 93% isolated yield). LCMS (m/z): 174.1 [M+H] ⁺ . Synthesis of tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carb amate (h) To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (4.0 g, 21.3 mmol) in DMF (50 mL) was added Et ₃ N (4.30 g, 42.6 mmol) and tert-butyl (3-aminophenyl)carbamate (6.64 g, 32.0 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-2/1) to afford compound (h) as yellow solid (3.0 g, 39% isolated yield). LCMS (m/z): 361.1 [M+H] ⁺ . Synthesis of tert-butyl (3-(2-(methylthio)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H )- yl)phenyl)carbamate (j) To a solution of 4 tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (1.6 g, 4.44 mmol) in NMP (20 mL) was added K ₂ CO ₃ (1.23 g, 8.89 mmol) and ethyl 2-phenylacetate (1.09 g, 6.67 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (40 mL × 3). The combined organic phase was washed with water (40 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 2/1-1/1) to afford compound (j) as yellow oil (0.6 g, 29% isolated yield). LCMS (m/z): 461.1 [M+H] ⁺ . Synthesis of tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin- 8(7H)- yl)phenyl)carbamate (k) To a solution of tert-butyl (3-(2-(methylthio)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (600 mg, 1.30 mmol) in DCM (10 mL) was added m-CPBA (790 mg, 0.91 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (k) as yellow oil (530 mg, 83% isolated yield). LCMS (m/z): 510.1 [M+18] ⁺ . Synthesis of tert-butyl (3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (l) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (132 mg, 0.76 mmol) in DMF (5 mL) was added NaH (31 mg, 0.76 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (250 mg, 0.51 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (l) as light yellow solid (72 mg, 26% isolated yield). LCMS (m/z): 544.2 [M+H] ⁺ . Synthesis of 8-(3-aminophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amin o)-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one (m) To a solution of tert-butyl (3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (72 mg, 0.10 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to compound (m) as light yellow solid (75 mg, crude), which used directly for the next step. LCMS (m/z): 444.1 [M+H] ⁺ . Synthesis of N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-p henylpyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 31) To a solution of crude 8-(3-aminophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.13 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (14 mg, 0.16 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, the crude product was purified by Prep-HPLC to afford compound 31 as white solid (25 mg, 38 % isolated yield for two steps). LCMS (m/z): 498.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (s, 1H), 9.63 (s, 1H), 8.89 (s, 1H), 8.16 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.78 – 7.67 (m, 3H), 7.65 – 7.60 (m, 1H), 7.48 – 7.33 (m, 3H), 7.14 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 6.45 (dd, J = 17.2, 10.0 Hz, 1H), 6.27 (dd, J = 17.2, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.51 (s, 3H). Example 32. Synthesis of 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 1- meth 32) Synthesis of 2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (c) To a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (2 g, 11.8mmol) in NMP (50 mL) was added K ₂ CO ₃ (3.88 g, 23.7 mmol) and ethyl 2-phenylacetate (3.27 g, 23.7 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 2/1-1/1) to afford compound (c) as white solid (1.1 g, 35% isolated yield). LCMS (m/z): 270.1 [M+H] ⁺ . Synthesis of tert-butyl (trans)-3-methoxy-4-((2-(methylthio)-7-oxo-6-phenylpyrido[2, 3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-carboxylate (e) To a solution of 2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (850 mg, 3.16 mmol), tert-butyl (trans)-3-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate (487 mg, 2.11 mmol) and triphenylphosphine (1.10 g, 4.21 mmol) in THF (10 mL) was added DIAD (1.28 g, 6.32 mmol) at 0 ^o C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (e) as light yellow solid (420 mg, 43% isolated yield). LCMS (m/z): 483.1 [M+H] ⁺ . Synthesis of tert-butyl trans-3-methoxy-4-((2-(methylsulfonyl)-7-oxo-6-phenylpyrido[ 2,3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-carboxylate (f) To a solution of tert-butyl (trans)-3-methoxy-4-((2-(methylthio)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-c arboxylate (420 mg, 0.87 mmol) in DCM (10 mL) was added m-CPBA (530 mg, 2.61 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO3 solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (f) as light yellow solid (380 mg, 85% isolated yield). LCMS (m/z): 415.0 [M+H-Boc] ⁺ . Synthesis of N-(1-methyl-1H-pyrazol-4-yl)acetamide (h) To a solution of 1-methyl-1H-pyrazol-4-amine (2.0 g, 20.6 mmol) and Et ₃ N (4.16 g, 41.2 mmol) in DCM (20 mL) was added a solution of AcCl (1.93 g, 24.7 mmol) in DCM (10 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 100/1-50/1) to afford compound (h) as light yellow solid (2.5 g, 87% isolated yield). LCMS (m/z): 140.1 [M+H] ⁺ . Synthesis of tert-butyl (trans)-3-methoxy-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)-7- oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-c arboxylate (i) To a solution of N-(1-methyl-1H-pyrazol-4-yl)acetamide (82 mg, 0.58 mmol) in DMF (5 mL) was added NaH (29 mg, 0.73 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl trans-3-methoxy-4-((2-(methylsulfonyl)-7- oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrrolidi ne-1-carboxylate (150 mg, 0.29 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (i) as light yellow solid (50 mg, 32% isolated yield). LCMS (m/z): 532.2 [M+H] ⁺ . Synthesis of 8-(((trans)-4-methoxypyrrolidin-3-yl)methyl)-2-((1-methyl-1H -pyrazol-4- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (j) To a solution of tert-butyl (trans)-3-methoxy-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)- 7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrroli dine-1-carboxylate (50 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to compound (j) as light yellow solid (45 mg, crude), which used directly for the next step. LCMS (m/z): 432.1 [M+H] ⁺ . Synthesis of 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 1-methyl-1H- pyrazol-4-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (compound 32) To a solution of crude 8-(((trans)-4-methoxypyrrolidin-3-yl)methyl)-2-((1-methyl-1H - pyrazol-4-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (40 mg, 0.09 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (10 mg, 0.11 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, the crude product was purified by Prep- HPLC to afford compound 32 as an off-white solid (6 mg, 13 % isolated yield for two steps). LCMS (m/z): 486.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 8.79 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.68 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 17.6 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.40 – 7.33 (m, 1H), 6.55 – 6.45 (m, 1H), 6.15 – 6.05 (m, 1H), 5.67 – 5.60 (m, 1H), 4.50 – 4.38 (m, 2H), 3.90 – 3.75 (m, 5H), 3.72 –3.52 (m, 3H), 3.11 (d, J = 3.2 Hz, 3H), 2.96 –2.85 (m, 1H). Example 33. Synthesis of 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 3- chloro-1-methyl-1H-pyrazol-4-yl)amino)-6-phenylpyrido[2,3-d] pyrimidin-7(8H)-one (compound 33) Synthesis of 3-chloro-1-methyl-1H-pyrazole (b) To a solution of 1-methyl-1H-pyrazol-3-amine (7.5 g, 77.3 mmol) in concentrated HCl (30 mL) was added a solution of sodium nitrite (5.87 g, 85.1 mmol) in H ₂ O (10.0 mL) over a 10 min period at 0 °C. The reaction solution was stirred for 0.5 hour at 0 °C, and then added a solution of copper(I) chloride (7.58 g, 77.3 mmol) in concentrated HCl (10 mL) drop-wisely. The mixture was stirred at room temperature overnight, and extracted with DCM (80 mL × 3), and the combined organic phase was washed with aq. sat. NaHCO ₃ (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 100/1- 50/1) to afford compound (b) as a white solid (5.7 g, 64% isolated yield). LCMS (m/z): 117.2 [M+H] ⁺ . Synthesis of 3-chloro-1-methyl-4-nitro-1H-pyrazole (c). To a solution of 3-chloro-1-methyl-1H-pyrazole (7.7 g, 66.4 mmol) in concentrated sulfuric acid (30 mL) was added fuming nitric acid (10 mL, 240 mmol) over 30 min 0 °C. The reaction mixture was stirred at room temperature for 2 hours, and then poured in ice/water, the precipitate was formed and filtered. The filtered cake was dried under reduced pressure to give compound (c) as a yellow solid (6 g, 56% yield), which was used directly for the next step. LCMS (m/z): 162.1 [M+H] ⁺ . Synthesis of 3-chloro-1-methyl-1H-pyrazol-4-amine (d) To a solution of 3-Chloro-1-methyl-4-nitro-1H-pyrazole (5.0 g, 31 mmol) in EtOH (50 mL) was added Raney Ni (1 g), the mixture was heated to reflux, and then hydrazine monohydrate (6.5 mL, 130 mmol) was added dropwise, the mixture was stirred under reflux for 2 hours and filtered through celite, the filtrate was concentrated under reduced pressure to give the crude compound (d) as an light yellow oil (1.8 g, 44% yield). LCMS (m/z): 132.1[M+H] ⁺ . Synthesis of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (e) To a solution of 3-chloro-1-methyl-1H-pyrazol-4-amine (1.4 g, 8.70 mmol) and Et ₃ N (1.76 g, 17.4 mmol) in DCM (20 mL) was added a solution of AcCl (0.82 g, 10.4 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (e) as brown oil (1.4 g, 93% isolated yield). LCMS (m/z): 174.1 [M+H] ⁺ . Synthesis of tert-butyl (trans)-3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-o xo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-4-methoxypyrro lidine-1-carboxylate (g) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (102 mg, 0.58 mmol) in DMF (5 mL) was added NaH (29 mg, 0.73 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl trans-3-methoxy-4-((2- (methylsulfonyl)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)- yl)methyl)pyrrolidine-1- carboxylate (150 mg, 0.29 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (g) as light yellow solid (80 mg, 48% isolated yield). LCMS (m/z): 566.0 [M+H] ⁺ . Synthesis of 2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-8-(((trans)-4- methoxypyrrolidin-3-yl)methyl)-6-phenylpyrido[2,3-d]pyrimidi n-7(8H)-one (h) To a solution of tert-butyl (trans)-3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7- oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-4-methox ypyrrolidine-1-carboxylate (80 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to compound (h) as light yellow solid (80 mg, crude), which used directly for the next step. LCMS (m/z): 466.1 [M+H] ⁺ . Synthesis of 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 3-chloro-1-methyl- 1H-pyrazol-4-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)- one (compound 33) To a solution of crude 2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-8-(((trans)-4- methoxypyrrolidin-3-yl)methyl)-6-phenylpyrido[2,3-d]pyrimidi n-7(8H)-one (80 mg, crude) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (15 mg, 0.17 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, the crude product was purified by Prep- HPLC to afford compound 33 as a white solid (15 mg, 20 % isolated yield for two steps). LCMS (m/z): 520.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.81 (s, 1H), 8.08 – 7.92 (m, 2H), 7.67 (d, J = 7.2 Hz, 2H), 7.47 – 7.33 (m, 3H), 6.60 – 6.45 (m, 1H), 6.17 – 6.08 (m, 1H), 5.73 – 5.60 (m, 1H), 4.42 – 4.15 (m, 2H), 3.85 (d, J = 5.2 Hz, 3H), 3.78 –3.43 (m, 5H), 3.07 (s, 3H), 2.89 – 2.70 (m, 1H). Example 34. Synthesis of 1-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-7-(( 3- chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydrop yrimido[4,5-d]pyrimidin- 2(1H)-one (compound 34) Prepared according to the procedure for compound 39. Example 35. Synthesis of N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound tert-butyl (3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenylpyrido [2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (b) To a solution of N-(6-morpholinopyridin-3-yl)acetamide (162 mg, 0.73 mmol) in DMF (5 mL) was added 60% NaH (35 mg, 0.88 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (240 mg, 0.49 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (b) as white solid (100 mg, 35% isolated yield). LCMS (m/z): 592 [M+H] ⁺ . 8-(3-aminophenyl)-2-((6-morpholinopyridin-3-yl)amino)-6-phen ylpyrido[2,3-d]pyrimidin- 7(8H)-one (c) To a solution of tert-butyl (3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (100 mg, 0.17 mmol) in DCM (4 mL) was added TFA (1 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to give compound (c) as light yellow solid (83 mg, crude), which used directly for the next step. LCMS (m/z): 492 [M+H] ⁺ . N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenylpyri do[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide (91) To a solution of crude 8-(3-aminophenyl)-2-((6-morpholinopyridin-3-yl)amino)-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one (83 mg, 0.17 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (23 mg, 0.25 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to afford compound 91 as yellow solid (40 mg, 43 % isolated yield for two steps). LCMS (m/z): 546 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 9.99 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.71 – 7.67 (m, 3H), 7.56 – 7.36 (m, 5H), 7.10 (d, J = 7.6 Hz, 1H), 6.45– 6.23 (m, 1H), 6.27-6.23 (m, 2H), 5.78-5.75 (m, 1H), 3.69-3.67 (m, 4H), 3.28 – 3.20 (m, 4H).

Example 36. Synthesis of N-(3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phen yl)acrylamide (compound 36) 36 Synthesis of 4-(3-chloro-1H-pyrazol-1-yl)-1-methylpiperidine (b) To a solution of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-amine (1.8 g, 10 mmol) in concentrated hydrochloric acid (20 mL) at 0 °C was added a solution of sodium nitrite (759 mg, 11 mmol) in water (6 mL) dropwise while maintaining the temperature below 10 °C. The reaction mixture was stirred for 30 min, a solution of copper (I) chloride (825 mg , 8.33 mmol) in concentrated hydrochloric acid (8 mL) was added dropwise and the resulting reaction mixture was then heated to 60 °C. A catalytic amount of copper chloride (100 mg) was added at 60 °C. The reaction mixture was stirred for 5 min and then poured onto 100 mL of crushed ice containing 50 % sodium hydroxide (5 mL) and stirred well. The aqueous solution was extracted with dichloromethane (2 × 150 mL), and the combined organic phase was washed with water (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 0-10%) to give compound (b) (1.08 g, yellow oil, yield 54.3%). LCMS (m/z): 200.0 [M+H] ⁺ . Synthesis of 4-(3-chloro-4-nitro-1H-pyrazol-1-yl)-1-methylpiperidine--met hane (c) To a solution of 4-(3-chloro-1H-pyrazol-1-yl)-1-methylpiperidine (1.08 g, 5.43 mmol) in concentrated sulfuric acid (3 mL) at 0 ^o C was added dropwise fuming nitric acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours, and then poured into ice/water. The aqueous phase was extracted with EtOAc (2 × 20 mL), and the combined organic phase was washed with sat. aq. NaHCO ₃ (2 × 20 mL), brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 0-23%) to give Compound (c) (yellow solid, 1.2 g, yield 90.6%). LCMS (m/z): 245.1 [M+H] ⁺ . Synthesis of 3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (d) To a solution of 4-(3-chloro-4-nitro-1H-pyrazol-1-yl)-1-methylpiperidine--met hane (500 mg, 2.04 mmol) in EtOH (5 mL) was added Raney Ni (100 mg), the mixture was heated to reflux, and then hydrazine monohydrate (0.5 mL) was added dropwise, the mixture was stirred under reflux for 2 hours and filtered through celite, the filtrate was concentrated under reduced pressure to give the crude compound (d) as brown oil (500 mg, crude),which was used directly for the next step. LCMS (m/z): 215.1[M+H] ⁺ . Synthesis of N-(3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)aceta mide (e) To a solution of 3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (500 mg, crude) and Et ₃ N (414 mg, 4.10 mmol) in DCM (5 mL) was added a solution of AcCl (192 mg, 2.46 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (20 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (e) as yellow solid (180 mg, 34% isolated yield of 2 steps). LCMS (m/z): 257.1 [M+H] ⁺ . Synthesis of tert-butyl (3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) amino)- 7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbama te (g) To a solution of N-(3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)aceta mide (185 mg, 0.723 mmol) in THF (10 mL) at 0 ^o C was added NaH (96 mg, 2.41 mmol) and the mixture was stirred at 0 ^o C for 30min. tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6-phenylpyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (296 mg, 0.60 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting with dichloromethane: methanol = 0-20%) to give compound (g) (178 mg, yellow solid, yield 47.3%). LCMS (m/z): 627.2 [M+H] ⁺ . Synthesis of 8-(3-aminophenyl)-2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H -pyrazol-4- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (h) To a solution of tert-butyl (3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phen yl)carbamate (178 mg, 0.28 mmol) in dichloromethane (4 mL) was added TFA (3 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to give compound h (138 mg, crude), which used directly for the next step. LCMS (m/z): 527.2 [M+H] ⁺ . Synthesis of N-(3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-y l)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (Compound 36) To a solution of 8-(3-aminophenyl)-2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H -pyrazol- 4-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (138 mg, crude) and 5% NaHCO ₃ (1.5 mL) in dichloromethane (4 mL) at 0 ^o C was added acryloyl chloride (35 mg, 0.38 mmol) at 0 ^o C, and the mixture was stirred for 30 min, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated, the crude product was purified by Prep-HPLC to give 36 (36.4 mg, white solid, two step yield 40 %). LCMS (m/z): 581.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (s, 1H), 8.64 (s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.73 – 7.69 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.46 – 7.32 (m, 4H), 7.13 – 7.05 (m, 2H), 7.01 (s, 1H), 6.40 (d, J = 16.4 Hz, 1H), 6.21 – 6.11 (m, 1H), 5.73 (d, J = 11.2 Hz, 1H), 3.90 – 3.75 (m, 1H), 3.01 – 2.90 (m, 2H), 2.33 (s, 3H), 2.13 – 2.04 (m, 2H), 1.90 – 1.70 (m, 4H). Example 37. Synthesis of N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-6-(2,4- difluorophenyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) acrylamide (compound 37) Prepared according to the procedure for compound 31. Example 38. Synthesis of N-(5-((6-(bicyclo[1.1.1]pentan-1-yl)-8-methyl-7-oxo-5,6,7,8- tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylami de (compound 38) Prepared according to the procedure for compound 14 to afford 26.2 mg of compound 38. LCMS (m/z): 521.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.99 (s, 1H), 8.00 (s, 1H), 6.93 (s, 1H), 6.51 (dd, J = 16.8, 10.0 Hz, 1H), 6.35 (dd, J = 16.8, 1.6 Hz, 1H), 5.78 (dd, J = 10.0, 1.6 Hz, 1H), 4.32 (s, 2H), 3.92 (s, 3H), 3.36 (s, 3H), 3.10 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.57 (s, 2H), 2.48 (s, 1H), 2.38 (s, 6H), 2.20 (s, 6H). Example 39. Synthesis of 1-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-7-(( 1- methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (compound 39) 39 Synthesis of N-(1-methyl-1H-pyrazol-4-yl)acetamide To a solution of 1-methyl-1H-pyrazol-4-amine (1.0 g, 10.3 mmol) and Et ₃ N (2.08 g, 20.6 mmol) in DCM (10 mL) was added a solution of AcCl (0.96 g, 12.4 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-15/1) to afford N- (1-methyl-1H-pyrazol-4-yl)acetamide as white solid (1.0 g, 70% yield). LCMS (m/z): 140.1 [M+H] ⁺ . Prepared according to the procedure for compound 32 or 33 to afford 50 mg of compound 39. LCMS (m/z): 489.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.04 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 4.4 Hz, 1H), 7.48 – 7.34 (m, 4H), 7.34 – 7.28 (m, 1H), 6.60 – 6.45 (m, 1H), 6.29 – 6.16 (m, 1H), 5.74 – 5.65 (m, 1H), 4.73 (s, 2H), 4.25 – 4.06 (m, 2H), 4.03 – 3.77 (m, 5H), 3.72 – 3.45 (m, 3H), 3.28 (s, 3H), 3.01 – 2.82 (m, 1H).

Example 40. Synthesis of 8-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 6- morpholinopyridin-3-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin -7(8H)-one (compound 40) Synthesis of N-(6-fluoropyridin-3-yl)acetamide (b) To a solution of 6-fluoropyridin-3-amine (1.0 g, 8.93 mmol) and Et ₃ N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (b) as white solid (1.2 g, 87% isolated yield). LCMS (m/z): 155.1 [M+H] ⁺ . Synthesis of N-(6-morpholinopyridin-3-yl)acetamide (d) To a solution of N-(6-fluoropyridin-3-yl)acetamide (1.1 g, 7.14 mmol) in DMSO (20 mL) was added morpholine (1.24 g, 14.3 mmol) and K ₂ CO ₃ (1.97 g, 14.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (d) as pale solid (700 mg, 44% isolated yield). LCMS (m/z): 222.2 [M+H] ⁺ . Synthesis of tert-butyl (3R,4R)-3-cyano-4-methoxypyrrolidine-1-carboxylate (f) A suspension of tert-butyl (3R,4R)-3-cyano-4-hydroxypyrrolidine-1-carboxylate (2.50 g, 11.8 mmol) in 100 ml of THF and 2.32 g of Ag ₂ O (10.9 g, 47.2 mmol) and CH ₃ I (5.03 g, 35.4 mmol) was heated in a sealed tube to 50°C for 16 h. The suspension was filtered and the filtrate was concentrated, the residue was purified by flash column chromatography on silica gel (eluting with petrol ether: ethyl acetate=0- 25%) to give compound (f) as light yellow oil (1.5 g, 56% isolated yield). LCMS (m/z): 171.1 [M-56+H] ⁺ . Synthesis of tert-butyl (3S,4R)-3-(aminomethyl)-4-methoxypyrrolidine-1-carboxylate (g) To a solution of tert-butyl (3R,4R)-3-cyano-4-methoxypyrrolidine-1-carboxylate (1.5 g, 6.64 mmol) in 100 ml of THF was added Raney Ni (0.5 g), the resulting mixture was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered and the filtrate was concentrated to give compound (g) as colorless oil (2.0 g, crude), which was used directly for the next step. LCMS (m/z): 231.3 [M+H] ⁺ . Synthesis of tert-butyl (3S,4R)-3-(((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)met hyl)-4- methoxypyrrolidine-1-carboxylate (i) To a solution of tert-butyl (3S,4R)-3-(aminomethyl)-4-methoxypyrrolidine-1-carboxylate (2.0 g, crude) and triethylamine (1.34 g, 13.3 mmol) in 1,4-dioxane (40 mL) was added 4-chloro- 2-(methylthio)pyrimidine-5-carbaldehyde (1.25 g, 6.64 mmol). The mixture was refluxed overnight and then concentrated, the residue was added water (50 mL) and EtOAc (50 mL). The organic phase was seperated, the aqueous phase was extracted with EtOAc (30 mL× 3). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, the residue was purified by flash column chromatography on silica gel (eluting with petrol ether: ethyl acetate=0- 50%) to give compound (i) (850 mg, 2 steps yield 34%) as yellow solid. LCMS (m/z): 383.1 [M+H] ⁺ . Synthesis of tert-butyl (3R,4S)-3-methoxy-4-((2-(methylthio)-7-oxo-6-phenylpyrido[2, 3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-carboxylate (k) To a solution of tert-butyl (3S,4R)-3-(((5-formyl-2-(methylthio)pyrimidin-4- yl)amino)methyl)-4-methoxypyrrolidine-1-carboxylate (800 mg, 2.09 mmol) and ethyl 2- phenylacetate (690 mg, 4.19 mmol) in NMP (5 mL) was added K ₂ CO ₃ (580 mg, 4.19 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (40 mL × 3). The combined organic phase was washed with water (40 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 2/1-1/1) to afford compound (k) as light yellow solid (300 mg, 30% isolated yield). LCMS (m/z): 483.2 [M+H] ⁺ . Synthesis of tert-butyl (3R,4S)-3-methoxy-4-((2-(methylsulfonyl)-7-oxo-6-phenylpyrid o[2,3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-carboxylate (l) To a solution of tert-butyl (3R,4S)-3-methoxy-4-((2-(methylthio)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-c arboxylate (300 mg, 0.62 mmol) in DCM (10 mL) was added m-CPBA (376 mg, 1.88 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (30 mL), saturated aqueous NaHCO ₃ solution (30 mL× 2) and water (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (l) as yellow solid (210 mg, 66% isolated yield). LCMS (m/z): 415.2 [M-Boc+1] ⁺ . Synthesis of tert-butyl (trans)-3-methoxy-4-((2-((6-morpholinopyridin-3-yl)amino)-7- oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-c arboxylate (m) To a solution of N-(6-morpholinopyridin-3-yl)acetamide (200 mg , 0.90 mmol) in DMF( 10 mL) was added at 0 ^o C was added NaH (84 mg, 2.09 mmol) and the mixture was stirred at 0 ^o C for 30 min. Tert-butyl (3R,4S)-3-methoxy-4-((2-(methylsulfonyl)-7-oxo-6-phenylpyrid o[2,3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-1-carboxylate (358 mg, 0.70 mmol) was added, the mixture was stirred at room temperature under nitrogen for 2 hours. The resulting mixture was quenched by water (10 mL) at 0 ^o C , the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was concentrated, the residue was purified by flash column chromatography on silica gel (eluting with dichloromethane: 10% methanol in dichloromethane =0-45%) to give compound (m) (80 mg, yellow oil, yield 18.7%). LCMS (m/z): 614.2 [M+H] ⁺ . Synthesis of 8-(((3R,4R)-4-methoxypyrrolidin-3-yl)methyl)-2-((6-morpholin opyridin-3- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (n) To a solution of tert-butyl (3R,4S)-3-methoxy-4-((2-((6-morpholinopyridin-3-yl)amino)- 7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)pyrroli dine-1-carboxylate (80 mg , 0.13 mmol) in dichloromethane ( 5 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 1h. The reaction solution was concentrated to give compound (n) (65 mg, crude), which was used direclty for the next step. LCMS (m/z): 514.2 [M+H] ⁺ . Synthesis of 8-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-(( 6- morpholinopyridin-3-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin -7(8H)-one (compound 40) To a solution of 8-(((3R,4R)-4-methoxypyrrolidin-3-yl)methyl)-2-((6- morpholinopyridin-3-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin -7(8H)-one (65 mg, crude) and 5% NaHCO ₃ (1.0 mL) in dichloromethane (4 mL) at 0 ^o C was added a solution of acryloyl chloride (27 mg, 0.30 mmol) in DCM (1 mL), the mixture was stirred at 0 ^o C for 1 hour. The resulting mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL × 3). The combined organic was concentrated, the residue was purified by Prep- HPLC to give compound 40 (19 mg, two step yield 25.7%) as white solid. LCMS (m/z): 568.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.49 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.94 – 7.87 (m, 1H), 7.73 – 7.64 (m, 2H), 7.49 – 7.32 (m, 3H), 6.91 – 6.81 (m, 1H), 6.57 – 6.40 (m, 1H), 6.16 – 6.05 (m, 1H), 5.69 – 5.58 (m, 1H), 4.42 – 4.20 (m, 2H), 3.91 – 3.75 (m, 2H), 3.77 – 3.69 (m, 4H), 3.67 – 3.49 (m, 2H), 3.47 – 3.35 (m, 7H), 3.09 (d, J = 2.3 Hz, 3H), 2.93 – 2.76 (m, 1H). Example 41. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxy-5-((8 - methyl-7-oxo-6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrim idin-2-yl)amino)pyridin-3- yl)acrylamide (compound 41) Prepared according to the procedure for 42. LCMS (m/z): 532.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.45 – 7.30 (m, 5H), 6.57 – 6.43 (m, 2H), 5.87 (dd, J = 9.6, 2.4 Hz, 1H), 4.77 (s, 2H), 4.03 (s, 3H), 3.85 (t, J = 5.6 Hz, 2H), 3.44 (s, 3H), 3.38 (t, J = 5.6 Hz, 2H), 2.91 (s, 6H), 2.86 (s, 3H).

Example 42. Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-methyl-7- oxo-6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl )amino)-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)acrylamide (compound 42) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate(5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride(2.17 g, 32.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours, and then concentrated. The residue was added water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 5/1-2/1) to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as light yellow solid (4.7 g, 96% isolated yield).LCMS (m/z): 228.1 [M+H] ⁺ . Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol To a solution LAH (2.36 g, 62.1 mmol) in THF (50 mL) was added a solution of ethyl 4- (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.7 g, 20.7 mmol)in THF (30 mL)at 0 ^o C. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and then quenched with water (3 mL) drop-wisely at 0 ^o C. The mixture was stirred at room temperature for 1 hour, and then filtered through the celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-1/1) to afford to give (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol as light yellow solid (3.0 g, 78% isolated yield). LCMS (m/z): 186.1 [M+H] ⁺ . Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde To a solution (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (1.0 g, 5.41 mmol) in THF/DCM (20 mL) was added MnO2 (2.35 g, 27.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered through the celite. The filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde as light yellow solid(1.0 g, crude), which was used directly for the next step.LCMS (m/z): 183.9 [M+H] ⁺ . Synthesis of N-methyl-2-(methylthio)-5-((phenylamino)methyl)pyrimidin-4-a mine A solution 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (10 g, 54.6mmol) and aniline(7.63 g, 82.0 mmol)in toluene (120 mL) was refluxed for 16 hours using a Dean-Stark apparatus to remove the water as it is formed. The reaction mixture was concentrated, and the residue was dissolved with MeOH (50 mL). The resulting mixture was added NaBH ₄ (4.15 g, 109 mmol) portion-wisely, and then stirred at 50 ^o C for 5 hours. The solution was quenched by aq. sat. NH ₄ Cl (6 mL)at 0 ^o C, and then diluted with brine (100 mL), the aqueous phase was extracted with EtOAc (50 mL× 3). The combined organic phase was concentrated under reduced pressure,the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/1-1/4) to afford N-methyl-2-(methylthio)-5- ((phenylamino)methyl)pyrimidin-4-amine as white solid(8 g, 56% isolated yield).LCMS (m/z): 261.1 [M+H] ⁺ . Synthesis of 1-methyl-7-(methylthio)-3-phenyl-3,4-dihydropyrimido[4,5-d]p yrimidin-2(1H)- one To a solution N-methyl-2-(methylthio)-5-((phenylamino)methyl)pyrimidin-4-a mine(8.0 g, 30.8mmol) and DIPEA (11.9 g, 92.3mmol) in acetonitrile (100 mL) was added protion- wiselytriphosgene(3.08mg, 10.5 mmol) at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 1 hour, and then warmed to room temperature for 4 hours. The reaction mixture was diluted with water (100 mL), the aqueous phase was extracted with EtOAc (80 mL× 3). The combined organic phase was concentrated under reduced pressure,the residue was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford -methyl- 7-(methylthio)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin- 2(1H)-one as white solid(8.0 g, 91% isolated yield).LCMS (m/z): 287.0 [M+H] ⁺ . Synthesis of 1-methyl-7-(methylsulfonyl)-3-phenyl-3,4-dihydropyrimido[4,5 -d]pyrimidin- 2(1H)-one To a solution of 1-methyl-7-(methylthio)-3-phenyl-3,4-dihydropyrimido[4,5-d]p yrimidin- 2(1H)-one(8.0 g, 30.0 mmol) in DCM (100 mL) was added m-CPBA (16.98 g, 83.9 mmol, 85% ) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then filtered. The filtrate was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / DCM = 1/5-1/20) to afford 1-methyl-7-(methylsulfonyl)-3- phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as white solid(8.0 g, 90% isolated yield). LCMS (m/z): 319.0 [M+H] ⁺ . Synthesis of 7-((6-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro-2-(2,2 ,2- trifluoroethoxy)pyridin-3-yl)amino)-1-methyl-3-phenyl-3,4-di hydropyrimido[4,5- d]pyrimidin-2(1H)-one To a solution of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro-2-(2,2, 2- trifluoroethoxy)pyridin-3-yl)acetamide (750 mg, 1.98 mmol) in Tol (8 mL) was added LiHMDS(1 N in THF, 2 mL, 2.0 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then 1-methyl-7-(methylsulfonyl)-3-phenyl-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (420 mg, 1.32 mmol) was added. The reaction mixture was stirred at 100 ^o C for 16 hours, and cooled to room temperature, diluted with water. The aqueous phase was extracted with EtOAc, the combined organic phase was concentrated, the residue was purified by flash column chromatography on silica gel (eluting with MeOH / DCM = 1/50-1/10) to afford 7-((6-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro-2-(2,2 ,2- trifluoroethoxy)pyridin-3-yl)amino)-1-methyl-3-phenyl-3,4-di hydropyrimido[4,5-d]pyrimidin- 2(1H)-one as orange solid (80 mg, 11% yield). LCMS (m/z): 576.2 [M+H] ⁺ . Synthesis of 7-((5-amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(2,2 ,2- trifluoroethoxy)pyridin-3-yl)amino)-1-methyl-3-phenyl-3,4-di hydropyrimido[4,5- d]pyrimidin-2(1H)-one To a solution of 7-((6-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro-2-(2,2 ,2- trifluoroethoxy)pyridin-3-yl)amino)-1-methyl-3-phenyl-3,4-di hydropyrimido[4,5-d]pyrimidin- 2(1H)-one (80 mg, 0.36mmol) in EtOAc (10 mL) was added Pd/C (30 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours.The reacition mixture was filtered through the celite, the filtrate was concentrated under reduced pressure to give 7-((5- amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(2,2,2-tri fluoroethoxy)pyridin-3- yl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimi din-2(1H)-one as pale solid (60 mg, 79% yield), which was used directly for the next step. LCMS (m/z): 546.2 [M+H] ⁺ . Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-methyl-7- oxo-6-phenyl- 5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-(2, 2,2-trifluoroethoxy)pyridin-3- yl)acrylamide (compound 42) To a solution of 7-((5-amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(2,2 ,2- trifluoroethoxy)pyridin-3-yl)amino)-1-methyl-3-phenyl-3,4-di hydropyrimido[4,5-d]pyrimidin- 2(1H)-one (60 mg, 0.11 mmol) in THF (5 mL) was added NaHCO3 solution(5%, 3 mL), the mixture was cooled down to 0 ^o C and then the acryloyl chloride solution (1 M in DCM, 0.13 mL, 0.13 mmol) was added drop-wisely. The reaction mixture was stirred at room temperature for 1 hour and diluted with DCM, the organic phase was washed with brine, water and concentrated. The residue was purified by Prep-HPLC to afford compound 42 as pale solid (12 mg, 18% yield). LCMS (m/z): 600.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.93 (s, 1H), 8.06 (s, 1H), 7.47 – 7.41 (m, 2H), 7.38 (t, J = 4.4 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.58 – 6.33 (m, 2H), 5.83 (dd, J = 10.0, 2.0 Hz, 1H), 5.01 – 4.95 (m, 2H), 4.74 (s, 2H), 3.49 – 3.40 (m, 5H), 2.89 – 2.68 (m, 5H), 2.48 (s, 6H).

Example 43. Synthesis of N-(3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 43) tert-butyl (3-(6-benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H )- yl)phenyl)carbamate (b) To a mixture of ethyl 3-phenylpropanoate (2.22 g, 12.5 mmol) in NMP (40 mL) was added 60% NaH (0.5 g, 12.5 mmol) at 0 ^o C. After addition, tert-butyl (3-((5-formyl-2- (methylthio)pyrimidin-4-yl)amino)phenyl)carbamate in NMP (10 mL) was added. The resulting mixture was stirred at 60 ^o C for 3h. The mixture was diluted with brine (250 mL), and the aqueous phase was extracted with EtOAc (70 mL × 3). The combined organic phase was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petrol ether / ethyl acetate = 2/1-1/1) to afford compound (d) as yellow solid (600 mg, 15% isolated yield). LCMS (m/z): 475 [M+H] ⁺ . tert-butyl (3-(6-benzyl-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)- yl)phenyl)carbamate (c) To a solution of tert-butyl (3-(6-benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (600 mg, 1.27 mmol) in DCM (20 mL) was added m-CPBA (1.1 g, 6.32 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (c) as yellow solid (540 mg, 84% isolated yield). LCMS (m/z): 507 [M+18] ⁺ . tert-butyl (3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7-oxopyrido [2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (d) To a solution of N-(6-morpholinopyridin-3-yl)acetamide (131 mg, 0.59 mmol) in DMF (5 mL) was added 60% NaH (28.4 mg, 0.71 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(6-benzyl-2-(methylsulfonyl)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (200 mg, 0.39 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (d) as white solid (167 mg, 70% isolated yield). LCMS (m/z): 606 [M+H] ⁺ . 8-(3-aminophenyl)-6-benzyl-2-((6-morpholinopyridin-3-yl)amin o)pyrido[2,3-d]pyrimidin- 7(8H)-one (e) To a solution of tert-butyl (3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (167 mg, 0.27 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to afford compound (e) as light yellow solid (139 mg, crude), which used directly for the next step. LCMS (m/z): 506 [M+H] ⁺ . N-(3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7-oxopyri do[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide (compound 43) To a solution of crude 8-(3-aminophenyl)-6-benzyl-2-((6-morpholinopyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (139 mg, 0.27 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (36 mg, 0.41 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to afford compound 43 as yellow solid (15.4 mg, 10 % isolated yield for two steps). LCMS (m/z): 560 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.85 (s, 1H), 8.72 (s, 1H), 8.05 (s, 1H), 7.865 (d, J = 6.4 Hz, 1H), 7.66 (s, 1H), 7.59 – 7.52 (m, 3H), 7.33 (m, 4H), 7.21 (t, J = 4.4 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.46 – 6.22 (m, 3H), 5.78 – 5.76 (m, 1H), 3.84 (s, 2H), 3.69 – 3.64 (m, 1H), 3.26 – 3.21 (m, 4H). Example 44. Synthesis of N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 44) tert-butyl (3-(2-(methylthio)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin-8(7 H)- yl)phenyl)carbamate (b) To a solution of tert-butyl (3-(2-(methylthio)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (150 mg, 0.315 mmol) in DCM (10 mL) was added m-CPBA (271 mg, 1.575 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (b) as yellow oil (14 mg, 88% isolated yield). LCMS (m/z): 510.1 [M+18] ⁺ . tert-butyl (3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-phe noxypyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (c) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (72 mg, 0.412 mmol) in DMF (5 mL) was added NaH (23 mg, 0.412 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (140 mg, 0.275 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (c) as white solid (130 mg, 84% isolated yield). LCMS (m/z): 561.1 [M+H] ⁺ . 8-(3-aminophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amin o)-6-phenoxypyrido[2,3- d]pyrimidin-7(8H)-one (d) To a solution of tert-butyl (3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (130 mg, 0.232 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to afford compound (d) as light yellow solid (105 mg, crude), which used directly for the next step. LCMS (m/z): 460.9 [M+H] ⁺ . N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7-oxo-6-p henoxypyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 44) To a solution of crude 8-(3-aminophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-6-phenoxypyrido[2,3-d]pyrimidin-7(8H)-one (105 mg, 0.228 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (24.3mg, 0.27 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep- HPLC to afford compound 44 as white solid (20 mg, 14.1 % isolated yield for two steps). LCMS (m/z): 514 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 9.47 (s, 1H), 8.79 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.65 – 7.61 (m, 2H), 7.40 – 7.37 (m, 2H), 7.14 – 7.11 (m, 4H), 6.83 (s, 1H), 6.47-6.41 (m, 1H), 6.28-6.25 (m, 1H), 5.79-5.77 (m, 1H), 3.49 (s, 3H). Example 45. Synthesis of N-(3-(6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)- 7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 45) tert-butyl (3-(6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7- oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (b) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (105 mg, 0.592 mmol) in DMF (5 mL) was added NaH (27 mg, 0.592 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(6-benzyl-2-((6- morpholinopyridin-3-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8( 7H)-yl)phenyl)carbamate (200 mg, 0.395 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (b) as white solid (95 mg, 43% isolated yield). LCMS (m/z): 558 [M+H] ⁺ . 8-(3-aminophenyl)-6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol- 4-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one (c) To a solution of tert-butyl (3-(6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (95 mg, 0.17 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to afford compound (c) as light yellow solid (79 mg, crude), which used directly for the next step. LCMS (m/z): 458 [M+H] ⁺ . N-(3-(6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)- 7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 45) To a solution of crude 8-(3-aminophenyl)-6-benzyl-2-((3-chloro-1-methyl-1H-pyrazol- 4- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (79 mg, 0.17 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (23 mg, 0.255 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to afford compound 45 as white solid (20 mg, 22.7 % isolated yield for two steps). LCMS (m/z): 514.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H), 9.46 (s, 1H), 8.76 (s, 1H), 8.76 (s, 1H), 7.84 (s, 1H), 7.82 – 7.61 (m, 3H), 7.33 (m, 4H), 7.25 – 7.22 (m, 1H), 7.08 (m, 1H), 6.82 (m, 1H), 6.28-6.27 (m, 1H), 6.24-6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.84 (s, 2H), 3.48 (s, 3H). Example 46. Synthesis of N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 46) 4-(6-methoxy-5-nitropyridin-2-yl)morpholine (b) To a solution of 6-chloro-2-methoxy-3-nitropyridine (2 g, 10.638 mmol) in CH ₃ CN (20 mL) was added morpholine (1.85 g, 21.276 mmol) and K ₂ CO ₃ (2.93 g, 21.276 mmol). The reaction mixture was stirred at 80 ^o C for 16 hours After cooled down to room temperature the mixture was concentrated under reduced pressure and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford compound (b) (2 g, 80% isolated yield). LCMS (m/z): 240.2 [M+H] ⁺ . 2-methoxy-6-morpholinopyridin-3-amine (c) To a solution of 4-(6-methoxy-5-nitropyridin-2-yl)morpholine (2 g, 8.368 mmol) in MeOH (50 mL) was added Pd/C (500 mg). The resulting mixture was stirred at room temperature for 4 hour under H ₂ . and then filtered concentrated to afford compound (c) as light yellow solid (79 mg, crude), which used directly for the next step. LCMS (m/z): 210.2 [M+H] ⁺ . N-(2-methoxy-6-morpholinopyridin-3-yl)acetamide (intermediate C) To a solution of 2-methoxy-6-morpholinopyridin-3-amine (1.5 g, 8.368 mmol) and Et ₃ N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford intermediate C as white solid (0.9 g, 50% isolated yield). tert-butyl (3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-oxo-6-ph enylpyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (e) To a solution of N-(4-methoxy-6-morpholinopyridin-3-yl)acetamide (153 mg, 0.609 mmol) in DMF (5 mL) was added NaH (28 mg, 0.609 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(2-(methylsulfonyl)-7-oxo- 6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (200 mg, 0.406 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (e) as white solid (200 mg, 80% isolated yield). LCMS (m/z): 622.7 [M+H] ⁺ . 8-(3-aminophenyl)-2-((2-methoxy-6-morpholinopyridin-3-yl)ami no)-6-phenylpyrido[2,3- d]pyrimidin-7(8H)-one (f) To a solution of tert-butyl (3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (200 mg, 0.322 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to give compound (f) as light yellow solid (167 mg, crude), which used directly for the next step. LCMS (m/z): 522.6 [M+H] ⁺ . N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenylpyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 46) To a solution of crude 8-(3-aminophenyl)-2-((2-methoxy-6-morpholinopyridin-3- yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (79 mg, 0.322 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (33 mg, 0.385 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to afford compound 46 as white solid (24 mg, 13 % isolated yield for two steps). LCMS (m/z): 576 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.64 (s, 1H), 7.51 – 7.36 (m, 5H), 7.07 (d, J = 8.8 Hz, 1H), 6.48-6.41 (m, 1H), 6.28-6.24 (m, 1H), 5.79-5.76 (m, 2H), 3.80 (s, 3H), 3.71-3.69 (m, 4H), 3.33- 3.31 (m, 4H).

Example 47. Synthesis of N-(5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-morpholinopyridin-3-yl)acrylamide (compound 47) 2-morpholino-5-nitronicotinic acid (b) A solution of 2-chloro-5-nitronicotinic acid (5.0 g, 24.8 mmol), morpholine (3.23 g, 37.2 mmol), DIPEA (6.38 g, 49.6 mmol) in CH ₃ CN (60.0 mL) was stirred for 12 hour at 80 °C. LCMS showed the reaction was completed. The mixture was concentrated and the resiude was washed with ether (30 mL*3) to afford compound (b) as a yellow solid (5.0 g, 79% isolated yield). LCMS (m/z): 254 [M+H] ⁺ . tert-butyl (2-morpholino-5-nitropyridin-3-yl)carbamate (c) To a solution of 2-morpholino-5-nitronicotinic acid (3.0 g, 11.8 mmol), TEA (2.38 g, 23.6 mmol) in t-BuOH (20 mL) and toluene (30 mL) was added DPPA (4.2 g, 15.34 mmol). The reaction mixture was stirred at 100 °C for 12 hours under Ar atmosphere. LCMS showed the reaction was completed. The mixture was concentrated and the resiude was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (c) as a yellow solid (0.38 g, 10% yield). LCMS (m/z): 325 [M+H] ⁺ . tert-butyl (5-amino-2-morpholinopyridin-3-yl)carbamate (d) A mixture of tert-butyl (2-morpholino-5-nitropyridin-3-yl)carbamate (0.38 g, 2.34 mmol), 10% Pd/C (0.19 g, cat.) in ethyl acetate (30 mL) was stirred at room temperature for 12 hours under H ₂ atmosphere. LCMS showed the reaction was completed. The mixture was filtered and concentrated to give the crude compound (d) as an light yellow oil (0.34 g, 99% yield). LCMS (m/z): 295[M+H] ⁺ . tert-butyl (5-acetamido-2-morpholinopyridin-3-yl)carbamate (e) To a solution of tert-butyl (5-amino-2-morpholinopyridin-3-yl)carbamate (0.34 g, 1.15 mmol) and Et ₃ N (0.35 g, 3.45 mmol) in DCM (20 mL) was added a solution of AcCl (0.14 g, 1.73 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (e) as brown oil (0.33 g, 85% isolated yield). LCMS (m/z): 337 [M+H] ⁺ . 8-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H) -one (g) To a solution of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (5 g, 27.3 mmol) in NMP (100 mL) was added K ₂ CO ₃ (7.5 g, 54.6 mmol) and ethyl 2-phenoxyacetate (6.72 g, 40.95 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (500 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 2/1-1/1) to afford compound (g) as yellow solid (3.86 g, 50% isolated yield). LCMS (m/z): 284 [M+H] ⁺ . 8-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7 (8H)-one (h) To a solution of 8-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H) -one (3.86 g, 13.6 mmol) in DCM (60 mL) was added m-CPBA (11.7 g, 68 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (150 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (150 mL), water (150 mL), saturated aqueous NaHCO ₃ solution (150 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (h) as yellow oil (2.1 g, 50% isolated yield). LCMS (m/z): 334 [M+18] ⁺ . tert-butyl (5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimid in-2-yl)amino)-2- morpholinopyridin-3-yl)carbamate (i) To a solution of tert-butyl (5-acetamido-2-morpholinopyridin-3-yl)carbamate (336 mg, 1.0 mmol) in DMF (5 mL) was added NaH (48 mg, 1.2 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added 8-methyl-2-(methylsulfonyl)-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one (210 mg, 0.67 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (l) as light yellow solid (106 mg, 30% isolated yield). LCMS (m/z): 530 [M+H] ⁺ . 2-((5-amino-6-morpholinopyridin-3-yl)amino)-8-methyl-6-pheny lpyrido[2,3-d]pyrimidin- 7(8H)-one (j) To a solution of tert-butyl (5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-morpholinopyridin-3-yl)carbamate (106 mg, 0.2 mmol) in DCM (5 mL) was added TFA (2.0 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to afford compound (m) as light yellow solid (86 mg, crude), which used directly for the next step. LCMS (m/z): 430 [M+H] ⁺ . N-(5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrim idin-2-yl)amino)-2- morpholinopyridin-3-yl)acrylamide (compound 47) To a solution of crude 2-((5-amino-6-morpholinopyridin-3-yl)amino)-8-methyl-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one (86 mg, 0.2 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (27 mg, 0.3 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to afford compound 47 as white solid (14.1 mg, 14.5% isolated yield for two steps). LCMS (m/z): 484 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.46 – 7.37 (m, 3H), 6.72-6.67 (m, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.4Hz, 1H), 3.80 (m, 4H), 3.69 (s, 3H), 3.02 (m, 4H).

Example 48. Synthesis of N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 48) N-(6-fluoropyridin-3-yl)acetamide (b) To a solution of 6-fluoropyridin-3-amine (1.0 g, 8.93 mmol) and Et ₃ N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 ^o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 50/1-20/1) to afford compound (b) as white solid (1.2 g, 87% isolated yield). LCMS (m/z): 155.1 [M+H] ⁺ . N-(6-morpholinopyridin-3-yl)acetamide (d) To a solution of N-(6-fluoropyridin-3-yl)acetamide (1.1 g, 7.14 mmol) in DMSO (20 mL) was added morpholine (1.24 g, 14.3 mmol) and K ₂ CO ₃ (1.97 g, 14.3 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (d) as pale solid (700 mg, 44% isolated yield). LCMS (m/z): 222.2 [M+H] ⁺ . ethyl 2-phenoxyacetate (h) To a solution of phenol (1.88 g, 20.0 mmol) in acetone (40 mL) was added K ₂ CO ₃ (5.52 g, 40.0 mmol) and ethyl 2-bromoacetate (3.99 g, 24.1 mmol), the mixture was refluxed for 4 hours and filtered, the filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1) to afford compound (h) as colorless oil (14.2 g, 97% purity, 68% isolated yield). LCMS (m/z): 181.2 [M+H] ⁺ . tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carb amate (k) To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (4.0 g, 21.3 mmol) in DMF (50 mL) was added Et ₃ N (4.30 g, 42.6 mmol) and tert-butyl (3-aminophenyl)carbamate (6.64 g, 32.0 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (100 mL), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 4/1-2/1) to afford compound (k) as yellow solid (3.0 g, 39% isolated yield). LCMS (m/z): 361.1 [M+H] ⁺ . tert-butyl (3-(2-(methylthio)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin-8(7 H)- yl)phenyl)carbamate (l) To a solution of 4 tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (1.5 g, 4.17 mmol) in NMP (20 mL) was added K ₂ CO ₃ (1.15 g, 8.33 mmol) and ethyl 2-phenoxyacetate (1.12 g, 6.25 mmol). The reaction mixture was stirred at 100 ^o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (40 mL × 3). The combined organic phase was washed with water (40 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 2/1-1/1) to afford compound (l) as pale solid (780 mg, 39% isolated yield). LCMS (m/z): 477.1 [M+H] ⁺ . tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin -8(7H)- yl)phenyl)carbamate (m) To a solution of tert-butyl (3-(2-(methylthio)-7-oxo-6-phenoxypyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (780 mg, 1.64 mmol) in DCM (20 mL) was added m-CPBA (995 mg, 4.92 mmol) at 0 ^o C, the reaction mixture was stirred at room temperature for 16 hours, and then diluted with DCM (40 mL). The organic phase was washed with saturated aqueous NaHSO ₃ solution (50 mL), water (50 mL), saturated aqueous NaHCO ₃ solution (50 mL× 2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with petroleum ether / EtOAc = 1/1-1/2) to afford compound (m) as yellow solid (750 mg, 90% isolated yield). LCMS (m/z): 526.1 [M+18] ⁺ . tert-butyl (3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenoxypyrid o[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (n) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-4-yl)acetamide (163 mg, 0.74 mmol) in DMF (5 mL) was added NaH (30 mg, 0.74 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 0.5 hour, and then added tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (250 mg, 0.49 mmol). The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL).The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (80 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with DCM / MeOH = 20/1-10/1) to afford compound (n) as white solid (80 mg, 27% isolated yield). LCMS (m/z): 560.1 [M+H] ⁺ . 8-(3-aminophenyl)-2-((6-morpholinopyridin-3-yl)amino)-6-phen oxypyrido[2,3-d]pyrimidin- 7(8H)-one (o) To a solution of tert-butyl (3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 ^o C. The resulting mixture was stirred at room temperature overnight, and then concentrated to compound o as light yellow solid (80 mg, crude), which used directly for the next step. LCMS (m/z): 496.1 [M+H] ⁺ . N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6-phenoxypyr ido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide (compound 48) To a solution of crude 8-(3-aminophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-6-(2,4-difluorophenoxy)pyrido[2,3-d]pyrimidin-7(8H )-one (80 mg, 0.13 mmol) in DCM (5 mL) and NaHCO ₃ solution (5%, 3 mL) was added a solution of acryloyl chloride (14 mg, 0.16 mmol) in DCM (1 mL) drop-wisely at 0 ^o C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and DCM (20 mL). The organic phase was separated and concentrated under reduced pressure, the crude product was purified by Prep- HPLC to afford compound 48 as yellow solid (50 mg, 68 % isolated yield for two steps). LCMS (m/z): 562.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 9.86 (s, 1H), 8.75 (s, 1H), 8.08 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.73 – 7.48 (m, 4H), 7.41 – 7.35 (m, 2H), 7.17 – 7.03 (m, 4H), 6.50 – 6.20 (m, 3H), 5.82 – 5.72 (m, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.30 – 3.25 (m, 4H). Example 49. Biological Assays Proliferation inhibition assays: Cell growth inhibition was assessed by MTS assay for Ba/F3, DFCI58-229, and DFCI127c cells, or by Cell Titer Glo (CTG) Luminescent Cell viability assay (Promega®) for DFCI362JC cells. 3000 Ba/F3 cells were seeded for per well in 96-well plates, and were exposed to representative compounds of the disclosure (3.3 nM to 10 µM) for 72 hours. For DFCI58-229, DFCI127c, and DFCI362JC cells, 5000 cells were seeded per well. All experimental points included 6 to 12 wells. Data were normalized to untreated cells and displayed graphically using GraphPad Prism (GraphPad Software, Inc.). The growth curves were fitted using a nonlinear regression model with sigmoidal dose response. Western blot analysis: Cells were plated at 5x10 ⁵ cells per well in 6-well plates and treated with representative compounds of the disclosure the following day. After 6 hours of treatment, cells were washed with PBS and lysed with NP40 buffer (Calbiochem®) supplemented with Complete ^TM Mini protease inhibitor and PhosSTOP ^TM phosphatase inhibitors (Roche®). Lysates were separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the following antibodies: phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), and HSP90 (SC- 7947) (Santa Cruz Biotechnology®). Example 50. Assessing the activity of representative compounds in inhibiting EGFR and HER2 Activities of representative compounds of the present disclosure in inhibiting EGFR and HER2 were tested by MTS assay (for Ba/F3 cell, DFCI58-229 cell, and DFCI127c cells) or by CellTiter-Glo® luminescent cell viability assay (for DFCI362JC cells). For assays with Ba/F3 cells, 3000 cells were seeded for per well in 96-well plates and were exposed to indicated compounds with a concentration of 3.3 to 10 µM for 72 hours. For assays with DFCI58-229 cell, DFCI127c cell, or DFCI362JC cell, 5000 cells were seeded per well in 96-well plates and were exposed to indicated compounds with a concentration of 3.3 to 10 µM for 72 hours. Western blot analysis was then performed on the cells. The cells were plated at 5x10 ⁵ cells per well in 6-well plates and treated with the indicated concentrations of the compound. After 6 hours of treatment, cells were washed with PBS and lysed with NP40 buffer (Calbiochem) supplemented with Complete Mini protease inhibitor and PhosSTOP phosphatase inhibitors (Roche). Lysates were then separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the following antibodies: phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), and HSP90 (SC-7947) (Santa Cruz Biotechnology). Activities of representative compounds of the present disclosure in inhibiting EGFR were tested by CellTiter-Glo® luminescent cell viability assay. Briefly, 1000 cells were seeded for per well in 384-well plates and were exposed to indicated compounds with concentrations of 3-fold series dilution from 10 μM for 72 hours. Activities of representative compounds of the present disclosure in inhibiting EGFR and HER2 were tested by CellTiter-Glo® luminescent cell viability assay. Briefly, 1000 cells were seeded for per well in 384-well plates and were exposed to indicated compounds with concentrations of 3-fold series dilution from 10 μM for 72 hours. The chemical structure of the compound referred to herein as “DDC-02-085” or “DDC- 02-85” can be found in WO2019046775A1 on page 62, as compound 29. The chemical structure of the compound referred to herein as TAK-788 may also be referred to herein as mobocertinib. Activities of representative compounds of the present disclosure are shown in Tables 3- 10. Table 3 shows IC ₅₀ values in proliferation inhibition assays against wild-type or insertion mutants EGFRs transformed Ba/F3 cells (A = over 1000 nM; B = 600 to 1000 nM; C = 200 to 600 nM; D = below 200 nM). Table 4 shows IC ₅₀ values in proliferation inhibition assays against wild-type or insertion mutants HER2s transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). Table 5 shows IC ₅₀ values in proliferation inhibition assays against wild-type or insertion mutants EGFRs transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM) for various compounds of the disclosure. Table 6 shows IC ₅₀ values in proliferation inhibition assays of compound 35, compound 43, compound 44, compound 45, compound 46, compound 47, DDC-02-85, and TAK-788 against A431, wild-type EGFR, or insertion mutant EGFRs/HER2s transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). Table 7 shows IC ₅₀ values in cell viability assays of DDC-02-85, TAK-788, Osimertinib, compound 41, compound 48, compound 36, compound 31, compound 33, compound 40, PS-III- 100, and PS-III-108 against A431 cell lines (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). Table 8 shows IC ₅₀ values in cell viability assays of compound 14, Osimertinib, and TAK-788 against insertion mutant EGFRs/HER2s transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). Table 9 shows IC ₅₀ values in cell viability assays of compound 48, compound 31, Osimertinib, and TAK-788 against insertion mutant EGFRs/HER2s transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). Table 10 shows IC ₅₀ values in cell viability assays of compound 41, compound 42, DDC-02- 085, and TAK-788 against A431, wild-type EGFR, and insertion mutant EGFRs/HER2s transformed Ba/F3 cells (A = over 500 nM; B = 250 to 500 nM; C = 100 to 250 nM; D = below 100 nM).

EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.