Erbb / BTK inhibitors

Abstract

To provide: compounds inhibiting ErbBs (e.g., EGFR or Her 2), especially mutant forms of ErbBs, and BTK; pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof; and pharmaceutical compositions comprising the compounds.SOLUTION: The invention provides compounds represented by the formula (I), pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to compounds that inhibit ErbBs (e.g., EGFR or Her2), particularly mutant forms of ErbBs, and / or inhibit Bruton's tyrosine kinase (BTK). The disclosure also relates to pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and the use of the compounds in the manufacture of a medicament for treating disorders associated with mutant forms of ErbBs (e.g., EGFR or Her2) and / or BTK. [Background technology]

[0002] ErbB family receptor tyrosine kinases act to transduce signals from the outside of the cell to the inside by activating secondary messaging effectors through phosphorylation events at their tyrosine-phosphorylated residues. These signals regulate diverse cellular processes, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. Deregulation of ErbB family signaling modulates proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and may be associated with many human cancers, including lung, head and neck, and breast cancer. Detailed reviews of ErbB receptor signaling and its involvement in tumorigenesis are provided in New England Journal of Medicine, 2008, Vol. 358: 1160-74 and Biochemical and Biophysical Research Communications, 2004, Vol. 319:1-11.

[0003] EGFR has been found to be overexpressed and / or mutated in many cancers, such as gliomas and non-small cell lung cancer. Currently, anticancer drugs targeting EGFR are clinically available, including gefitinib (IRESSAT®), erlotinib (TARCEVA®), lapatinib (TYKERB®, TYVERB®), panitumumab (VECTIBIX), cetuximab (ERBITUX), osimertinib (TAGRISSO, AZD9291), and afatinib (GIOTRIF). Drug-resistant mutations at residue T790M in EGFR have been detected in the majority of patients who relapse, and in at least half of those with clinical resistance. Furthermore, the T790M mutation may be pre-existing; for example, there are patients with the L858R / T790M mutation who have never received gefitinib treatment, and the association of germline EGFR T790M mutations with certain familial lung cancers suggests that the T790M mutation may have an independent, phenotypic role. Current drugs in development, including second-generation covalent inhibitors such as BIBW2992, HKI-272, and PF-0299804, are effective against T790M mutations resistant to existing drugs but exhibit dose-limiting toxicities due to simultaneous inhibition of wild-type (WT) EGFR. More than 60% of NSCL patients treated with gefitinib or erlotinib also report side effects such as skin rash and diarrhea, which are thought to be related to inhibition of the wild-type EGFR signaling pathway in normal skin and intestinal cells (Zhou CC et al. Journal of Clinical Oncology, 2011, Vol. 12: 735-42; Mok TS et al. New England Journal of Medicine, 2009, Vol. 361: 947-57).

[0004] EGFR exon 20 insertions have been found in approximately 4-9.2% of EGFR-mutated lung cancers (Mitsudomin and Yatabe FEBS J., 2010; 277 (2):301-8), and the majority of these occur in the region encoding amino acids 767-774 of exon 20, located within the loop following the C-helix of the EGFR kinase domain (Yasuda et al. Lancet Oncol., 2012; 13(1): e23-31). Lung cancer patients harboring typical EGFR exon 20 insertion mutations have been reported to be unresponsive to gefitinib, erlotinib, or afatinib (Yasuda et al. Lancet Oncol., 2012, 13(1): e23-31; Yasuda et al. Sci Transl Med., 2013, 5 (216):216ra177).

[0005] Overexpression of Her2 can occur in breast cancer, ovarian cancer, bladder cancer, non-small cell lung cancer, and several other tumor types. Clinically available anticancer drugs targeting Her2 include trastuzumab (also known as Herceptin). Although two-thirds of breast cancer patients respond well to Herceptin, some Her2-positive breast cancer patients do not respond to this drug. These non-responders may harbor drug-resistance mutations in Her2. Approximately 2-4% of non-smoking non-small cell lung cancer patients also harbor a four-amino acid YVMA insertion mutation at codon 775 of Her2 exon 20. Patients with this Her2 YVMA mutation were generally resistant to known EGFR inhibitors (Arcila et al. Clin Cancer Res., 2012, 18:4910-4918).

[0006] Bruton's tyrosine kinase (BTK) is a member of the src-related Tec family of cytoplasmic tyrosine kinases. It is predominantly expressed in B cells and distributed throughout the lymphoid, hematopoietic, and hematopoietic systems. BTK plays a critical role in the B cell receptor signaling pathway in B cells, which is required for B cell development, activation, and survival. Therefore, BTK inhibitors have been developed to treat B cell malignancies that depend on BCR signaling, such as chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), and diffuse large B cell lymphoma (DLBCL). BTK has also been implicated in promoting Toll-like receptor signaling, which regulates macrophage activation and the production of pro-inflammatory cytokines. Several studies have demonstrated crosstalk between the BTK signaling pathway and TLR signaling pathways, mediating the transactivation of downstream cascades. BTK has also been found to play an important role in immune regulation. BTK has become an attractive target not only for the treatment of B-cell malignancies but also for the treatment of autoimmune diseases (see Ping et al., Oncotarget, 2017, 8(24): 39218-39229). Currently, ibrutinib [CLL] Anticancer drugs targeting BTK are clinically available, including [[Bio-Rad, an irreversible small molecule BTK inhibitor approved for the treatment of mantle cell lymphoma (MCL) and Waldenström macroglobulinemia (WM)].

[0007] Thus, there remains a need to develop new ErbB (particularly EGFR or Her2) inhibitors that have better selectivity for EGFR mutants over WT (wild-type) EGFR or better selectivity for Her2 mutants over wild-type Her2. There also remains a need to develop new BTK inhibitors. Summary of the Invention

[0008] In one aspect, the present disclosure provides a compound of formula (I):

[0009] [ka]

[0010] or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof. In another aspect, the disclosure provides pharmaceutical compositions comprising one or more compounds of formula (I), pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof.

[0011] In another aspect, the present disclosure further provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or one or more pharmaceutical compositions of the foregoing, for use as a medicament for inhibiting ErbB, preferably EGFR or HER2, more preferably inhibiting one or more mutant forms of EGFR or HER2.

[0012] In yet another aspect, the present disclosure provides the use of a compound of formula (I), a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or one or more pharmaceutical compositions thereof, in the manufacture of a medicament for inhibiting one or more mutant forms of ErbB, preferably EGFR or HER2, more preferably EGFR or HER2, in a subject.

[0013] In another aspect, the present disclosure provides methods for inhibiting one or more mutant forms of ErbB, preferably EGFR or HER2, more preferably EGFR or HER2, by using one or more compounds of formula (I), pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, or one or more pharmaceutical compositions of the above.

[0014] In another aspect, the present disclosure provides methods for treating ErbB-associated disorders (e.g., cancer) by using a compound of formula (I), a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or one or more pharmaceutical compositions of the above.

[0015] In a further aspect, the disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, in combination with a second therapeutic agent, preferably an anti-tumor agent.

[0016] In another aspect, the present disclosure provides a combination of a compound of formula (I), a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, and a second therapeutic agent, preferably an anti-tumor agent. DETAILED DESCRIPTION OF THE INVENTION

[0017] compound In one aspect, the present disclosure provides a compound of formula (I):

[0018] [ka]

[0019] [In the formula, A1 is N or CR8; A2, A3, A4, and A5 are each independently N or CR9, where no more than one of A2, A3, A4, and A5 is N; R1 and R2 are each independently hydrogen, halogen, hydroxyl, -NR a R b , C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, 3- to 10-membered saturated or unsaturated heterocyclyl (wherein C 1-12 Alkyl, C 1-12 Each of the alkoxy, the 3- to 10-membered saturated or unsaturated carbocyclyl, and the 3- to 10-membered saturated or unsaturated heterocyclyl may be unsubstituted or unsubstituted. 1-12C, which may be mono- or polysubstituted by one or more of the following alkyl groups: 1-12 alkyl {where R a and R b are each independently hydrogen or C 1-12 Alkyl (which can contain deuterium, tritium, halogen, hydroxyl, or C 1-12 or R a and R b together with the nitrogen atom to which they are attached, are halogen, hydroxyl, or C 1-12 forming a 3- to 10-membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl; Alternatively, R1 and R2, together with the nitrogen atom to which they are attached, may form a 3-12 membered monocyclic or polycyclic ring which may contain one or more additional heteroatoms selected from N, O, and S (which may include halogen, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, -NR a R b , or -C 1-12 Alkyl-NR a R b which may be mono- or independently polysubstituted by R3 is H, C 1-12 Alkyl or -C 1-12 Alkyl-NR a R b and; R4 and R5 are each independently deuterium, tritium, halogen, hydroxyl, or C 1-12 Alkyl or C 1-12 C may be mono- or polysubstituted independently by one or more of alkoxy 1-6 is alkyl, Alternatively, R4 and R5, together with the carbon atoms to which they are attached, may form a 3-10 membered monocyclic or polycyclic ring which may contain one or more heteroatoms selected from N, O, and S (which may include deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C1-12 and forming a substituted or unsubstituted alkyl group, which may be mono- or polysubstituted independently with one or more of alkoxy; R6 is hydrogen or deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 C, which may be mono- or independently polysubstituted by alkoxy; 1-12 is alkyl, R7 is hydrogen or a C group which may be mono- or polysubstituted by deuterium, tritium, halogen, or hydroxyl. 1-12 is alkyl, R8 is hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 alkyl); R9 is null, hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl or C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 alkyl); n is 0, 1, 2, 3, or 4; Each R is independently hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, or 3- to 10-membered saturated or unsaturated heterocyclyl fused to the ring to which it is attached (which may be fused with deuterium, tritium, halogen, or C 1-12 or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof.

[0020] In some embodiments, A1 in formula (I) is N. In some embodiments, A1 in formula (I) is N. A1 is CR8, where R8 is hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 In some embodiments, A1 in formula (I) is CH.

[0021] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, have the formula (Ia):

[0022] [ka]

[0023] [In the formula, A2, A3, A4, and A5 are each independently N or CR9, where no more than one of A2, A3, A4, and A5 is N; R1 and R2 are each independently hydrogen, halogen, hydroxyl, -NR a R b , C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, 3- to 10-membered saturated or unsaturated heterocyclyl (wherein C 1-12 Alkyl, C 1-12 Each of the alkoxy, the 3- to 10-membered saturated or unsaturated carbocyclyl, and the 3- to 10-membered saturated or unsaturated heterocyclyl may be unsubstituted or unsubstituted. 1-12 C, which may be mono- or polysubstituted by one or more of the following alkyl groups: 1-12 alkyl {where R a and R b are each independently hydrogen or C 1-12 Alkyl (which can contain deuterium, tritium, halogen, hydroxyl, or C 1-12 or Ra and R b together with the nitrogen atom to which they are attached, are halogen, hydroxyl, or C 1-12 forming a 3- to 10-membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl; Alternatively, R1 and R2, together with the nitrogen atom to which they are attached, may form a 3-12 membered monocyclic or polycyclic ring which may contain one or more additional heteroatoms selected from N, O, and S (which may include halogen, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, -NR a R b , or -C 1-12 Alkyl-NR a R b which may be mono- or independently polysubstituted by R3 is H, C 1-12 Alkyl or -C 1-12 Alkyl-NR a R b and; R4 and R5 are each independently deuterium, tritium, halogen, hydroxyl, or C 1-12 Alkyl or C 1-12 C may be mono- or polysubstituted independently by one or more of alkoxy 1-6 is alkyl, Alternatively, R4 and R5, together with the carbon atoms to which they are attached, may form a 3-10 membered monocyclic or polycyclic ring which may contain one or more heteroatoms selected from N, O, and S (which may include deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 and forming a substituted or unsubstituted alkyl group, which may be mono- or polysubstituted independently with one or more of alkoxy; R6 is hydrogen or deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 C, which may be mono- or independently polysubstituted by alkoxy; 1-12 is alkyl, R7 is hydrogen or a C group which may be mono- or polysubstituted by deuterium, tritium, halogen, or hydroxyl. 1-12 is alkyl, R9 is null, hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl or C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 alkyl); n is 0, 1, 2, 3, or 4; Each R is independently hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, or 3- to 10-membered saturated or unsaturated heterocyclyl fused to the ring to which it is attached (which may be fused with deuterium, tritium, halogen, or C 1-12 The alkyl group may be mono- or polysubstituted independently with one or more of alkyl.

[0024] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, have the formula (Ib):

[0025] [ka]

[0026] [In the formula, A2, A3, A4, and A5 are each independently N or CR9, where no more than one of A2, A3, A4, and A5 is N; R1 and R2 are each independently hydrogen, halogen, hydroxyl, -NR a R b , C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, 3- to 10-membered saturated or unsaturated heterocyclyl (wherein C1-12 Alkyl, C 1-12 Each of the alkoxy, the 3- to 10-membered saturated or unsaturated carbocyclyl, and the 3- to 10-membered saturated or unsaturated heterocyclyl may be unsubstituted or unsubstituted. 1-12 C, which may be mono- or polysubstituted by one or more of the following alkyl groups: 1-12 alkyl {where R a and R b are each independently hydrogen or C 1-12 Alkyl (which can contain deuterium, tritium, halogen, hydroxyl, or C 1-12 or R a and R b together with the nitrogen atom to which they are attached, are halogen, hydroxyl, or C 1-12 forming a 3- to 10-membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl; Alternatively, R1 and R2 together with the nitrogen atom to which they are attached may form a 3- to 12-membered monocyclic or polycyclic ring which may contain one or more additional heteroatoms selected from N, O, and S. Cyclic rings (which can contain halogens, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, -NR a R b , or -C 1-12 Alkyl-NR a R b which may be mono- or independently polysubstituted by R3 is H, C 1-12 Alkyl or -C 1-12 Alkyl-NR a R b and; R4 and R5 are each independently deuterium, tritium, halogen, hydroxyl, or C 1-12 Alkyl or C 1-12 C may be mono- or polysubstituted independently by one or more of alkoxy 1-6 is alkyl, Alternatively, R4 and R5, together with the carbon atoms to which they are attached, may form a 3-10 membered monocyclic or polycyclic ring which may contain one or more heteroatoms selected from N, O, and S (which may include deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 and forming a substituted or unsubstituted alkyl group, which may be mono- or polysubstituted independently with one or more of alkoxy; R6 is hydrogen or deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 C, which may be mono- or independently polysubstituted by alkoxy; 1-12 is alkyl, R7 is hydrogen or a C group which may be mono- or polysubstituted by deuterium, tritium, halogen, or hydroxyl. 1-12 is alkyl, R8 is hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 alkyl); R9 is null, hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl or C 1-12 Alkoxyl (these are alkoxylated with deuterium, tritium, halogen, or C 1-12 alkyl); n is 0, 1, 2, 3, or 4; Each R is independently hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, or 3- to 10-membered saturated or unsaturated heterocyclyl fused to the ring to which it is attached (which may be fused with deuterium, tritium, halogen, or C 1-12The alkyl group may be mono- or polysubstituted independently with one or more of alkyl.

[0027] In some embodiments, one of A2, A3, A4, and A5 in Formula (I), Formula (Ia), or Formula (Ib) is N, and the rest are each independently CR9. In some embodiments, A2, A3, A4, and A5 in Formula (I), Formula (Ia), or Formula (Ib) are each independently CR9. In some embodiments, when A2, A3, A4, or A5 in Formula (I), Formula (Ia), or Formula (Ib) is CR9 further substituted by R, then R9 is absent.

[0028] In some embodiments, n is 2, A2 and A5 are CH, and A3 and A4 are each independently CH further substituted with R, and R is independently halogen. In some embodiments, R and R in Formula (I), Formula (Ia), or Formula (Ib) are each independently a halogen, a hydroxyl, or -NR a R b , C 1-12 Alkyl, C 1-12 Substituted or unsubstituted C which may be mono- or polysubstituted independently by one or more of alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, and 3- to 10-membered saturated or unsaturated heterocyclyl; 1-12 alkyl, where C 1-12 Alkyl, C 1-12 Each of the alkoxy, the 3- to 10-membered saturated or unsaturated carbocyclyl, and the 3- to 10-membered saturated or unsaturated heterocyclyl may be unsubstituted or unsubstituted. 1-12 may be mono- or polysubstituted by alkyl; where R a and R b are each independently hydrogen, deuterium, tritium, halogen, hydroxyl, or C 1-12 It may be mono- or polysubstituted independently by alkoxy. Good C 1-12 selected from alkyl, or R a and R btogether with the nitrogen atom to which they are attached, are halogen, hydroxyl, or C 1-12 It forms a 3- to 10-membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl.

[0029] In some embodiments, R1 and R2 in Formula (I), Formula (Ia), or Formula (Ib) together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic or polycyclic ring which may contain one or more additional heteroatoms selected from N, O, and S, which may contain halogen, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, -NR a R b , or -C 1-12 Alkyl-NR a R b may be mono- or independently polysubstituted by where R a and R b are each independently hydrogen, deuterium, tritium, halogen, hydroxyl, or C 1-12 C, which may be mono- or independently polysubstituted by alkoxy; 1-12 selected from alkyl, or R a and R b together with the nitrogen atom to which they are attached, are halogen, hydroxyl, or C 1-12 It forms a 3-10 membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl.

[0030] In some embodiments, R1 and R2 in Formula (I), Formula (Ia), or Formula (Ib) are each independently:

[0031] [ka]

[0032] These are selected from deuterium, tritium, halogen, hydroxyl, C 1-12 Alkoxy or C1-12 may be mono- or polysubstituted independently by alkyl, where C 1-12 The alkyl may be mono- or polysubstituted independently with deuterium, tritium, halogen, or hydroxyl.

[0033] In some embodiments, R1 and R2 in Formula (I), Formula (Ia), or Formula (Ib) are each independently:

[0034] [ka]

[0035] is selected from. In some embodiments, R1 and R2 in Formula (I), Formula (Ia), or Formula (Ib), together with the nitrogen atom to which they are attached, are:

[0036] [ka]

[0037] and forming a 3- to 12-membered monocyclic or polycyclic ring selected from the group consisting of halogen, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, -NR a R b , or -C 1-12 Alkyl-NR a R b may be mono-substituted or independently poly-substituted by:

[0038] In some embodiments, R1 and R2 in Formula (I), Formula (Ia), or Formula (Ib), together with the nitrogen atom to which they are attached, are:

[0039] [ka]

[0040] Form. In some embodiments, R and R in Formula (I), Formula (Ia), or Formula (Ib) are each independently deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 substituted or unsubstituted C, which may be mono- or polysubstituted independently by one or more of alkoxy; 1-6 In some embodiments, R and R in Formula (I), Formula (Ia), or Formula (Ib) are each independently an unsubstituted C 1-6 It is alkyl.

[0041] In some embodiments, R4 and R5 in Formula (I), Formula (Ia), or Formula (Ib) together with the carbon atoms to which they are attached form a 3-10 membered monocyclic or polycyclic ring which may contain one or more heteroatoms selected from N, O, and S, which may contain deuterium, tritium, halogen, hydroxyl, C 1-12 Alkyl or C 1-12 It may be mono- or polysubstituted independently with one or more of the alkoxy.

[0042] In some embodiments, R6 in Formula (I), Formula (Ia), or Formula (Ib) is hydrogen, deuterium, or tritium. In some embodiments, R7 in Formula (I), Formula (Ia), or Formula (Ib) is methyl, difluoromethyl, or trifluoromethyl.

[0043] Exemplary compounds 1 to 98 of formula (I) are shown in Table 1 below. Table 1. Exemplary Compounds 1 to 98

[0044] [Table 1-1]

[0045] [Table 1-2]

[0046] [Table 1-3]

[0047] Table 1-4

[0048] Table 1-5

[0049] Table 1-6

[0050] Table 1-7

[0051] Table 1-8

[0052] Table 1-9

[0053] Table 1-10

[0054] Table 1-11

[0055] Table 1-12

[0056] Table 1-13

[0057] Table 1-14

[0058] Table 1-15

[0059] Table 1-16

[0060] Table 1-17

[0061] Table 1-18

[0062] Table 1-19

[0063] Table 1-20

[0064] Table 1-21

[0065] Table 1-22

[0066] Table 1-23

[0067] [Table 1-24]

[0068] [Table 1-25]

[0069] It will be understood that certain features of the disclosure that are, for clarity, described in the context of separate embodiments, may also be provided together in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in a single context, may also be provided separately or in any suitable subcombination.

[0070] At various places in this disclosure, linking substituents are described. When a linking group is clearly required for the structure, a Markush variable is listed for that group. s) is understood to mean multiple linking groups. For example, if the structure requires a linking group, If "alkyl" appears in a Markush group definition for that variable, it is understood to represent the linking alkylene group.

[0071] As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms removed and replaced by a substituent. As used herein, the term "substituent" has its ordinary meaning known in the art to mean a chemical moiety that is covalently attached to or optionally fused to a parent group. As used herein, the terms "optionally substituted" or "optionally ... substituted" The term means that the chemical group may have no substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted), with the understanding that substitution at a given atom is limited by valence.

[0072] As used herein, "C i-j " refers to a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer between them, where the set of i includes {1, 2, 3, 4, 5, 6, 7, 8, 9, or 10}, and j is greater than i, and the set of j includes {2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40}. For example, C 1-6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.

[0073] As used herein, the term "alkyl," whether used as part of another term or independently, refers to a saturated or unsaturated hydrocarbon chain, the latter of which may be further subdivided into hydrocarbon chains having at least one double or triple bond (alkenyl or alkynyl). The hydrocarbon chains referred to above may be straight or branched. "C i-jThe term "alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

[0074] As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine. As used herein, the term "cyano" refers to a group of the formula: --CN.

[0075] As used herein, the term "hydroxyl" means a group of the formula: --OH. As used herein, the term "alkoxy," whether used as part of another term or independently, refers to a group of the formula: -O-alkyl. i-j The term "alkoxy" means the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkyl portion has 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and alkoxy groups. oxy), t-butoxy, etc.

[0076] As used herein, the term "carbocyclyl," whether used as part of another term or independently, refers to any ring in which all ring atoms are carbon and which contains at least three ring-forming carbon atoms. In some embodiments, a carbocyclyl can contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, or 4 to 8 ring-forming carbon atoms. A carbocyclyl group can be saturated or partially unsaturated. In some embodiments, a carbocyclyl group can be a saturated cyclic alkyl group. In some embodiments, a carbocyclyl group can be an unsaturated cyclic alkyl group containing at least one double bond in its ring system. In some embodiments, an unsaturated carbocyclyl group can contain one or more aromatic rings.

[0077] Carbocyclyl groups can contain monocyclic or polycyclic ring(s) (e.g., having 2, 3, or 4 fused, bridged, or spiro rings). Examples of monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like. As used herein, the term "spirocycle" refers to a ring system in which two rings are connected through only one common atom; the term "fused ring" refers to a ring system in which two rings share two adjacent atoms; and the term "bridged ring" refers to a ring system in which two rings share three or more atoms. Examples of spirocarbocyclyls include, but are not limited to, spiro[5.5]undecane, spiro-pentadiene, spiro[3.6]-decane, and the like. Examples of fused carbocyclyls include, but are not limited to, naphthalene, benzopyrene, anthracene, acenaphthene, fluorene, etc. Examples of bridged carbocyclyls include, but are not limited to, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, bicyclo[3.3.3]undecane, etc.

[0078] As used herein, the term "heterocyclyl" refers to a carbocyclyl group in which one or more (e.g., 1, 2, or 3) ring atoms are replaced by a heteroatom, including, but not limited to, oxygen, sulfur, nitrogen, phosphorus, etc. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the unsaturated heterocyclyl group can contain one or more aromatic rings.

[0079] Heterocyclyl groups can contain monocyclic or polycyclic ring(s) (e.g., having 2, 3, or 4 fused, bridged, or spiro rings). Exemplary monocyclic heterocyclyl groups include, but are not limited to, pyrrolidyl, tetrahydrofuran, piperidyl, piperazinyl, morpholinyl, and the like. Examples of spiroheterocyclyls include, but are not limited to, spiropyran, spirooxazine, and the like. Examples of fused heterocyclyls include, but are not limited to, quinoline, isoquinoline, quinolizine, quinazoline, pteridine, chromene, isochromene, indole, isoindole, indolizine, indazole, purine, benzofuran, isobenzofuran, benzimidazole, benzothienyl, carbazole, phenazine, phenothiazine, phenanthridine groups, and the like. Examples of bridged heterocyclyls include, but are not limited to, morphan, hexamethylenetetramine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0080] As used herein, the term "i- to j-membered" refers to a carbocyclyl or heterocyclyl group having i- to j-ring atoms. For example, a "3- to 10-membered carbocyclyl" refers to a carbocyclyl group having 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) ring members; a "3- to 10-membered heterocyclyl" refers to a carbocyclyl group having 3 to 10 (e.g., 3, "Carbocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, or 10 ring members. In some embodiments, the carbocyclyl or heterocyclyl group is 3 to 10, 3 to 8, 3 to 6, or 4 to 6 membered. For example, piperidinyl is an example of a 6-membered heterocyclyl, pyrazolyl is an example of a 5-membered heterocyclyl, pyridyl is an example of a 6-membered heterocyclyl, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered carbocyclyl.

[0081] As used herein, the term "aromatic group" or "aromatic ring" refers to a monocyclic or polycyclic carbocyclyl or heterocyclyl moiety having alternating double and single bonds between ring-forming atoms in at least one ring. In some embodiments, the aromatic ring has 5 to 12, 5 to 10, 5 to 8, 6 to 12, 6 to 10, or 6 to 8 ring-forming atoms (i.e., 5 to 12, 5 to 10, 5 to 8, 6 to 12, 6 to 10, or 6 to 8 members). Examples of carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. In some embodiments, heterocyclic aromatic groups are 5- or 6-membered. Exemplary 5-membered heteroaromatic groups are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc. Exemplary 6-membered heteroaromatic groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0082] "Compounds" of the present disclosure are intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted, unless otherwise specified. The term "stereoisomer" refers to any of the various stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of asymmetric compounds (e.g., compounds having one or more asymmetrically substituted carbon atoms—"chiral centers"). Compounds of the present disclosure containing chiral centers can be isolated in optically active forms (enantiomers and diastereomers) or optically inactive forms (racemates). The term "enantiomer" includes pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture." The terms "diastereomer" or "diastereoisomer" include stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Certain compounds containing one or more chiral centers may give rise to enantiomers, diastereomers, or other stereoisomeric forms, which may be defined with respect to absolute configuration as (R)- or (S)- at each chiral center according to the Cahn-Ingold-Prelog ranking rules. Resolved compounds whose absolute configuration is unknown can be designated at the asymmetric center using the term "or." Methods on how to prepare optically active forms from racemic mixtures are known in the art, such as resolution by HPLC or stereoselective synthesis.

[0083] "Geometric isomers" or "cis and trans isomers" refer to compounds with the same formula but whose functional groups are rotated into different orientations in three-dimensional space. The term "tautomers" includes prototropic tautomers, which are compounds with isomeric protonation states having the same formula and total charge. Prototropic tautomers Examples of tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which one proton can occupy more than one position on a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers may be in equilibrium or sterically constrained to one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form may also have other tautomeric forms unless otherwise specified. It is contemplated that molds are also included.

[0084] The "compounds" of the present disclosure are intended to include all isotopes of atoms in the compound. Isotopes of atoms include atoms with the same atomic number but different mass numbers. For example, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the "compounds" of the present disclosure: 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I, and 131 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes protium, deuterium, and tritium. 12 C and 13 Contains C.

[0085] It should also be understood that the "compounds" of the present disclosure can exist in solvated, e.g., hydrated, solid forms as well as unsolvated forms, and that the present disclosure is intended to include all such solvated and unsolvated forms.

[0086] It is further understood that the "compounds" of the present disclosure can exist in the form of pharmaceutically acceptable salts or esters. As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable compounds, substances, compositions, and / or dosage forms refer to those approved by a regulatory authority (such as the U.S. Food and Drug Administration, the Chinese Food and Drug Administration, or the European Medicines Agency) or listed in a generally recognized pharmacopoeia (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia) for use in animals, more particularly humans.

[0087] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic (e.g., carboxyl, etc.) or basic (e.g., amine, alkali, etc.) moiety into its salt form. In many cases, the disclosed compounds are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Thus, "pharmaceutically acceptable salts" typically include acid addition salts or base addition salts that retain the biological effectiveness and properties of the parent compound, which are not biologically or otherwise undesirable.

[0088] As used herein, "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo and breaks down readily in the human body to leave the parent compound or its derivatives. These esters include those that release salts. Such esters can act as prodrugs as defined herein. Esters can be formed with amine, hydroxy, or carboxyl side chains on the compounds described herein. For example, if a disclosed compound contains an alcohol functional group, an ester can be formed by replacing the hydrogen atom of the alcohol group with an acidic group, including, but not limited to, carboxylic acid, phosphoric acid, phosphinic acid, sulfinic acid, sulfonic acid, and boronic acid groups. Procedures and specific groups for making such esters are well known to those skilled in the art and can be readily found in reference sources such as Greene and Wuts, "Protective Groups in Organic Synthesis," 3rd Edition, John Wiley & Sons, New York, NY (1999), which is incorporated herein by reference in its entirety.

[0089] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, salts of compounds derived from inorganic acids such as Included are acid addition salts that can be derived from organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, napadisilic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.). In some embodiments, a pharmaceutically acceptable salt of a compound of the present disclosure is a formic acid salt. In some embodiments, a pharmaceutically acceptable salt of a compound of the present disclosure is a TFA salt. Suitable pharmaceutically acceptable salts of the compounds of the present disclosure also include, for example, base addition salts that can be derived from inorganic bases (e.g., sodium, potassium, ammonium salts, and hydroxides, carbonates, bicarbonates of metals from columns I-XII of the periodic table, such as calcium, magnesium, iron, silver, zinc, copper, etc.) or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc.). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, Examples of suitable salts include lysine, meglumine, piperazine, and tromethamine. Those skilled in the art will recognize that additional acids or bases may be capable of forming acid / base addition salts other than those shown in the examples. See, for example, "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, PA (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth, Wiley-VCH, Wiley-VCH. A list of additional suitable salts can be found in Inheim, Germany (2002).

[0090] The present disclosure also includes active intermediates, active metabolites, and prodrugs of the compounds of the present disclosure. As used herein, "active intermediate" means an intermediate compound in a synthetic process that exhibits the same or essentially the same biological activity as the final synthetic compound.

[0091] As used herein, "active metabolite" refers to a breakdown product or end-product of a compound of the present disclosure, or a salt or prodrug thereof, produced by metabolism or biotransformation in an animal or human body, that exhibits the same or essentially the same biological activity as the specified compound. Such metabolic products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound or its salt or prodrug.

[0092] As used herein, "prodrug" refers to a compound or conjugate that releases the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modification is cleaved to the parent compound either in routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, or carboxyl group is attached to a group that, when administered to a mammalian subject, cleaves to produce the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present disclosure. The preparation and use of prodrugs are described in detail in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," vol. 1, no. 1, pp. 111-114, 1997, both of which are incorporated herein by reference in their entireties. "Pro-drugs as Novel Delivery Systems" ACS Symposium Series, Volume 14 and "Bioreversible Carriers in Drug Design" This is discussed in "Patient Design" edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (1987).

[0093] Unless otherwise specified, "ErbB" or "wild-type ErbB" refers to a normal ErbB phagocytosis. In one aspect, the present disclosure provides compounds that inhibit ErbB family kinases (e.g., EGFR, Her2, Her3, and / or Her4). In some embodiments, the compounds of the present disclosure can inhibit both wild-type (WT) and mutant forms of ErbB family kinases. In some embodiments, the compounds of the present disclosure are selective inhibitors of at least one mutation of an ErbB family kinase compared to the corresponding wild-type ErbB family kinase. As used herein, the term "mutation" refers to any mutation to an ErbB protein, and "mutant" or "mutant form" refers to a protein containing said mutation. Exemplary ErbB mutations include, but are not limited to, L858R, T790M, G719S, G719X, delE746-A750, A763_Y764insFQEA, V769_D770insASV, H773_V774insNPH, etc. in EGFR, and exon20insYVMA in Her2. In some embodiments, compounds of the present disclosure are selective inhibitors of at least one mutation in EGFR compared to wild-type EGFR. In some embodiments, compounds of the present disclosure are selective inhibitors of at least one mutation in Her2 compared to wild-type Her2. In some embodiments, the at least one mutation in EGFR is a point mutation (e.g., L858R, T790M). In some embodiments, the at least one mutation in EGFR is a deletion mutation (e.g., delE746-A750). In some embodiments, at least one mutation in EGFR is an insertion mutation (e.g., EGFR exon 20V769_D770insASV, exon 20H773_V774insNPH). In some embodiments, at least one mutation in EGFR is an activating mutation (e.g., L858R, G719S, or delE746-A750). In some embodiments, at least one mutation in EGFR is a drug resistance mutation (e.g., exon 20_T790M). In some embodiments, at least one mutation in EGFR is T790M. In some embodiments, provided compounds selectively inhibit T790M / L858R co-mutations and are sparing with respect to wild-type EGFR inhibition.

[0094] As used herein, the term "selectively inhibits," when used in comparison to inhibition of wild-type EGFR / Her2, means that a provided compound is a more potent inhibitor of at least one mutation of EGFR / Her2 (i.e., at least one point mutation, at least one deletion mutation, at least one insertion mutation, at least one activating mutation, at least one resistance mutation, or a combination of at least one deletion mutation and at least one point mutation) in at least one assay (e.g., a biochemical assay or a cellular assay) described herein. In some embodiments, the term "selectively inhibit" when used in comparison to the inhibition of wild-type EGFR means that provided compounds are at least 100-fold, at least 50-fold, at least 45-fold, at least 40-fold, at least 35-fold, at least 30-fold, at least 25-fold, at least 20-fold, at least 15-fold, at least 10-fold, at least 5-fold, at least 4-fold, at least 3-fold, at least 2-fold, at least 1.5-fold, or at least 1.25-fold more potent as inhibitors of at least one mutation of EGFR, as defined and described herein, than wild-type EGFR. In some embodiments, the term "selectively inhibits" when used in comparison to the inhibition of wild-type EGFR means that the provided compounds are up to 1500-fold, up to 1200-fold, up to 1000-fold, up to 800-fold, up to 600-fold, up to 400-fold, up to 200-fold, up to 100-fold, up to 50-fold, or up to 10-fold more potent than wild-type EGFR as inhibitors of at least one mutation of EGFR, as defined and described herein. As used herein, the term "modest with respect to wild-type EGFR" means that the selective inhibitor of at least one mutation of EGFR, as defined above and described herein, cannot inhibit wild-type EGFR within the upper limit of detection in at least one assay as described herein (e.g., a biochemical assay or a cellular assay, as described in detail in the Examples). In some embodiments, the term "modest with respect to wild-type EGFR" means that the provided compounds are at least IC of at least 10 μM, at least 9 μM, at least 8 μM, at least 7 μM, at least 6 μM, at least 5 μM, at least 3 μM, at least 2 μM, or at least 1 μM 50 This means that wild-type EGFR is inhibited.

[0095] In some embodiments, compounds of the present disclosure inhibit phosphorylation of wild-type EGFR and / or EGFR mutants with an IC50 of 0.1 to 1000 nM, preferably 0.1 to 600 nM, 1 to 600 nM, 0.1 to 500 nM, 1 to 500 nM, 0.1 to 400 nM, 1 to 400 nM, 0.1 to 300 nM, 1 to 300 nM, 0.1 to 200 nM, 1 to 200 nM, 0.1 to 100 nM, 1 to 100 nM, 0.1 to 80 nM, 0.1 to 50 nM, 0.1 to 40 nM, 0.1 to 30 nM, 0.1 to 20 nM, 0.1 to 10 nM, or 0.1 to 5 nM, more preferably 0.1 to 20 nM, 0.1 to 10 nM, or 0.1 to 5 nM. 50 Inhibit by value.

[0096] In some embodiments, compounds of the present disclosure inhibit phosphorylation of wild-type Her2 and / or Her2 mutants with an IC50 of 0.1 to 1000 nM, preferably 0.1 to 600 nM, 1 to 600 nM, 0.1 to 500 nM, 1 to 500 nM, 0.1 to 400 nM, 1 to 400 nM, 0.1 to 300 nM, 1 to 300 nM, 0.1 to 200 nM, 1 to 200 nM, 0.1 to 100 nM, 1 to 100 nM, 0.1 to 80 nM, 0.1 to 50 nM, 0.1 to 40 nM, 0.1 to 30 nM, 0.1 to 20 nM, 0.1 to 10 nM, or 0.1 to 5 nM, more preferably 0.1 to 20 nM, 0.1 to 10 nM, or 0.1 to 5 nM. 50 Inhibit by value.

[0097] In some embodiments, compounds of the present disclosure inhibit proliferation of wild-type EGFR and / or EGFR mutant-bearing cells at a GI of 1 to 1000 nM, preferably 1 to 800 nM, 1 to 600 nM, 1 to 500 nM, 1 to 400 nM, 1 to 300 nM, 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM, more preferably 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM. 50 Inhibit by value.

[0098] In some embodiments, compounds of the present disclosure inhibit proliferation of wild-type Her2 and / or Her2 mutant-bearing cells with a GI of 1 to 1000 nM, preferably 1 to 800 nM, 1 to 600 nM, 1 to 500 nM, 1 to 400 nM, 1 to 300 nM, 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM, more preferably 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM. 50 Inhibit by value.

[0099] In some embodiments, compounds of the present disclosure inhibit proliferation of BTK-bearing cells at a GI of 1 to 1000 nM, 1000 nM or more, 2000 nM or more, or 3000 nM or more, preferably 1 to 800 nM, 1 to 600 nM, 1 to 500 nM, 1 to 400 nM, 1 to 300 nM, 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM, more preferably 1 to 300 nM, 1 to 200 nM, 1 to 100 nM, 1 to 80 nM, 1 to 60 nM, 1 to 40 nM, 1 to 20 nM, or 1 to 10 nM. 50 Inhibit by value.

[0100] In some embodiments, the IC of the compound against EGFR mutants 50 and / or G.I. 50 is the IC of the compound against wild-type EGFR 50 and / or G.I. 50at least 2-fold, 3-fold, 4-fold, 5-fold, preferably 10-fold, 20-fold, 30-fold, 50-fold, or 100-fold higher than

[0101] Synthesis method The synthesis of compounds provided herein (including salts, esters, hydrates, solvates, or stereoisomers thereof) is illustrated in the synthetic schemes in the Examples. Because compounds provided herein can be prepared using known organic synthesis techniques and synthesized according to any of numerous possible synthetic routes, these schemes are merely illustrative and do not limit other possible methods that can be used to prepare compounds provided herein. Additionally, the steps in the schemes are provided for better illustration and can be modified as appropriate. Compound embodiments in the Examples were synthesized in China for research purposes and potential regulatory submissions.

[0102] The reaction for producing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Those skilled in the art can select a suitable solvent for a particular reaction step depending on the particular reaction step.

[0103] Preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, New York (1999), which is incorporated herein by reference in its entirety. It is possible.

[0104] Reactions can be monitored according to any suitable method known in the art, for example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 Product formation can be followed by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-visible), mass spectroscopy, or by chromatographic techniques such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Those skilled in the art will appreciate that high performance liquid chromatography (HPLC) (see "Preparative LC-MS Purification: Improved Compounds specific Method Optimization," incorporated herein by reference in its entirety) can be used to monitor the formation of a compound. The compounds can be purified by a variety of methods, including cyclohexane-coated silica gel (Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883) and normal phase silica chromatography.

[0105] Abbreviations as used herein are defined as follows: "1x" or "x1" means one time, "2x" or "x2" means two times, "3x" or "x3" means three times, "4x" or "x4" means four times, "5x" or "x5" means five times, "°C" means degrees Celsius, "eq" or "eq." means equivalent(s), "g" means gram(s), "mg" means milligram(s), "L" means liter(s), "mL" or "ml" means milliliter(s), "μL" is microliter(s), "N" is normal concentration, "M" is molar concentration, "mmol" is millimole(s), "min" is minute(s), "h" or "hr" is hour(s), "rt" or "rt" is room temperature, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrated, "sat" or "sat'd" is saturated, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RP" is reversed phase, "TLC or "tlc" is thin layer chromatography, "SM" is starting material, "NMR" is nuclear magnetic resonance spectroscopy, 1 "H" stands for proton, "δ" stands for delta, "s" stands for singlet, and "d" stands for "t" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, and "Hz" is Hertz. "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to those skilled in the art.

[0106] Listed below are abbreviations for chemicals used in the synthesis of compounds provided herein:

[0107] [Table 2-1]

[0108] [Table 2-2]

[0109] [Table 2-3]

[0110] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises more than one compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure and a pharmaceutically acceptable carrier.

[0111] Pharmaceutically acceptable carriers are pharmaceutical carriers commonly used in the art and can be prepared in a manner well known in the pharmaceutical art. In some embodiments, the compounds of the present disclosure can be mixed with pharmaceutically acceptable carriers to prepare pharmaceutical compositions.

[0112] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a compound provided herein from one site, body fluid, tissue, organ (internal or external), or body part to another site, body fluid, tissue, organ, or body part. A pharmaceutically acceptable carrier is one that is capable of carrying or transporting a compound provided herein without undue toxicity or side effects. The pharmaceutically acceptable carrier may be a vehicle, diluent, excipient, or other substance that can be used to contact animal tissue without contacting the tissue. Exemplary pharmaceutically acceptable carriers include sugars, starch, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginic acid, isotonic saline, buffers, and the like. Pharmaceutically acceptable carriers that can be utilized in this disclosure include those generally known in the art, such as those disclosed in "Remington's Pharmaceutical Sciences," Mack Publishing Company, NJ (1991), incorporated herein by reference.

[0113] Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) propylene glycol. (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-depyrogenated water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols such as ethyl alcohol and propane alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0114] Pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, etc., e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

[0115] The form of the pharmaceutical composition depends on several criteria, including but not limited to the route of administration, the extent of the disease, or the dose to be administered. The pharmaceutical composition can be formulated for oral, nasal, rectal, subcutaneous, intravenous, or intramuscular administration. Depending on the desired route of administration, the pharmaceutical composition can be formulated in the form of tablets, capsules, pills, dragees, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories.

[0116] Pharmaceutical compositions can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by utilizing techniques known in the art. In some embodiments, the pharmaceutical composition is formulated in an extended-release form. As used herein, the term "extended-release" refers to release of an active agent from a pharmaceutical composition primarily in the gastrointestinal tract of a subject over an extended period (extended release) or at a specific site (controlled release), such that bioabsorption occurs in the subject. In some embodiments, the extended period can be about 1 hour to 24 hours, 2 hours to 12 hours, 3 hours to 8 hours, 4 hours to 6 hours, 1 to 2 days, or longer. In some embodiments, the extended period is at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours. The pharmaceutical composition can be formulated in tablet form. For example, the release rate of the active agent can be controlled not only by dissolution of the active agent in gastrointestinal fluids and subsequent diffusion from the tablet or pill, which is pH-independent, but can also be affected by the physical processes of tablet disintegration and erosion. In some embodiments, polymeric materials can be used for sustained release, such as those disclosed in "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Press, Boca Raton, FL (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NY (1984); Langer and Peppas (1983), J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, See also J. Neurosurg. 71:105. The above references are incorporated herein by reference in their entireties.

[0117] In one embodiment, the pharmaceutical composition comprises about 0.0001 mg to about 5000 mg (e.g., about 0.0001 mg to about 10 mg, about 0.001 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, about 1 mg to about 10 mg, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg to about 40 mg, about 5 mg to about 50 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 300 mg, about 50 mg to about 500 mg) of a compound of the present disclosure. about 400 mg, about 50 mg to about 500 mg, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 500 mg to about 1000 mg, about 600 mg to about 1000 mg, about 700 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, about 1000 mg to about 2000 mg, about 2000 mg to about 3000 mg, about 3000 mg to about 4000 mg, or about 4000 mg to about 5000 mg). A suitable daily dose per subject may be about 5 mg to about 500 mg, preferably about 5 mg to about 50 mg, about 50 mg to about 100 mg, or about 50 mg to about 500 mg.

[0118] In certain embodiments, the pharmaceutical compositions may be formulated in unit dosage form, each dosage form containing from about 0.0001 mg to about 10 mg, from about 0.001 mg to about 10 mg, from about 0.01 mg to about 10 mg, from about 0.1 mg to about 10 mg, from about 1 mg to about 10 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 30 mg, from about 5 mg to about 40 mg, from about 5 mg to about 50 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 300 mg, from about 50 mg to about Contains 400mg, about 50mg to about 500mg, about 100mg to about 200mg, about 100mg to about 300mg, about 100mg to about 400mg, about 100mg to about 500mg, about 200mg to about 500mg, about 300mg to about 500mg, about 400mg to about 500mg, about 500mg to about 1000mg, about 600mg to about 1000mg, about 700mg to about 1000mg, about 800mg to about 1000mg, about 900mg to about 1000mg, about 1000mg to about 2000mg, about 2000mg to about 3000mg, about 3000mg to about 4000mg, or about 4000mg to about 5000mg. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary administration to a human subject or other mammal, each unit containing a predetermined amount of an active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical carrier. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure as a first active ingredient and further comprises a second active ingredient. The second active ingredient can be an anti-cancer agent known in the art, such as a cell signaling inhibitor, a cell signaling inhibitor, an alkylating agent, a topoisomerase inhibitor, an immunotherapeutic agent, a mitotic inhibitor, an antihormonal agent, a chemotherapeutic agent, an EGFR inhibitor, a BTK inhibitor, a CTLA-4 inhibitor, a MEK inhibitor, a PD-L1 inhibitor, an OX40 agonist, etc.Representative examples of anti-cancer agents for treating cancer or tumors include, but are not limited to, sorafenib, sunitinib, dasatinib, vorinostat, temsirolimus, everolimus, pazopanib, trastuzumab, ado-trastuzumab, emtansine, pertuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, tremelimumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, crizotinib, These may include ruxolitinib, paclitaxel, vincristine, vinblastine, cisplatin, carboplatin, gemcitabine, tamoxifen, raloxifene, cyclophosphamide, clomadulin, carmustine, methotrexate, fluorouracil, actinomycin, doxorubicin, epirubicin, anthracyclines, bleomycin, mitomycin-C, irinotecan, topotecan, teniposide, interleukins, interferons, etc. In some embodiments, the second active agent is bevacizumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, or the like. One or more of the following: izumab, avelumab, durvalumab, or crizotinib.

[0119] Treatment methods The present disclosure provides methods for treating diseases associated with ErbB (including, for example, EGFR or Her2), particularly ErbB mutations, comprising administering to a subject an effective amount of one or more compounds of the present disclosure, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition.

[0120] The present disclosure also provides methods for treating a BTK-associated disease. In certain embodiments, the methods include administering to a subject an effective amount of one or more compounds of the present disclosure, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition.

[0121] As used herein, the term "ErbB-associated disease" or "ErbB-related disorder" refers to a disorder whose onset or development, or both, is associated with ErbB expression or activity. Examples include, but are not limited to, immune-related disorders, proliferative disorders, cancer, and other disorders.

[0122] As used herein, the terms "EGFR-associated disease" or "EGFR-associated disease" or "Her2-associated disease" or "Her2-associated disease" refer to diseases whose onset or development, or both, are associated with genomic alterations, expression, or activity of EGFR or Her2, as the case may be. Examples include, but are not limited to, immune-related diseases, proliferative disorders, cancer, and other diseases.

[0123] As used herein, the terms "BTK-associated disease" or "BTK-related disease" refer to diseases whose onset or development, or both, as the case may be, are associated with genomic alterations, expression, or activity of BTK. In certain embodiments, BTK-associated diseases include oncological diseases and autoimmune diseases. Oncological diseases include, but are not limited to, lymphoma and leukemia. Autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome.

[0124] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or arresting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, a therapeutic agent may be administered after one or more symptoms have manifested. In other embodiments, a therapeutic agent may be administered in the absence of symptoms. For example, a susceptible individual may be administered a therapeutic agent prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0125] In some embodiments, one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are administered parenterally or non-parenterally. In some embodiments, the one or more compounds, their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are administered orally, enterally, bucally, nasally, intranasally, transmucosally, epidurally, transdermally, cutaneously, ophthalmologically, pulmonary, sublingually, rectally, vaginally, topically, subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcuticularly, intraarticularly, subcapsularly, subarachnoidally, intraspinally, or intrasternally.

[0126] The compounds provided herein can be administered in pure form, in combination with other active ingredients, or in the form of a pharmaceutical composition of the present disclosure. In some embodiments, the compounds provided herein are administered to a subject in need thereof in combination with one or more anti-cancer agents (e.g., anti-cancer drugs) known in the art. In some embodiments, the administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0127] In some embodiments, one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are orally administered. For oral administration, any dose that achieves the desired purpose is appropriate. In some embodiments, a suitable daily dose is between about 0.001 and 5000 mg, preferably between 0.1 mg and 5 g, more preferably between 5 mg and 1 g, and more preferably between 10 mg and 500 mg, administered once daily, twice daily, three times daily, every other day, or 3 to 5 days per week. In some embodiments, the dosage of one or more compounds provided herein, pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, or pharmaceutical compositions ranges from about 0.0001 mg, preferably 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 2000 mg, 3000 mg, 4000 mg, or up to about 5000 mg per day.

[0128] Use of the compound In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with ErbB (e.g., EGFR, Her2, Her3, or Her4). In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with an ErbB mutant. In some embodiments, the ErbB mutant is an EGFR mutant. In some embodiments, the ErbB mutant is a Her2 mutant. In certain embodiments, the ErbB-related disease is an ErbB mutant-related disease, including cancer.

[0129] In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with BTK. In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with BTK. In certain embodiments, the disease associated with BTK includes cancer.

[0130] In particular, cancers include, but are not limited to, leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenocarcinoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, gastric cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal carcinoma, or oral cancer. In some embodiments, the cancer is lung cancer, breast cancer, ovarian cancer, bladder cancer, or glioblastoma. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, adenocarcinoma, squamous cell lung cancer, and large cell lung cancer). In some embodiments, the cancer is metastatic lung cancer. In some embodiments, the cancer is one with one or more ErbB mutations (eg, EGFR or Her2 point mutations, deletion mutations, insertion mutations, activating mutations, or drug resistance mutations).

[0131] The compounds and pharmaceutical compositions thereof disclosed herein can be used to prevent or treat the onset or development of any ErbB / BTK-associated disease or condition (expression or activity) in mammals, particularly humans. In some embodiments, the compounds and pharmaceutical compositions disclosed herein can prevent or treat the onset or development of any ErbB / BTK-associated disease or condition in mammals, particularly humans. It can be used for the prevention or treatment of diseases or development.

[0132] In this context, the present disclosure also provides methods for screening patients suitable for treatment with the compounds or pharmaceutical compositions of the present disclosure, alone or in combination with other ingredients (e.g., a second active ingredient, e.g., an anti-cancer agent), including sequencing a tumor sample from the patient to detect accumulation of ErbB (e.g., EGFR or Her2) or BTK in the patient, or to detect the mutational status of ErbB (e.g., EGFR or Her2) or BTK in the patient. [Example]

[0133] The general method of the present disclosure will be further described below.The compounds of the present disclosure can be prepared by methods known in the art.The following illustrates the detailed preparation methods of the preferred compounds of the present disclosure.However, they do not limit the preparation methods of the compounds of the present disclosure in any way.

[0134] Synthesis Examples The structures of the compounds in the following examples are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS ) and the NMR shifts (δ) were 10 -6 The units are shown in ppm. 1 H-NMR spectra were obtained using an ICON-NMR (under TopSpin program control) or a Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (under VnmrJ program control). A Bruker AVANCE NMR (400 MHz) spectrometer was used, recordings were made in dimethylsulfoxide-d6 (DMSO-d6) or CDCl3 or CD3OD or D2O (from Aldrich or Cambridge Isotope Lab.) with tetramethylsilane as the internal standard.

[0135] MS measurements were performed using a Shimadzu 2010 mass spectrometer or an Agilent 6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical, and electron impact ionization techniques from various instruments.

[0136] High performance liquid chromatography (HPLC) measurements were performed using an Ultimate XB-C18 column (3.0*50mm, 3μm or 3.0*150mm, 3μm), an Xbridge shield RP18 column (5μm, 50mm*2.1mm), or an Xtimate C18 column (3μm, 2.1*30mm). Shimadzu LC-20A system or Shimadzu LC-2010HT series, Agilent 1200 LC or Agilent 1100 series, using a column such as a MERCK RP18 (2.5-2 mm), or an Agilent Zorbax Eclipse Plus C18 column (4.6 mm*150 mm, 5 μm). I went there with my friend.

[0137] Thin-layer chromatography (TLC) was performed using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates. The silica gel plates used for separating and purifying the products by TLC were 0.4 mm to 0.5 mm.

[0138] The purified chromatography columns used silica gel (100-200, 200-300, or 300-400 mesh, manufactured by Yantai Huanghais Co., Ltd. or Anhui Liang Chen Gui Yuan Co., Ltd., etc.) as a carrier, or flash columns (silica-CS flash columns 40-60 μm, or reversed-phase C18 columns 20-35 μm, manufactured by Agela Technologies, etc.) or flash columns silica-CS (40-60 μm) or C18 columns (20-40 μm) (manufacturer: Agela Technologies) as a carrier. For use in flash or Biotage flash systems. Column dimensions are The amount was adjusted according to the amount of the mixture.

[0139] Known starting materials of the present disclosure can be synthesized using or according to methods known in the art or can be purchased from suppliers such as Alfa Aesar, Langcaster, TCI, Aldrich, Bepharm, and others. It can be purchased from Scochem (or PharmaBlock, Bide, Amatek, Stru Chem, Firster Pharmaceutical, Titan (Adamas), etc.).

[0140] Unless otherwise specified, all reactions in the examples were carried out under an argon or nitrogen atmosphere. By argon or nitrogen atmosphere, we mean that the reaction flask was connected to an argon or nitrogen balloon of approximately 1 L capacity. Hydrogenations were typically carried out under pressure. Unless otherwise specified, reaction temperatures in the examples were ambient, between 20°C and 30°C.

[0141] The reaction progress in the examples was monitored by TLC. The eluent systems used in the reactions included dichloromethane-methanol and petroleum ether-ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0142] The eluent systems for column chromatography and TLC used to purify the compounds include dichloromethane-methanol and petroleum ether-ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds. A small amount of alkaline or acidic agent (0.1%-1%), such as formic acid, acetic acid, TFA, or ammonia, can be added for adjustment.

[0143] Example 1 (R)-N-(2-(3-(dimethylamino)piperidin-1-yl)-5-(4-(2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0144] [ka]

[0145] Preparation of Compound 1b: To a solution of compound 1a (25 g, 1.0 equiv., 133.59 mmol) in THF (250 mL) was added CHMgBr (222.65 mL, 5.0 equiv., 667.95 mmol) in an ice-water bath at 0-5°C. The resulting black mixture was stirred at 26-36°C for 2 h. TLC (petroleum ether / EtOAc = 5 / 1 (v / v)) showed that the starting material (R f =0.70) was consumed. The reaction mixture was diluted with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (2x300 mL). The combined organic layers were concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether / EtOAc=10 / 1 (v / v)) gave compound 1b (22 g, 88% yield) as a yellow oil.

[0146] LCMS: R t = 0.678 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 169.9 [M+H-18] + . 1 H NMR (400MHz, MeOH-d4) δ 6.97 (dd, J=8.9, 12.7 Hz, 1H), 6.52 (dd, J=7.3, 12.8 Hz, 1H), 1.57 (s, 6H). Preparation of compound 1c: To a solution of compound 1b (1 g, 5.3 mmol) and DIEA (1 g, 7.9 mmol) in CHCl (10 mL) was added 2,4-dichloro-1,3,5-triazine (0.96 g, 6.4 mmol). The mixture was stirred at 26–34 °C for 12 h. The reaction was directly purified by column chromatography on silica gel (20% EtOAc in petroleum ether (v / v)) to give the title product 1c (900 mg, 56% yield) as a white solid.

[0147] LCMS: R t = 0.803 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 300.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.84 (s, 1H), 8.68 (s, 1H), 8.10 (s, 1H), 7.46 (dd, J=8.8, 12.4 Hz, 1H), 6.35 (br s, 1H), 1.51 (s, 6H). Preparation of Compound 1d: To a solution of compound 1c (300 mg, 1.0 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (185 mg, 1.0 mmol) in n-BuOH (10 mL) was added TFA (0.1 mL). The resulting mixture was stirred at 26-33 °C for 2 h. The precipitated solid was collected by filtration and then dried under high vacuum to give the title product 1d (400 mg, 99% purity, 88% yield) as a yellow solid.

[0148] LCMS: R t = 0.828 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 451.1 [M+H] + . Preparation of Compound 1e: A solution of compound 1d (1.144 g, 2.76 mmol), (R)-N,N-dimethylpiperidin-3-amine hydrochloride (500 mg, 3.04 mmol), and KCO (764 mg, 5.52 mmol) in DMSO (30 mL) was stirred at 100 °C for 12 h. The reaction mixture was added to cold water (200 mL). A yellow solid precipitated, and the residue was purified by column chromatography on silica gel (gradient elution: CHCl / MeOH 100 / 0 to 90 / 10) to give the title product 1e (298 mg, 84.0% purity, 20% yield) as a yellow solid.

[0149] LCMS: R t =0.717 min / 5-95AB_ 220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 523.5 [M+H] + Preparation of compound 1f: A solution of compound 1e (298 mg, 0.57 mmol) and Pd / C (30 mg, 0.1 eq) in MeOH (10 mL) was stirred under 1 atmosphere of H2 at 25 °C for 1 h. The reaction was filtered through Celite and washed with methanol (5 mL x 3). The combined filtrate was evaporated in vacuo to give the title product (206 mg, 73% yield) as a brown oil.

[0150] LCMS: R t =0.630 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 493.3 [M+H] + Manufacturing Procedure for Example 1: 1f (194 mg, 0.39 mmol) and DIEA (78 mg, 1.5 equiv., 0.5 To a solution of 1,2-dichloro-2,4 ...

[0151] LCMS: R t =2.100 min / 0-60AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 547.1 [M+H] + . HPLC: t = 3.88 min / 0-60_AB_1.2ml.met. Chromatography (Ultimate C18 3.0um 3.0*50mm); SFC: Rt =3.763 min, purity 96.5%. 1 H NMR (400MHz, CDCl3) δ 10.67 (br s, 1H), 9.91 (br s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.61 (br s, 1H), 7.35-7.30 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.72 (s, 1H), 6.50-6.27 (m, 2H), 5.82 (br d, J=11.0 Hz, 1H), 5.60 (s, 1H), 4.06-3.95 (m, 1H), 3.07 (br s, 1H), 2.89 (br s, 1H), 2.67 (br s, 2H), 2.45-2.38 (m, 1H), 2.34 (s, 6H), 1.98 (br s, 2H), 1.80 (s, 6H), 1.72-1.68 (m, 2H), 1.68-1.64 (m, 2H). Example 2 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(1-hydroxycyclopropyl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0152] [ka]

[0153] Procedure for preparing compound 2b: To a mixture of compound 2a (50 g, 253.5 mmol) in THF (500 mL) was added n-BuLi (140 mL, 2.5 M, 354.8 mmol) dropwise over 30 minutes at −60° C., and the mixture was stirred at −60° C. for 1 hour. 2-Fluorobenzoic acid (32 g, 228.1 mmol) was then added, and the resulting mixture was stirred at room temperature for 20 hours. The reaction was quenched with aqueous NH4Cl (1000 mL) at 0° C. The resulting mixture was extracted with EtOAc (300 mL×3). The combined organic layers were dried over Mg2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc). c=3:1) to give compound 2b (25 g, 31% yield) as a colorless oil.

[0154] LCMS: R t = 0.753 min (MERCK RP18 2.5-2mm), MS (ESI) m / z= 318.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.17 (dd, J=8.0, 1.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.40-7.35 (m, 2H), 7.31-7.25 (m, 5H), 7.24-7.16 (m, 4H), 4.18 (s, 4H). Preparation of compound 2c: To a mixture of compound 2b (25 g, 70.89 mmol) and KCO (29.4 g, 212.67 mmol) in DMF (500 mL) was added MeI (20.1 g, 141.78 mmol). The reaction mixture was then stirred at 25 °C for 1 hour. The reaction mixture was poured into water (1200 mL) and extracted with EtOAc (400 mL × 3). The combined organic layer was washed with brine (300 mL × 3), dried over sodium sulfate, filtered, and the filtrate was concentrated to give compound 2c (27 g, crude) as a yellow oil.

[0155] LCMS: R t = 0.822 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 332.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.72 (dd, J=1.6 Hz, 8.0 Hz, 1H), 7.34-7.23 (m, 11H), 7.00-6.95 (m, 2H), 4.27 (s, 4H), 3.91 (s, 3H). Preparation of compound 2d: To a mixture of compound 2c (27 g, 81.47 mmol) in THF (250 mL) was added Ti(OiPr) (6.9 mg, 24.44 mmol) dropwise under a N balloon at 80 °C. EtMgBr (109 mL, 325.88 mmol) was then added, and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was poured into saturated NH Cl solution (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give compound 2d (17 g, 63% yield) as a yellow oil.

[0156] LCMS: R t= 0.760 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 330.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.87 (br s, 1H), 7.25-7.15 (m, 6H), 7.14-7.08 (m, 5H), 7.05-6.97 (m, 2H), 6.92 (dd, J=1.2 Hz, 8.0 Hz, 1H), 4.11 (s, 4H), 1.09-1.03 (m, 2H), 0.93-0.87 (m, 2H). Preparation of compound 2e: To a mixture of compound 2d (0.5 g, 1.52 mmol) in MeOH (8 mL) was added Pd / C (wet) (100 mg) and AcOH (0.1 mL) under a H balloon. The reaction mixture was stirred at 20-25 °C for 40 h. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc = 3:1) to give compound 2e (200 mg, 29% yield) as a colorless oil.

[0157] 1 H NMR (400MHz, CDCl3) δ 7.19-7.12 (m, 2H), 6.75-6.70 (m, 2H), 4.30 (br s, 2H), 1.19-1.15 (m, 2H), 0.10-0.95 (m, 2H). Preparation of compound 2f: To a mixture of compound 2e (200 mg, 1.34 mmol) and DIEA (346 mg, 2.68 mmol) in CHCl (8 mL) was added 2,4-dichloro-1,3,5-triazine (241 mg, 1.61 mmol). The reaction mixture was then stirred at 25 °C for 12 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (30% EtOAc in petroleum ether) to give 1-(2-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)cyclopropanol: 2f (22 0 mg, 62% yield, was obtained as a yellow oil.

[0158] LCMS: R t = 0.718 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 262.9 [M +H] + . 1 H NMR (400MHz, CDCl3) δ 8.79 (br s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.41-7.33 (m, 1H), 7.33-7.30 (m, 1H), 7.18-7.13 (m, 1H), 1.28-1.24 (m, 2H), 1.03-0.99 (m, 2H). Preparation of compound 2g:

[0159] [ka]

[0160] A solution of 4-fluoro-2-methoxy-5-nitroaniline (20 g, 0.11 mol) and KCO (29 g, 0.22 mol) in DMF (200 mL) was 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (13 g, 0.13 mol) was added. The mixture was stirred at 25° C. for 48 hours. The reaction was treated with 1 L of water and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (500 mL×3). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give compound 2g (30 g, 100% yield) as a red oil.

[0161] LCMS: R t = 0.125 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 269.0 [M +H] + . 1 H NMR: (400MHz, CDCl3) δ 7.28 (s, 1H), 6.62 (s, 1H), 3.92 (s, 3H), 3.17 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.25 (s, 6H). Preparation of compound 2h: To a mixture of compound 2f (140 mg, 0.53 mmol) and compound 2g (56 mg, 0.58 mmol) in n-BuOH (5 mL) was added TFA (0.5 mL). The reaction mixture was then stirred at 22-28 °C for 12 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (5% MeOH in CHCl) to give compound 2h (160 mg, 61% yield) as a brown oil.

[0162] LCMS: R t = 0.682 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 495.3 [M +H] + . Preparation of compound 2i: To a mixture of compound 2h (110 mg, 0.22 mmol) and NH4Cl (59 mg, 1.10 mmol) in MeOH (5 mL) and water (0.5 mL) was added Zn (72 mg, 1.10 mmol). The reaction mixture was then stirred at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated to give compound 2i (140 mg, crude) as a brown oil.

[0163] LCMS: R t = 0.636 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 465.2 [M +H] + . 1H NMR (400MHz, CDCl3) δ 8.24 (br s, 1H), 7.83 (br s, 1H), 7.60 (br s, 1H), 7.71-7.40 (m, 2H), 7.20-6.93 (m, 1H), 6.61 (s, 1H), 3.80 (s, 3H), 3.20-2.85 (m, 2H).2.70-2.25 (m, 11H), 1.16-1.08 (m, 2H), 0.91-0.82 (m, 2H). Manufacturing Procedure for Example 2: To a mixture of compound 2i (140 mg, 0.21 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (2 mL) was added acryloyl chloride (21 mg, 0.23 mmol) at 0°C. The reaction mixture was stirred at 24-27°C for 0.5 h. The reaction mixture was purified by preparative HPLC: [Column: Phenomenex Gemini C18 250*50 mm*10 μm; Conditions: 35-65% B (A: 0.05% ammonia; B: CH3CN); Flow rate: 30 ml / min]. The fractions containing the desired compound were lyophilized to give Example 2 (32.0 mg, 6% yield) as a white solid.

[0164] LCMS: R t = 1.999 min / 10-80CD_3min_ 220&254 Chromatography (B: XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 519.3 [M +H] + . 1 H NMR (400MHz, CDCl3) δ 10.34 (br s, 1H), 10.05 (br s, 1H), 8.78 (br s, 1H), 8.37-8.31 (m, 2H), 7.60 (br s, 1H), 7.30-7.24 (m, 2H), 6.95 (t, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.23-6.21 (m, 2H), 5.64 (t, J=6.0 Hz, 1H), 3.81 (s, 3H), 2.81-2.78 (m, 2H), 2.63 (s, 3H), 2.23-2.18 (m, 9H), 1.31-1.22 (m, 2H), 0.97-0.94 (m, 2H). HPLC: t =3.56 min / 10-80CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). Example 3 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(6-fluoro-4-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0165] [ka]

[0166] Procedure for preparing compound 3b: To a solution of compound 3a (700 mg, 4.48 mmol) in EtOAc (20 mL) and MeOH (20 mL) was added TMSCHN (4.48 mL, 8.97 mmol, 2 M in hexane). The mixture was stirred at 27-34 °C (room temperature) for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 5 / 1) to give compound 3b (650 mg, 85% yield) as a white solid.

[0167] LCMS: R t =0.576 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 170.8 [M+H]+. 1 H NMR (400MHz, CDCl3) δ 7.78 (s, 1H), 7.30 (d, J=2.6 Hz, 1H), 5.47 (br s, 2H), 3.94 (s, 3H). Preparation of compound 3c: To a solution of compound 3b (650 mg, 3.82 mmol) in THF (40 mL) was added CHMgBr (5.1 mL, 3 M in ether) at 0–5°C. The mixture was stirred at 26–33°C for 1.5 h. The reaction mixture was quenched by the addition of aqueous NHCl (20 mL) and then extracted with EtOAc (3 × 40 mL). The organic layer was washed with brine, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether / EtOAc = 3 / 1) to give compound 3c (600 mg, 92% yield) as a pale yellow solid.

[0168] LCMS: R t =1.572 min / 10-80_7min_220&254.1cm Chromatography (MERCK RP-18e 25-2mm), MS (ESI) m / z= 283.9 [M+H]+. 1 H NMR(400MHz, CDCl3) δ 7.47 (d, J=1.4 Hz, 1H), 6.58 (d, J=1.6 Hz, 1H), 1.62-1.58 (m, 6H). Preparation of compound 3d: To a solution of compound 3c (600 mg, 3.52 mmol) and DIEA (683 mg, 5.95 mmol) in CHCl (40 mL) was added 2,4-dichloro-1,3,5-triazine (581 mg, 3.87 mmol). The resulting mixture was stirred at 26-33 °C (room temperature) for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 1 / 1) to give compound 3d (650 mg, 65% yield) as a white solid.

[0169] LCMS: R t = 1.299 min / 10-80CD_3MIN_220&254.1cm Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 283.9 [M+H]+. 1H NMR(400MHz, CDCl3) δ 9.85-9.51 (m, 1H), 8.97 (br s, 1H), 8.54 (br s, 1H), 6.85 (d, J=1.6 Hz, 1H), 2.97-2.37 (m, 1H), 1.70 (s, 6H). Preparation of compound 3e: To a solution of compound 3d (600 mg, 2.11 mmol) and compound 2g (624 mg, 2.32 mmol) in n-BuOH (10 mL) was added TFA (0.1 mL). The resulting mixture was stirred at 26-32 °C for 18 h. The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 x 40 mL). The organic layer was washed with brine (40 mL), dried, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl2 / MeOH = 10 / 1) to give compound 3e (80 mg, 7.3% yield) as a red solid.

[0170] LCMS: R t = 0.662 min / 5-95AB_220&254.1 cm Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 516.2 [M+H]+. Preparation of compound 3f: To a solution of compound 3e (80 mg, 0.16 mmol) in THF (1 mL) and HO (1 mL) was added Zn (30 mg, 0.47 mmol) and NH4Cl (25 mg, 0.47 mmol). The mixture was stirred under N2 at 50 °C for 1.5 h. The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 × 40 mL). The organic layer was washed with brine, dried, and concentrated under reduced pressure to give compound 3f (35 mg) as a brown solid.

[0171] LCMS: R t=0.596 min / 5-95AB_220&254.1 cm Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 486.2 [M+H]+. Manufacturing Procedure for Example 3: To a solution of compound 3f (35 mg, 0.07 mmol) and DIEA (14 mg, 0.11 mmol) in DMF (1 mL) was added acryloyl chloride (6.5 mg, 0.07 mmol) in DMF (1 mL). The resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was collected by aliquoting. The resulting mixture was purified by commercial HPLC [column: Phenomenex Gemini C18 250*50 mm*10 μm; conditions: 43-53% B (A: 0.05% ammonia; B: CH3CN); flow rate: 30 ml / min]. The fractions containing the desired compound were lyophilized to give Example 3 (4.2 mg, 10.8% yield) as a white solid.

[0172] LCMS: R t = 3.921 min / 10-80CD_7MIN_220&254.1cm Chromatography (XBridge Shield RP18 2.1*50mm), MS (ESI) m / z= 540.3 [M+H]+. HPLC: t =3.26 min / 10-80 cd / 1.2 ml. MET. Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, CDCl3) δ 10.40 (br s, 1H), 10.11 (br s, 1H), 9.88 (br s, 1H), 9.01 (s, 1H), 8.34 (s, 1H), 7.62 (br s, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 6.30 (br s, 3H), 5.75-5.63 (m, 1H), 3.81 (s, 3H), 2.81 (br s, 2H), 2.63 (s, 3H), 2.21 (br s, 8H), 1.71 (s, 6H). Example 4 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0173] [ka]

[0174] Procedure for preparing compound 4a: Compound 1d (400 mg, 0.89 mmol), N 1 ,N 1 ,N 2 A solution of 4a-trimethylethane-1,2-diamine (91 mg, 0.89 mmol) and KCO (184 mg, 1.45 mmol) in DMF (5 mL) was stirred under N at 27-34 °C for 2 h. This mixture was added dropwise to water (50 mL), and the resulting mixture was stirred at room temperature for 15 min. The precipitated solid was collected by filtration and dried under high vacuum to give the title product 4a (270 mg, 57% yield) as an orange solid.

[0175] LCMS: R t = 0.707 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 533.1 [M+H] + . Procedure for preparing compound 4b: A solution of compound 4a (270 mg, 0.50 mmol) and Pd / C (20 mg) in MeOH (10 mL) was degassed by purging with H three times and then stirred under H (15 psi) at 27–34 °C for 2 h. The reaction was filtered through Celite and washed with methanol (3 × 5 mL). The combined filtrate was evaporated in vacuo to give the title product 4b (200 mg, 93% yield) as a black oil.

[0176] LCMS: R t = 1.224 min / 10-80AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 503.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 10.02 (s, 1H), 8.17-8.12 (m, 2H), 7.66 (s, 1H), 6.98 (dd, J= 11.2, 8.8 Hz, 2H), 6.58 (s, 1H), 3.73 (s, 3H), 2.87-2.84 (m, 2H), 2.55 (s, 3H), 2.32 (t, J= 6.8 Hz, 2H), 2.15 (s, 6H), 1.55 (s, 6H). Manufacturing Procedure for Example 4: To a solution of compound 4b (100 mg, 0.20 mmol) and DIEA (38 mg, 0.30 mmol) in DMF (3 mL) was added acryloyl chloride (18 mg, 0.20 mmol) dropwise at 0°C. The mixture was stirred at 26-33°C for 2 hours. The reaction mixture was purified by preparative HPLC (column: Phenomenex Gemini C18; 150 x 25 mm x 5 μm; 45-75% B( A: 0.05% ammonia in water; B: CHCN; flow rate: 30 mL / min). The fractions containing the desired compound were lyophilized to give Example 4 (14.5 mg, 95.7% purity, 13% yield) as a white solid.

[0177] LCMS: R t=2.053 min / 10-80CD_3min_ 220&254.1cm, Chromatography (Xtimate C18, 2.1*30mm3um), MS (ESI) m / z= 557.3 [M+H]+. HPLC: Rt = 4.88 min / 10-80 CD 1.2 ml metre chromatography (Ultimate C18 3.0 um 3.0*50 mm). 1 H NMR (400MHz, CDCl3) δ 10.69 (s, 1H), 10.45 (s, 1H), 9.99 (s, 1H), 8.43 (s, 1H), 8.34 (dd, J=8.0, 12.8 Hz, 1H), 7.70 (s, 1H), 7.13 (dd, J=8.4, 12.0 Hz, 1H), 6.80 (s, 1H), 6.39 (s, 2H), 5.78 (d, J=11.2 Hz, 1H), 3.90 (s, 3H), 2.90 (s, 2H), 2.72 (s, 3H), 2.29 (s, 8H), 1.79 (s, 6H). Example 5 (E)-N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0178] [ka]

[0179] Manufacturing Procedure for Example 5: A mixture of compound 4b (80 mg, 0.16 mmol), compound 5a (31 mg, 0.19 mmol), HATU (91 mg, 0.24 mmol), and DIEA (62 mg, 0.48 mmol) in CHCl (4 mL) was stirred at 28-35 °C for 2 h. The reaction was purified by preparative HPLC (column: Phenomenex Gemini C18 150*25 mm*5 μm; 55-85% B (A: 0.05% ammonia in water; B: CHCN); flow rate: 30 mL / min). The fractions containing the desired compound were lyophilized to give Example 5 (17.8 mg, 18% yield) as a white solid.

[0180] LCMS: R t = 1.755 min / 0-60AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2m m), MS (ESI) m / z = 614.3 [M+H] + . HPLC: t = 2.15 min / 0-60CD_1.2ml.met. Chromatography (Ultimate C18 3.0um 3.0*50mm). 1 H NMR (400MHz, CDCl3) δ 10.69 (s, 1H), 10.29 (s, 1H), 9.98 (s, 1H), 8.42 (s, 1H), 8.33 (dd, J=13.2, 8.0 Hz, 1H), 7.69 (s, 1H), 7.12 (dd, J=12.0, 8.8 Hz, 1H), 6.92 (td, J=15.2, 6.0 Hz, 1H), 6.79 (s, 1H), 6.25 (s, 1H), 3.89 (s, 3H), 3.73 (s, 1H), 3.18 (d, J=5.6 Hz, 2H), 2.89 (t, J=5.2 Hz, 2H), 2.71 (s, 3H), 2.33 (s, 8H), 2.30 (s, 6H), 1.79 (s, 6H). Example 6 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(4-(2-hydroxypropan-2-yl)-6-methylpyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0181] [ka]

[0182] Procedure for preparing compound 6b: To a solution of compound 6a (4.0 g, 23.2 mmol) in 1:1 EtOAc / MeOH (60 mL) was added TMSCHN (23.2 mL, 46.4 mmol, 2 M in hexane). The resulting mixture was stirred at 24-30 °C for 30 min. The reaction mixture was poured into H O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (20 mL × 3) and brine (20 mL), dried over Na SO , and concentrated in vacuo to give the title compound 6b (3.1 g, 67.7% yield) as a yellow solid.

[0183] LCMS: Rt = 0.672 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=186.9 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1H), 7.50 (s, 1H), 6.79 (br s, 2H), 3.84 (s, 3H). Preparation of compound 6c: To a solution of compound 6b (3.1 g, 16.6 mmol) in THF (40 mL) was added CHMgBr (22.2 mL, 66.5 mmol, 3 M in ether) dropwise at 0 °C. The resulting mixture was stirred under N at 26-34 °C for 1.5 h. The reaction mixture was poured into saturated NHCl (100 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water (30 mL × 3) and brine (30 mL), dried over NaSO, and concentrated in vacuo to give the title compound 6c (2.79 g, 85.6% yield) as a yellow solid.

[0184] LCMS: Rt = 0.471 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2mm), MS (ESI) m / z=187.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.71 (s, 1H), 6.98 (s, 1H), 5.63 (s, 2H), 5.52 (s, 1H), 1.46 (s, 6H). Preparation of compound 6d: To a solution of compound 6c (1.0 g, 5.36 mmol), methylboronic acid (1.28 g, 21.44 mmol), and KCO (1.48 g, 10.72 mmol) in HO / dioxane (1:5, 20 mL) was added Pd(PPh) (929 mg, 0.15 equiv., 0.80 mmol). The reaction mixture was heated at 100 °C under N for 24 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (4% MeOH in CHCl) to give compound 6d (235 mg, 26.1% yield) as a yellow solid.

[0185] LCMS: Rt = 0.142 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=167.0 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ 7.79 (s, 1H), 6.81 (s, 1H), 5.34 (s, 1H), 5.25 (br s, 2H), 2.26 (s, 3H), 1.46 (s, 6H). Procedure for preparing compound 6e:

[0186] [ka]

[0187] To a stirred solution of compound 6e1 (100 g, 537.2 mmol) and DIEA (138.9 g, 1074.4 mmol) in CHCl (1500 mL) was added compound 6e2 (96.7 g, 644.6 mmol) at 10 °C and then stirred at 25 °C for 1 hour. The reaction mixture was directly concentrated in vacuo to give the crude product, which was triturated with CHCl (800 mL) for 30 minutes, filtered, and the solid cake was washed with CHCl (100 mL × 2). The filter cake was dried in vacuo to give the title compound 6e (118 g, 73% yield) as a yellow solid.

[0188] LCMS: R t = 0.760 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 299.9 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ 10.27 (s, 1H), 8.60 (s, 1H), 8.37 (d, J= 8.0 Hz, 1H), 7.41 (d, J=13.6 Hz, 1H), 3.95 (s, 3H). Preparation of compound 6f: A mixture of compound 6d (200 mg, 1.20 mmol) and compound 6e (433 mg, 1.44 mmol) in pyridine (6 mL) was heated at 50° C. for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (5% MeOH in CHCl) to give compound 6f (240 mg, 16% yield) as a dark red solid.

[0189] LCMS: Rt = 0.688 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=430.1 [M+H] + . Procedure for preparing compound 6g: Compound 6f (240 mg, 0.191 mmol) and compound N 1 ,N 1 ,N 2 To a solution of 29 mg (0.286 mmol) of 1,2-trimethylethanediamine in 5 mL of DMF was added KCO (53 mg, 0.382 mmol). The reaction mixture was stirred at 27-34 °C for 12 h. The reaction mixture was poured into 30 mL of H2O and 100 mL of EtOAc was added. The combined organic layers were washed with water (20 mL x 3) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give compound 6g (120 mg, yield 91.8%) as an orange oil.

[0190] LCMS: Rt = 0.633 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=512.2 [M+H] + . Preparation of compound 6h: To a solution of compound 6g (90 mg, 0.131 mmol) in MeOH / H2O = 2 / 1 (9 mL) was added Zn (26 mg, 0.394 mmol) and NH4Cl (21 mg, 0.394 mmol). The resulting mixture was heated at 90 °C for 3 h. TLC (CHCl2 / MeOH = 5 / 1 (v / v)) showed one major spot (R f =0.25) and the starting material (R f =0.5) was completely consumed. The reaction mixture was extracted with CHCl3 / isopropanol = 3 / 1 (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give compound 6h (85 mg, yield 94%) as a brown solid.

[0191] LCMS: Rt = 0.571 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=482.3 [M+H] + . Manufacturing Procedure for Example 6: To a solution of compound 6h (85 mg, 0.123 mmol) and DIEA (24 mg, 0.185 mmol) in DMF (2 mL) was added acryloyl chloride (11 mg, 0.123 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50 mm*10 μm; conditions: 25-55% B (A: 0.05% ammonia, B: CHCN); flow rate: 30 mL / min) and lyophilized to give the impure product as a white solid, which was further purified by preparative TLC (CHCl:MeOH = 7:1 (v / v)) to give Example 6 (18.4 mg, 27.9% yield) as a white solid.

[0192] LCMS: Rt = 1.969 min / 10-80CD_3 min_220&254 Chromatography (ACSSH-LCMS-AS A:Xtimate C18,2.1*30mm,3um; B:XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=537.3 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 10.40 (br s, 1H), 10.20 (br s, 1H), 9.93 (br s, 1H), 9.32 (s, 1H), 8.39 (s, 1H), 7.67 (br s, 1H), 7.04 (s, 1H), 6.77 (s, 1H), 6.47-6.27 (m, 2H), 6.14 (br s, 1H), 5.80-5.69 (m, 1H), 3.87 (s, 3H), 2.90-2.84 (m, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 2.31-2.25 (m, 8H), 1.75 (s, 6H). Example 7 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(2-hydroxypropan-2-yl)-6-methylpyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0193] [ka]

[0194] Procedure for preparing compound 7b: To a mixture of compound 7a (5 g, 26.73 mmol) in anhydrous THF (70 mL) was added DMAP (6.35 g, 53.46 mmol). The reaction mixture was stirred at room temperature for 10 min, and (Boc)O (17.50 g, 80.19 mmol) was added followed by stirring at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (5-10% EtOAc in petroleum ether) to give the desired product 7b (10 g, 96.6% yield) as a pale yellow solid.

[0195] LCMS: Rt = 0.875 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2 mm), MS (ESI) m / z = 388.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.40 (d, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 2.57 (s, 3H), 1.41 (s, 18H) Procedure for preparing compound 7c: To a mixture of compound 7b (3.5 g, 9.04 mmol) in anhydrous MeOH (50 mL) and anhydrous DMF (150 mL) under nitrogen was added Pd(OAc) (150 mg, 0.1 equiv., 0.904 mmol), followed by DPPF (501 mg, 0.904 mmol) and EtN (1.37 g, 13.56 mmol). The resulting mixture was stirred at 80 °C under a CO atmosphere (50 Psi) for 16 h. The reaction mixture was filtered, and the filtrate was poured into water (10 mL), stirred for an additional 10 min, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (5-8% in petroleum ether). EtOAc) to give compound 7c (2.0 g, 60.4% yield) as a white solid.

[0196] LCMS: Rt = 0.812 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2mm), MS (ESI) m / z =367.1 [M+H] + . Procedure for preparing compound 7d: To a mixture of compound 7c (2.0 g, 5.46 mmol) in anhydrous THF (20 mL) was added MeMgBr (9.1 mL, 27.3 mmol, 3 M in ether). The resulting mixture was stirred at 0 °C under N atmosphere for 2.5 h. The reaction mixture was poured into aqueous NH Cl (25 mL) and stirred for 10 min, then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na SO and concentrated in vacuo. This gave the title product 7d (1.4 g, 49.8% yield) as a yellow oil, which was used directly in the next step without further purification.

[0197] LCMS: Rt = 0.616 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2mm), MS (ESI) m / z=267.1 [M+H] + . Procedure for preparing compound 7e: To a mixture of compound 7d (1.4 g, 1.13 mmol) in anhydrous CHCl (9 mL) was added TFA (3 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into aqueous NaHCO (25 mL) to adjust the pH to 8.0, stirred for 10 minutes, and then extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (gradient eluent: petroleum ether: ethyl acetate = 20 / 1 (v / v)) to give compound 7e (230 mg, 26.3% yield) as a white solid.

[0198] LCMS: Rt = 0.129 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2 mm), MS (ESI) m / z = 167.0 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ6.97 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 2.35 (s, 3H), 1.58 (s, 6H). Preparation of compound 7f: To a mixture of compound 7e (311 mg, 2.076 mmol) in anhydrous CHCl (5 mL) was added DIEA (358 mg, 2.768 mmol), followed by 2,4-dichloro-1,3,5-triazine (230 mg, 1.0 equiv., 1.384 mmol). The resulting mixture was stirred at 25 °C for 1.5 h. The reaction mixture was poured into water (20 mL) and EtOAc (20 mL), stirred for 5 min, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude residue, which was purified by flash column chromatography on silica gel (15-30% EtOAc in petroleum ether) to give compound 7f (290 mg, 74.9% yield) as an off-white solid.

[0199] LCMS: Rt = 0.352 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2 mm), MS (ESI) m / z = 279.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.93-9.54 (m, 1H), 8.50 (s, 1H), 8.30 (br d, J=14.4 Hz, 1H), 7.12 (br d, J=8.4 Hz, 1H), 3.07-2.87 (m, 1H), 2.51 (s, 3H), 1.69 (s, 6H). Procedure for preparing compound 7g: To a mixture of compound 7f (290 mg, 1.038 mmol) in n-BuOH (10 mL) was added compound 2g (289 mg, 1.038 mmol) and TFA (0.1 mL). The resulting mixture was stirred at room temperature for 16 hours to give a dark red, cloudy solution. The mixture was directly concentrated in vacuo to give a crude residue, which was purified by flash column chromatography on silica gel (0-15% MeOH in CHCl, with 1% ammonia) to give compound 7g (110 mg, 20.7% yield) as a yellow solid.

[0200] LCMS: Rt = 0.604 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-Q MERCK RP18 2.5-2mm), MS (ESI) m / z =512.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.91 (br s, 1H), 8.36 (br s, 1H), 8.24 (br s, 1H), 7.47 (br s, 1H), 7.15 (br d, J=8.4 Hz, 1H), 6.66 (s, 1H), 3.96 (s, 3H), 3.29 (t, J=7.2 Hz, 2H), 2.89 (s, 3H), 2.54 (s, 3H), 2.28 (s, 6H), 1.69 (s, 8H). Preparation of compound 7h: Compound 7g (110 mg, 0.215 mmol) in MeOH / HO = 5 / 1 (6 mL To a solution of 7h (70 mg, 1.075 mmol) was added Zn (70 mg, 1.075 mmol) and NH4Cl (58 mg, 5.0 equiv., 1.075 mmol). The resulting mixture was heated at 90 °C for 3 h. The reaction mixture was filtered, and the filtrate was extracted with CHCl (20 mL × 3). The combined organic layers were washed with water (10 mL × 3) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give compound 7h (93 mg, 79.6% yield) as a brown solid.

[0201] LCMS: Rt = 0.554 min / 5-95AB_220&254.1 cm Chromatography ((ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z = 482.1 [M+H] + . Manufacturing Procedure for Example 7: To a solution of compound 7h (93 mg, 0.171 mmol) and DIEA (33 mg, 1.5 equivalents, 0.256 mmol) in DMF (2 mL) was added acryloyl chloride (15 mg, 1.0 equivalents, 0.171 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (CHCl:MeOH = 7:1 (v / v)) to give the impure product as a yellow solid. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: Purification by 30-55% B (A: 0.05% ammonia, B: CH3CN; flow rate: 25 ml / min) and lyophilization gave Example 7 (20.3 mg, 22.2% yield) as a yellow solid.

[0202] LCMS: Rt = 2.002 min / 10-80CD_3 min_220&254 Chromatography (ACSSH-LCMS-AS A:Xtimate C18,2.1*30mm,3um; B:XBrige Shield RP18 2.1*50mm), MS (ESI) m / z =536.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ 10.34 (br s, 2H), 9.95 (br s, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.37 (br s, 1H), 7.64 (br s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.52-6.31 (m, 2H), 5.77 (br d, J=10.4 Hz, 1H), 3.87 (s, 3H), 2.88 (t, J=4.8 Hz, 2H), 2.70 (s, 3H), 2.49 (s, 3H), 2.28 (s, 8H), 1.78 (s, 6H). Example 8 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0203] [ka]

[0204] Procedure for preparing compound 8b: To a solution of compound 8a (1.0 g, 6.57 mmol) in CHCl (20 mL) was added (Boc)O (3.6 g, 16.42 mmol) and DMAP (1.2 g, 1.5 equiv., 9.85 mmol). The resulting mixture was stirred at 28-38 °C for 4 h. This reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc=50 / 1 (v / v)) to give compound 8b (2.5 g, yield 99%) as a white solid.

[0205] LCMS: R t = 0.784 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 353.0 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.63 (dd, J=1.4, 4.6 Hz, 1H), 7.85 (dd, J=1.5, 8.0 Hz, 1H), 7.69 (dd, J=4.8, 8.0 Hz, 1H), 3.94 (s, 3H), 1.36 (s, 18H). Procedure for preparing compound 8c: To a solution of compound 8b (2.3 g, 6.52 mmol) in THF (30 mL) was degassed by purging with N three times, and MeMgBr (10.87 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 29–34 °C for 1 h. The reaction mixture was diluted with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1) to give compound 8c (1 g, 61% yield) as a white solid.

[0206] LCMS: R t = 0.697 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 253.0[M +H] + . Preparation of compound 8d: To a solution of compound 8c (1 g, 1.0 equiv., 3.70 mmol) in CHCl (6 mL) was added TFA (2 mL). The resulting mixture was stirred at 29-36 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 8d (TFA salt) (1.2 g, 94% yield) as a yellow oil.

[0207] 1 H NMR (400MHz, methanol-d4) δ 7.85 (dd, J=1.0, 5.3 Hz, 1H), 7.72 (dd, J=1.3, 8.5 Hz, 1H), 7.61 (dd, J=5.5, 8.5 Hz, 1H), 1.70 (s, 6H). Procedure for preparing compound 8e: To a solution of compound 8d (200 mg, 1.0 equiv., 0.67 mmol) in pyridine (5 mL) was added compound 6e (256 mg, 1.1 equiv., 0.74 mmol). The resulting mixture was stirred at 28-36 °C for 6 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (CHCl / MeOH = 10 / 1) to give compound 8e (240 mg, 58% yield) as a yellow solid.

[0208] LCMS: R t = 0.687 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 438.1[M +H] + . Preparation of compound 8f: To a solution of compound 8e (240 mg, 1.0 equiv., 0.58 mmol) in DMF (10 mL) was added K2CO3 (160 mg, 2.0 equiv., 1.16 mmol) and compound N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (118 mg, 2.0 equiv., 1.16 mmol) was added. The resulting mixture was stirred at 28-36 °C for 2 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl / MeOH = 10 / 1) to give compound 8f (170 mg, 59% yield) as a yellow solid.

[0209] LCMS: R t = 0.643 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 498.2[M +H] + . Procedure for preparing compound 8g: Compound 8f (170 mg, 1.0 equiv.) in MeOH (10 mL) and HO (5 mL) To a solution of Zn (111 mg, 5.0 equiv., 1.70 mmol) and NH4Cl (182 mg, 10.0 equiv., 3.40 mmol) was added. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 8g (140 mg, 88% yield) as a white solid.

[0210] LCMS: R t = 0.554 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 468.2[M +H] + . Manufacturing Procedure for Example 8: To a solution of compound 8g (140 mg, 1.0 equivalent, 0.30 mmol) and DIEA (58 mg, 1.5 equivalent, 0.45 mmol) in DMF (3 mL) was added acryloyl chloride (27 mg, 1.0 equivalent, 0.30 mmol). The resulting mixture was stirred at 0°C for 30 minutes. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: Purification was performed by elution with 28-58% B (A: 0.05% NH3H2O; B: CH3CN); flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 8 (58.7 mg, 37% yield) as a white solid.

[0211] LCMS: R t = 1.844 min / 10-80CD_3min_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 522.3 [M +H] + . HPLC: t = 3.65 min / 10-80_CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1H NMR (400MHz, CDCl3) δ 10.85 (br s, 1H), 10.41 (br s, 1H), 9.99 (br s, 1H), 8.69 (d, J=7.0 Hz, 1H), 8.41 (s, 1H), 8.23 ​​(dd, J=1.5, 4.5 Hz, 1H), 7.68 (br s, 1H), 7.23 (dd, J=4.9, 8.2 Hz, 1H), 6.79 (s, 1H), 6.48-6.41 (m, 1H), 6.37 (br d, J=10.0 Hz, 1H), 5.78 (br d, J=11.0 Hz, 1H), 3.88 (s, 3H), 2.88 (br s, 2H), 2.71 (s, 3H), 2.28 (s, 8H), 1.83 (s, 6H). Example 9 N-(5-(4-(3,4-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0212] [ka]

[0213] Procedure for preparing compound 9b: To a solution of compound 9a (340 mg, 1.0 equiv., 1.18 mmol) in CHCl (6 mL) was added TFA (2 mL). The resulting mixture was stirred at 26-32 °C for 2 h. The resulting mixture was concentrated under reduced pressure to give the TFA salt of compound 9b (400 mg, 94% yield) as a yellow solid. was obtained as a solid.

[0214] LCMS: R t= 0.698 min / 5-95AB_220&254.1 cm Chromatography (Agilent Pursit 5 C18 20*2.0 mm), MS (ESI) m / z= 188.1 [M+H] + . Procedure for preparing compound 9c: To a solution of compound 9b (286 mg, 1.0 equivalent, 0.95 mmol) in pyridine (10 mL) was added compound 6e (400 mg, 1.1 equivalent, 1.05 mmol). The resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc=1 / 1 (v / v)) to give compound 9c (200 mg, 42% yield) as a yellow solid.

[0215] LCMS: R t = 0.946 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25-2mm), MS (ESI) m / z= 451.1 [M+H] + . Procedure for preparing compound 9d: A solution of compound 9c (200 mg, 0.44 mmol) in DMF (5 mL) was treated with K2CO3 (122 mg, 0.88 mmol) and compound N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (54 mg, 0.53 mmol) was added. The resulting mixture was stirred at 26-33 °C for 2 h. The reaction mixture was poured into HO (50 mL) and filtered. The filter cake was concentrated under reduced pressure to give compound 9d (200 mg, 85% yield) as a yellow solid.

[0216] LCMS: R t = 0.807 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25-2mm), MS (ESI) m / z= 533.2 [M+H] + . Procedure for preparing compound 9e: To a solution of compound 9d (200 mg, 0.38 mmol) in MeOH (5 mL) was added Pd / C (20 mg). The resulting mixture was degassed by purging with H three times and then stirred under H (hydrogen balloon, 30 Psi) at 26-34 °C (room temperature) for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 9e (150 mg, 78% yield) as a brown solid.

[0217] LCMS: R t = 0.752 min / 5-95AB_1.5 min_220&254 Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z= 503.2 [M+H] + . Manufacturing Procedure for Example 9: To a solution of compound 9e (150 mg, 0.30 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (3 mL) was added compound acryloyl chloride (27 mg, 0.30 mmol). The resulting mixture was stirred at 0°C for 30 minutes. This reaction mixture was analyzed by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 42-72% B (A: 0. The resulting mixture was purified by elution with 0.05% NH3H2O; B: CH3CN; flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 9 (39.4 mg, 23% yield) as a white solid.

[0218] LCMS: R t = 1.784 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 557.0 [M+H] + . HPLC: t = 3.12 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 11.29 (br s, 1H), 10.45 (br s, 1H), 9.89 (br s, 1H), 8.38 (s, 1H), 8.14 (br dd, J=5.2, 7.2 Hz, 1H), 7.65 (br s, 1H), 7.09 (q, J=9.2 Hz, 1H), 6.78 (s, 1H), 6.44-6.29 (m, 2H), 6.08 (br s, 1H), 5.81-5.74 (m, 1H), 3.88 (s, 3H), 2.92-2.84 (m, 2H), 2.70 (s, 3H), 2.35-2.20 (m, 8H), 1.88 (d, J=3.6 H z, 6H). Example 10 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(3-hydroxyoxetan-3-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0219] [ka]

[0220] Procedure for preparing compound 10a: Compound: To a mixture of aniline (5 g, 53.69 mmol) in CHCl (80 mL) was added BocO (23.4 g, 107.38 mmol). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was directly concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (2% EtOAc in petroleum ether) to give the title compound 10a (8 g, 100% yield) as a white solid.

[0221] LCMS: R t = 0.793 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 137.9 [M+55] + . 1H NMR(400MHz, CDCl3) δ 7.38 (d, J=8.0 Hz, 2H), 7.33-7.28 (m, 2H), 7.08-7.03 (m, 1H), 6.50 (br s, 1H), 1.54 (s, 9H). Procedure for preparing compound 10b: To a solution of compound 10a (3.0 g, 1.55 mmol) in THF (50 mL) was added t-BuLi (30 mL, 38.81 mmol) dropwise at −78° C. for 1 hour. The reaction mixture was warmed to 0° C. for 15 minutes and then cooled to −78° C. Oxetan-3-one (3.36 g, 46.61 mmol) was added dropwise at −78° C. for 15 minutes. The resulting mixture was stirred at −78° C. for 1 hour. The reaction was quenched by the addition of 100 mL of water and then extracted with EtOAc (3×100 mL). The organic layer was washed with brine (3×100 mL), dried, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether: EtOAc = 3 / 1 (v / v)) to give compound 10b (580 mg, 14.1% yield) as a white solid.

[0222] LCMS: R t = 0.722 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 209.9 [M-55] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.40 (dd, J=1.4, 7.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.16-7.11 (m, 1H), 4.88 (d, J=7.0 Hz, 2H), 4.71 (d, J=7.0 Hz, 2H), 1.45 (s, 9H). Procedure for preparing compound 10c: To a solution of compound 10b (500 mg, 1.89 mmol) in MeOH (20 mL) and H2O (10 mL) was added K2CO3 (780 mg, 5.66 mmol). The mixture was stirred at 70° C. for 2 hours. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc=3 / 1 (v / v)) to give compound 10c (240 mg, yield 77.1%) as a brown solid.

[0223] LCMS: R t = 0.553 min / 10-80CD_3MIN_220&254; XBrige Shield RP18 2.1*50mm, MS (ESI) m / z= 166.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.14 (d, J=7.8 Hz, 1H), 7.05-6.99 (m, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.59 (dt, J=1.0, 7.4 Hz, 1H), 6.18 (br s, 1H), 4.89 (d, J=6.8 Hz, 2H), 4.79 (s, 2H), 4.71 (d, J=6.8 Hz, 2H). Procedure for preparing compound 10d: To a solution of compound 10c (500 mg, 1.89 mmol) in MeOH (20 mL) and HO (10 mL) was added KCO (780 mg, 5.66 mmol). The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 3 / 1 (v / v)) to give compound 10d (240 mg, yield 77.1%) as a brown solid.

[0224] LCMS: R t= 0.553 min / 10-80CD_3MIN_220&254; XBrige Shield RP18 2.1*50mm, MS (ESI) m / z= 166.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.14 (d, J=7.8 Hz, 1H), 7.05-6.99 (m, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.59 (dt, J=1.0, 7.4 Hz, 1H), 6.18 (br s, 1H), 4.89 (d, J=6.8 Hz, 2H), 4.79 (s, 2H), 4.71 (d, J=6.8 Hz, 2H). Preparation of compound 10e: To a solution of compound 10d (220 mg, 1.33 mmol) in pyridine (10 mL) was added compound 6e (439 mg, 1.47 mmol). The resulting mixture was stirred at 50 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC on silica gel (CHCl / MeOH = 15 / 1 (v / v)) to give compound 10e (150 mg, 26.3% yield) as a brown solid.

[0225] LCMS: R t = 0.723 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z= 429.1 [M+H] + . Preparation of compound 10f: A solution of compound 10e (190 mg, 0.44 mmol) and K2CO3 (122 mg, 0.89 mmol) in DMF (2 mL) was added to the solution of compound N 1 ,N 1 ,N 2-trimethylethane-1,2-diamine (54 mg, 0.53 mmol) was added. The mixture was stirred at 25-33 °C for 2 hours. 10 mL of water was added to the reaction, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried, and concentrated in vacuo to give a crude residue, which was purified by preparative TLC on silica gel (CHCl / MeOH = 15 / 1 (v / v)) to give compound 10f (140 mg, 62% yield) as a brown solid.

[0226] LCMS: R t =0.714 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z= 511.3 [M-OH] + . Procedure for preparing compound 10g: To a solution of compound 10f (130 mg, 0.25 mmol) in MeOH (3 mL) under N was added Pd / C (13 mg). The mixture was stirred at 26-31 °C under H (15 Psi) for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 10g (95 mg, The product was obtained in a 78% yield as a brown oil.

[0227] LCMS: R t =0.669 min / 5-95AB_1.5 min_220&254 Chromatography (5-95AB_1.5MIN_1500), MS (ESI) m / z= 481.3 [M+H] + . Preparation procedure for Example 10: To a solution of compound 10h (85 mg, 0.18 mmol) and DIEA (34 mg, 0.26 mmol) in DMF (1 mL) was added acryloyl chloride (16 mg, 0.18 mmol) in DMF (1 mL). The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 25-50% B( A: 0.05% ammonia; B: CHCN; flow rate: 25 ml / min]. The fractions containing the desired compound were lyophilized to give Example 10 (25.2 mg, 26.7% yield) as a brown solid.

[0228] LCMS: R t = 3.452 min / 10-80CD_7MIN_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 535.3 [M +H] + . HPLC: t = 2.91 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, DMSO-d6) δ 10.08 (s, 1H), 8.85 (br s, 1H), 8.47-8.33 (m, 2H), 8.23 (s, 1H), 7.92 (br s, 1H), 7.38 (brd, J=6.6 Hz, 1H), 7.08 (br s, 1H), 6.98 (s, 1H), 6.83 (br s, 1H), 6.47-6.33 (m, 1H), 6.27-6.17 (m, 1H), 5.75 (br d, J=11.4 Hz, 1H), 4.86 (br d, J=6.8 Hz, 2H), 4.70 (brd, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.85 (br t, J=5.6 Hz, 2H), 2.71 (s, 3H), 2.34-2.28 (m, 2H), 2.20 (s, 6H). Example 11 N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0229] [ka]

[0230] Procedure for preparing compound 11b: To a solution of compound 11a (2.0 g, 9.83 mmol) in THF (20 mL) was added CHMgBr (16.4 mL, 49.2 mmol, 3 M in ether) dropwise at 0 °C. The resulting mixture was stirred under N at 27-34 °C for 2 h. The reaction mixture was poured into saturated NHCl (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (20 mL × 3) and brine (20 mL), dried over NaSO, and concentrated in vacuo to give compound 11b (2.0 g, 95% yield) as a brown oil.

[0231] LCMS: Rt = 0.558 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=185.9 [M-OH]+. 1 H NMR (400MHz, CDCl3) δ 6.91 (d, J=10.8 Hz, 1H), 6.63 (d, J=6.4 Hz, 1H), 1.64 (s, 6H). Procedure for preparing compound 11c: A mixture of compound 11b (1.9 g, 9.3 mmol) and compound 6e (2.8 g, 9.3 mmol) in pyridine (20 mL) was heated at 50° C. for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (50% EtOAc in petroleum ether) to give compound 11c (2.6 g, 60% yield) as a pale yellow solid.

[0232] LCMS: Rt = 0.821 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=467.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ 9.73 (br s, 1H), 9.42 (br s, 1H), 8.49 (s, 1H), 8.33 (br s, 1H), 7.54 (s, 1H), 7.09 (d, J=10.4 Hz, 1H), 6.78 (d, J=12.0 Hz, 1H), 4.03 (s, 3H), 2.51 (br s, 1H), 1.71 (s, 6H). Procedure for preparing compound 11d: A solution of compound 11c (740 mg, 1.59 mmol) and K2CO3 (439 mg, 3.18 mmol) in DMF (10 mL) was added with N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (244 mg, 2.39 mmol) was added. The reaction mixture was stirred at 26-31 °C for 4 h. The reaction mixture was added dropwise to HO (100 mL) in an ice-water bath, filtered, and the filter cake was washed with HO (15 mL x 3) and dried under high vacuum to give compound 11d (800 mg, 91.65% yield) as an orange solid.

[0233] LCMS: Rt = 0.717 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=549.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.70 (br s, 1H), 9.00 (br s, 1H), 8.39 (br s, 2H), 7.42 (br s, 1H), 7.08 (d, J=10.5 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.28 (t, J=7.2 Hz, 2H), 2.88 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.25 (s, 6H), 1.69 (s, 6H). Procedure for preparing compound 11e: To a solution of compound 11d (200 mg, 0.364 mmol) in 8 mL of MeOH / HO (5 / 1 (v / v)) was added Zn (119 mg, 1.82 mmol) and NH4Cl (97 mg, 1.82 mmol). The resulting mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was dissolved in CHCl (30 mL), washed with water (20 mL × 3) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give compound 11e (180 mg, 95.3% yield) as a brown oil.

[0234] LCMS: Rt = 0.679 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=519.1 [M+H] + . Preparation procedure for Example 11: To a solution of compound 11e (180 mg, 0.35 mmol) and DIEA (68 mg, 0.53 mmol) in DMF (3 mL) was added acryloyl chloride (32 mg, 0.35 mmol) at 0°C. The resulting mixture was stirred at 0°C for 1 h. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 52-82% B (A: 0.05% ammonia, B: CH3CN); flow rate: 25 ml / min) and lyophilized to give Example 11 (52.9 mg, 26.4% yield) as a white solid.

[0235] LCMS: Rt = 2.124 min / 10-80CD_3 min_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=573.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 10.60 (br s, 1H), 10.44 (br s, 1H), 9.96 (br s, 1H), 8.47 (d, J=7.6 Hz, 1H), 8.42 (s, 1H), 7.69 (br s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.78 (s, 1H), 6.49-6.28 (m, 2H), 6.18 (br s, 1H), 5.91-5.65 (m, 1H), 3.88 (s, 3H), 2.88 (t, J=5.6 Hz, 2H), 2.70 (s, 3H), 2.27 (s, 8H), 1.77 (s, 6H). Example 12 N-(5-(4-(4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0236] [ka]

[0237] Procedure for preparing compound 12b: To a solution of compound 12a (2 g, 13.74 mmol) in CHCl (20 mL) was added ICl (3.3 g, 20.61 mmol) at 0 °C. The resulting mixture was stirred at 27-34 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 100 / 1) to give compound 12b (2.5 g, 67% yield) as a brown solid.

[0238] LCMS: R t = 0.811 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18 25-2 mm), MS (ESI) m / z= 271.8 [M+H] + . 1 H NMR (400 MHz, methanol-d₄) δ 7.59 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 11.6 Hz, 1H). Procedure for preparing compound 12c: To a solution of compound 12b (450 mg, 1.66 mmol) in MeOH (10 mL) and DMF (20 mL) were added Pd(OAc) (38 mg, 0.17 mmol), DPPF (94 mg, 0.17 mmol), and EtN (504 mg, 4.98 mmol). The resulting mixture was degassed by purging with CO three times and then stirred at 80 °C under CO (50 Psi) for 24 h. The reaction mixture was filtered and diluted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 50 / 1 (v / v)) to give compound 12c (320 mg, 95% yield) as a white solid.

[0239] LCMS: R t = 0.941 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25- 2mm), MS (ESI) m / z= 203.9[M +H] + . 1 H NMR (400MHz, MeOH-d4) δ 7.83 (d, J=8.4 Hz, 1H), 6.59 (d, J=11.6 Hz, 1H), 3.85 (s, 3H). Procedure for preparing compound 12d: To a solution of compound 12c (320 mg, 1.57 mmol) in THF (10 mL) was added CHMgBr (2.62 mL, 7.85 mmol) at 0 °C. The resulting mixture was stirred at 26–31 °C for 2 h. The reaction mixture was diluted with saturated aqueous NHCl (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 (v / v)) to give compound 12d (250 mg, 78% yield) as a colorless oil.

[0240] LCMS: R t= 0.826 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25-2mm), MS (ESI) m / z= 185.9 [M+H-18] + . 1 H NMR (400MHz, MeOH-d4) δ 7.08 (d, J=8.4 Hz, 1H), 6.49 (d, J=11.6 Hz, 1H), 1.57 (s, 6H). Procedure for preparing compound 12e: To a solution of compound 12d (200 mg, 0.98 mmol) in CHCl (10 mL) was added DIEA (253 mg, 1.96 mmol) and 2,4-dichloro-1,3,5-triazine (162 mg, 1.08 mmol). The resulting mixture was stirred at 26–32 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 (v / v)) to give compound 12e (210 mg, 67% yield) as a white solid.

[0241] LCMS: R t = 0.971 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25-2mm), MS (ESI) m / z= 316.9 [M+H] + . Preparation of compound 12f: To a solution of compound 12e (210 mg, 0.66 mmol) and compound 2g (177 mg, 0.66 mmol) in n-BuOH (5 mL) was added TFA (0.05 mL). The resulting mixture was stirred at 26-33 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (CHCl / MeOH = 10 / 1 (v / v)) to give compound 12f (150 mg, 41% yield) as a brown oil.

[0242] LCMS: R t= 0.821 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 25-2mm), MS (ESI) m / z= 549.1[M+H] + . Procedure for preparing compound 12g: To a solution of compound 12f (150 mg, 0.27 mmol) in MeOH (5 mL) was added 10% Pd / C (15 mg). The resulting mixture was degassed by purging with H three times and then stirred under H (30 Psi) at 26-34 °C (room temperature) for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 12g (110 mg, 78% yield) as a brown solid.

[0243] LCMS: R t = 0.771 min / 5-95AB_1.5 min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 519.1 [M+H] + . Preparation procedure for Example 12: To a solution of compound 12g (110 mg, 0.21 mmol) and DIEA (41 mg, 0.32 mmol) in DMF (3 mL) was added acryloyl chloride (19 mg, 0.21 mmol). The resulting mixture was stirred at 0°C for 30 minutes. This reaction mixture was analyzed by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 50-80% B (A: 0.05% NH3H2O; B: CH3CN; flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 12 (13.5 mg, 11% yield) as a white solid. was obtained as a solid.

[0244] LCMS: R t = 2.167 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 573.0 [M+H] + . HPLC: t= 3.38 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.85 (br s, 1H), 10.45 (br s, 1H), 9.96 (br s, 1H), 8.43 (s, 1H), 8.39 (d, J=11.8 Hz, 1H), 7.72 (br s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.43-6.32 (m, 2H), 6.10 (br s, 1H), 5.81-5.73 (m, 1H), 3.88 (s, 3H), 2.91-2.85 (m, 2H), 2.70 (s, 3H), 2.35-2.20 (m, 8H), 1.78 (s, 6H). Example 13 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0245] [ka]

[0246] Procedure for preparing compound 13b: To a solution of compound 13a (0.92 g, 4.2 mmol) and BocO (3.17 g, 14.7 mmol) in THF (15 mL) was added DMAP (256 mg, 2.1 mmol) at 26-32° C. The reaction was stirred at 26-32° C. for 4 h. The reaction solution was concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (0-10% EtOAc in petroleum ether) to give the desired product: compound 13b (1.43 g, 81.2% yield) as an off-white solid.

[0247] LCMS: Rt = 1.078 min / 5-95AB_220&254.1 cm chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 442.1 [M+23]+. 1 H NMR (400MHz, CDCl3) δ 8.28 (d, J=1.6 Hz, 1H), 7.95 (dd, J=2.0, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 1.36 (s, 18H). Procedure for preparing compound 13c: To a solution of compound 13b (1.43 g, 3.41 mmol) in THF (25 mL) was added MeMgBr (4.54 mL, 13.63 mmol, 3 M in ether) dropwise in an ice-water bath. The mixture was stirred at 26-32 °C for 3 h. Saturated NH4Cl (30 mL) was added to the reaction, and the aqueous portion was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude residue, which was purified by column chromatography on silica gel (3-30% EtOAc in petroleum ether) to give the desired product: compound 13c (0.84 g, 77.8% yield) as a yellow solid.

[0248] LCMS: Rt = 0.889 min / 5-95AB_220&254.1 cm chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 246.0 [M+H]+. 1 H NMR (400 MHz, methanol-d4): δ 8.22 (d, J=8.8 Hz, 1H), 7.54-7.51 (m, 2H), 1.64 (s, 6H), 1.54 (s, 9H). Procedure for preparing compound 13d: To a solution of compound 13c (640 mg, 2.0 mmol) in CHCl (10 mL) was added dropwise HCl / EtOAc (20 mL, 4 M) in an ice-water bath. The mixture was stirred at 26-34 °C for 6 h. The reaction mixture was basified to pH = 8 with saturated NaHCO and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (3-30% EtOAc in petroleum ether) to give the desired product: compound 13d (260 mg, 45.1% yield) as a yellow oil.

[0249] LCMS: R t = 0.726 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 202.0 [M-17]+. 1 H NMR (400 MHz, methanol-d4): δ 7.33 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 1.63 (s, 6H). Procedure for preparing compound 13e: To a solution of compound 13d (260 mg, 1.18 mmol) and DIEA (304 mg, 2.56 mmol) was added 2,4-dichloro-1,3,5-triazine (267 mg, 1.78 mmol) at 0 °C. After stirring the reaction at 28-34 °C for 4 h, the reaction was quenched with saturated NH4Cl (5 mL), and the aqueous portion was extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (320 mg), which was purified by flash column chromatography (3-30% EtOAc in petroleum ether) to give compound 13e (200 mg, 50.8% yield) as a white solid.

[0250] LCMS: R t= 0.832 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 332.9 [M+H]+. Preparation of compound 13f: To a solution of compound 13e (200 mg, 0.61 mmol) and compound 2g (183 mg, 0.68 mmol) in n-BuOH (10 mL) was added TFA (0.8 mL) dropwise in an ice-water bath. The mixture was stirred at 28-34 °C for 2 h. The reaction solution was directly concentrated in vacuo to give a crude residue, which was purified by flash column chromatography on silica gel (eluting with 0-15% MeOH in dichloromethane) to give an impurity (350 mg), which was further purified by preparative TLC (MeOH / CHCl = 10 / 1) to give compound 13f (80 mg, 50.8% yield) as a brown solid.

[0251] LCMS: R t = 0.755 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 565.1 [M+H]+. 1 H NMR (400MHz, CDCl3): δ ppm 8.48-8.43 (m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.52-7.48 (m, 2H), 6.96 (s, 1H), 4.00 (s, 3H), 3.40 (t, J=6.4 Hz, 2H), 2.90 (s, 3H), 2.65 (t, J=6.4 Hz, 2H), 2.30 (s, 6H), 1.75 (s, 6H). Procedure for preparing compound 13g: A mixture of compound 13f (80 mg, 0.14 mmol) and Pd / C (70 mg, 10%) in EtOAc (30 mL) was stirred under H (15 psi) for 30 min. The reaction was filtered and the cake was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo to give compound 13g (60 mg, 80.0% yield) as a gray solid.

[0252] LCMS: R t = 0.712 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 535.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δ 9.83-9.80 (m, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.27-8.25 (m, 1H), 7.77 (s, 1H), 7.68-7.49 (m, 2H), 7.41 (s, 1H), 6.59 (s, 1H), 3.95(s, 3H), 2.88 (t, J=6.8 Hz, 2H), 2.59 (s, 3H), 2.37 (t, J=6.8 Hz, 2H), 2.35-2.34 (m, 2H), 2.25 (s, 6H), 2.21-2.20 (m, 1H), 1.67 (s, 6H). Preparation procedure for Example 13: To a mixture of compound 12g (60 mg, 0.112 mmol) and DIEA (29 mg, 0.224 mmol) in DMF (1 mL) was added compound acryloyl chloride (16.5 mg in 1 mL DMF) dropwise over 30 min in an ice-water bath. After stirring the reaction at 0-5 °C for 30 min, the reaction became a brown solution. The reaction was quenched with HO (45 mg) and then directly purified by preparative TLC (CHCl / MeOH = 10 / 1) to give Example 13 (18.2 mg, 27.5% yield) as a white solid.

[0253] LCMS: R t = 2.698 min / 0-60AB_4.0 min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 589.0 [M+H] + . 1H NMR (400MHz, CDCl3): δ 10.88 (br s, 1H), 10.37 (br s, 1H), 9.89 (br s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 7.64 (br s, 1H), 7.54-7.43 (m, 2H), 6.71 (s, 1H), 6.39-6.22 (m, 2H), 5.71 (br d, J=11.2 Hz, 1H), 3.81 (s, 3H), 2.81 (m, 2H), 2.63 (s, 3H), 2.21 (m, 8H), 1.75 (s, 6H). Example 14 N-(5-(4-(4-chloro-3-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0254] [ka]

[0255] Procedure for preparing compound 14b: A solution of compound 14a (5 g, 34.35 mmol) and BocO (15 g, 68.70 mmol) in THF (80 mL) was stirred for 12 h at 60° C. The reaction mixture was directly concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (2% EtOAc in petroleum ether) to give compound 14b (8.2 g, 69% yield) as a yellow solid.

[0256] LCMS: R t = 0.866 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18 2.5-2 mm). 1H NMR (400MHz, CDCl3) δ 7.36 (d, J=9.6 Hz, 1H), 7.19 (t, J=6.8 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.45 (s, 1H), 1.45 (s, 9H). Procedure for preparing compound 14c: To a solution of compound 14b (8 g, 32.56 mmol) in THF (120 mL) was added t-BuLi (1.3 M) (50 mL, 65.12 mmol) under N at −78°C. After stirring for 1 h, DMF (3.6 g, 48.84 mmol) was added, and the reaction mixture was stirred at −78 to 33°C for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (300 mL) and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give compound 14c (8.2 g, 92% yield) as a yellow solid.

[0257] LCMS: R t = 0.929 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm). 1 H NMR (400 MHz, methanol-d4) δ 10.49 (br s, 1H), 10.28 (s, 1H), 8.18 (dd, J = 0.8 Hz, 9.2 Hz, 1H), 7.48 (t, J = 8.8 Hz, 1H), 1.46 (s, 9H). Procedure for preparing compound 14d: To a solution of compound 14c (4 g, 14.62 mmol) in THF (40 mL) was added MeMgBr (3.0 M) (19.5 mL, 58.48 mmol) under N at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH Cl solution (80 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give compound 14d (4 g, 94% yield) as a yellow oil, which was used directly in the next step without further purification.

[0258] LCMS: R t = 0.871 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm). Procedure for preparing compound 14e: To a solution of compound 14d (4 g, 14.62 mmol) in CHCl (40 mL) was added DMP (9.3 g, 21.93 mmol) under N at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Saturated NaHCO solution (40 mL) and saturated NaSO solution (30 mL) were added, and the mixture was stirred at 25–33 °C for 30 min. The organic layer was separated and extracted with CHCl (30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (1% EtOAc in petroleum ether) to give compound 14e (2.5 g, 59% yield) as a yellow solid.

[0259] LCMS: R t = 0.924 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 187.9 [M-101+H] + . 1 H NMR (400MHz, CDCl3) δ 10.20 (br s, 1H), 8.19 (d, J=9.6 Hz, 1H), 7.47 (t, J=9.2 Hz, 1H), 2.67 (d, J=8.0 Hz, 1H), 1.52 (s, 9H). Preparation of compound 14f: To a solution of compound 14e (2.5 g, 8.69 mmol) in THF (40 mL) was added MeMgBr (3.0 M) (10 mL, 30.42 mmol) under N at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH Cl solution (80 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (0.5% EtOAc in petroleum ether) to recover compound 14e (1.2 g), which was subsequently eluted with 2% EtOAc in petroleum ether to give the title product 14f (1.5 g, 57% yield) as a yellow solid.

[0260] LCMS: R t = 1.066 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 270.1 [M-55+Na] + . 1 H NMR (400MHz, CDCl3) δ 9.67 (br s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.23 (t, J=8.4 Hz, 1H), 1.75 (d, J=3.6 Hz, 6 H), 1.51 (s, 9H). Procedure for preparing compound 14g: To a solution of compound 14f (1.5 g, 4.94 mmol) in CH2Cl2 (15 mL) was added TFA (5 mL) under N2 at 0 °C. The reaction mixture was stirred at 36-34 °C for 1 h. The reaction mixture was concentrated in vacuo to give compound 14g (700 mg, 94% yield) as a yellow oil.

[0261] LCMS: R t = 0.652 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 185.9 [M -OH] + . 1H NMR (400MHz, CDCl3) δ 6.92 (t, J= 8.0 Hz, 1H), 6.24 (dd, J= 1.2 Hz, 8.4 Hz, 1H), 1.65 (d, J= 3.6 Hz, 6H). Preparation of compound 14h: A solution of compound 14g (200 mg, 0.98 mmol) and compound 6e (294 mg, 0.98 mmol) in pyridine (1.5 mL) was stirred for 4 hours at 50° C. The reaction mixture was directly concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (EtOAc:petroleum ether=7:3 (v / v)) to give the title product 14h (150 mg, 21% yield) as a brown solid.

[0262] LCMS: R t = 0.864 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 467.0 [M+H] + . Preparation of compound 14i: A solution of compound 14h (150 mg, 0.32 mmol) and KCO (89 mg, 0.64 mmol) in DMF (3 mL) was added with N 1 ,N 1 ,N 2 To the reaction mixture was added 14i (240 mg, crude) as a yellow solid. The reaction mixture was stirred at 28-33° C. for 2 hours. The reaction mixture was poured into water (10 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with water (10 mL×3). The filter cake was dried under high vacuum to give compound 14i (240 mg, crude) as a yellow solid.

[0263] LCMS: R t = 0.738 min / 5-95AB_220&254 Chromatography (B: XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 549.1 [M+H] + . Preparation of compound 14j: To a solution of compound 14i (200 mg, 0.35 mmol) and NH4Cl (95 mg, 1.75 mmol) in MeOH (4 mL) and water (0.5 mL) was added Zn (115 mg, 1.75 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered, and the filtrate was poured into water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give compound 14j (180 mg, crude) as a black solid.

[0264] LCMS: R t = 0.699 min / 5-95AB_1.5min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 519.1 [M +H] + . Preparation procedure for Example 14: To a mixture of 14j (180 mg, crude, 0.35 mmol) and DIEA (90 mg, 0.70 mmol) in DMF (3 mL) was added acryloyl chloride (32 mg, 0.35 mmol) at 0 °C. The reaction mixture was stirred at 26-32 °C for 0.5 h. The reaction mixture was purified by preparative HPLC: [Column: Waters Xbridge 150*255 μm; Conditions: 65- The fractions containing the desired compound were lyophilized to give Example 14 (24.5 ml). g, 12% yield) as a white solid.

[0265] LCMS: R t = 2.204 min / 10-80CD_3min_220&254 Chromatography (B: XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 573.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ 11.61 (br s, 1H), 10.30 (br s, 1H), 9.86 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.66 (br s, 1H), 7.35-7.26 (m, 1H), 6.75 (br s, 1H), 6.40 (d, J=16.0 Hz, 1H), 6.01 (br s, 1H), 5.78 (d, J=11.2 Hz, 1H), 3.88 (s, 3H), 3.07-2.87 (m, 2H), 2.71 (s, 3H), 2.58-2.13 (m, 8 H), 1.87 (d, J=3.6 Hz, 6 H). HPLC: t =3.86 min / 10-80CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). Example 15 N-(5-(4-(4,5-dichloro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0266] [ka]

[0267] Procedure for preparing compound 15b: To a solution of compound 15a (2.0 g, 9.71 mmol) in EtOAc (40 mL) and MeOH (40 mL) was added TMSCHN2 (9.7 mL, 25.78 mmol, 2 M in hexanes). The mixture was stirred at 26-33 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to give compound 15b (2.0 g, 94.1% yield) as a white solid.

[0268] LCMS: R t= 0.988 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 187.8 [M-31] + . 1 H NMR (400MHz, CDCl3) δ 7.85 (s, 1H), 6.72 (s, 1H), 5.71 (br s, 2H), 3.80 (s, 3H). Procedure for preparing compound 15c: To a solution of compound 15b (1.0 g, 4.54 mmol) in THF (30 mL) was added CHMgBr (6 mL, 3 M in ether) at 0-5 °C. The mixture was stirred at 26-34 °C for 1.5 h (yellow solution). The reaction mixture was quenched by the addition of aqueous NHCl (20 mL) and then extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (3 × 100 mL) and concentrated under reduced pressure to give compound 15c (950 mg, 95% yield) as a white solid.

[0269] LCMS: R t = 0.867 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 201.8 [M-OH] + . 1 H NMR (400MHz, CDCl3) δ7.13 (s, 1H), 6.70 (s, 1H), 1.64 (s, 6H). Procedure for preparing compound 15d: To a solution of compound 15c (500 mg, 2.27 mmol) in pyridine (5 mL) was added compound 6e (749 mg, 2.50 mmol). The resulting mixture was stirred at 50 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC on silica gel (CHCl / MeOH = 15 / 1 (v / v)) to give compound 15d (300 mg, 29.2% yield) as a brown solid.

[0270] LCMS: R t= 0.991 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 483.1 [M+H] + . Procedure for preparation of compound 15e: A solution of compound 15d (300 mg, 0.62 mmol) and K2CO3 (171 mg, 1.24 mmol) in DMF (4 mL) was 1 ,N 1 ,N 2 To the resulting mixture was added 1,2-trimethylethane-1,2-diamine (76 mg, 0.74 mmol). The mixture was stirred at 28-33 °C for 2 hours. 10 mL of water was added to the reaction mixture and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by preparative TLC on silica gel (CHCl / MeOH = 15 / 1 (v / v)) to give compound 15e (250 mg, 71% yield) as a brown solid.

[0271] LCMS: R t = 0.745 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 565.1 [M+H] + . Preparation of compound 15f: To a solution of compound 15e (220 mg, 0.39 mmol) in MeOH (5 mL) and HO (1 mL) was added Zn (127 mg, 1.95 mmol) and NH4Cl (208 mg, 3.89 mmol). The mixture was stirred under N2 at 70 °C for 1.5 h (becoming a brown mixture). The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL), dried, and concentrated in vacuo to give compound 15f (190 mg, 91.4% yield).

[0272] LCMS: R t= 0.799 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 535.1 [M+H] + . Preparation procedure for Example 15: To a solution of compound 15f (190 mg, 0.35 mmol) and DIEA (69 mg, 0.53 mmol) in DMF (1 mL) was added acryloyl chloride (32 mg, 0.35 mmol) in DMF (1 mL). The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 25-55% B (A: 0.05% ammonia; B: CHCN; flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 15 (37.8 mg, 12.2% yield) as a white solid.

[0273] LCMS: R t = 5.084 min / 10-80CD_7MIN_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 589.3 [M+H] + . HPLC: t = 4.32 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, DMSO-d6) δ 10.32 (br s, 1H), 10.03 (s, 1H), 9.15 (br s, 1H), 8.42 (br s, 1H), 8.29 (br d, J=14.8 Hz, 2H), 7.38 (br s, 1H), 7.03 (br s, 1H), 6.43-6.34 (m, 1H), 6.33 (s, 1H), 6.25-6.13 (m, 1H), 5.73 (br d, J=11.6 Hz, 1H), 3.78 (s, 3H), 2.86 (br t, J=5.6 Hz, 2H), 2.72 (s, 3H), 2.37-2.30 (m, 2H), 2.21 (s, 6H), 1.52 (s, 6H). Example 16 N-(5-(4-(4-chloro-3,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0274] [ka]

[0275] Procedure for preparing compound 16b: To a solution of compound 16a (5.0 g, 28.89 mmol) in EtOAc (50 mL) and MeOH (50 mL) was added TMSCHN2 (29 mL, 57.76 mmol, 2 M in hexane) at 0-5 °C. The mixture was stirred at 28-36 °C (room temperature) for 1.5 h. The reaction mixture was concentrated under reduced pressure to give compound 16b (4.8 g, 82.5% yield) as a brown solid.

[0276] LCMS: R t = 0.882 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 187.8 [M+H] + . 1H NMR: (400MHz, CDCl3) δ 6.05-5.94 (m, 2H), 5.93-5.72 (m, 2H), 3.76 (s, 3H). Procedure for preparing compound 16c: A stirred solution of compound 16b (2.70 g, 14.42 mmol) in i-PrOH (50 mL) was cooled to 0 °C, and NCS (2.02 g, 15.15 mmol) was added portionwise. The resulting yellow suspension was stirred at 0 °C–30 °C for 12 h while being monitored by LCMS (gradually becoming clear). The reaction mixture was directly concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica gel (conditions: 65–75% B (A: 0.05% TFA in water; B: MeOH); flow rate: 40 mL / min)) to give compound 16c (1000 mg, 87.20% purity and 500 mg starting material) as a white solid.

[0277] LCMS: R t = 0.905 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 189.9 [M-32] + . 1 H NMR (400MHz, DMSO-d6) δ 7.04 (br s, 2H), 6.61 (dd, J=1.8, 11.8 Hz, 1H), 3.82 (s, 3H). Procedure for preparing compound 16d: A solution of compound 16c (500 mg, 2.26 mmol) in THF (10 mL) was added to CH3M gBr (3 mL, 3 M in ether) was added at 0-5 °C. The yellow solution was stirred at 24-29 °C for 1.5 h (yellow solution). The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (3 x 10 mL) and directly concentrated in vacuo to give compound 16d (450 mg, 74% yield) as a white solid.

[0278] LCMS: R t= 0.900 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 203.9 [M-OH] + . Procedure for preparation of compound 16e: To a solution of compound 16d (450 mg, 2.03 mmol) and DIEA (394 mg, 3.05 mmol) in CHCl (10 mL) was added 2,4-dichloro-1,3,5-triazine (335 mg, 2.23 mmol). The resulting white mixture was stirred at 24-29 °C (room temperature) for 2 h. The reaction mixture was quenched by the addition of aqueous NHCl (20 mL) and then extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL) and directly concentrated in vacuo to give compound 16e (500 mg, 30% yield) as a white solid.

[0279] LCMS: R t = 0.927 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 334.9 [M +H] + . Preparation of compound 16f: To a solution of three portions of compound 16e (100 mg x 3, 0.90 mmol) and compound 2g (80 mg, 0.30 mmol) in n-BuOH (2 mL), TFA (0.02 mL) was added. The resulting mixture was stirred at 25-33 °C for 3 h (red mixture). The reaction mixture was directly concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica gel (conditions: 87-89% B (A: 0.05% TFA in water; B: MeOH); flow rate: 40 mL / min)) to give compound 16f (150 mg, 97.18% purity, 30% yield) as a red solid.

[0280] LCMS: R t= 0.792 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 567.3[M +H] + . Procedure for preparing compound 16g: To a solution of compound 16f (150 mg, 0.26 mmol) in MeOH (5 mL) and HO (1 mL) was added Zn (87 mg, 1.32 mmol) and NH4Cl (142 mg, 2.65 mmol). The mixture was stirred under N2 at 70 °C for 1.5 h (black mixture). The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL), dried, and directly concentrated in vacuo to give compound 16g (120 mg, 84.6% yield) as a brown oil.

[0281] LCMS: R t = 0.802 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 537.1 [M+H] + . Preparation procedure for Example 16: To a solution of compound 16g (120 mg, 0.22 mmol) and DIEA (43 mg, 0.33 mmol) in DMF (1 mL) was added acryloyl chloride (20 mg, 0.22 mmol) in DMF (1 mL). The resulting brown mixture was stirred at 0°C for 30 minutes. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 62-92 % B (A: 0.05% ammonia; B: CHCN); flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 16 (27.6 mg, 21% yield) as a white solid.

[0282] LCMS: R t= 2.310 min / 10-80CD_3MIN_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 591.2 [M+H] + . HPLC: t = 4.78 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50mm. 1 H NMR (400MHz, DMSO-d6) δ11.23 (br s, 1H), 10.05 (br s, 1H), 9.24 (br s, 1H), 8.35-8.27 (m, 2H), 7.01 (s, 1H), 6.82 (br s, 1H), 6.42 (br s, 1H), 6.18 (br d, J=16.8 Hz, 1H), 5.72 (br d, J=10.8 Hz, 1H), 3.77 (s, 3H), 2.90 (br s, 2H), 2.77-2.68 (m, 3H), 2.45-2.31 (m, 2H), 2.24 (br s, 6H), 1.61 (br s, 6H). Example 17 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0283] [ka]

[0284] Procedure for preparing compound 17b: To a solution of compound 1d (200 mg, 0.444 mmol) and KCO (123 mg, 0.888 mmol) in DMSO (6 mL) was added compound 17a (67 mg, 0.533 mmol). The reaction mixture was stirred at 85 °C for 1 hour (the color changed from light yellow to orange). The reaction mixture was added dropwise to HO (80 mL) in an ice-water bath, and the precipitated solid was collected by filtration. The filter cake was washed with HO (15 mL x 3) and then dried under high vacuum to give compound 17b (200 mg, 81% yield) as an orange solid.

[0285] LCMS: Rt = 0.717 min / 5-95AB_220&254.1 cm chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z==557.1 [M+H]+. 1 H NMR (400MHz, methanol-d4) δ 8.24 (br s, 2H), 8.03 (br s, 1H), 7.21 (dd, J=8.4, 12.0 Hz, 1H), 6.58 (s, 1H), 4.56-4.39 (m, 1H), 3.96 (s, 3H), 3.61 (dt, J=6.8, 10.4 Hz, 1H), 3.18 (t, J=8.8 Hz, 1H), 3.07 (quin, J=7.6 Hz, 1H), 2.83 (t, J=8.8 Hz, 1H), 2.79-2.69 (m, 1H), 2.39 (dd, J=7.2, 9.6 Hz, 1H), 2.26 (s, 3H), 2.20 (dd, J=3.2, 10.0 Hz, 1H), 2.14-2.02 (m, 1H), 1.92 (dd, J=6.4, 12.4 Hz, 1H), 1.60 (s, 6H). Procedure for preparing compound 17c: To a solution of compound 17b (200 mg, 0.36 mmol) in MeOH (15 mL) was added Pd / C (10%, 20 mg). The reaction mixture was stirred under a H balloon (15 Psi) at 25-31 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give compound 17c (168 mg, 88.6% yield) as a grayish-green solid.

[0286] LCMS: Rt = 0.675 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=527.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.21 (br s, 2H), 7.47 (br s, 1H), 7.22 (dd, J=9.0, 12.4 Hz, 1H), 6.86 (s, 1H), 4.15-4.03 (m, 1H), 3.79 (s, 3H), 3.48-3.38 (m, 1H), 3.00-2.88 (m, 1H), 2.74-2.65 (m, 2H), 2.62 (d, J=10.0 Hz, 1H), 2.45 (dd, J=7.8, 9.2 Hz, 1H), 2.33 (s, 3H), 2.19-2.09 (m, 2H), 1.85-1.71 (m, 1H), 1.60 (s, 6H). Preparation procedure for Example 17: To a solution of compound 17c (155 mg, 0.294 mmol) and DIEA (57 mg, 0.441 mmol) in DMF (2 mL) was added acryloyl chloride (27 mg, 0.294 mmol) under ice-water bath. The resulting mixture was stirred at 5-10 °C for 0.5 h. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 30-60% B (A: 0.0 5% ammonia, B: CH3CN); flow rate: 25 ml / min) and lyophilized to give Example 17 (39.1 mg, 22.90% yield) as a white solid.

[0287] LCMS: Rt = 1.990 min / 10-80CD_3min_220&254. lcm chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=581.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 10.65 (br s, 1H), 9.90 (br s, 1H), 9.59 (br s, 1H), 8.40 (s, 1H), 8.32 (dd, J=8.0, 12.8 Hz, 1H), 7.67 (br s, 1H), 7.10 (dd, J=8.8, 12.0 Hz, 1H), 6.78 (s, 1H), 6.56-6.44 (m, 1H), 6.44-6.33 (m, 1H), 6.00 (br s, 1H), 5.76 (d, J=10.0 Hz, 1H), 3.87 (s, 3H), 3.68 (dd, J=4.4, 7.8 Hz, 1H), 3.22 (t, J=7.2 Hz, 1H), 2.93-2.78 (m, 3H), 2.72 (d, J=10.0 Hz, 1H), 2.29 (s, 5H), 1.90 (dd, J=4.4, 10.4 Hz, 1H), 1.87-1.80 (m, 1H), 1.76 (s, 6H). Example 18 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0288] [ka]

[0289] Procedure for preparing compound 18b: To a solution of compound 1d (200 mg, 1.0 equiv., 0.44 mmol) and K2CO3 (243 mg, 4.0 equiv., 1.76 mmol) in DMSO (5 mL) was added compound 18a (133 mg, 1.5 equiv., 0.66 mmol). The resulting mixture was stirred at 85 °C for 4 h, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The yellow precipitated solid was collected by filtration, dissolved in CHCl2 (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 18b (230 mg, 93% yield) as a yellow solid.

[0290] LCMS: R t = 0.754 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 559.3 [M+H]+. Preparation of compound 18c: To a solution of compound 18b (230 mg, 1.0 equiv., 0.41 mmol) in MeOH (10 mL) was added Pd / C (23 mg). The resulting mixture was degassed by purging with H three times and then stirred under a hydrogen balloon (15 psi) at 25-28 °C (room temperature) for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 18c (200 mg, 92% yield) as a brown solid.

[0291] LCMS: R t = 0.678 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25- 2mm), MS (ESI) m / z= 529.1 [M+H] + . Preparation procedure for Example 18: To a solution of compound 18c (200 mg, 1.0 equiv., 0.38 mmol) and DIEA (98 mg, 2.0 equiv., 0.76 mmol) in DMF (2.5 mL) was added acryloyl chloride (34 mg, 1.0 equiv., 0.38 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 30 min in an ice-water bath. The reaction mixture was purified by RP-HPLC (reverse-phase HPLC) [column: reverse-phase column; conditions: 50-70% B (A: 0.25% NH3HCO3; B: MeOH); flow rate: 40 mL / min]. The relevant fractions were concentrated under reduced pressure and lyophilized to give compound Example 18 (45.7 mg, 20% yield) as a white solid.

[0292] LCMS: R t = 1.716 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 583.2 [M+H] + . HPLC: t = 3.24 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.65 (br s, 1H), 9.89 (br s, 2H), 8.40 (s, 1H), 8.32 (dd, J=8.0, 12.8 Hz, 1H), 7.67 (br s, 1H), 7.10 (dd, J=8.4, 12.0Hz, 1H), 6.74 (s, 2H), 6.38 (d, J=16.8 Hz, 1H), 5.77 (br d, J=10.8 Hz, 1H), 3.88 (s, 3H), 3.06 (br s, 2H), 2.91-2.74 (m, 4H), 2.70 (s, 5H), 1.94 (br s, 4H), 1.76 (s, 6H). Example 19 (R)-N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0293] [ka]

[0294] Procedure for preparing compound 19a: To a solution of compound 1d (300 mg, 1.0 equiv., 0.67 mmol) and K2CO3 (926 mg, 10.0 equiv., 6.70 mmol) in DMSO (5 mL) was added (R)-1-(azetidin-2-yl)-N,N-dimethylmethanamine·TFA salt (2.0 g, 10.0 equiv., 6.70 mmol). The resulting mixture was stirred at 85 °C for 4 h, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The precipitated solid was collected by filtration, dissolved in CHCl2 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 19a (300 mg) as a yellow solid.

[0295] LCMS: R t = 0.734 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 567.2[M+Na] + . Procedure for preparing compound 19b: To a solution of compound 19a (300 mg, 1.0 equiv., 0.55 mmol) in MeOH (10 mL) was added Pd / C (30 mg). The resulting mixture was degassed by purging with H2 three times and then stirred under H2 (hydrogen balloon, 15 Psi) at 24-29 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 19b (270 mg) as a brown solid. Ta.

[0296] LCMS: Rt = 0.679 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 515.3[M+H] + . Preparation procedure for Example 19: To a solution of compound 19b (270 mg, 1.0 equiv., 0.52 mmol) and DIEA (134 mg, 2.0 equiv., 1.04 mmol) in DMF (2.5 mL) was added acryloyl chloride (47 mg, 1.0 equiv., 0.52 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 30 min in an ice-water bath. This reaction mixture was analyzed by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 20-50% B (A: 0.05% N] B: CH3CN; flow rate: 25 ml / min]. The fractions containing the desired compound were lyophilized to give Example 19 (77.5 mg) as a white solid.

[0297] LCMS: R t = 1.658 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 568.8 [M+H] + . HPLC: t = 2.89 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.49 (br s, 1H), 9.40 (br s, 1H), 8.94 (br s, 1H), 8.38 (s, 1H), 8.30 (dd, J=7.9, 12.9 Hz, 1H), 7.67-7.44 (m, 1H), 7.09 (dd, J=8.7, 12.2 Hz, 1H), 6.63 (s, 1H), 6.43-6.29 (m, 2H), 5.80 (br d, J=10.3 Hz, 1H), 4.30-4.17 (m, 1H), 3.90 (s, 3H), 3.86 (br s, 1H), 3.58 (q, J=8.0 Hz, 1H), 2.66 (dd, J=5.9, 12.9 Hz, 1H), 2.49-2.37 (m, 2H), 2.26 (s, 6H), 2.15-2.05 (m, 1H), 1.74 (s, 6H). Example 20 (R)—N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide

[0298] [ka]

[0299] Procedure for preparing compound 20b: To a solution of compound 1d (300 mg, 0.666 mmol) and KCO (184 mg, 1.332 mmol) in DMSO (6 mL) was added compound 20a (160 mg, 0.793 mmol). The reaction mixture was stirred at 85 °C for 6 h, during which time the color changed from light yellow to orange. The reaction mixture was added dropwise to HO (80 mL) in an ice-water bath, and a solid precipitated. The solid was collected by filtration. The filter cake was washed with HO (15 mL × 3) and dried in vacuo to give compound 20b (300 mg, 81% yield) as an orange solid.

[0300] LCMS: Rt = 0.731 min / 5-95AB_220&254.1 cm chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=559.1 [M+H]+. 1H NMR (400MHz, methanol-d4) δ 8.37 (br s, 1H), 8.27 (br s, 1H), 8.05 (br s, 1H), 7.22 (dd, J=8.8, 12.4 Hz, 1H), 6.83 (s, 1H), 3.97 (s, 3H), 3.54 (dd, J=5.2, 13.6 Hz, 1H), 3.23-3.00 (m, 2H), 2.90 (s, 3H), 2.67-2.54 (m, 1H), 2.44 (s, 3H), 2.29 (q, J=9.2 Hz, 1H), 2.12-1.97 (m, 1H), 1.81-1.68 (m, 2H), 1.60 (s, 6H), 1.57-1.47 (m, 1H). Procedure for preparing compound 20c: To a solution of compound 20b (300 mg, 0.537 mmol) in MeOH (15 mL) was added Pd / C (10%, 30 mg). The reaction mixture was stirred under a H balloon (15 Psi) at 25-31 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give compound 20c (260 mg, 79.4% yield) as a brown solid.

[0301] LCMS: Rt = 0.686 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z = 529.2 [M+H] + . Preparation procedure for Example 20: To a solution of compound 20c (260 mg, 0.427 mmol) and DIEA (83 mg, 0.64 mmol) in DMF (3 mL) was added acryloyl chloride (39 mg, 0.427 mmol) in an ice-water bath. The resulting mixture was stirred at 5-10 °C for 0.5 h. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 50-80% B (A: 0.05% ammonium hydroxide)). The product was purified by HPLC (HPLC: HCl, B: CH3CN; flow rate: 25 ml / min) and lyophilized to give Example 20 (44.4 mg, 17.9% yield) as a white solid.

[0302] LCMS: Rt = 2.208 min / 10-80CD_3min_220&254. lcm chromatography (XBridge Shield RP18 2.1*50mm), MS (ESI) m / z=583.3 [M+H] + . HPLC: t = 4.39 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, CDCl3) δ 10.58 (br s, 1H), 10.08 (br s, 1H), 10.01 (br s, 1H), 8.40 (s, 1H), 8.31 (dd, J=8.0, 13.2 Hz, 1H), 7.65 (br s, 1H), 7.10 (dd, J=8.8, 12.0 Hz, 1H), 6.71 (s, 1H), 6.39 (br s, 1H), 6.38 (br s, 1H), 6.04 (br s, 1H), 5.77 (t, J=5.6 Hz, 1H), 3.88 (s, 3H), 3.18-3.03 (m, 1H), 2.87-2.80 (m, 1H), 2.74 (s, 3H), 2.71-2.64 (m, 2H), 2.56 (s, 3H), 2.41-2.33 (m, 1H), 1.97 (qd, J=8.8, 12.4 Hz, 1H), 1.79-1.72 (m, 8H), 1.43-1.35 (m, 1H). Example 21 (R)-N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0303] [ka]

[0304] Procedure for preparing compound 21b: A solution of compound 1d (150 mg, 0.33 mmol), compound 21a (101 mg, 0.50 mmol), and K2CO3 (91 mg, 0.66 mmol) in DMSO (3 mL) was stirred at 90 °C for 3 h. The reaction mixture was poured into ice water (15 mL) and stirred for 30 min. The precipitated solid was collected and the filter cake was dissolved in CHCl2 (35 mL). The mixture was washed, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give compound 21b (220 mg, crude) as a yellow solid.

[0305] 1 H NMR (400MHz, CDCl3) δ 9.75 (br s, 1H), 8.88 (br s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.26 (s, 1H), 7.01 (dd, J=8.4 Hz, 12.0 Hz, 1H), 6.63 (s, 1H), 3.88 (s, 3H), 3.58-3.50 (m, 1H), 2.61-2.56 (m, 2H), 2.36-2.28 (m, 1H), 2.26-2.19 (m, 7H), 1.96-1.91 (m, 1H), 1.83-1.65 (m, 3H), 1.62 (s, 6H). Procedure for preparing compound 21c: A solution of compound 21b (200 mg, crude, 0.33 mmol) and Pd / C (20 mg) in MeOH (3 mL) was stirred under a H balloon at 25-31 °C for 1 h (dark mixture). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give compound 21c (180 mg, crude) as a green solid.

[0306] 1H NMR (400MHz, CDCl3) δ 9.75 (br s, 1H), 8.29-8.15 (m, 2H), 7.80-7.50 (m, 2H), 7.01 (dd, J=9.2 Hz, 12.4 Hz, 1H), 6.64 (s, 1H), 3.74 (s, 3H), 3.36-3.31 (m, 2H), 2.60-2.53 (m, 1H), 2.25-2.15 (m, 2H), 2.13 (s, 6H), 1.87-1.82 (m, 2H), 1.68-1.63 (m, 1H), 1.61-1.56 (m, 7H). Preparation procedure for Example 21: To a solution of compound 21c (180 mg, crude, 0.33 mmol) and DIEA (85 mg, 0.66 mmol) in DMF (3 mL) was added acryloyl chloride (30 mg, 0.33 mmol) dropwise at 0°C. The black mixture was stirred at 0°C for 1 hour. The reaction mixture was purified by preparative HPLC: [Column: Waters Xbridge 150*255 μm; Conditions: 40-70% B (A: 0.05% ammonia; B: CHCN; flow rate: 25 ml / min). Fractions containing the desired compound were lyophilized to give Example 21 (40.6 mg, 21% over three steps) as a white solid.

[0307] LCMS: R t = 1.856 min / 10-80AB_4min_ 220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 583.0 [M +H] + . 1H NMR (400MHz, CDCl3) δ 11.65 (br s, 1H), 10.06 (br s, 1H), 9.88 (s, 1H), 8.40 (s, 1H), 8.32 (dd, J=8.0 Hz, 12.8 Hz, 1H), 7.68 (s, 1H), 7.10 (dd, J=8.8 Hz, 12.4 Hz, 1H), 6.71 (s, 1H), 6.41-6.30 (m, 2H), 6.05 (br s, 1H), 5.78 (dd, J=3.2 Hz, 8.0 Hz, 1H), 3.86 (s, 3H), 3.33-3.28 (m, 2H), 3.02-2.93 (m, 1H), 2.29 (dd, J=8.0 Hz, 12.4 Hz, 1H), 2.17-2.07 (m, 7H), 2.01-1.84 (m, 3H), 1.76 (s, 6H), 1.72-1.64 (m, 1H). HPLC: t =3.26 min / 10-80AB_1.2ml Chromatography (Ultimate C18 3*50mm 3um). Example 22 N-(2-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-5-((4-((4,5-difluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0308] [ka]

[0309] Procedure for preparing compound 22b: To a solution of compound 22a (500 mg, 2.87 mmol) and KCO (793 mg, 5.74 mmol) in THF (20 mL) was added CD3I (624 mg, 4.30 mmol). The mixture was stirred at 26-33 °C for 1 h, and a white solid precipitated. CD3I (208 mg, 0.5 equiv., 1.43 mmol) was then added to the mixture, and the mixture was stirred at 26-33 °C for an additional 1 h. The reaction mixture was filtered, and the organic layer was concentrated under reduced pressure to give compound 22b (300 mg, 50% yield) as a colorless solid. LCMS: R t = 0.743 min / 0-60AB_2MIN_E.M Chromatography (Xtimate C18, 2.1 x 30mm, 3um), MS (ESI) m / z= 209.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 3.24-3.18 (m, 1H), 3.12 (t, J=6.8 Hz, 1H), 2.78 (br s, 3H), 2.62 (br t, J=6.7 Hz, 1H), 2.34-2.26 (m, 1H), 1.38 (s, 9H). Procedure for preparing compound 22c: To a solution of compound 22b (300 mg, 1.0 equiv., 1.44 mmol) in CHCl (5 mL) was added HCl-dioxane (5 mL, 4 M). The resulting mixture was stirred at 22-27 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 22c (250 mg, 95% yield) as a yellow oil.

[0310] LCMS: R t = 0.098 min / 0-60AB_2MIN_E.M Chromatography (Xtimate C18, 2.1 x 30mm, 3um), MS (ESI) m / z = 109.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 3.43-3.37 (m, 1H), 3.36-3.22 (m, 1H), 3.16 (br s, 2H), 2.56 (br s, 3H). Procedure for preparing compound 22d: To a solution of compound 22c (250 mg, 0.55 mmol) and K2CO3 (304 mg, 2.20 mmol) in DMSO (5 mL) was added compound 6d (250 mg, 1.38 mmol). The resulting mixture was stirred at 22-27 °C for 12 h, during which time its color changed from light brown to deep yellow. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (2 × 30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl2 / MeOH = 10 / 1) to give compound 22d (90 mg, 30% yield) as a yellow solid.

[0311] LCMS: R t = 2.414 min / 10-80AB_7min_220&254.1cm Chromatography (Xtimate C18 2.1 x 30mm), MS (ESI) m / z= 539.0 [M+H] + . Procedure for preparing compound 22e: To a solution of compound 22d (90 mg, 1.0 equiv., 0.17 mmol) in MeOH (10 mL) was added Pd / C (9 mg). The resulting mixture was degassed by purging with H2 three times and then stirred under a hydrogen balloon (15 Psi) at 23-28 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 22e (70 mg, 81% yield) as a colorless oil. The structure and purity were confirmed by LCMS (R t =0.698 minutes, 509.4[M+H] + ) was confirmed.

[0312] LCMS: R t= 0.698 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 509.4 [M+H] + . Preparation Procedure for Example 22: To a solution of compound 22e (70 mg, 0.14 mmol) and DIEA (36 mg, 0.28 mmol) in DMF (2.5 mL) was added dropwise a solution of compound acryloyl chloride (13 mg, 0.14 mmol) in DMF (0.5 mL) at 0° C. The resulting mixture was stirred in an ice-water bath at 0° C. for 30 minutes. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 15 Purification was performed by HPLC using a 500×255 μm column; conditions: 38-68% B (A: 0.05% NH 3 H 2 O; B: CH 3 CN); flow rate: 25 mL / min. Fractions containing the desired compound were lyophilized to give Example 22 (21.9 mg, 28% yield) as a white solid.

[0313] LCMS: R t = 1.790 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1 x 30mm), MS (ESI) m / z= 563.0 [M +H] + . HPLC: t = 3.06 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3 x 50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.68 (br s, 1H), 10.46 (br s, 1H), 9.97 (br s, 1H), 8.41 (s, 1H), 8.32 (dd, J=8.0, 12.8 Hz, 1H), 7.69 (br s, 1H), 7.11 (dd, J=8.8, 12.2 Hz, 1H), 6.78 (s, 1H), 6.44-6.30 (m, 2H), 6.11 (br s, 1H), 5.80-5.73 (m, 1H), 3.88 (s, 3H), 2.88 (br s, 2H), 2.71 (s, 3H), 2.29 (br s, 2H), 1.77 (s, 6H). Example 23 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0314] [ka]

[0315] Procedure for preparing compound 23b: A mixture of compound 1d (150 mg, 0.318 mmol), compound 23a (60 mg, 0.318 mmol), and KCO (175 mg, 1.27 mmol) in DMSO (2 mL) was stirred at 90° C. for 3 h (brown suspension). The reaction was quenched with ice water (8 mL), filtered, and the cake was washed with HO (5 mL) and dried under high vacuum to give compound 23b (180 mg, 74.3% yield) as a yellow solid.

[0316] LCMS: R t = 0.710 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 545.2 [M+H]+. 1H NMR (400MHz, CDCl3) δ 10.05 (br s, 1H), 8.98 (br s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.28 (m, 1H), 7.11-7.05 (m, 1H), 5.97 (s, 1H), 4.17 (d, J=8.0 Hz, 2H) , 3.93 (s, 3H), 3.67-3.63 (m, 2H), 2.95-2.88 (m, 1H), 2.57 (d, J=7.6 Hz, 2H), 2.43 (s, 6H), 1.69 (s, 6H). Procedure for preparing compound 23c: A mixture of compound 23b (180 mg, 0.33 mmol) and Pd / C (180 mg, 10%) in EtOAc (20 mL) and MeOH (5 mL) was stirred under a H balloon at 23-28 °C for 3 h (becoming a black mixture). The reaction was filtered, the cake was rinsed with EtOAc (50 mL), and the filtrate was concentrated in vacuo to give compound 23c (140 mg, 82.3% yield) as a yellow solid.

[0317] LCMS: R t = 0.660 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 515.2 [M+H]+. 1 H NMR (400MHz, CDCl3): δ ppm 9.63 (br s, 1H), 8.23-8.17 (m, 2H), 7.59 (s, 1H), 7.49 (s, 1H), 7.04-6.98 (m, 1H), 6.17 (m, 1H), 3.94 (t, J=7.2 Hz, 2H), 3.50 (s, 3H), 3.41 (t, J=7.6 Hz, 2H), 2.85-2.77 (m, 1H), 2.55-2.48 (m, 2H), 2.17 (s, 6H), 1.59 (s, 6H). Preparation procedure for Example 23: To a mixture of compound 23c (140 mg, 0.27 mmol) and DIEA (105 mg, 0.81 mmol) in DMF (3 mL) was added a solution of acryloyl chloride (29.9 mg, 0.33 mmol) in DMF (1 mL) dropwise over 1 h under ice-water bath. After stirring the reaction at 0-5 °C for 30 min (brown solution), the reaction was quenched with HO (0.1 mL) and the resulting solution was purified by preparative HPLC [Waters Xbridge 150*25.5 μm Conditions: 37-57% B (A: 0.05% ammonia; B: CHCN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 23 (32.4 mg, 20.9% yield) as a yellow solid.

[0318] LCMS: R t = 2.172 min / 0-60AB_4.0 min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 569.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.35-8.27 (m, 2H), 7.50 (s, 1H), 7.30-7.27 (m, 1H), 7.10-7.25 (m, 1H), 6.41-6.27 (m, 3H), 5.80 (d, J=10.0 Hz, 2H), 3.99 (t, J=7.6 Hz, 2H), 3.87 (s, 3H), 3.50 (t, J=7.2 Hz, 2H), 2.94-2.87 (m, 1H), 2.54 (d, J=8.0 Hz, 2H), 2.23 (s, 6H), 1.71 (s, 6H). HPLC: Rt=2.24 min. HPLC-P Venusil XBP C18 3*50 mm, method / 0-60AB_1.2 ML.MET Example 24 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl(2-(piperidin-1-yl)ethyl)amino)phenyl)acrylamide

[0319] [ka]

[0320] Procedure for preparing compound 24b: To a solution of compound 24a (1.0 g, 6.77 mmol) and methanamine (1.4 g, 20.31 mmol) in MeOH (10 mL) was added KOH (760 mg, 13.55 mmol) in 5 mL of water along with a catalytic amount of KI (225 mg, 1.35 mmol). The resulting mixture was heated at 50°C to 80°C for 18 h. The reaction was treated with HCl (1 M) to adjust the pH to 7 and then extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (3 x 10 mL), dried, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl / MeOH = 10 / 1 (v / v)) to give compound 24b (120 mg, 12.5% ​​yield) as a colorless oil.

[0321] LCMS: R t = 1.688 min (MSD TIC) / 10-80CD_4MIN (XBrige Shield RP18 2.1 x50mm), MS (ESI) m / z= 143.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 2.57-2.47 (m, 2H), 2.46-2.30 (m, 8H), 2.28-2.15 (m, 2H), 1.59-1.54 (m, 5H), 1.42 (br d, J=5.2 Hz, 2H). Procedure for preparing compound 24c: To a solution of compound 1d (190 mg, 0.42 mmol) and KCO (116 mg, 0.84 mmol) in DMSO (2 mL) was added compound 24b (60 mg, 0.42 mmol). The mixture was stirred at 28-33 °C for 2 h. The reaction mixture was purified by flash column chromatography on silica gel (conditions: 65-75% B (A: 0.05% TFA in water; B: MeOH); flow rate: 40 mL / min)) to give compound 24c (90 mg, 37.3% yield) as a red solid.

[0322] LCMS: R t = 0.805 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 573.2 [M+H] + . Procedure for preparing compound 24d: To a solution of compound 24c (90 mg, 0.16 mmol) in MeOH (3 mL) was added Pd / C (10 mg) under N protection. The black mixture was stirred at 26-33 °C for 1 h under a H balloon (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give compound 24d (70 mg, 82.1% yield) as a brown oil.

[0323] LCMS: R t = 0.764 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 543.1 [M-OH] + . Preparation procedure for Example 24: To a solution of compound 24d (70 mg, 0.13 mmol) and DIEA (25 mg, 0.19 mmol) in DMF (1 mL) was added a solution of acryloyl chloride (12 mg, 0.13 mmol) in DMF (1 mL). The resulting brown mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150 × 255 μm; conditions: 40-70 % B (A: 0.05% ammonia; B: CHCN); flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 24 (12.9 mg, 16.8% yield) as a white solid.

[0324] LCMS: R t = 5.224 min / 10-80CD_7MIN_ 220&254 Chromatography (XBrige Shield RP18 2.1*50 mm), MS (ESI) m / z= 597.3 [M+H] + . HPLC, t = 4.81, purity 96.87% (220nm); 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1 x50mm 5um). 1 H NMR (400MHz, DMSO-d6) δ10.26 (br s, 1H), 9.33 (s, 1H), 9.14 (br s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.26 (br s, 1H), 6.96 (br s, 1H), 6.59 (dd, J=10.4, 16.8 Hz, 1H), 6.31-6.12 (m, 2H), 5.72 (br d, J=10.4 Hz, 1H), 3.77 (s, 3H), 2.98 (br t, J=6.4 Hz, 2H), 2.70 (s, 3H), 2.40-2.22 (m, 6H), 1.57-1.44 (m, 10H), 1.37 (br d, J=4.0 Hz, 2H), 1.24 (br s, 1H). Example 25 N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0325] [ka]

[0326] Procedure for preparing compound 25b: To a solution of compound 1d (200 mg, 0.444 mmol) and KCO (123 mg, 0.888 mmol) in DMSO (4 mL) was added compound 25a (196 mg, 1.554 mmol). The pale yellow reaction mixture was stirred at 85 °C for 3 h (the color changed from brown to orange). The reaction mixture was added dropwise to HO (40 mL) in an ice-water bath, during which time a solid precipitated. The precipitated solid was collected by filtration, washed with HO (15 mL x 3), and then dried under high vacuum to give compound 25b (230 mg, 89.8% yield) as an orange solid.

[0327] LCMS: R t = 0.709 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z = 557.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δ 10.04 (br s, 1H), 8.30 (br s, 1H), 8.19 (s, 1H), 7.48 (br s, 1H), 7.06 (dd, J=8.4, 12.0 Hz, 1H), 6.37 (s, 1H), 4.45-4.33 (m, 1H), 3.92 (s, 3H), 3.53 (dt, J=6.4, 10.4 Hz, 1H), 3.15 (t, J=8.4 Hz, 1H), 3.01 (quin, J=7.2 Hz, 1H), 2.67 (t, J=8.8 Hz, 1H), 2.61-2.51 (m, 1H), 2.39 (br dd, J=6.4, 9.2 Hz, 1H), 2.23 (d, J=9.2 Hz, 1H), 2.19 (s, 3H), 2.12-1.99 (m, 1H), 1.86 (dd, J=6.0, 12.4 Hz, 1H), 1.65 (s, 6H). Procedure for preparing compound 25c: To a solution of compound 25b (230 mg, 0.338 mmol) in MeOH (15 mL) was added Pd / C (10%, 25 mg). The reaction mixture was stirred under a H balloon (15 Psi) at 22-28 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give compound 25c (180 mg, 82% yield) as a grayish-green oil.

[0328] LCMS: R t = 0.667 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z= 527.2 [M+H] + . Preparation procedure for Example 25: To a solution of compound 25c (170 mg, 0.33 mmol) and DIEA (64 mg, 0.50 mmol) in DMF (2 mL) was added acryloyl chloride (29 mg, 0.33 mmol) under ice-water bath. The resulting mixture was stirred at 5-10 °C for 0.5 h. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 30-60% B (A: 0.05% ammonia)). B: CH3CN; flow rate: 25 ml / min) and lyophilized to give Example 25 (48.0 mg, 25.1% yield) as a white solid.

[0329] LCMS: R t = 1.982 min / 10-80CD_3 min_220&254 (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=581.3 [M+H] + . HPLC: t = 3.94 Purity 96.04% (220nm); 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1*50mm 5um). 1H NMR (400MHz, CDCl3) δ 10.66 (br s, 1H), 9.92 (br s, 1H), 9.59 (br s, 1H), 8.40 (s, 1H), 8.33 (dd, J=8.0, 12.8 Hz, 1H), 7.68 (br s, 1H), 7.10 (dd, J=8.8, 12.0 Hz, 1H), 6.78 (s, 1H), 6.53-6.34 (m, 2H), 5.99 (br s, 1H), 5.76 (d, J=9.6 Hz, 1H), 3.87 (s, 3H), 3.72-3.60 (m, 1H), 3.21 (t, J=7.2 Hz, 1H), 2.92-2.78 (m, 3H), 2.71 (d, J=10.0 Hz, 1H), 2.33-2.31 (m, 1H), 2.29 (s, 3H), 2.23-2.17 (m, 1H), 1.90 (dd, J=4.0, 10.0 Hz, 1H), 1.87-1.80 (m, 1H), 1.76 (br s, 6H). Example 26 N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl(2-(piperidin-1-yl)ethyl)amino)phenyl)acrylamide

[0330] [ka]

[0331] Procedure for preparing compound 26b: To a solution of compound 26a (1.0 g, 6.77 mmol) in MeOH (10 mL) was added DIEA (1.8 g, 13.55 mmol) and methanamine hydrochloride (10 mL, 20.31 mmol, 2 M in THF). The resulting mixture was stirred for 18 h. The reaction was treated with HCl (1 M) to adjust the pH to 7 and then extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL), dried, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl / MeOH = 10 / 1 (v / v)) to give compound 26b (120 mg, 12.5% ​​yield) as a colorless oil.

[0332] LCMS: R t = 1.688 min / 10-80CD_4MIN (XBrige Shield RP18 2.1 x50mm), MS (ESI) m / z= 143.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 2.57-2.47 (m, 2H), 2.46-2.30 (m, 8H), 2.28-2.15 (m, 2H), 1.59-1.54 (m, 5H), 1.42 (br d, J=5.0 Hz, 2H). Procedure for preparing compound 26c: To a solution of compound 26b (197 mg, 0.42 mmol) and K2CO3 (116 mg, 0.84 mmol) in DMSO (2 mL) was added compound 11c (60 mg, 0.42 mmol). The mixture was stirred at 23-28 °C for 2 h. This was purified by Biotage flash reversed-phase C-18 column chromatography eluted with MeOH / HO (55%-60% MeOH in water). Purification by chromatography gave compound 26c (150 mg, 60.4% yield) as a red solid.

[0333] LCMS: R t= 0.826 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 589.1 [M+H] + . Procedure for preparing compound 26d: To a solution of compound 26c (150 mg, 0.26 mmol) in MeOH (5 mL) and HO (1 mL) was added Zn (87 mg, 1.32 mmol) and NH4Cl (142 mg, 2.65 mmol). The mixture was stirred under N2 at 70 °C for 1.5 h (black mixture). The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and then extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL), dried, and directly concentrated in vacuo to give compound 26d (120 mg, 84.4% yield) as a brown oil.

[0334] LCMS: R t = 0.783 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 559.1 [M-OH]+. Preparation procedure for Example 26: To a solution of compound 26d (120 mg, 0.21 mmol) and DIEA (42 mg, 0.32 mmol) in DMF (1 mL) was added a solution of acryloyl chloride (19 mg, 0.21 mmol) in DMF (1 mL) dropwise at 0° C. The resulting brown mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by Biotage flash reversed-phase C-18 column chromatography [conditions: 7 The resulting mixture was purified by elution with 5-80% B (A: 0.05% NHHCO aqueous solution; B: CHCN; flow rate: 40 ml / min). The fractions containing the desired compound were lyophilized to give Example 26 (47.2 mg, 35.9% yield) as a white solid.

[0335] LCMS: Rt = 5.365 min / 10-80CD_7MIN_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 613.3 [M+H] + . HPLC: Rt = 4.83, purity 97.09% (220nm), 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1 x 50mm 5um). 1 H NMR (400MHz, DMSO-d6) δ10.19 (br s, 1H), 9.34 (br s, 1H), 9.08 (br s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.26 (br s, 1H), 6.97 (br s, 1H), 6.60 (br s, 1H), 6.30 (s, 1H), 6.19 (br d, J=17.1 Hz, 1H), 5.72 (br d, J=10.3 Hz, 1H), 3.79 (s, 3 H), 2.98 (br s, 2H), 2.69 (s, 3H), 2.34 (br s, 6H), 1.57-1.31 (m, 13H). Example 27 (R)-N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0336] [ka]

[0337] Procedure for preparing compound 27a: To a solution of compound 1d (180 mg, 0.40 mmol) and K2CO3 (110.6 mg, 0.80 mmol) in DMSO (4 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (54.8 mg, 0.48 mmol). The resulting mixture was stirred at 24-27 °C for 2 h. This reaction mixture was combined with that of batch 1359-035 and stirred carefully. The mixture was poured into water (50 mL) to precipitate a yellow solid, which was collected by filtration, dissolved in CH2Cl2 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 27a (210 mg, 87% yield) as a yellow solid.

[0338] LCMS: R t = 0.705 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 545.1 [M+H] + . Procedure for preparing compound 27b: To a solution of compound 27a (210 mg, 0.39 mmol) in MeOH (5 mL) was added Pd / C (35 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 23-29 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 27b (170 mg, 84.7% yield) as a brown solid.

[0339] LCMS: R t = 0.667 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 515.2 [M+H] + . Preparation procedure for Example 27: To a solution of compound 27b (100 mg, 0.19 mmol) and DIEA (50 mg, 0.38 mmol) in DMF (2 mL) was added acryloyl chloride (17 mg, 0.19 mmol) in DMF (1 mL). The resulting mixture was stirred at 0 °C under an ice-water bath for 20 min. The reaction mixture was quenched with three drops of water and purified by preparative TLC (CHCl / MeOH = 7 / 1 (v / v)) to give the impure product (100 mg) as a white solid, which was purified by preparative HPLC (column: Waters Xbridge 150*255 μm: 30- Further purification by 60% B (A: water (0.05 (v / v)% ammonium hydroxide), B: CHCN), flow rate: 25 mL / min) gave Example 27 (15 mg, 13.9% yield) as a white solid.

[0340] LCMS: R t = 1.651 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z=568.9 [M+H] + . HPLC: t = 3.17 min / 10-80_CD_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.59 (br s, 1H), 9.80 (br s, 1H), 8.49 (br s, 1H), 8.40 (s, 1H), 8.33 (dd, J=8.0, 13.2 Hz, 1H), 7.64 (br s, 1H), 7.10 (dd, J=8.4, 1 2.2 Hz, 1H), 6.76 (s, 1H), 6.40-6.36 (m, 2H), 5.84-5.78 (m, 1H), 3.88 (s, 3H), 3.15-3.07 (m, 4H), 2.90 (br t, J=7.2 Hz, 1H), 2.31 (s, 6H), 2.19 (dt, J=7.2, 12.8 Hz, 1H), 2.00-1.90 (m, 1H), 1.76 (s, 6H), 3.87 (s, 3H), 2.40 (s, 6H). Example 28 N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0341] [ka]

[0342] Procedure for preparing compound 28b: To a solution of compound 11c (300 mg, 0.64 mmol) in DMSO (5 mL) were added potassium carbonate (450 mg, 3.25 mmol) and compound 28a (120 mg, 0.95 mmol). The mixture was stirred at 85° C. for 3 hours. The mixture was poured into ice water (30 mL), and a solid precipitated. The solid was isolated by suction filtration and dried in vacuo to give compound 28b (320 mg, 87% yield) as an orange solid.

[0343] LCMS: R t = 1.868 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18, 2.1 x30mm, 3um), MS (ESI) m / z = 573.2 [M+H] + . 1H NMR: (400MHz, CDCl3) δ 9.60 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.32 (s, 1H), 7.00 (d, J = 10.4 Hz, 1H), 6.32 (s, 1H), 4.40-4.29 (m, 1H), 3.88 (s, 3H), 3.53-3.43 (m, 1H), 3.18-3.08 (m, 1H), 3.01-2.90 (m, 1H), 2.61-2.55 (m, 1H), 2.47-2.40 (m, 1H), 2.39-2.33 (m, 1H), 2.24-2.17 (m, 1H), 2.13 (s, 3H), 2.05-1.95 (m, 1H), 1.86-1.75 (m, 1H), 1.62 (s, 6H). Procedure for preparing compound 28c: To a solution of compound 28b (200 mg, 0.35 mmol) in methanol / water (5 mL / 1 mL) was added NH4Cl (112 mg, 2.09 mmol) and Zn (114 mg, 1.75 mmol). The resulting mixture was stirred under nitrogen at 90 °C for 1 h. The mixture was poured into water (20 mL) and extracted with dichloromethane (15 mL x 4). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown gum, which was purified by flash column chromatography on silica gel (0-10% methanol in CHCl2) to give compound 28c (110 mg, 57.8% yield) as a green solid.

[0344] LCMS: R t = 0.716 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z = 543.0 [M+H] + . 1H NMR: (400MHz, DMSO-d6) δ 10.15 (s, 1H), 8.82 (br. s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.27 (d, J= 10.4 Hz, 1H), 6.80 (br. s, 3H), 6.29 (s, 1H), 4.28-4.20 (m, 1H), 3.69 (s, 3H), 3.07-2.95 (m, 2H), 2.70-2.59 (m, 2H), 2.53 (s, 3H), 2.49-2.36 (m, 2H), 2.32-2.18 (m, 1H), 2.15-2.02 (m, 1H), 1.85-1.72 (m, 1H), 1.52 (s, 6H). Preparation Procedure for Example 28: To a solution of compound 28c (90 mg, 0.17 mmol) in DMF (3 mL), DIEA (43 mg, 0.33 mmol) was added followed by acryloyl chloride (15 mg, 0.17 mmol) three times at 0 °C. This mixture was quenched with water and combined with the previous batch and analyzed by preparative HPLC (column: Waters Xbridge 150x25, 5 μm, conditions: 46% to 66% B( Further purification by elution with hexane (A: water / 10 mM NH4HCO3, B: CH3CN), flow rate: 25 mL / min) gave Example 28 (29.4 mg, 23.8% yield) as a white solid.

[0345] LCMS: R t = 1.870 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1 x 30mm), MS (ESI) m / z = 597.1 [M+H] + . HPLC: t = 3.84 min / 10-80_CD_1.2ml Chromatography (XBridge Shield RP 18 2.1 x 50mm 5um). 1H NMR (400MHz, CDCl3) δ 10.53 (s, 1H), 9.85 (s, 1H), 9.52 (s, 1H), 8.40 (d, J = 7.2 Hz, 1H), 8.34 (s, 1H), 7.60 (s, 1H), 7.02 (d, J = 10.8 Hz, 1H), 6.70 (s, 1H), 6.42 (br. s, 1H), 6.35-6.26 (m, 1H), 5.98 (br. s, 1H), 5.69 (d, J = 10.8 Hz, 1H), 3.79 (s, 3H), 3.65-3.53 (m, 1H), 3.19-3.09 (m, 1H), 2.85-2.73 (m, 3H), 2.72-2.56 (m, 1H), 2.31-2.08 (m, 5H), 1.84-1.75 (m, 2H), 1.69 (s, 6H). Example 29 N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0346] [ka]

[0347] Procedure for preparing compound 29b: To a solution of compound 11c (200 mg, 0.43 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMSO (5 mL) was added compound 29a (105 mg, 0.52 mmol). The resulting mixture was stirred at 85 °C for 4 hours, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The precipitated solid was collected by filtration, dissolved in CHCl2 (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 29b (230 mg, 93% yield) as a yellow solid.

[0348] LCMS: R t = 0.814 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 575.1 [M+H] + . Procedure for preparing compound 29c: To a solution of compound 29b (230 mg, 0.40 mmol) in MeOH (10 mL) and HO (2 mL) was added Zn (130 mg, 2.00 mmol) and NHCl (214 mg, 4.00 mmol). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was partitioned between EtOAc (2 × 10 mL) and water (10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound 29c (180 mg, 82% yield) as a white solid.

[0349] LCMS: R t = 0.766 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 545.1 [M +H] + . Preparation procedure for Example 29: To a solution of compound 29c (180 mg, 0.33 mmol) and DIEA (85 mg, 0.66 mmol) in DMF (2.5 mL) was added a solution of acryloyl chloride (30 mg, 0.33 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 30 min in an ice-water bath. The reaction mixture was purified by RP-HPLC (reverse-phase HPLC) [Column: reverse-phase column; Conditions: 42-72% B (A: 0.25% NH3HCO3; B: MeOH); Flow rate: 40 mL / min]. The relevant fraction was concentrated under reduced pressure and lyophilized to give Example 29 (47.4 mg, 20% yield) as a white solid.

[0350] LCMS: R t= 1.912 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1 x 30mm), MS (ESI) m / z= 599.0 [M+H] + . HPLC: t = 3.41 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3 x 50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.61 (br s, 1H), 10.06 (br s, 1H), 9.96 (br s, 1H), 8.48 (d, J=7.6 Hz, 1H), 8.43 (s, 1H), 7.69 (br s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.78 (s, 1H), 6.38 (br d, J=4.8 Hz, 2H), 6.13 (br s, 1H), 5.80-5.72 (m, 1H), 3.88 (s, 3H), 2.95 (br s, 2H), 2.69 (s, 3H), 2.55 (br s, 4H), 2.42 (br s, 2H), 1.83 (br s, 4H), 1.78 (s, 6H). Example 30 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide

[0351] [ka]

[0352] Procedure for preparing compound 30a: To a solution of compound 11c (180 mg, 0.386 mmol) and KCO (107 mg, 0.772 mmol) in DMSO (3 mL) was added (R)-N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (93 mg, 0.463 mmol). The reaction mixture was stirred at 85 °C for 1 hour (the color changed from yellow to deep orange). The reaction mixture was added dropwise to HO (40 mL) in an ice-water bath, and a solid precipitated. The solid was collected by filtration, washed with HO (15 mL x 3), and dried in vacuo to give compound 30a (227 mg, 82% yield) as an orange solid.

[0353] LCMS: R t = 0.743 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=575.1 [M+H]+. 1 H NMR (400MHz, CDCl3) δ 9.96 (br s, 1H), 8.88 (br s, 1H), 8.29 (br s, 2H), 7.51 (br s, 1H), 7.02 (d, J=10.4 Hz, 1H), 6.62 (s, 1H), 3.89 (s, 3H), 3.48-3.39 (m, 1H), 3.07 (dd, J=7.6, 13.2 Hz, 1H), 3.01-2.95 (m, 1H), 2.80 (s, 3H), 2.54-2.43 (m, 1H), 2.34 (s, 3H), 2.22-2.15 (m, 1H), 2.02-1.91 (m, 1H), 1.75-1.65 (m, 2H), 1.63 (s, 6H), 1.54-1.46 (m, 1H). Procedure for preparing compound 30b: To a solution of compound 30a (227 mg, 0.316 mmol) in MeOH / HO = 5 / 1 (5 mL) was added Zn (124 mg, 6.0 equiv., 1.896 mmol) and NH4Cl (101 mg, 1.896 mmol). The resulting mixture was heated at 90 °C for 1 h (color changed from orange to brown). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was dissolved in CHCl2 (20 mL), washed with water (15 mL x 3), dried over Na2SO4, and concentrated in vacuo to give compound 30b (170 mg, 98% yield) as a brown solid.

[0354] LCMS: R t = 0.700 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=545.2 [M+H] + . Preparation procedure for Example 30: To a solution of compound 30b (170 mg, 0.312 mmol) and DIEA (60 mg, 0.468 mmol) in DMF (2 mL) was added acryloyl chloride (28 mg, 0.312 mmol) under ice-water bath. The resulting mixture was stirred at 5-10 °C for 10 min. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 50-80% B (A: 0.05%)). A: ammonia, B: CH3CN; flow rate: 25 ml / min) and then freeze-dried to give Example 30 (78.1 mg, yield 41.8%).

[0355] LCMS: R t = 1.983 min / 10-80AB_4min_220&254. lcm chromatography (ACSSH-LCMS-D Xtimate C18 2.1*30mm), MS (ESI) m / z=599.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ 10.52 (br s, 1H), 10.09 (br s, 1H), 10.02 (br s, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.41 (s, 1H), 7.65 (br s, 1H), 7.09 (d, J=10.8 Hz, 1H), 6.71 (s, 1H), 6.39 (br s, 1H), 6.38 (br s, 1H), 6.11 (br s, 1H), 5.77 (t, J=5.6 Hz, 1H), 3.88 (s, 3H), 3.20-3.02 (m, 1H), 2.89-2.78 (m, 1H), 2.74 (s, 3H), 2.71-2.63 (m, 2H), 2.56 (s, 3H), 2.45-2.30 (m, 1H), 2.06-1.88 (m, 1H), 1.77 (br s, 6H), 1.73-1.69 (m, 2H), 1.45-1.32 (m, 1H). Example 31 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0356] [ka]

[0357] Procedure for preparing compound 31a: A solution of compound 11c (180 mg, 0.38 mmol), (R)-N,N-dimethyl-1-(pyrrolidin-2-yl)-methanamine dihydrochloride (74 mg, 0.58 mmol), and KCO (106.6 mg, 0.77 mmol) in DMSO (2 mL) was stirred for 1 h at 85° C. The reaction mixture was added to HO (10 mL) in an ice-water bath with stirring, and the precipitated solid was collected by filtration, then dissolved in DCM (30 mL), dried over NaSO, and concentrated in vacuo to give product 31a (310 mg, 88% yield) as an orange oil.

[0358] LCMS: R t = 0.758 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=575.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.79 (br s, 1H), 8.86 (br s, 1H), 8.34 (br s, 2H), 7.33 (br s, 1H), 7.05 (d, J=10.4 Hz, 1H), 6.68 (s, 1H), 4.13-3.98 (m, 1H), 3.93 (s, 4H), 3.70-3.58 (m, 1H), 3.58 (dt, J=6.0, 10.4 Hz, 2H), 2.46-2.31 (m, 2H), 2.05-1.93 (m, 1H), 1.92-1.79 (m, 9H), 1.73-1.62 (m, 6H). Procedure for preparing compound 31b: To a solution of compound 31a (300 mg, 0.52 mmol) in MeOH / HO = 5 / 1 (9 mL) was added Zn (170.55 mg, 2.61 mmol) and NH4Cl (139.5 mg, 2.61 mmol). The resulting mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was dissolved in CHCl2 (30 mL), washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give product 31b (160 mg, 56% yield) as a brown solid.

[0359] LCMS: R t = 0.693 min / 5-95AB_ 220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=545.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ 9.58 (br s, 1H), 8.35 (br d, J=7.2Hz, 1H), 7.81 (br s, 1H), 7.71-7.48 (m, 1H), 7.07 (br d, J=10.4 Hz, 1H), 6.71 (br s, 1H), 5.30 (s, 1H), 4.05-3.85 (m, 2H), 3.81 (br s, 3H), 3.52-3.33 (m, 2H), 2.69-2.59 (m, 2H), 2.29-2.15 (m, 8H), 1.68 (br d, J=4.4 Hz, 6H). Preparation procedure for Example 31: To a solution of compound 31b (90 mg, 0.165 mmol) and DIEA (31.9 mg, 0.53 mmol) in DMF (2 mL) was added acryloyl chloride (14.9 mg, 0.165 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with HO (0.1 mL) and then filtered. The combined filtrate was purified by preparative HPLC (column: Gemini 150*255 μm; mobile phase A: water (0.05 (v / v) % ammonium hydroxide)). Further purification by elution with hexane, mobile phase B: DMF, flow rate: 25 ml / min, gradient time: 10 min, profile description: 35% to 65%, gave Example 31 (20.1 mg, 11.4% yield) as a yellow solid.

[0360] LCMS: R t = 1.826 min / 10-80AB_4 min_220&254 Chromatography (ACSSH-LCMS-AS A: Xtimate C18, 2.1*30mm, 3um; B: XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=599.3 [M+H] + . HPLC: t = 3.98 10-80_CD_1.2ml.met XBridge Shield RP 18 2.1*50mm 5um. 1H NMR (400MHz, CDCl3) δ 10.59 (br s, 1H), 10.05 (br s, 1H), 9.89 (br s, 1H), 8.56-8.32 (m, 2H), 7.67 (br s, 1H), 7.09 (d, J=10.8 Hz, 1H), 6.69 (s, 1H), 6.37 (br s, 2H), 6.08 (br s, 1H), 5.86-5.72 (m, 1H), 3.86 (s, 3H), 3.31 (br s, 2H), 3.08-2.86 (m, 1H), 2.39 (br s, 1H), 2.29-2.13 (m, 6H), 2.09-1.91 (m, 3H), 1.76 (s, 8H). Example 32 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(6-(2-hydroxypropan-2-yl)-1-methyl-1H-indol-5-ylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide

[0361] [ka]

[0362] Procedure for preparing compound 32a: To a solution of 2-fluoro-4-methylbenzoic acid (10.0 g, 64.87 mmol) in EtOAc (100 mL) and MeOH (100 mL) was added TMSCHN2 (64.87 mL, 129.75 mmol, 2 M in hexane). The mixture was stirred at 28-36 °C (room temperature) for 1.5 h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 (v / v)). Purification by v)) gave compound 32a (9 g, 82.5% yield) as a white solid.

[0363] LCMS: R t= 0.780 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 169.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.76 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.4 Hz, 1H), 6.88 (d, J=12.0 Hz, 1H), 3.84 (s, 3H), 2.32 (s, 3H). Procedure for preparing compound 32b: To a solution of compound 32a (9.0 g, 53.52 mmol) in HSO (100 mL) was added KNO (10.8 g, 107.04 mmol) in several portions at 0-5 °C. The resulting mixture was stirred at 28-36 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1) to give compound 32b (10 g, 87% yield) as a brown solid.

[0364] LCMS: R t = 0.781 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z NA. 1 H NMR (400MHz, CDCl3) δ 8.66 (d, J=6.6 Hz, 1H), 7.16 (d, J=10.6 Hz, 1H), 3.98 (s, 3H), 2.69 (s, 3H). Procedure for preparing compound 32c: To a solution of compound 32b (6.0 g, 28.15 mmol) in DMSO (100 mL) were added the compounds dibenzylamine (8.3 g, 42.22 mmol) and DIEA (7.3 g, 56.29 mmol). The mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 (v / v)) to give compound 32c (4.8 g, 44% yield) as a brown solid.

[0365] LCMS: R t = 0.947 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 391.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.46 (s, 1H), 7.33–7.22 (m, 10H), 6.96 (s, 1H), 4.44 (s, 4H), 3.91 (s, 3H), 2.54 (s, 3H). Procedure for preparing compound 32d: To a solution of compound 32c (4.8 g, 12.30 mmol) in DMF (20 mL) was added DMF-DMA (4.4 g, 36.88 mmol), and the mixture was stirred at 150 °C for 2 h. The reaction mixture was concentrated under reduced pressure, then CHCl (20 mL) and Pd / C (480 mg) were added, and the mixture was stirred under a hydrogen atmosphere (15 Psi) for 2 h. The reaction was filtered, and CHCl (100 mL) and HO (300 mL) were added to the filtrate. The organic layer was separated, washed with brine (3 × 100 mL), dried, and concentrated in vacuo to give the crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 5 / 1 (v / v)) to give compound 32d (3.0 g, 66.7% yield) as a brown solid.

[0366] LCMS: R t= 1.395 min / 10-80AB_3MIN_220&254 Chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 371.2 [M +H] + . 1 H NMR (400MHz, DMSO-d6) δ 11.18 (br s, 1H), 7.98-7.93 (m, 1H), 7.63 (s, 1H), 7.42 (t, J=2.8 Hz, 1H), 7.35 (s, 2H), 7.34 (s, 2H), 7.31 (s, 1H), 7.27 (s, 1H), 7.25 (s, 2H), 7.23 (s, 1H), 7.18 (s, 1H), 6.31 (br s, 1H), 4.12 (s, 4H), 3.86 (s, 3H). Procedure for preparing compound 32e: Compound 32d (2.7 g, 7.29 mmol) and Cs2CO3 (7.1 g, 21.8 mmol) To a solution of 32e (37 mmol) in acetone (50 mL) was added CHCl (1.6 g, 10.93 mmol). The resulting suspension was stirred at 18–25°C for 18 h. The reaction mixture was filtered, and the filtrate was treated with aqueous NHCl (20 mL) and then extracted with CHCl (25 mL × 2). The combined organic layers were dried and concentrated under reduced pressure to give compound 32e (2.6 g, 92.9% yield) as a brown solid.

[0367] LCMS: R t = 0.849 min / 5-95AB_1.5MIN_220&254.1cm; Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 385.2 [M +H] + . Procedure for preparing compound 32f: To a solution of compound 32e (3.5 g, 9.10 mmol) in MeOH (50 mL) was added Pd / C (10%, 300 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 29-40 °C for 18 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 32f (1.6 g, 86.5% yield) as a brown solid.

[0368] LCMS: R t = 0.536 min / 5-95AB_1.5MIN_220&254.1cm Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 205.0 [M +H] + . 1 H NMR (400MHz, CDCl3) δ 7.91 (s, 1H), 7.11 (d, J=3.2 Hz, 1H), 6.87 (s, 1H), 6.24 (d, J=2.4 Hz, 1H), 5.31 (br s, 2H), 3.93 (s, 3H), 3.76 (s, 3H). Procedure for preparing compound 32g: To a solution of compound 32f (1.0 g, 4.90 mmol) in THF (50 mL) was added CHMgBr (8.2 mL, 3 M in ether) dropwise at 0–5°C. The mixture was stirred at 17–21°C for 1.5 h. The reaction mixture was quenched by the addition of aqueous NHCl (100 mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 20 / 1 (v / v)) to give compound 32g (700 mg, 70% yield) as a brown solid.

[0369] LCMS: R t = 0.865 min / 10-80AB_7min_220&254.1cm Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 186.9 [M-17]+ . 1 H NMR (400MHz, CDCl3) δ 7.14 (s, 1H), 6.98-6.96 (m, 2H), 6.27 (d, J=2.4 Hz, 1H), 4.11-3.80 (m, 2H), 3.74 (s, 3H), 1.77 (s, 6H). Preparation of compound 32h: To a solution of compound 32g (200 mg, 0.98 mmol) in DMF (3 mL) was added compound 6e (323 mg, 1.08 mmol). The resulting mixture was stirred at 50 °C for 2 hours. The reaction mixture was poured into ice water (50 mL) with stirring, and a yellow solid precipitated. The solid was collected by filtration, dissolved in CHCl (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 32h (380 mg, 83.1% yield) as a yellow solid.

[0370] LCMS: R t = 0.796 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 490.1 [M+Na] + . Preparation of compound 32i: A solution of compound 32h (300 mg, 0.64 mmol) in DMSO (4 mL) was 1 ,N 1 ,N 2 32i (280 mg, 80% yield) was obtained from the reaction mixture 32i (280 mg, 80% yield) as a yellow solid.

[0371] LCMS: R t= 0.703 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 550.2 [M+H] + . Preparation of compound 32j: To a solution of compound 32i (250 mg, 0.45 mmol) in MeOH (5 mL) was added Pd / C (25 mg, 10%) under N. The resulting black mixture was stirred at 15–21 °C for 1 h under a H balloon (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give compound 32j (200 mg, 84.7% yield) as a brown oil.

[0372] LCMS: R t = 0.653 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 520.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.47 (br s, 1H), 8.24 (s, 2H), 7.96 (br s, 1H), 7.73 (br s, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.67-6.64 (m, 1H), 6.50 (d, J=2.4 Hz, 1H), 3.81-3.79 (m, 6H), 3.49 (s, 3H), 2.91 (br t, J=6.8 Hz, 2H), 2.62 (s, 4H), 2.37 (br t, J=6.8 Hz, 2H), 2.26-2.22 (m, 6H), 1.77 (s, 6H). Preparation Procedure for Example 32: To a solution of compound 32j (200 mg, 0.38 mmol) and DIEA (75 mg, 0.58 mmol) in DMF (1 mL) was added acryloyl chloride (35 mg, 0.38 mmol) in DMF (1 mL) dropwise at 0° C. The resulting brown mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 3 0-50% B (A: 0.05% ammonia; B: CHCN); flow rate: 25 ml / min) and then lyophilized to give Example 32 (57.8 mg, 26.2% yield) as a white solid. LCMS: R t = 4.478 min / 10-80CD_7MIN_220&254 chromatograph (XBrige Shield RP18 2.1*50mm), MS (ESI) m / z= 574.3 [M+H] + . HPLC: t = 3.90 min / 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, CDCl3) δ 10.61 (br s, 1H), 10.42 (br s, 1H), 10.03 (br s, 1H), 8.41-8.39 (m, 2H), 7.59 (br s, 1H), 7.02 (d, J=2.8 Hz, 1H), 6.78 (s, 1H), 6.48-6.44 (m, 2H), 6.37-6.30 (m, 1H), 6.00 (br s, 1H), 5.78 (br d, J=10.8 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 2.88 (br t, J=5.2 Hz, 2H), 2.71 (s, 3H), 2.27 (s, 8H), 1.90 (s, 6H). Example 33 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0373] [ka]

[0374] Procedure for preparing compound 33a: To a solution of compound 11c (200 mg, 0.43 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMSO (4 mL) was added compound (R)-N,N-dimethylpyrrolidin-3-amine (59 mg, 0.51 mmol). The resulting mixture was stirred at 24-27 °C for 1 h. The reaction mixture was poured into water (50 mL), and a yellow solid precipitated. The yellow solid was collected by filtration, dissolved in CHCl2 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title product 33a (220 mg, 91% yield) as a yellow solid.

[0375] LCMS: R t = 0.789 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 583.1[M+Na] + . 1 H NMR (400MHz, CDCl3) δ 9.69 (br s, 1H), 8.91 (br s, 1H), 8.38 (br s, 2H), 7.35 (br s, 1H), 7.08 (d, J=10.4 Hz, 1H), 6.28 (s, 1H), 3.92 (s, 3H), 3.59-3.51(m, 1H), 3.37-3.31 (m, 1H), 3.23-3.18 (m, 1H), 3.15-3.07(m, 1H), 2.86-2.75 (m, 1H), 2.29 (s, 6H), 2.25-2.15 (m, 1H), 1.99-1.88 (m, 1H), 1.69 (s, 6H). Procedure for preparing compound 33b: To a solution of compound 33a (220 mg, 0.39 mmol) and Zn (224 mg, 4.19 mmol) in MeOH / HO (6 mL, 5 / 1) was added NH4Cl (236 mg, 3.6 mmol). The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo to give a residue which was dissolved in CHCl (20 mL), washed with water (15 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give the title product 33b (180 mg, 87% yield) as a brown solid.

[0376] LCMS: R t = 0.732 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 531.2[M+H] + . Preparation Procedure for Example 33: To a solution of compound 33b (180 mg, 0.34 mmol) and DIEA (66 mg, 0.51 mmol) in DMF (2 mL) was added dropwise a solution of acryloyl chloride (31 mg, 0.34 mmol) in DMF (0.5 mL). The resulting mixture was stirred in an ice-water bath at 0°C for 20 minutes. The reaction mixture was quenched with three drops of water and purified by preparative HPLC (column: Waters Xbridge 150*255μm:30~60% B(A:Water(0.05(v / v)% hydroxy acid Purification by HCl (ammonium chloride, B: CH3CN, flow rate: 25 mL / min) gave the title product Example 33 (53.6 mg, 27% yield) as a white solid.

[0377] LCMS: R t = 1.726 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z=584.9 [M+H] + . HPLC: t = 2.85 min / 10-80_CD_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400 MHz, CDCl3) δ 10.53 (br s, 1H), 9.79 (br s, 1H), 8.54-8.45 (m, 2H), 8.41 (s, 1H), 7.64 (br s, 1H), 7.09 (d, J=10.8 Hz, 1H), 6.75 (s, 1H), 6.40-6.35 (m, 2H), 5.84-5.79 (m, 1H), 3.87 (s, 3H), 3.14-3.06 (m, 4H), 2.93-2.84 (m, 1H), 2.30 (s, 6H), 2.23-2.13 (m, 1H), 2.00-1.90 (m, 1H), 1.76 (s, 6H). Example 34 N-(5-(4-(4-cyclopropyl-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0378] [ka]

[0379] Procedure for preparing compound 34b: To a solution of compound 34a (1.0 g, 4.91 mmol) in dioxane (20 mL) and HO (4 mL) was added cyclopropylboronic acid (1.1 g, 12.28 mmol), followed by Pd(OAc) (772 mg, 3.44 mmol), PCy (1.9 g, 6.87 mmol), and CsCO (4.8 g, 3.0 equiv., 14.73 mmol) under a N atmosphere. The resulting mixture was degassed with N for 1 min and stirred at 100 °C under microwave irradiation for 1 h. The reaction mixture was filtered, diluted with EtOAc (50 mL), washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (petroleum ether / EtOAc = 100 / 1 (v / v)) to give compound 34b (700 mg, 68% yield) as a brown solid.

[0380] LCMS: R t = 0.797 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 209.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.45 (d, J=8.8 Hz, 1H), 6.41 (d, J=12.4 Hz, 1H), 3.82 (s, 3H), 1.88-1.81 (m, 1H), 0.89-0.81 (m, 2H), 0.60-0.50 (m, 2H). Procedure for preparing compound 34c: To a solution of compound 34b (700 mg, 3.35 mmol) in THF (10 mL) was added CHMgBr (5.58 mL, 16.75 mmol) at 0° C. The resulting mixture was stirred at 24–26° C. for 2 h. The reaction mixture was diluted with saturated aqueous NHCl (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1) to give compound 34c (450 mg, 64% yield) as a colorless oil.

[0381] LCMS: R t = 0.672 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 191.9 [M+H-18] + . 1 H NMR (400MHz, DMSO-d6) δ 6.65-6.56 (m, 1H), 6.34 (d, J=12.8 Hz, 1H), 1.84-1.72 (m, 1H), 1.44 (s, 6H), 0.82-0.75 (m, 2H), 0.55-0.48 (m, 2H). Procedure for preparing compound 34d: A solution of compound 34c (400 mg, 1.91 mmol) in CH2Cl2 (10 mL) was added with DIEA (494 mg, 3.82 mmol) and 2,4-dichloro-1,3,5-triazine. (315 mg, 2.10 mmol) was added. The resulting mixture was stirred at 24-27° C. for 2 hours. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc=10 / 1 (v / v)) to give compound 34d (450 mg, 73% yield) as a colorless oil.

[0382] LCMS: R t = 0.999 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 323.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.69–8.44 (m, 1H), 7.99 (br d, J=14.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 2.08–2.02 (m, 1H), 1.59 (s, 6H), 1.02–0.93 (m, 2H), 0.77–0.68 (m, 2H). Procedure for preparing compound 34e: To a solution of compound 34d (450 mg, 1.39 mmol) and B (259 g, 1.39 mmol) in n-BuOH (5 mL) was added TFA (0.05 mL). The resulting mixture was stirred at 25-30 °C for 3 h, during which time a gray solid precipitated. The reaction mixture was filtered, and the filter cake was washed with 30 mL of petroleum ether and dried under reduced pressure to give compound 34e (450 mg, 68% yield) as a gray solid.

[0383] LCMS: R t = 0.890 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 473.2 [M +H] + . 1 H NMR (400MHz, methanol-d4) δ 8.80 (s, 1H), 8.31 (br s, 1H), 8.16-7.58 (m, 1H), 7.15 (d, J=12.8 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 1.99 (br s, 1H), 1.59 (s, 6H), 0.95 (br d, J=7.2 Hz, 2H), 0.74-0.67 (m, 2H). Procedure for preparing compound 34f: A solution of compound 34e (150 mg, 0.32 mmol) and KCO (88 mg, 0.64 mmol) in DMSO (5 mL) was added with N 1 ,N 1 ,N 2 To the resulting mixture was added 34f (150 mg, 84% yield) as a yellow solid. The resulting mixture was stirred at 22-32 °C for 12 h, during which time its color changed from light brown to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The precipitated solid was filtered, dissolved in CHCl (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 34f (150 mg, 84% yield) as a yellow solid.

[0384] LCMS: R t = 0.831 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 555.2 [M +H] + . Procedure for preparing compound 34g: To a solution of compound 34f (150 mg, 0.27 mmol) in MeOH (10 mL) was added Pd / C (15 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 23-29 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 34g (130 mg, 92% yield) as a brown oil.

[0385] LCMS: Rt = 0.765 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 525.1 [M +H] + . Preparation procedure for Example 34: To a solution of compound 34g (130 mg, 0.25 mmol) and DIEA (85 mg, 0.66 mmol) in DMF (2.5 mL) was added acryloyl chloride (30 mg, 0.33 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 30 min under an ice-water bath. The reaction mixture was purified by RP-HPLC (reverse-phase HPLC) [column: reverse-phase column; conditions: 0-30% B (A: 0.25% NH3HCO3; B: MeOH); flow rate: 40 mL / min] and then lyophilized to give Example 34 (24.4 mg, 17% yield) as a white solid.

[0386] LCMS: R t = 1.994 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 601.3 [M+Na] + . HPLC: t = 3.41 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.72 (br s, 1H), 10.39 (br s, 1H), 9.97 (br s, 1H), 8.41 (s, 1H), 8.11 (d, J=12.4 Hz, 1H), 7.66 (br s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.45-6.30 (m, 2H), 5.93 (br s, 1H), 5.79-5.72 (m, 1H), 3.88 (s, 3H), 2.92-2.83 (m, 2H), 2.70 (s, 3H), 2.33-2.23 (m, 8H), 2.06-1.97 (m, 1H), 1.76 (s, 6H), 0.97-0.86 (m, 2H), 0.73-0.65 (m, 2H). Example 35 (S)-N-(5-(4-(4,5-difluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-((dimethylamino)methyl)morpholino)-4-methoxyphenyl)acrylamide

[0387] [ka]

[0388] Procedure for preparing compound 35b: To a solution of compound 35a (1.4 g, 6.44 mmol) in CHCl (40 mL) was added DMP (4.1 g, 9.67 mmol) in small portions at 0–5° C. The resulting white mixture was stirred at 0–5° C. for 1 h. The reaction was treated with aqueous NaHCO (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 5 / 1 (v / v)) to give compound 35b (1.1 g, 79.7% yield) as a pale yellow oil.

[0389] 1 H NMR (400MHz, DMSO-d6) δ 9.60 (br d, J=10.0 Hz, 1H), 4.52-4.36 (m, 2H), 3.94-3.67 (m, 2H), 3.60 (dd, J=4.4, 12.2 Hz, 2H), 3.05-2.79 (m, 1H), 1.43-1.36 (m, 9H). Procedure for preparing compound 35c: To a solution of compound 35b (1.0 g, 4.65 mmol) in MeOH (10 mL) was added MeN.HCl (1.1 g, 13.94 mmol), NaOAc (572 mg, 6.97 mmol), and the white mixture was stirred at 24-26 °C for 2 h. NaBHCN (584 mg, 9.29 mmol) was then added, and the resulting mixture was stirred at 22-27 °C for 18 h. The reaction mixture was quenched by the addition of aqueous NHCl (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried. Drying and concentration in vacuo gave compound 35c (800 mg, 70.5% yield) as a colorless oil.

[0390] LCMS: R t = 2.519 min / 10-80CD_4MIN_E.M, XBrige Shield RP18 2.1*50mm, MS (ESI) m / z= 245.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 3.99-3.63 (m, 2H), 3.46-3.33 (m, 1H), 2.98 (br s, 1H), 2.71 (br t, J=10.8 Hz, 1H), 2.31-2.18 (m, 6H), 1.41 (s, 9H). Procedure for preparing compound 35d: To a solution of compound 35c (500 mg, 2.30 mmol) in CHCl (6 mL) was added TFA (2 mL). The resulting colorless solution was stirred at 22-32 °C for 3 h. The reaction solution was directly concentrated in vacuo to give the TFA salt of compound 35d (300 mg, 61.1% yield) as a colorless oil.

[0391] LCMS: R t = 0.306 min / 10-80CD_4MIN_E.M; XBrige Shield RP18 2.1*50mm, MS (ESI) m / z= 145.2 [M-OH] + . Procedure for preparing compound 35e: To a solution of compound 35d (187 mg, 0.42 mmol) and K2CO3 (116 mg, 0.84 mmol) in DMSO (2 mL) was added compound 1d (60 mg, 0.42 mmol). The mixture was stirred at 28-33 °C for 2 h. The mixture was eluted with MeOH / HO (56%-60% MeOH in water) on a Biotage flash reversed-phase C-18 column. Direct purification by HPLC gave the desired product 35e (50 mg, 20.9% yield) as a red solid, which was used directly in the next step.

[0392] Procedure for preparing compound 35f: To a solution of compound 35e (90 mg, 0.16 mmol) in MeOH (3 mL) was added Pd / C (10 mg) under N protection. The black mixture was stirred at 26-33 °C for 1 h under a hydrogen balloon (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give compound 35f (70 mg, 82.1% yield) as a brown oil.

[0393] LCMS: R t = 1.791 min / 10-80CD_3MIN_220&254; XBrige Shield RP18 2.1*50mm MS (ESI) m / z= 545.3 [M+H]+. Preparation procedure for Example 35: To a solution of compound 35f (70 mg, 0.13 mmol) and DIEA (25 mg, 0.19 mmol) in DMF (1 mL) was added a solution of acryloyl chloride (12 mg, 0.13 mmol) in DMF (1 mL). The resulting brown mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm; conditions: 35-6 5% B (A: 0.05% ammonia; B: CHCN); flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 35 (11.9 mg, 16.8% yield) as a white solid.

[0394] LCMS: Rt = 1.816 min / 10-80CD_3MIN_220&254; XBrige Shield RP18 2.1*50mm, MS (ESI) m / z= 599.3 [M+H] + . HPLC, Rt = 3.45 min, purity 92.56% (220nm), 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, DMSO-d6) δ 10.29 (br s, 1H), 9.14 (s, 2H), 8.31 (s, 1H), 8.27 (s, 1H), 7.26 (br s, 1H), 7.11 (s, 1H), 6.64 (br dd, J=10.4, 17.1 Hz, 1H), 6.27 (s, 1H), 6.18 (br d, J=16.8 Hz, 1H), 5.73 (br d, J=10.4 Hz, 1H), 4.02 (br d, J=9.2 Hz, 1H), 3.78 (s, 5H), 3.55-3.48 (m, 1H), 3.28 (br s, 1H), 2.85 (br s, 2H), 2.68 (br s, 1H), 2.34 (s, 1H), 2.25 (br t, J=11.2 Hz, 1H), 2.01 (s, 6H), 1.92 (br d, J=9.2 Hz, 1H), 1.52 (br s, 6H). Example 36 (N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide)

[0395] [ka]

[0396] Procedure for preparing compound 36a: To a solution of compound 11b (500 mg, 2.46 mmol) and DIEA (634 mg, 4.92 mmol) in isopropanol (10 mL) was added 2,4-dichloropyrimidine (442 mg, 2.95 mmol). The resulting mixture was heated at 90° C. for 27 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (25-40% EtOAc in petroleum ether) to give compound 36a (390 mg, 50.14% yield) as an off-white solid.

[0397] LCMS: Rt = 0.796 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=315.9 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.12 (d, J=6.0 Hz, 1H), 8.08 (br d, J=6.8 Hz, 1H), 7.31 (d, J=10.8 Hz, 1H), 6.70 (d, J=6.0 Hz, 1H), 1.57 (s, 6H). Procedure for preparing compound 36b: A solution of compound 36a (760 mg, 2.4 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (448 mg, 2.4 mmol) in TFA / n-BuOH = 1 / 10 (11 mL) was heated at 50 ° C. for 4 h, and an additional 30 mg of compound 4-fluoro-2-methoxy-5-nitroaniline was added, and the reaction time was extended for another 22 h at 50 ° C. The reaction mixture was filtered, and the solid cake was washed with petroleum ether (20 mL × 3) and then dried under high vacuum to give compound 36b (960 mg, 86% yield) as an off-white solid.

[0398] LCMS: R t = 0.753 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=466.1 [M+H]+ . 1 H NMR (400MHz, methanol-d4) δ 8.52 (d, J=8.0 Hz, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.33 (d, J=10.8 Hz, 1H), 7.20 (d, J=12.8 Hz, 1H), 6.48 (d, J=7.2 Hz, 1H), 4.00 (s, 3H), 1.59 (s, 6H). Procedure for preparing compound 36c: A solution of compound 36b (200 mg, 0.43 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMF (3 mL) was added with N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (66 mg, 0.644 mmol) was added. The reaction mixture was heated at 22-32°C. The mixture was stirred for 15 hours (the color changed from brown to deep orange). The reaction mixture was added dropwise to 40 mL of H2O under ice-water bath with stirring, and a solid precipitated. The solid was collected by filtration, washed with 3 x 15 mL of H2O, and then dried under high vacuum to give compound 36c (210 mg, 89% yield) as an orange solid.

[0399] LCMS: R t = 0.669 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=548.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.60 (s, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.26 (d, J=10.8 Hz, 1H), 6.82 (s, 1H), 6.20 (d, J=6.0 Hz, 1H), 3.99 (s, 3H), 3.24 (t, J=7.4 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.28 (s, 6H), 1.59 (s, 6H). Procedure for preparing compound 36d: To a solution of compound 36c (200 mg, 0.365 mmol) in MeOH / HO = 5 / 1 (5 mL) was added Zn (143 mg, 2.190 mmol) and NH4Cl (117 mg, 2.190 mmol). The resulting mixture was heated at 90 °C for 2 h (color changed from orange to brown). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was dissolved in CHCl2 (20 mL), washed with water (15 mL x 3), dried over Na2SO4, and concentrated in vacuo to give compound 36d (170 mg, 89.9% yield) as a brown solid.

[0400] LCMS: R t = 0.646 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=518.2 [M+H] + . Preparation Procedure for Example 36: To a solution of compound 36d (170 mg, 0.329 mmol) and DIEA (64 mg, 0.494 mmol) in DMF (2 mL) was added acryloyl chloride (30 mg, 1.0 equiv., 0.329 mmol) in an ice-water bath. The resulting mixture was stirred at 5–10 °C for 10 min. The reaction was quenched with HO (0.1 mL) and filtered. The filtrate was purified by preparative HPLC (Column: Xtimate C18 150 × 25 mm × 5 μm; Conditions: 53–83% B (A: 0.04% NH HO + 10 mM NHHCO , B: CH CN); Flow rate: 25 mL / min) and lyophilized to give Example 36 (17.0 mg, 8.1% yield) as an off-white solid.

[0401] LCMS: R t= 2.356 min / 10-80CD_3 min_220&254 Chromatography (ACSSH-LCMS-AS A:Xtimate C18,2.1*30mm,3um; B:XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=572.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 10.34 (br s, 1H), 9.72 (s, 1H), 9.43 (s, 1H), 8.02 (d, J=6.0 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.08 (d, J=10.8 Hz, 1H), 6.69 (s, 1H), 6.36-6.21 (m, 3H), 6.02 (br s, 1H), 5.70-5.63 (m, 1H), 3.79 (s, 3H), 2.85-2.78 (m, 2H), 2.61 (s, 3H), 2.20 (s, 8H), 1.66 (s, 6H). Example 37 N-(2-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-5-((4-((4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0402] [ka]

[0403] Procedure for preparing compound 37b: To a solution of compound 37a (500 mg, 2.87 mmol) and KCO (793 mg, 5.74 mmol) in three portions in THF (10 mL) was added CDI (624 mg, 4.30 mmol). The mixture was stirred at 24–26 °C for 1 h, during which time a white solid precipitated. The three reaction mixtures were filtered, and the organic layer was concentrated under reduced pressure to give a crude residue that was diluted with EtOAc (20 mL), washed with HO (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 37b (350 mg, 19% yield) as a colorless oil.

[0404] LCMS: R t = 0.744 min / 0-60AB_2MIN_E.M Chromatography (Xtimate C18, 2.1*30mm, 3um), MS (ESI) m / z= 209.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 3.19-3.13 (m, 1H), 3.13-3.10 (m, 1H), 2.68 (br d, J=6.4 Hz, 3H), 2.56 (t, J=6.8 Hz, 1H), 2.32-2.24 (m, 1H), 1.30-1.23 (m, 9H). Procedure for preparing compound 37c: To a solution of compound 37b (300 mg, 1.44 mmol) in CHCl (5 mL) was added HCl / dioxane (5 mL, 4 M) at 0° C. The resulting mixture was stirred at 22-32° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 37c (260 mg, crude) as a white solid.

[0405] LCMS: R t = 0.097 min / 0-60AB_2MIN_E.M Chromatography (Xtimate C18, 2.1*30mm, 3um), MS (ESI) m / z= 109.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 3.38 (s, 1H), 3.35 (br d, J=4.0 Hz, 1H), 3.27-3.11 (m, 2H), 2.58 (br d, J=4.4 Hz, 3H). Procedure for preparing compound 37d: To a solution of compound 37c (250 mg, 0.54 mmol) and K2CO3 (149 mg, 1.08 mmol) in DMSO (5 mL) was added compound 11d (230 mg, 1.27 mmol). The resulting mixture was stirred at 22–29 °C for 12 h, during which time its color changed from light brown to deep yellow. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (2 × 30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (CHCl2 / MeOH = 10 / 1) to give compound 37d (90 mg, 30% yield) as a yellow solid.

[0406] LCMS: R t = 0.820 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 555.2 [M+H] + . Procedure for preparation of compound 37e: To a solution of compound 37d (90 mg, 0.16 mmol) in MeOH (4 mL) and HO (2 mL) was added Zn (52 mg, 0.80 mmol) and NH4Cl (85 mg, 1.60 mmol). The resulting mixture was degassed by purging with N2 three times and then stirred at 80 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was dissolved in EtOAc (20 mL), washed with HO (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 37e (80 mg, 95% yield) as a brown solid.

[0407] LCMS: R t= 0.709 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 525.0 [M +H] + . Preparation procedure for Example 37: To a solution of compound 37e (80 mg, 0.15 mmol) and DIEA (39 mg, 0.30 mmol) in DMF (2.5 mL) was added dropwise a solution of acryloyl chloride (14 mg, 0.15 mmol) in DMF (0.5 mL). The resulting mixture was stirred in an ice-water bath at 0°C for 30 minutes. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm Conditions: 43-73% B (A: 0.05% NH3H2O; B: CH3CN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 37 (35.0 mg, 40% yield) as a white solid.

[0408] LCMS: R t = 1.882 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 579.3 [M +H] + . HPLC: t = 3.23 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR (400MHz, CDCl3) δ 10.60 (br s, 1H), 10.46 (br s, 1H), 9.96 (br s, 1H), 8.47 (d, J=7.6 Hz, 1H), 8.42 (s, 1H), 7.69 (br s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.78 (s, 1H), 6.45-6.30 (m, 2H), 6.18 (br s, 1H), 5.81-5.70 (m, 1H), 3.88 (s, 3H), 2.87 (br d, J=4.8 Hz, 2H), 2.70 (s, 3H), 2.29 (br s, 2H), 1.78 (s, 6H). Example 38 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0409] [ka]

[0410] Procedure for preparing compound 38b: A solution of compound 11c (180 mg, 0.385 mmol), compound 38a (440.3 mg, 3.86 mmol), and KCO (532.9 mg, 3.86 mmol) in DMSO (2 mL) was stirred for 2 h at 85° C. The reaction mixture was added to HO (10 mL) in an ice-water bath with stirring, the solid precipitate was filtered, and the filter cake was dissolved in DCM (30 mL), dried, and concentrated in vacuo to give product 38b (230 mg, 95.7% yield) as an orange solid.

[0411] LCMS: R t = 0.718 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=560.1, 583.1 [M+H, M+Na] + . 1H NMR (400MHz, CDCl3) δ 9.71 (br s, 1H), 8.98 (br s, 1H), 8.37 (br s, 2H), 7.35 (br s, 1H), 7.06 (d, J=10.4 Hz, 1H), 6.83 (s, 1H), 4.45-4.35 (m, 1H), 4.30 (dt, J=5.1, 9.2 Hz, 1H), 3.93 (s, 3H), 3.33-3.24 (m, 1H), 2.80 (m, 1H), 2.49 (dd, J=5.6, 13.2 Hz, 1H), 2.46-2.36 (m, 1H), 2.30 (s, 6H), 2.20-2.08 (m, 1H), 1.69 (s, 6H). Procedure for preparing compound 38c: To a solution of compound 38b (230 mg, 0.410 mmol) in 6 mL of MeOH / HO = 5 / 1 (v / v) was added Zn (134.02 mg, 2.05 mmol) and NH4Cl (109.65 mg, 2.05 mmol). The resulting mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was dissolved in CHCl2 (30 mL), washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give product 38c (197 mg, 90.5% yield) as a brown solid.

[0412] LCMS: R t = 0.657 min / 5-95AB_220&254.1 cm Chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2 mm), MS (ESI) m / z=531.3 [M+H] + . Preparation procedure for Example 38: To a solution of compound 38c (197 mg, 0.351 mmol) and DIEA (67.9 mg, 0.527 mmol) in DMF (3 mL) was added acryloyl chloride (31.7 mg, 0.351 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with HO (0.1 mL) and purified by preparative HPLC (instrument: DB column: Gemini Purification by 150*255 μm. Mobile phase A: 0.05 (v / v)% ammonium hydroxide aqueous solution, mobile phase B: DMF, flow rate: 25 ml / min, gradient time: 10 min, profile description: 30%-60% gave Example 38 (36.6 mg, 18% yield) as a pale yellow solid.

[0413] LCMS: R t =1.295min / 10-80AB_4 min_220&254 Chromatography (ACSSH-LCMS-AS A: Xtimate C18, 2.1*30mm, 3um; B: XBrige Shield RP18 2.1*50mm), MS (ESI) m / z=585.3 [M+H] + . HPLC: t =3.37 min / 10-80_CD_1.2ml. met XBridge Shield RP 18 2.1*50mm 5um. 1 H NMR (400MHz, CDCl3) δ 10.41 (br s, 1H), 9.38 (br s, 1H), 8.95 (br s, 1H), 8.38 (m, 1H), 7.56 (m, 1H), 7.08 (m, 1H), 6.62 (m, 1H), 6.37 (m, 1H), 6.82-6.21 (m, 2H), 5.80 (br s, 1H), 4.23 (m, 1H), 3.89 (m, 5H), 3.56 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H), 2.25 (m, 7H), 1.90-1.73 (s, 6H). Example 39 N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0414] [ka]

[0415] Procedure for preparing compound 39b: A mixture of compound 11c (100 mg, 0.22 mmol), compound 39a (40 mg, 0.22 mmol), and KCO (110 mg, 0.85 mmol) in DMSO (2 mL) was stirred at 90 °C for 3 h (yellow suspension). After completion, ice water (10 mL) was added to the mixture. The solid precipitate was filtered, and the filter cake was washed with HO (10 mL) and dried under high vacuum to give compound 39b (150 mg, 83.4% yield) as a yellow solid.

[0416] LCMS: R t = 0.710 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z = 583.1 [M+Na]+. 1 H NMR: (400MHz, DMSO-d6) δ ppm 10.23 (br s, 1H), 9.27-8.91 (m, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.29 (s, 1H), 6.30 (br s, 1H), 6.21 (s, 1H), 4.09 (t, J=8.4 Hz, 2H), 3.86 (s, 3H), 3.62 (t, J=8.4 Hz, 2H), 2.91-2.82 (m, 1H), 2.55 (s, 2H), 2.15 (s, 6H), 1.51 (s, 6H). Procedure for preparing compound 39c: To a mixture of compound 39b (150 mg, 0.267 mmol) in MeOH / HO (50 / 10 mL) was added Zn (87 mg, 1.34 mmol) and NH4Cl (71 mg, 1.34 mmol). The resulting suspension was stirred at 85 °C for 3 h. The reaction was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was treated with water (20 mL) and extracted with CHCl2 (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give product 39c (120 mg, 85.1% yield) as a yellow solid.

[0417] LCMS: R t = 0.665 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z= 529.1 [M+H-2]+. 1 H NMR: (400MHz, DMSO-d6) δ 10.11 (br s, 1H), 8.84 (br s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.26 (s, 1H), 6.53 (br s, 1H), 6.27-6.21 (m, 2H), 4.05-3.91 (m, 4H), 3.67 (s, 3H), 3.46-3.39 (m, 2H), 2.76-2.67 (m, 1H), 2.16 (s, 6H), 1.51 (s, 6H). Preparation procedure for Example 39: To a mixture of compound 39c (120 mg, 0.225 mmol) and DIEA (87 mg, 0.675 mmol) in DMF (3 mL) was added acryloyl chloride (26.6 mg, 0.293 mmol) in DMF (1 mL) dropwise over 1 h in an ice-water bath. The resulting mixture was stirred at 0-5 °C for 30 min (brown solution), then quenched with HO (0.05 mL) and purified by preparative HPLC [Waters Xbridge 150*25.5 μm; conditions: 28-58% HCl]. B (A: 0.05% ammonia; B: CHCN; flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 39 (48.0 mg, 20.9% yield) as a white solid.

[0418] LCMS: R t = 2.325 min / 0-60AB_4.0 min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 585.1 [M +H] + . HPLC: t = 4.92 min / 0-60 CD 1.2 ml Chromatography (XBridge Shield RP 18 2.1* 50 mm 5um). 1 H NMR: (400MHz, CDCl3) δ ppm 10.23 (br s, 1H), 9.07 (br s, 1H), 8.36-8.28 (m, 2H), 743-7.32 (m, 2H), 6.99 (d, J=10.8 Hz, 1H), 6.34-6.19 (m, 3H), 5.72 (d, J=9.2 Hz, 1H), 3.90 (t, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.42 (t, J=6.4 Hz, 2H), 2.86-2.79 (m, 1H), 2.45 (d, J=7.2 Hz, 2H), 2.16 (s, 6H), 1.64 (s, 6H). Example 40 (S)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-((dimethylamino)methyl)morpholino)-4-methoxyphenyl)acrylamide

[0419] [ka]

[0420] Procedure for preparing compound 40b: To a solution of compound 40a (1.4 g, 6.44 mmol) in CHCl (40 mL) was added DMP (4.1 g, 9.67 mmol) in small portions at 0-5 °C. The resulting white mixture was stirred at 0-5 °C for 1 h. The reaction was treated with aqueous NaHCO (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / EtOAc = 5 / 1 (v / v)) to give compound 40b (1.1 g, 79.7% yield) as a pale yellow oil.

[0421] LCMS: R t = 1.300-1.400 min / 10-80CD_3MIN_220&254, Chromatography (XBrige Shield RP18 2.1 x 50 mm). 1 H NMR: (400MHz, DMSO-d6) δ 9.60 (br d, J=10.0 Hz, 1H), 4.52-4.36 (m, 2H), 3.94-3.67 (m, 2H), 3.63-3.52 (m, 2H), 3.08-2.79 (m, 1H), 1.43-1.36 (m, 9H). Procedure for preparing compound 40c: To a solution of compound 40b (1.0 g, 4.65 mmol) in MeOH (10 mL) was added MeN.HCl (1.1 g, 13.94 mmol) and NaOAc (572 mg, 6.97 mmol), and the white mixture was stirred at 24–26 °C for 2 h. NaBHCN (584 mg, 9.29 mmol) was then added, and the resulting mixture was stirred at 22–27 °C for 18 h. The reaction mixture was quenched by the addition of aqueous NHCl (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried, and concentrated in vacuo to give compound 40c (800 mg, 70.5% yield) as a colorless oil.

[0422] LCMS: R t= 2.475 min / 10-80CD_7MIN_220&254, Chromatography (XBrige Shield RP18 2.1 x 50mm), MS (ESI) m / z = 245.1 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 4.15-3.40 (m, 5H), 3.53-3.44 (m, 2H), 3.06 (br s, 1H), 2.79 (br t, J=10.8 Hz, 1H), 2.32 (br s, 6H), 1.48 (s, 9H). Procedure for preparing compound 40d: To a solution of compound 40c (500 mg, 2.30 mmol) in CHCl (6 mL) was added TFA (2 mL). The resulting colorless solution was stirred at 22-32 °C for 3 h. The reaction solution was directly concentrated in vacuo to give the TFA salt of compound 40d (300 mg, 61.1% yield) as a colorless oil.

[0423] LCMS: R t = 0.561 min / 10-80CD_4MIN_E, Chromatography (XBrige Shield RP18 2.1 x50mm), MS (ESI) m / z= 145.2 [M+H] + . Procedure for preparation of compound 40e: To a solution of compound 40d (375 mg, 0.42 mmol) and K2CO3 (230 mg, 1.67 mmol) in DMSO (2 mL) was added compound 11c (120 mg, 0.83 mmol). The mixture was stirred at 28-33 °C for 8 h. This was purified by Biotage flash reversed-phase C-18 column eluting with MeOH / HO (56%-60% MeOH in water). Purification by chromatography gave compound 40e (120 mg, 20.9% yield) as a red solid.

[0424] LCMS: R t= 0.809 min / 5-95AB_1.5MIN_220&254, Chromatography (MERCK RP18 2.5-2mm). MS (ESI) m / z= 591.3 [M+H] + . Procedure for preparing compound 40f: To a solution of compound 40e (120 mg, 0.20 mmol) in MeOH (5 mL) and HO (1 mL) was added Zn (67 mg, 1.02 mmol) and NH4Cl (109 mg, 2.04 mmol). The black suspension was stirred at 70 °C under N2 for 1.5 h. The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL x 3), dried, and directly concentrated in vacuo to give compound 40f (70 mg, 82.1% yield) as a brown oil.

[0425] LCMS: R t = 0.760 min / 5-95AB_1.5MIN_220&254.1cm, Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z= 561.2 [M+H] + . Preparation procedure for Example 40: To a solution of compound 40f (70 mg, 0.12 mmol) and DIEA (24 mg, 0.19 mmol) in DMF (1 mL) was added a solution of acryloyl chloride (11 mg, 0.12 mmol) in DMF (1 mL) dropwise. The resulting brown mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150 × 255 μm; conditions: 35-6 5% B (A: 0.05% ammonia; B: CHCN); flow rate: 25 ml / min). The fractions containing the desired compound were lyophilized to give Example 40 (10.2 mg, 15.5% yield) as a white solid.

[0426] LCMS: R t= 4.015 min / 10-80CD_7MIN_220&254, Chromatography (XBrige Shield RP18 2.1 x 50 mm), MS (ESI) m / z = 615.3 [M+H] + . HPLC: t = 3.76 minutes, 10-80_CD_1.2mL.MET (XBridge Shield RP 18 2.1 x50mm 5um). 1 H NMR: (400MHz, DMSO-d6) δ 10.20 (br s, 1H), 9.15-9.00 (m, 2H), 8.29 (br d, J=15.6 Hz, 2H), 7.26 (br s, 1H), 7.12 (br s, 1H), 6.63 (dd, J=10.0, 16.8 Hz, 1H), 6.30 (s, 1H), 6.17 (br d, J=16.8 Hz, 1H), 5.73 (br d, J=11.0 Hz, 1H), 4.01 (br d, J=9.4 Hz, 1H), 3.82-3.77 (m, 5H), 3.55-3.49 (m, 1H), 3.32-3.23 (m, 1H), 2.84 ( br s, 2H), 2.29-2.18 (m, 1H), 2.02 (s, 6H), 1.91 (br d, J=9.4 Hz, 1H), 1.51 (d, J=7.2 Hz, 6H). Example 41 N-(5-(4-(4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0427] [ka]

[0428] Procedure for preparing compound 41a: To a solution of 4-chloro-3-fluoroaniline (15 g, 103.05 mmol) in dichloromethane (150 mL) was added ICl (25 g, 154.57 mmol) dropwise. The resulting black mixture was stirred at 24–29 °C for 2 h. The mixture was diluted with 100 mL of dichloromethane and washed with a saturated solution of sodium bicarbonate (200 mL). The organic layer was concentrated to give a crude residue, which was purified by flash column chromatography on silica gel (0–0.5% ethyl acetate in petroleum ether) to give compound 41a (8 g of a brown solid and 12 g of a black solid, combined yield 71.5%).

[0429] LCMS: R t = 0.974 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z = 271.8 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 10.4 Hz, 1H), 4.12 (s, 2H). Procedure for preparing compound 41b: To a solution of compound 41a (20 g, 73.67 mmol) in DMF (60 mL) and methanol (120 mL) was added DPPF (4.08 g, 7.37 mmol), EtN (31 mL, 221.03 mmol), and Pd(OAc) (1.65 g, 7.37 mmol) under nitrogen. The reaction mixture was degassed by purging with CO three times and stirred at 80 °C under CO (50 psi) for 24 h. The mixture was filtered, and the methanol was removed in vacuo to give a residue that was poured into brine (300 mL), resulting in the precipitation of a black solid. The solid was collected by filtration and further purified by flash column chromatography on silica gel (0–1% ethyl acetate in petroleum ether) to give compound 41b (11.8 g, 78.6% yield) as a pink solid.

[0430] 1H NMR: (400MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 10.8 Hz, 1H), 5.80 (s, 2H), 3.79 (s, 3H). Procedure for preparing compound 41c: To a solution of compound 41b (6 g, 29.47 mmol) in THF (100 mL) was added CHMgBr (49.1 mL, 147.35 mmol) dropwise under nitrogen at 0 °C. The resulting brown mixture was stirred at 24–31 °C for 2 h. The mixture was quenched with a saturated solution of NHCl (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column chromatography on silica gel (0–15% ethyl acetate in petroleum ether) to give compound 41c (5.17 g, 84% yield) as a yellow oil.

[0431] LCMS: R t = 0.821 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z = 185.9 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 7.09 (d, J= 8.4 Hz, 1H), 6.42 (d, J = 11.2 Hz, 1H), 4.84 (s, 2H), 1.66 (s, 6H). Procedure for preparing compound 41d: To a solution of compound 41c (5.17 g, 25.39 mmol) in dichloromethane (100 mL) was added DIEA (6.56 g, 50.78 mmol) and 2,4-dichloro-1,3,5-triazine (4.19 g, 27.93 mmol). The resulting solution was stirred at 23-29 °C for 3 h. The solution was concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica gel (0-10% ethyl acetate in petroleum ether) to give compound 41d (5.74 g, 71.3% yield) as a white solid.

[0432] LCMS: R t = 2.614 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 316.7 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 10.20 (s, 1H), 8.49 (s, 1H), 8.16 (d, J = 10.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 2.24 (s, 1H), 1.62 (s, 6H). Procedure for preparing compound 41e: To a yellow solution of compound 41d (4.74 g, 14.95 mmol) in n-BuOH / TFA (50 mL / 0.5 mL) was added 4-fluoro-2-methoxy-5-nitroaniline (2.8 g, 15.04 mmol). The resulting mixture was stirred at 21-24 °C for 1 h, during which time its color changed to brown and a yellow solid precipitated. The solid was collected by filtration, washed with petroleum ether (20 mL), and dried in vacuo to give compound 41e (5.42 g, 77.7% yield).

[0433] LCMS: R t = 0.971 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z = 467.1 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ 10.56 (s, 1H), 9.49 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.45-7.34 (m, 1H), 3.95 (s, 3H), 1.53 (s, 6H). Procedure for preparing compound 41f: To a solution of compound 41e (200 mg, 0.43 mmol) and KCO (119 mg, 0.86 mmol) in DMSO (5 mL) was added (3aR,6aR)-5-methyloctahydropyrrolo[3,4-b]pyrrole (65 mg, 0.52 mmol). The resulting mixture was stirred at 85 °C for 4 h, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The yellow precipitate was filtered, dissolved in CHCl (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 41f (230 mg, 93% yield) as a yellow solid.

[0434] LCMS: R t = 0.755 min / 5-95AB_220&254.1 cm Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z= 572.9 [M+H] + . Procedure for preparing compound 41g: To a solution of compound 41f (230 mg, 0.40 mmol) in MeOH (10 mL) and HO (5 mL) was added Zn (131 mg, 2.00 mmol) and NH4Cl (214 mg, 4.00 mmol). The resulting mixture was degassed by purging with N2 three times and then stirred at 80 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was dissolved in EtOAc (20 mL), washed with HO (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 41g (190 mg, 87% yield) as a brown solid.

[0435] LCMS: R t = 0.701 min / 5-95AB_1.5 min_220&254 Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z= 542.9 [M +H] + . Preparation procedure for Example 41: To a solution of compound 41g (190 mg, 0.35 mmol) and DIEA (90 mg, 0.70 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (32 mg, 0.35 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0°C for 30 minutes in an ice-water bath. The reaction mixture was analyzed by preparative HPLC [column: Waters Xbridge 150*255 μm Conditions: 40-70% B (A: 0.05% NH3H2O; B: CH3CN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 41 (74.4 mg, 36% yield) as a white solid.

[0436] LCMS: R t = 1.924 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 597.1 [M +H] + . HPLC: t = 3.30 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400MHz, CDCl3) δ 10.83 (br s, 1H), 9.91 (br s, 1H), 9.60 (br s, 1H), 8.42 (s, 1H), 8.40 (d, J=11.6 Hz, 1H), 7.70 (br s, 1H), 7.29 (s, 1H), 6.78 (s, 1H), 6.56-6.33 (m, 2H), 5.96 (br s, 1H), 5.77 (br d, J=10.8 Hz, 1H), 3.87 (s, 3H), 3.73-3.64 (m, 1H), 3.22 (br t, J=7.6 Hz, 1H), 2.93-2.79 (m, 3H), 2.72 (br d, J=10.4 Hz, 1H), 2.33 (br s, 1H), 2.30 (s, 3H), 2.25-2.16 (m, 1H), 1.95-1.86 (m, 2H), 1.78 (s, 6H). Example 42 (S)—N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl(2-(2-methylpyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0437] [ka]

[0438] Procedure for preparing compound 42b: To a solution of compound 42a (300 mg, 2.47 mmol) in MeOH (8 mL) was added NaOAc (404.74 mg, 4.93 mmol). The mixture was stirred at 23-28 °C for 10 min, and tert-butyl methyl(2-oxoethyl)carbamate (512.76 mg, 2.96 mmol) was added. The resulting mixture was stirred at 23-28 °C for 1 h, and then NaBHCN (310.05 mg, 4.93 mmol) was added to the above mixture. The mixture was stirred at 23-28 °C for 15 h. The mixture was concentrated in vacuo to give a residue, which was dissolved in CHCl (15 mL), washed with water (6 mL), brine (6 mL), dried over NaSO, and concentrated in vacuo to give the crude product. This was purified by column chromatography on silica gel (0.5% MeOH in CH2Cl2) to give compound 42b (350 mg, 58.5% yield) as a yellow oil.

[0439] 1 H NMR: (400MHz, CDCl3) δ 3.65-2.93 (m, 5H), 2.89 (s, 3H), 2.75-2.32 (m, 2H), 2.20 (br s, 1H), 2.06-1.65 (m, 3H), 1.46 (s, 9H), 1.26-1.06 (m, 3H). Procedure for preparing compound 42c: To a solution of compound 42b (350 mg, 1.44 mmol) in CHCl (3 mL) was added HCl-EtOAc (4 mL). The resulting mixture was stirred at 22-32 °C for 12 h. The reaction mixture was concentrated in vacuo to give compound 42c (200 mg, 64% yield) as a white solid.

[0440] LCMS: R t = 0.101 min / 0-60AB_2MIN_50_E.1cm Chromatography (Xtimate C18, 2.1*30mm, 3um), MS (ESI) m / z=143.1 [M+H]+. 1 H NMR: (400MHz, D2O) δ 3.81-3.61 (m, 2H), 3.60-3.33 (m, 4H), 3.24-3.12 (m, 1H), 2.77 (s, 3H), 2.39-2.23 (m, 1H), 2.17-2.04 (m, 1H), 2.03-1.94 (m, 1H), 1.79-1.63 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). Procedure for preparing compound 42d: To a solution of compound 11c (200 mg, 0.428 mmol) and KCO (118 mg, 0.856 mmol) in DMSO (3 mL) was added compound 42c (111 mg, 0.514 mmol). The reaction mixture was heated at 50 °C for 3 h, during which time the color changed from brown to orange. The reaction mixture was added dropwise to HO (40 mL) in an ice-water bath with stirring, during which time a solid precipitated and was filtered. The filter cake was washed with HO (15 mL x 3) and dried under high vacuum to give compound 42d (210 mg, 83% yield) as an orange solid.

[0441] LCMS: R t = 0.748 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=589.1 [M+H]+. 1H NMR: (400MHz, CD3OD) δ 8.53 (br s, 1H), 8.26 (br s, 1H), 8.18 (br s, 1H), 7.21 (d, J=10.8 Hz, 1H), 6.81 (s, 1H), 3.96 (s, 3H), 3.42-3.33 (m, 2H), 3.19-3.08 (m, 2H), 2.90 (s, 3H), 2.51-2.34 (m, 2H), 2.24 (q, J=9.2 Hz, 1H), 2.04-1.91 (m, 1H), 1.81-1.70 (m, 2H), 1.60 (s, 6H), 1.40 (qd, J=8.4, 12.4 Hz, 1H), 1.12 (d, J=6.0 Hz, 3H). Procedure for preparation of compound 42e: To a solution of compound 42d (200 mg, 0.34 mmol) in MeOH / HO (5 mL, 5 / 1) was added Zn (133 mg, 2.04 mmol) and NH4Cl (109 mg, 2.04 mmol). The resulting mixture was heated at 90 °C for 3 h, during which time its color changed from orange to brown. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was dissolved in CHCl2 (20 mL), washed with water (15 mL x 3), dried over Na2SO4, and concentrated in vacuo to give compound 42e (118 mg, 62% yield) as a brown solid.

[0442] LCMS: R t = 0.703 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=559.1 [M+H] + . Preparation procedure for Example 42: To a solution of compound 42e (115 mg, 0.206 mmol) and DIEA (40 mg, 0.309 mmol) in DMF (2 mL) was added acryloyl chloride (19 mg, 0.206 mmol) dropwise in an ice-water bath. The resulting mixture was stirred at 5-10 °C for 15 min. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 42-72% B (A: 0.05% A). A: ammonia, B: CH3CN; flow rate: 25 ml / min) and lyophilization gave Example 42 (23.7 mg, 16.8% yield) as an off-white solid.

[0443] LCMS: R t = 4.638 min / 30-90CD_7min_220&254. lcm chromatography (Xtimate 2.1*30mm 3um), MS (ESI) m / z=613.3 [M+H] + . HPLC: t = 4.56 min / 10-80CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR: (400MHz, CDCl3) δ 10.60 (br s, 1H), 9.92 (br s, 1H), 9.73 (br s, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.42 (s, 1H), 7.69 (br s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.78 (s, 1H), 6.53-6.30 (m, 2H), 6.10 (br s, 1H), 5.84-5.70 (m, 1H), 3.88 (s, 3H), 3.22-3.18 (m, 1H), 3.02-2.90 (m, 2H), 2.88-2.77 (m, 1H), 2.67 (s, 3H), 2.37-2.28 (m, 1H), 2.16-1.91 (m, 3H), 1.77 (s, 6H), 1.66 (br s, 1H), 1.49-1.40 (m, 1H), 1.36-1.20 (m, 1H), 1.04 (d, J=5.6 Hz, 3H). Example 43 (R)-N-(5-(4-(4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0444] [ka]

[0445] Procedure for preparing compound 43a: To a solution of compound 41e (200 mg, 0.428 mmol) and KCO (118 mg, 0.856 mmol) in DMSO (3 mL) was added (R)-N,N-dimethyl-1-(pyrrolidin-2-yl)methanamine (103 mg, 0.514 mmol). The reaction mixture was heated at 85 °C for 2.5 h, during which time the color changed from brown to orange. The reaction mixture was added dropwise to HO (40 mL) with stirring in an ice-water bath, during which time a solid precipitated and was filtered. The filter cake was washed with HO (15 mL × 3) and then dried under high vacuum to give compound 43a (200 mg, 73.7% yield) as an orange solid.

[0446] LCMS: R t= 0.745 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=575.2 [M+H]+. Procedure for preparing compound 43b: To a solution of compound 43a (200 mg, 0.348 mmol) in MeOH / HO = 5 / 1 (5 mL) was added Zn (136 mg, 2.087 mmol) and NH4Cl (112 mg, 2.087 mmol). The resulting mixture was heated at 90 °C for 1.5 h, during which time its color changed from orange to brown. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue which was dissolved in CHCl2 (20 mL), washed with water (15 mL × 3), dried over Na2SO4, and concentrated in vacuo to give compound 43b (175 mg, 92.3% yield) as a brown solid.

[0447] LCMS: R t = 0.725 min / 5-95AB_220&254.1 cm Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z=545.0 [M+H] + . Preparation procedure for Example 43: To a solution of compound 43b (175 mg, 0.321 mmol) and DIEA (62 mg, 0.482 mmol) in DMF (2 mL) was added acryloyl chloride (29 mg, 0.321 mmol) in an ice-water bath. The resulting mixture was stirred at 5-10 °C for 15 min. The reaction was quenched with HO (0.1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*255 μm; conditions: 42-72% B (A: 0.05% ammonia)). B: CH3CN; flow rate: 25 ml / min) and then lyophilized to give Example 43 (46.0 mg, 21.44% yield) as a white solid.

[0448] LCMS: R t= 2.066 min / 10-80AB_4min_220&254. lcm chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z=599.2 [M+H] + HPLC: t = 4.12 min / 10-80CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR: (400MHz, CDCl3) δ 10.82 (br s, 1H), 10.07 (br s, 1H), 9.88 (br s, 1H), 8.41 (s, 1H), 8.39 (d, J=12.0 Hz, 1H), 7.70 (br s, 1H), 7.32-7.25 (m, 1H), 6.71 (s, 1H), 6.44-6.28 (m, 2H), 6.03 (br s, 1H), 5.84-5.71 (m, 1H), 3.86 (s, 3H), 3.39-3.25 (m, 2H), 3.03-2.92 (m, 1H), 2.37 (dd, J=7.8, 12.0 Hz, 1H), 2.33-2.21 (m, 1H), 2.19 (s, 6H), 2.06 (dd, J=5.4, 12.0 Hz, 1H), 2.02-1.92 (m, 2H), 1.78 (s, 6H), 1.70-1.65 (m, 1H). Example 44 (S)—N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide

[0449] [ka]

[0450] Procedure for preparing compound 44b: To a solution of compound 36b (180 mg, 0.39 mmol) and KCO (216 mg, 1.56 mmol) in DMSO (10 mL) was added compound 44a (117 mg, 0.58 mmol). The resulting mixture was stirred at 50 °C for 12 h. This reaction mixture was combined with the previous batch and added dropwise to HO (100 mL) with stirring in an ice-water bath. The precipitated solid was filtered, and the filter cake was dissolved in CHCl (15 mL × 3), dried, and concentrated in vacuo to give target compound 44b (220 mg, average yield 89.0%) as an orange solid.

[0451] LCMS: R t = 0.738 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 575.1 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ 9.64 (s, 1H), 9.04 (s, 1H), 8.40 (br s, 1H), 8.38-8.30 (m, 1H), 7.42 (br s, 1H), 7.08 (d, J=10.4 Hz, 1H), 6.68 (s, 1H), 3.95 (s, 3H), 3.50 (dd, J=4.8, 13.6 Hz, 1H), 3.17-3.05 (m, 2H), 2.86 (s, 3H), 2.63 (s, 2H), 2.59-2.52 (m, 1H), 2.42 (s, 3H), 2.30-2.21 (m, 1H), 2.07-1.96 (m, 1H), 1.80-1.74 (m, 1H), 1.70 (s, 6H). Procedure for preparing compound 44c: Compound 44b (220 mg, 0.38 mmol) and Zn (125 mg, 1.9 mmol) To a solution of 44c (44d) in 6 mL of methanol / water = 5:1 (v / v) was added NH4Cl (102 mg, 1.9 mmol). The resulting mixture was stirred at 75 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo to give a residue, which was treated with water (10 mL) and extracted with CHCl2 (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give compound 44c (90 mg, 43.4% yield) as a brown solid.

[0452] LCMS: R t = 0.701 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 545.1[M+H] + . Preparation Procedure for Example 44: To a solution of compound 44c (90 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (31 mg, 0.34 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C (ice-water bath) for 20 min. The reaction mixture was quenched with 3 drops of water and then purified by preparative HPLC (column: Waters Xbridge 150*255 μm: 53-83% B (A: water; 0.05 (v / v)% water). Direct purification by HCl (ammonium hydroxide, B: CH3CN), flow rate: 25 mL / min) gave Example 44 (11.1 mg, 10.9% yield) as a white solid.

[0453] LCMS: R t = 1.994 min / 10-80AB_ 4 min_220&254 Chromatography (Xtimate C18 2.1*30 mm) MS (ESI) m / z=599.1 [M +H] + . HPLC: t = 4.42 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1H NMR (400MHz, CDCl3) δ 10.53 (br s, 1H), 10.10 (br s, 1H), 10.03 (br s, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.41 (s, 1H), 7.64 (br s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.71 (s, 1H), 6.43-6.32 (m, 2H), 6.12 (br s, 1H), 5.81-5.74 (m, 1H), 3.88 (s, 3H), 3.14-3.08 (m, 1H), 2.88-2.78 (m, 1H), 2.74 (s, 3H), 2.71-2.63 (m, 2H), 2.56 (s, 3H), 2.41-2.32(m, 1H), 2.06-1.90 (m, 1H), 1.81-1.72 (m, 7H), 1.45-1.23 (m, 2H). Example 45 N-(5-(4-(4-cyclopropyl-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0454] [ka]

[0455] Procedure for preparing compound 45b: To a solution of compound 34e (150 mg, 0.32 mmol) and KCO (88 mg, 0.64 mmol) in DMSO (5 mL) was added compound 45a (48 mg, 0.38 mmol). The resulting mixture was stirred at 85 °C for 4 h, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The solid was filtered, and the filter cake was dissolved in CHCl (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 45b (150 mg, 82% yield) as a yellow solid.

[0456] LCMS: R t = 0.834 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 579.3 [M+H] + . Procedure for preparing compound 45c: To a solution of compound 45b (150 mg, 0.26 mmol) in MeOH (10 mL) and HO (5 mL) was added Zn (85 mg, 1.30 mmol) and NH4Cl (139 mg, 2.60 mmol). The resulting mixture was degassed by purging with N2 three times and then stirred at 80 °C for 2 h. The reaction mixture was filtered, concentrated under reduced pressure, extracted with EtOAc (10 mL x 2), and the combined organic layers were washed with HO (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 45c (130 mg, 91% yield) as a brown solid.

[0457] LCMS: R t = 0.715 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 549.1 [M+H] + . Preparation Procedure for Example 45: To a solution of compound 45c (130 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (22 mg, 0.24 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0°C for 30 minutes in an ice-water bath. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm Conditions: 35-65% B (A: 0.05% NH3H2O; B: CH3CN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 45 (28.1 mg, 19% yield) as a white solid.

[0458] LCMS: R t= 1.778 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 603.3 [M+H] + . HPLC: t = 2.79 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400MHz, CDCl3) δ 10.72 (br s, 1H), 9.93 (br s, 1H), 9.56 (br s, 1H), 8.41 (s, 1H), 8.12 (d, J=12.4 Hz, 1H), 7.64 (br s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.55-6.45 (m, 1H), 6.44-6.35 (m, 1H), 5.76 (br d, J=11.2 Hz, 1H), 3.87 (s, 3H), 3.67 (br s, 1H), 3.22 (br t, J=7.6 Hz, 1H), 2.96-2.79 (m, 3H), 2.73 (br d, J=10.0 Hz, 1H), 2.30 (br s, 4H), 2.25-2.17 (m, 1H), 2.08-1.94 (m, 2H), 1.89 (br s, 1H), 1.76 (s, 6H), 1.05-0.88 (m, 2H), 0.75-0.55 (m, 2H). Example 46 (R)-N-(5-(4-(4-cyclopropyl-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0459] [ka]

[0460] Procedure for preparing compound 46b: To a solution of compound 34e (150 mg, 0.32 mmol) and K2CO3 (88 mg, 0.64 mmol) in DMSO (5 mL) was added compound 46a (96 mg, 0.48 mmol). The resulting mixture was stirred at 85 °C for 4 hours, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The yellow solid was filtered, and the filter cake was diluted with CHCl2 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 46b (140 mg, 75% yield) as a yellow solid.

[0461] LCMS: R t = 0.766 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 581.1 [M+H] + . Procedure for preparing compound 46c: To a solution of compound 46b (140 mg, 0.24 mmol) in MeOH (5 mL) was added Pd / C (15 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 21–24 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 46c (130 mg, 98% yield) as a brown oil.

[0462] LCMS: R t = 0.738 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 551.1 [M+H] + . Preparation Procedure for Example 46: To a solution of compound 46c (130 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (22 mg, 0.24 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0°C for 30 minutes in an ice-water bath. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm Conditions: 42-72% B (A: 0.05% NH3H2O; B: CH3CN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 46 (32.5 mg, 22% yield) as a white solid.

[0463] LCMS: R t = 1.883 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 605.3 [M+H] + . HPLC: t = 3.00 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400MHz, CDCl3) δ 10.71 (br s, 1H), 10.00 (br s, 1H), 9.91 (br s, 1H ), 8.41 (s, 1H), 8.11 (d, J=12.4 Hz, 1H), 7.65 (br s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.70 (s, 1H), 6.44-6.30 (m, 2H), 5.77 (br d, J=11.2 Hz, 1H), 3.86 (s, 3H), 3.39-3.24 (m, 2H), 3.03-2.90 (m, 1H), 2.41-2.31 (m, 1H), 2.25-2.15 (m, 7H), 2.10-1.96 (m, 4H), 1.76 (s, 6H), 1.69 (br d, J=4.4 Hz, 1H), 0.98-0.88 (m, 2H), 0.73-0.66 (m, 2H). Example 47 N-(5-(4-(4,5-difluoro-2-(2-hydroxybutan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0464] [ka]

[0465] Procedure for preparing compound 47c: To a mixture of compound 47a (10 g, 48.08 mmol) and compound 47b (20.84 g, 57.69 mmol) in toluene (200 mL) was added Pd(PPh) (2.78 g, 2.4 mmol) in one portion under N. The resulting black mixture was stirred at 100 °C for 12 h under N. The reaction was cooled to 25 °C and then treated with 6 N HCl (10 mL) with stirring at 25 °C for 1 h. It was diluted with water (400 mL) and extracted with EtOAc (120 mL × 3). The combined organic layers were washed successively with 20% KF solution (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to give compound 47c (4.2 g, 51% yield) as a yellow solid.

[0466] LCMS: R t = 0.709 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=171.9 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 7.50 (dd, J=8.8 Hz, 11.2 Hz, 1H), 6.41 (dd, J=6.8 Hz, 12.0 Hz, 1H), 6.37-6.17 (m, 2H), 2.52 (s, 3H). Procedure for preparing compound 47d: To a solution of compound 47c (2 g, 11.68 mmol) in THF (100 mL) was added EtMgBr (3.0 M) (16 mL, 46.72 mmol) under N at 0 °C. The reaction mixture was stirred at 23-27 °C for 2 h. The reaction mixture was then diluted with saturated NH4Cl solution (50 mL ), and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (0–30 (v / v)% EtOAc in petroleum ether) to give compound 47d (1.7 g, 72% yield) as a yellow oil.

[0467] LCMS: R t = 0.559 min / 5-95AB_220&254.1 cm Chromatography MERCK RP18 2.5-2 mm, MS (ESI) m / z=184.0 [M+H-18] + . 1 H NMR: (400MHz, MeOD-d4) δ6.91 (dd, J=8.8 Hz, 12.8 Hz, 1H), 6.51 (dd, J=7.6 Hz, 12.8 Hz, 1H), 2.07-2.01 (m, 1H), 1.86-1.76 (m, 1H), 1.53 (s, 3H), 0.80 (t, J=7.6 Hz, 3H). Procedure for preparation of compound 47e: To a solution of compound 47d (1.68 g, 8.4 mmol) in CHCl (15 mL) was added DIEA (1.6 g, 12.6 mmol) and 2,4-dichloropyrimidine (1.5 g, 10.0 mmol). The resulting mixture was stirred at 22–30° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (0–20% EtOAc in petroleum ether) to give compound 47e (1.58 g, 60% yield) as a yellow solid.

[0468] LCMS: R t= 0.825 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=314.9 [M+H] + . Procedure for preparing compound 47f: To a solution of compound 47e (1.58 g, 5.0 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (935 mg, 5.0 mmol) in n-BuOH (10 mL) was added TFA (0.1 mL). The resulting mixture was stirred at 18-25 °C for 2 h, during which time a gray solid precipitated. The reaction mixture was filtered, and the filter cake was collected and dried under reduced pressure to give compound 47f (1.5 g, 97% yield) as a pale solid.

[0469] LCMS: R t = 0.911 min / 5-95AB_220&254.1 cm Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z=464.9 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ 10.55 (br s, 1H), 9.46 (br s, 1H), 8.46 (br s, 1H), 8.37 (s, 1H), 7.39 (d, J=13.6 Hz, 1H), 7.33-7.29 (m, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 3.94 (s, 3H), 1.82-1.70 (m, 2H), 1.51 (s, 3H), 0.71 (br t, J=7.6 Hz, 3H). Preparation of compound 47h: To a solution of compound 47f (150 mg, 0.32 mmol) and KCO (88 mg, 0.64 mmol) in DMSO (3 mL) was added compound 47g (48 mg, 0.38 mmol). The resulting mixture was stirred at 85 °C for 2 hours, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and the precipitated yellow solid was filtered. The filter cake was dissolved in CHCl (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 47h (160 mg, 88% yield) as a yellow solid.

[0470] LCMS: R t = 0.766 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 571.0 [M+H] + . Preparation of compound 47i: To a solution of compound 47h (160 mg, 0.28 mmol) in MeOH (5 mL) was added Pd / C (16 mg). The resulting mixture was degassed by purging with H three times and then stirred under H (hydrogen balloon, 15 Psi) at 22-30 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound 47i (140 mg, 92% yield) as a colorless solid.

[0471] LCMS: R t = 0.732 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 541.0 [M+H] + . Preparation procedure for Example 47: To a solution of compound 47i (140 mg, 0.26 mmol) and DIEA (67 mg, 0.52 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (24 mg, 0.26 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0°C for 30 minutes in an ice-water bath. The reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150*255 μm Conditions: 45-75% B (A: 0.05% NH3H2O; B: CH3CN); Flow rate: 25 ml / min. The fractions containing the desired compound were lyophilized to give Example 47 (50.6 mg, 33% yield) as a white solid.

[0472] LCMS: R t = 1.855 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 595.1 [M+H] + . HPLC: t = 2.69 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400MHz, CDCl3) δ 10.91 (br s, 1H), 9.94 (br s, 1H), 9.57 (br s, 1H), 8.45-8.35 (m, 2H), 7.69 (br s, 1H), 7.03 (dd, J=8.8, 12.4 Hz, 1H), 6.79 (s, 1H), 6.49-6.33 (m, 2H), 5.78-5.73 (m, 1H), 3.96-3.81 (m, 3H), 3.62 (br dd, J=4.4, 7.6 Hz, 1H), 3.19 (br t, J=7.6 Hz, 1H), 2.98-2.76 (m, 3H), 2.70 (br d, J=10.4 Hz, 1H), 2.36-2.26 (m, 4H), 2.26-2.10 (m, 2H), 2.09-2.00 (m, 1H), 1.89 (br dd, J=4.0, 10.2 Hz, 1H), 1.86-1.78 (m, 1H), 1.70 (s, 3H), 0.89 (td, J=7.2, 11.2 Hz, 3H). Example 48 N-(5-(4-(4,5-difluoro-2-(2-hydroxybutan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0473] [ka]

[0474] Procedure for preparing compound 48a: To a solution of compound 47f (200 mg, 0.43 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMSO (5 mL) was added compound (R)-N,N-dimethylpyrrolidin-3-amine (60 mg, 0.52 mmol). The resulting mixture was stirred at 23-29 °C for 0.5 h. The reaction mixture was added dropwise to H2O (100 mL) under ice-water bath with stirring. The precipitated solid was filtered, and the filter cake was dissolved in CHCl2 (45 mL). It was then dried and concentrated in vacuo to give compound 48a (230 mg, 96% yield) as an orange solid.

[0475] LCMS: R t = 0.722 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=559.2 [M+H] + . Procedure for preparing compound 48b: To a solution of 48a (230 mg, 0.41 mmol) in MeOH (10 mL) was added Pd / C (35 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 23-30 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 48b (205 mg, 94% yield) as a brown solid.

[0476] LCMS: R t= 0.680 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=529.2 [M+H] + . Preparation Procedure for Example 48: To a solution of compound 48b (205 mg, 0.4 mmol) and DIEA (78 mg, 0.4 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (37 mg, 0.4 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 20 min under an ice-water bath. The reaction mixture was quenched with three drops of water and then purified by preparative HPLC (column: Waters Xbridge 150*255 μm; 40-70% B (A: water; 0.05 (v / v)% hydroxide). The resulting mixture was purified directly by HCl (HCl, B: CH3CN), flow rate: 25 mL / min) to give Example 48 (65.1 mg, 28% yield) as a white solid.

[0477] LCMS: R t = 1.795 min / 10-80CD_4 min_220&254 Chromatography (Xtimate C18 2.1*30 mm, MS (ESI) m / z=583.1 [M+H] + . HPLC: t = 3.45 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50 mm 5um). 1H NMR: (400 MHz, CDCl3) δ 10.84 (br s, 1H), 9.78 (br s, 1H), 8.43-8.35 (m, 2H), 7.64 (br s, 1H), 7.02 (dd, J=8.4 Hz, 12.0 Hz, 1H), 6.76 (s, 1H), 6.37-6.32 (m, 2H), 5.82-5.77 (m, 1H), 3.87 (s, 3H), 3.16-3.04 (m, 4H), 2.94-2.85 (m, 1H), 2.30 (s, 6H), 2.24-2.08 (m, 2H), 2.05-1.90 (m, 2H), 1.69 (s, 3H), 0.92-0.86 (m, 3H). Example 49 N-(5-(4-(4,5-difluoro-2-(2-hydroxybutan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0478] [ka]

[0479] Procedure for preparing compound 49a: To a solution of compound 47f (200 mg, 0.43 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMSO (5 mL) was added compound:N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine (53 mg, 0.52 mmol) was added. The resulting mixture was stirred at 18-25 °C for 0.5 h. The reaction mixture was added dropwise with stirring to HO (50 mL) in an ice-water bath, the precipitated solid was filtered, and the filter cake was dissolved in CHCl (50 mL), dried, and concentrated under reduced pressure to give compound 49a (230 mg, 97% yield) as an orange solid.

[0480] LCMS: Rt = 0.778 min / 5-95AB_220&254.1 cm Chromatography (Xtimate C18 2.1*30 mm), MS (ESI) m / z=547.0 [M+H] + . Procedure for preparing compound 49b: To a solution of compound 49a (230 mg, 0.42 mmol) in MeOH (10 mL) was added Pd / C (35 mg). The resulting mixture was degassed by purging with H three times and then stirred under a H balloon (15 Psi) at 18–20° C. for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 49b (150 mg, 69% yield) as a red-purple solid.

[0481] LCMS: R t = 0.691 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m / z=517.2 [M+H] + . 1 H NMR: (400MHz, MeOH-d4) δ 8.20 (br s, 2H), 7.16 (dd, J=8.8 Hz, 12.0 Hz, 1H), 6.83 (s, 1H), 3.80 (s, 3H), 3.07-3.01 (m, 2H), 2.65 (s, 3H), 2.48 (t, J=7.2 Hz, 2H), 2.27 (s, 6H), 1.90-1.83 (m, 2H), 1.58 (s, 3H), 0.81 (t, J=7.2 Hz, 3H). Preparation procedure for Example 49: To a solution of compound 49b (150 mg, 0.29 mmol) and DIEA (56 mg, 0.44 mmol) in DMF (2.5 mL) was added dropwise acryloyl chloride (26 mg, 0.29 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0 °C for 20 min in an ice-water bath. The reaction mixture was quenched with 3 drops of water and purified by preparative HPLC (column: Xbridge BEH C18, 250*50 mm, 10 μm, conditions: 44-84% B (A: water (0.04 % NH3H2O+10 mM NH4HCO3), B: CH3CN), flow rate: 25 mL / min) to give Example 49 (31.3 mg, 20% yield) as a pale yellow solid.

[0482] LCMS: R t =1.877 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z=571.1 [M+H] + . HPLC: t = 2.72 min / 10-80_CD_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400 MHz, CDCl3) δ 10.91 (br s, 1H), 10.42 (br s, 1H), 9.94 (br s, 1H), 8.40 (s, 1H), 8.39-8.33 (m, 1H), 7.70 (br s, 1H), 7.02 (dd, J=8.4 Hz, 12.0 Hz, 1H), 6.78 (s, 1H), 6.44-6.26 (m, 2H), 5.93 (br s, 1H), 5.78-5.72 (m, 1H), 3.88 (s, 3H), 2.87 (br t, J=4.8 Hz, 2H), 2.70 (s, 3H), 2.35-2.20 (m, 8H), 2.19-2.09 (m, 1H), 2.07-1.99 (m, 1H), 1.70 (s, 3H), 0.88 (t, J=7.6 Hz, 3H). Example 50 N-(5-(4-(4,5-difluoro-2-(2-hydroxybutan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxy-2-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)acrylamide

[0483] [ka]

[0484] Procedure for preparing compound 50a: To a mixture of compound 47f (150 mg, 0.32 mmol) in DMSO (3 mL) was added KCO (134 mg, 0.97 mmol) and (3aS,6aS)-5-methyloctahydropyrrolo[3,4-b]pyrrole (60 mg, 0.48 mmol). The resulting mixture was stirred at 50 °C for 12 hours and then at 80 °C for 2 hours. The reaction mixture was poured into water (15 mL), during which time an orange solid precipitated. The solid was collected by suction filtration and dried in vacuo to give compound 50a (190 mg, 91.7% yield).

[0485] LCMS: R t = 2.019 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 571.1 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 9.83 (br. s, 1H), 8.45-8.05 (m, 2H), 7.29 (br. s, 1H), 7.02-6.88 (m, 1H), 6.33 (s, 1H), 4.39-4.31 (m, 1H), 3.89 (s, 3H), 3.54-3.41 (m, 1H), 3.19-3.10 (m, 1H), 3.02-2.92 (m, 1H), 2.63-2.55 (m, 1H), 2.48-2.42 (m, 1H), 2.40-2.34 (m, 1H), 2.24-2.18 (m, 1H), 2.15 (d, J= 2.4 Hz, 3H), 2.07-1.99 (m, 1H), 1.90-1.87 (m, 1H), 1.82-1.76 (m, 2H), 1.59 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H). Procedure for preparing compound 50b: Compound 50a (190 mg, 0.33 mmol) in methanol / water (5 mL / 1 mL) To the yellow solution in HCl (125 mg, 2.33 mmol) and Zn (109 mg, 1.66 mmol) were added. The resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (15 mL) and extracted with dichloromethane / methanol (3 / 1, 10 mL x 4). The combined organic layers were dried and concentrated in vacuo to give compound 50b (170 mg, 95.2% yield) as a black solid.

[0486] LCMS: R t = 1.526 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 541.2 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 9.86 (br. s, 1H), 8.29-8.15 (m, 2H), 7.78-7.42 (m, 2H), 7.01-6.88 (m, 1H), 6.62 (s, 1H), 4.06-3.96 (m, 1H), 3.74 (s, 3H), 3.42-3.32 (m, 1H), 2.88-2.79 (m, 1H), 2.77-2.68 (m, 1H), 2.63-2.55 (m, 1H), 2.54-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.22 (s, 3H), 2.15-2.07 (m, 1H), 2.06-1.97 (m, 1H), 1.85 (q, J = 7.2 Hz, 2H), 1.77-1.73 (m, 1H), 1.57 (s, 3H), 0.79 (t, J = 7.2 Hz, 3H). Preparation Procedure for Example 50: To a solution of compound 50b (170 mg, 0.31 mmol) in DMF (3 mL), DIEA (81 mg, 0.63 mmol) and acryloyl chloride (28 mg, 0.31 mmol) were added three times in succession at 0 °C and then stirred for 2 h. The mixture was quenched with three drops of water and purified by preparative HPLC (column: Waters Xbridge 150*255 μm, conditions: 45%-75%). B (A: water / 10 mM NH4HCO3, B: CH3CN), flow rate: 25 mL / min) to give Example 50 (39.8 mg, 21.6% yield) as a white solid.

[0487] LCMS: R t = 1.697 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 595.1 [M+H] + . HPLC: t = 3.94 min / 10-80_CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, CDCl3) δ 10.84 (br. s, 1H), 9.87 (s, 1H), 9.49 (s, 1H), 8.37-8.25 (m, 2H), 7.60 (br. s, 1H), 6.95 (dd, J = 8.8, 12.4 Hz, 1H), 6.71 (s, 1H), 6.46-6.22 (m, 1H), 5.68 (d, J = 11.6 Hz, 1H), 3.79 (s, 3H), 3.60-3.53 (m, 1H), 3.17-3.08 (m, 1H), 2.88-2.78 (m, 2H), 2.77-2.72 (m, 1H), 2.68-2.60 (m, 1H), 2.28-2.24 (m, 1H), 2.22 (s, 3H), 2.18-2.03 (m, 2H), 2.00-1.89 (m, 1H), 1.85-1.72 (m, 2H), 1.65 (s, 3H), 0.86-0.77 (m, 3H). Example 51 (R)-N-(5-(4-(4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0488] [ka]

[0489] Procedure for preparing compound 51a: To a mixture of compound 41e (200 mg, 0.43 mmol) in DMSO (5 mL) was added KCO (178 mg, 1.29 mmol) and (R)-N,N-dimethylpyrrolidin-3-amine (59 mg, 0.51 mmol). The resulting orange mixture was stirred at 23-29 °C for 4 h. The mixture was poured into water (25 mL), and the precipitated orange solid was collected by suction filtration. The solid was dried in vacuo to give compound 51a (230 mg, 95% yield).

[0490] LCMS: R t = 0.778 min / 5-95AB_220&254 Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z = 583.0 [M+Na] + . 1 H NMR: (400MHz, CDCl3) δ 10.06 (br. s, 1H), 8.92 (br. s, 1H), 8.46-8.25 (m, 2H), 7.35 (br. s, 1H), 7.26 (s, 1H), 6.31 (s, 1H), 3.95 (s, 3H), 3.61-3.52 (m, 1H), 3.39-3.32 (m, 1H), 3.25-3.12 (m, 2H), 2.89-2.78 (m, 1H), 2.31 (s, 6H), 2.02-1.81 (m, 2H), 1.71 (d, J = 5.2Hz, 6H). Procedure for preparing compound 51b: To a yellow solution of compound 51a (230 mg, 0.41 mmol) in methanol / water (5 mL / 1 mL) was added NH4Cl (154 mg, 2.87 mmol) and Zn (134 mg, 2.05 mmol). The resulting mixture was stirred at 90 °C for 1 hour. The mixture was poured into water (20 mL) and extracted with dichloromethane (15 mL x 5). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give compound 51b (180 mg, 82.7% yield) as a green solid.

[0491] LCMS: R t = 0.713 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 531.0 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 9.86 (br. s, 1H), 8.30-8.16 (m, 2H), 7.79-7.39 (m, 2H), 7.18 (s, 1H), 6.59 (s, 1H), 3.75 (s, 3H), 3.16-2.98 (m, 4H), 2.95-2.84 (m, 1H), 2.29 (s, 6H), 1.88-1.79 (m, 2H), 1.61 (s, 6H). Preparation procedure for Example 51: To a solution of compound 51b (160 mg, 0.3 mmol) in DMF (2 mL), DIEA (78 mg, 0.6 mmol) was added and stirred at 0 ° C., and acryloyl chloride (27 mg, 0.3 mmol) was added three times in succession at 0 ° C. and stirred for 0.5 hours. This reaction mixture was combined with that of the previous batch and purified by preparative HPLC (column: Waters Xbridge 150 * 255 μm, conditions: 42%~72% B (A: water / 10mM NH4HCO3, B: CH3CN), flow rate: 2 5 mL / min) to afford Example 51 (91.4 mg, 46% yield) as a white solid.

[0492] LCMS: R t= 1.660 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z = 585.2 [M+H] + . HPLC: t = 3.46 min / 10-80_CD_1.2ml Chromatography (XBridge Shield RP 18 2.1*50mm 5um). 1 H NMR (400MHz, CDCl3) δ 10.67 (br. s, 1H), 9.63 (s, 1H), 8.53 (s, 1H), 8.38-8.26 (m, 2H), 7.57 (s, 1H), 7.22-7.16 (m, 1H), 6.63 (s, 1H), 6.51-6.38 (m, 1H), 6.35-6.25 (m, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.79 (s, 3H), 3.15-3.06 (m, 2H), 3.04-2.96 (m, 2H), 2.94-2.85 (m, 1H), 2.30 (s, 6H), 2.15-2.10 (m, 1H), 1.99-1.94 (m, 1H), 1.68 (s, 6H). Example 52 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)pyrimidin-2-ylamino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0493] [ka]

[0494] Procedure for preparing compound 52a: To a solution of compound 36b (200 mg, 0.429 mmol) and KCO (119 mg, 0.858 mmol) in DMSO (3 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (59 mg, 0.515 mmol). The reaction mixture was stirred at 22-30 °C for 4 h and then at 50 °C for 1 h, during which time the color changed from brown to deep orange. The reaction mixture was added dropwise to HO (40 mL) in an ice-water bath. The precipitated solid was collected by filtration and washed with HO (15 mL x 3). The filter cake was dissolved in CHCl (20 mL), dried over NaSO, and concentrated in vacuo to give compound 52a (210 mg, 87.4% yield) as an orange solid.

[0495] LCMS: R t =0.677 min / 5-95AB_220&254.1cm Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z=559.9 [M+H]+. 1 H NMR (400MHz, methanol-d4) δ 8.42 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.24 (d, J=10.8 Hz, 1H), 6.50 (s, 1H), 6.15 (d, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.54 (dt, J=6.4, 10.4 Hz, 1H), 3.36 (t, J=9.2 Hz, 1H), 3.28-3.24 (m, 1H), 3.09 (dd, J=6.8, 10.0 Hz, 1H), 2.93-2.81 (m, 1H), 2.33 (s, 6H), 2.30-2.25 (m, 1H), 1.97-1.82 (m, 1H), 1.59 (d, J=3.6 Hz, 6H). Procedure for preparing compound 52b: To a solution of compound 52a (210 mg, 0.375 mmol) in 5 mL of MeOH / HO = 5 / 1 (v / v) was added Zn (147 mg, 2.25 mmol) and NH4Cl (120 mg, 2.25 mmol). The resulting mixture was heated at 90 °C for 2 h, during which time its color changed from orange to brown. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was dissolved in CHCl2 (20 mL), washed with water (15 mL × 3), dried over Na2SO4, and concentrated in vacuo to give compound 52b (125 mg, 63% yield) as a brown solid.

[0496] LCMS: R t =0.629 min / 5-95AB_220&254.1cm Chromatography (MERCK RP18 2.5-2mm), MS (ESI) m / z=530.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.85 (s, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 7.08 (d, J=10.4 Hz, 1H), 6.66 (s, 1H), 6.05 (d, J=5.6 Hz, 1H), 3.81 (s, 3H), 3.20-3.11 (m, 2H), 3.06-2.97 (m, 2H), 2.91-2.83 (m, 1H), 2.28 (s, 6H), 2.17-2.09 (m, 1H), 1.92-1.81 (m, 1H), 1.65 (s, 6H). Preparation Procedure for Example 52: To a solution of compound 52b (125 mg, 0.236 mmol) and DIEA (46 mg, 0.354 mmol) in DMF (1.5 mL) was added acryloyl chloride (21 mg, 0.236 mmol) in an ice-water bath. The resulting mixture was stirred at 5-10 °C for 15 min. The reaction was quenched with HO (0.1 mL) and filtered. The filtrate was directly purified by preparative HPLC (Column: Xtimate C18 150*25 mm*5 μm; Conditions: 35-65% B (A: 0.04% NH₃·HO + 10 mM NH₄HCO₃, B: CH₃CN); Flow rate: 30 mL / min) and then lyophilized to give Example 52 (14.5 mg, 10.5% yield) as an off-white solid.

[0497] LCMS: R t =2.028 min / 10-80CD_3min_220&254. lcm chromatography (XBrige Shield RP18 2.1*50mm, 5um), MS (ESI) m / z=584.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.62 (s, 1H), 9.43 (br s, 1H), 8.59 (br s, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.47 (br s, 1H), 7.14 (d, J=10.8 Hz, 1H), 6.75 (s, 1H), 6.41-6.31 (m, 3H), 5.77 (t, J=5.4 Hz, 1H), 3.86 (s, 3H), 3.15-3.02 (m, 4H), 2.97-2.84 (m, 1H), 2.30 (s, 6H), 2.21-2.14 (m, 1H), 1.99-1.94 (m, 1H), 1.72 (s, 6H). Example 53 (R)-N-(5-(4-(5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenylamino)pyrimidin-2-ylamino)-2-(2-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0498] [ka]

[0499] Procedure for preparing compound 53a: To a solution of compound 36b (150 mg, 0.32 mmol) and K2CO3 (442 mg, 3.20 mmol) in DMSO (5 mL) was added (R)-1-(azetidin-2-yl)-N,N-dimethylmethanamine TFA salt (986 mg, 3.20 mmol). The resulting mixture was stirred at 85 °C for 4 h, during which time its color changed from light yellow to deep yellow. The reaction mixture was poured into ice water (50 mL), and a yellow solid precipitated. The solid was filtered, dissolved in CHCl2 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 53a (150 mg, 84% yield) as a yellow solid.

[0500] LCMS: R t = 0.692 min / 5-95AB_220&254.1 cm Chromatography (MERCK RP-18e 25-2 mm), MS (ESI) m / z= 559.9 [M+H] + . Procedure for preparing compound 53b: To a solution of compound 53a (150 mg, 0.27 mmol) in MeOH (5 mL) was added Pd / C (15 mg). The resulting mixture was degassed by purging with H three times and then stirred under a hydrogen balloon (15 Psi) at 22-30 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 53b (100 mg, 70% yield) as a black solid.

[0501] LCMS: R t= 0.663 min / 5-95AB_1.5 min_220&254 Chromatography (MERCK RP18e 25-2mm), MS (ESI) m / z= 530.0 [M+H] + . Preparation Procedure for Example 53: To a solution of compound 53b (100 mg, 0.19 mmol) and DIEA (49 mg, 2.0 equiv., 0.38 mmol) in DMF (2.5 mL) was added acryloyl chloride (17 mg, 0.19 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0°C for 30 minutes in an ice-water bath. This reaction mixture was purified by preparative HPLC [column: Waters Xbridge 150* Purification was performed by HPLC using a 255 μm column; conditions: 36-66% B (A: 0.05% NH3H2O; B: CH3CN); flow rate: 25 mL / min. Fractions containing the desired compound were lyophilized to give Example 53 (12.2 mg, 11% yield) as a white solid.

[0502] LCMS: R t = 1.378 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z= 584.1 [M +H] + . HPLC: t = 2.74 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1 H NMR: (400MHz, CDCl3) δ 9.41-9.33 (m, 2H), 8.95 (br s, 1H), 8.08 (d, J=6.0 Hz, 1H), 7.52 (br d, J=6.8 Hz, 1H), 7.44 (s, 1H), 7.15 (d, J=10.4 Hz, 1H), 6.68 (s, 1H), 6.38 (d, J=2.8 Hz, 1H), 6.36-6.30 (m, 2H), 5.81-5.75 (m, 1H), 5.62-5.36 (m, 1H), 4.19 (br d, J=6.8 Hz, 1H), 3.90 (s, 3H), 3.83-3.78 (m, 1H), 3.56 (q, J=8.4 Hz, 1H), 2.65 (br dd, J=5.6, 12.4 Hz, 1H), 2.45 (br dd, J=6.8, 12.8 Hz, 1H), 2.37 (br d, J=7.6 Hz, 1H), 2.26 (s, 6H), 2.16-2.08 (m, 1H), 1.71 (d, J=2.8 Hz, 6H). Example 54 (R)-N-(5-(4-(4,5-dichloro-2-(2-hydroxypropan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-(2-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0503] [ka]

[0504] This synthesis followed a similar experimental procedure to Example 19 to afford Example 54 as a pale white solid. LCMS: R t = 4.386 min / 10-80CD_7min_220&254.lcm; XBrige Shield RP18 2.1*50mm MS (ESI) m / z= 601.3 [M+H] + . HPLC: t = 3.72 min / 10-80_ab_1.2ML Chromatography (Ultimate C18 3*50mm 3um). 1H NMR (400MHz, DMSO-d6) δ 10.54 (br s, 1H), 9.32 (br s, 1H), 8.84 (br s, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 7.52 (br s, 1H), 7.25 (s, 1H), 6.59-6.52 (m, 1H), 6.34-6.26 (m, 2H), 5.76-5.68 (m, 1H), 4.22-4.12 (m, 1H), 3.82 (s, 3H), 3.78 (br s, 1H), 3.48 (q, J=8.0 Hz, 1H), 2.60 (br dd, J=5.6, 12.8 Hz, 1H), 2.45-2.26 (m, 2H), 2.20 (s, 6H), 2.09-1.90 (m, 2H), 1.67 (br s, 6H). Example 55 N-(5-(4-(4,5-difluoro-2-(2-hydroxybutan-2-yl)phenylamino)-1,3,5-triazin-2-ylamino)-2-((R)-2-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0505] [ka]

[0506] This synthesis followed a similar experimental procedure to Example 47 to afford Example 55 as a white solid. LCMS: R t = 1.741 min / 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1*30mm), MS (ESI) m / z=583.1 [M+H] + . HPLC: t = 3.49 min / 10-80_CD_1.2ML Chromatography (XBridge Shield RP 18 2.1*50 mm 5um). 1H NMR: (400 MHz, CDCl3) δ 10.70 (br s, 1H), 9.43 (br s, 1H), 8.87 (br s, 1H), 8.39-8.26 (m, 2H), 7.62-7.48 (m, 1H), 6.99 (dd, J=8.8 Hz, 12.4 Hz, 1H), 6.61 (br d, J=6.0 Hz, 1H), 6.40-6.26 (m, 2H), 5.80-5.74 (m, 1H),...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, A １ is N or CR ８ and A ２ , A ３ , A ４ , and A ５ are each independently N or CR ９ where A ２ , A ３ , A ４ , and A ５ at most one of is N; R １ and R ２ are each independently hydrogen or a halogen, hydroxyl, -NR ａ R ｂ , C １－１２ Alkyl, C １－１２ Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, 3- to 10-membered saturated or unsaturated heterocyclyl (wherein C １－１２ Alkyl, C １－１２ Each of the alkoxy, the 3- to 10-membered saturated or unsaturated carbocyclyl, and the 3- to 10-membered saturated or unsaturated heterocyclyl may be unsubstituted or unsubstituted. １－１２ C may be mono- or polysubstituted by one or more of the following alkyl groups: １－１２ alkyl {where R ａ and R ｂ are each independently hydrogen or C １－１２ Alkyl (which may contain deuterium, tritium, halogen, hydroxyl, or C １－１２ or R ａ and R ｂ together with the nitrogen atom to which they are attached, a halogen, a hydroxyl, or a C １－１２ forming a 3- to 10-membered saturated or unsaturated heterocyclyl which may be mono- or polysubstituted by alkyl; Or, R １ and R ２ together with the nitrogen atom to which they are attached, form a 3- to 12-membered monocyclic or polycyclic ring which may contain one or more additional heteroatoms selected from N, O, and S (which may include halogen, hydroxyl, C １－１２ Alkyl, C １－１２ Alkoxy, —NR ａ R ｂ , or -C １－１２ Alkyl-NR ａ R ｂ which may be mono- or independently polysubstituted by R ３ is H, C １－１２ Alkyl, or -C １－１２ Alkyl-NR ａ R ｂ and R ４ and R ５ are each independently deuterium, tritium, halogen, hydroxyl, C １－１２ Alkyl, or C １－１２ C may be mono- or polysubstituted independently by one or more of alkoxy. １－６ is alkyl, Or, R ４ and R ５ are, together with the carbon atoms to which they are attached, a 3- to 10-membered monocyclic or polycyclic ring which may contain one or more heteroatoms selected from N, O, and S (which may include deuterium, tritium, halogen, hydroxyl, C １－１２ Alkyl, or C １－１２ and forming a substituted or unsubstituted alkyl group, which may be mono- or polysubstituted independently with one or more of alkoxy; R ６ is hydrogen or deuterium, tritium, halogen, hydroxyl, C １－１２ Alkyl, or C １－１２ C, which may be mono- or polysubstituted independently by alkoxy; １－１２ is alkyl, R ７ is hydrogen or is substituted by deuterium, tritium, halogen, or hydroxyl C, which may be mono- or polysubstituted with １－１２ is alkyl, R ８ is hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C １－１２ Alkyl, C １－１２ Alkoxyl (these are substituted with deuterium, tritium, halogen, or C １－１２ may be mono- or polysubstituted independently with one or more alkyl; R ９ is null, hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C １－１２ Alkyl, or C １－１２ Alkoxyl (these are substituted with deuterium, tritium, halogen, or C １－１２ may be mono- or polysubstituted independently with one or more alkyl; n is 0, 1, 2, 3, or 4; Each R is independently hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C １－１２ Alkyl, C １－１２ Alkoxy, 3- to 10-membered saturated or unsaturated carbocyclyl, or 3- to 10-membered saturated or unsaturated heterocyclyl fused to the ring to which it is attached (which may be fused to a ring containing deuterium, tritium, halogen, or C １－１２ or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof.

2. A １ The compound of claim 1 wherein is N.

3. A １ The compound of claim 1 , wherein is CH.

4. A ２ , A ３ , A ４ , and A ５ However, each is independently CR ９ 2. The compound of claim 1, wherein:

5. R １ and R ２ are each independently 【Chemistry 2】 2. The compound of claim 1 selected from:

6. R １ and R ２ together with the nitrogen atom to which they are attached, halogen, hydroxyl, C １－１２ Alkyl, C １－１２ Alkoxy, —NR ａ R ｂ , or -C １－１２ Alkyl-NR ａ R ｂ may be mono- or independently polysubstituted by 【Transformation 3】 The compound of claim 1, which forms a 3- to 12-membered monocyclic or polycyclic ring selected from:

7. R １ and R ２ together with the nitrogen atom to which they are attached, 【Chemistry 4】 2. The compound of claim 1, wherein

8. n is 2, and A ２ and A ５ is CH, and A ３ and A ４ are each independently CH substituted by R, each R is independently halogen, and R ４ and R ５ are each independently an unsubstituted C １－６ The compound of claim 1, wherein the aryl group is alkyl. 【Request Item 9】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 Table 1-5 2. The compound of claim 1 selected from the group consisting of:

10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, in crystalline form.

11. A pharmaceutical composition comprising one or more compounds of formula (I) as a first active ingredient, a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof according to any one of claims 1 to 9, and a pharmaceutically acceptable diluent, excipient, or carrier.

12. A compound of formula (I) as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 11, for use as a medicament for inhibiting EGFR.

13. 12. A method of inhibiting ErbB or BTK by using one or more compounds of any of claims 1-9, pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, or the pharmaceutical composition of claim 11.

14. 12. A method of treating an ErbB-related disorder or a BTK-related disorder in a subject, comprising administering to the subject an effective amount of one or more compounds of any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 11.

15. 15. The method of claim 14, wherein the subject is a warm-blooded animal such as a human.

16. 15. The method of claim 14, wherein the ErbB-associated disease is cancer.

17. 15. The method of claim 14, wherein the BTK-associated disease is a tumor disease or an autoimmune disease.

18. 18. The method of claim 17, wherein the tumor disease is lymphoma or leukemia.

19. 18. The method of claim 17, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome.

20. The method according to any one of claims 13 to 16, wherein the ErbB is EGFR or Her2, preferably an EGFR mutant or a Her2 mutant.

21. The EGFR variants are EGFR D761_E762insEAFQ, EGFR A763_Y764insHH, EGFR M766_A767instAI, EGFR A767_V769dupASV, EGFR A767_S768insTLA, EGFR S768_D770dupSVD, EGFR S768_V769insVAS, EGFR S768_V769insAWT, EGFR V769_D770insASV, EGFR V769_D770insGV, EGFR V769_D770insCV, EGFR V769_D770insDNV, EGFR V769_D770insGSV, EGFR V769_D770insGVV, EGFR V769_D770insMASVD, EGFR D770_N771insSVD, EGFR D770_N771insNPG, EGFR D770_N771insAPW, EGFR D770_N771insD, EGFR D770_N771insDG, EGFR D770_N771insG, EGFR D770_N771insGL, EGFR D770_N771insN, EGFR D770_N771insNPH, EGFR D770_N771insSVP, EGFR D770_N771insSVQ, EGFR D770_N771insMATP, EGFR delD770insGY, EGFR N771_P772insH, EGFR N771_P772insN, EGFR N771_H773dupNPH, EGFR delN771insGY, EGFR delN771insGF, EGFR P772_H773insPR, EGFR P772_H773insYN, EGFR P772_H773insX, EGFR P772_H773insDPH, EGFR P772_H773insDNP, EGFR P772_H773insQV, EGFR P772_H773insTPH, EGFR P772_H773insN, EGFR P772_H773insV, EGFR H773_V774insNPH, EGFR H773_V774insH, EGFR H773_V774insPH, EGFR H773_V774insGNP, EGFR H77 _21. The method of claim 20, wherein the EGFR exon 19 deletion is selected from the group consisting of EGFR H773_V774insGH, EGFR V774_C775insHV, EGFR exon 19 deletion, EGFR L858R, EGFR T790M, EGFR L858R / T790M, EGFR exon 19 deletion / T790M, EGFR S768I, EGFR G719S, EGFR G719A, EGFR G719C, EGFR E709A / G719S, EGFR E709A / G719A, EGFR E709A / G719C, and EGFR L861Q.

22. 21. The method of claim 20, wherein the Her2 mutant is selected from the group consisting of Her2 A775_G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG, and Her2 P780_Y781insGSP.

23. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof, in combination with a second therapeutic agent, preferably an antitumor agent. solvates, or stereoisomers.

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