ERBB receptor inhibitors

Abstract

To provide compounds inhibiting for treating diseases associated with ErbBs (especially HER2), including cancer, and pharmaceutical compositions comprising the compounds.SOLUTION: The invention provides compounds represented by the formula (I) in the figure, and pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to compounds that inhibit ErbB (e.g., HER2). The present disclosure also relates to pharmaceutical compositions containing one or more of the compounds as active ingredients, and to the use of the compounds in the manufacture of medicaments for treating diseases associated with ErbB (e.g., HER2). [Background technology]

[0002] The ErbB receptor tyrosine kinase family consists of four closely related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (reviewed in Riese and Stern, Bioessays (1998) 20:41-48; Olayioye et al., EMBO Journal (2000) 19:3159-3167; and Schlessinger, Cell (2002) 110:669-672). These receptors act to transmit signals from the outside to the inside of the cell by activating second messenger effectors via phosphorylation events at their tyrosine-phosphorylated residues. Various cellular processes are modulated by these signals, 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 cancer, head and neck cancer and breast cancer. A detailed review of ErbB receptor signaling and its involvement in tumorigenesis is provided in New England Journal of Medicine, 2008, Vol. 358:1160-74 and Biochemical and Biophysical Research Communications, 2004, Vol. 319:1-11.

[0003] Several researchers have demonstrated the role of EGFR and ErbB2 in cancer development (reviewed in Salomon et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232; Klapper et al., Adv. Cancer Res. (2000) 77:25-79; and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). Squamous carcinomas of the head, neck, and lung express high levels of EGFR. Furthermore, constitutively active EGFR has been found in gliomas, breast cancer, and lung cancer. ErbB2 overexpression occurs in approximately 30% of all breast cancers and is associated with various other cancer types, including ovarian, colon, bladder, gastric, esophageal, lung, uterine, and prostate cancers. ErbB2 overexpression has also been correlated with poor prognosis in human cancers, including metastasis and early recurrence.

[0004] Several inhibitors of the EGFR and ErbB2 signaling pathways have demonstrated clinical efficacy in cancer treatment. Gefitinib (IRESSA), erlotinib (TARCEVA), lapatinib (TYKERB, TYVERB), panitumumab (VECTIBIX), cetuximab (ERBITUX), osimertinib (TAGRISSO, AZD9291), and afatinib (GIOTRIF) are clinically available EGFR inhibitors. Clinically available anticancer drugs targeting HER2 include trastuzumab (also known as Herceptin), trastuzumab emtansine (T-DM1), pertuzumab (Perjeta), lapatinib (Tyverb), and neratinib (Nerlynx). Two-thirds of breast cancer patients respond well to Herceptin-trastuzumab, but some HER2-positive breast cancer patients do not respond to the drug.

[0005] Therefore, there remains a need to develop novel ErbB (especially HER2) inhibitors. . Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a compound of formula (I):

[0007] [ka]

[0008] 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), a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0009] In yet another aspect, the present disclosure 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 (e.g., HER2).

[0010] In another aspect, the present disclosure provides methods of inhibiting ErbB (e.g., 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 foregoing.

[0011] In another aspect, the present disclosure provides a method of treating a disease associated with HER2 in a subject, comprising administering to the subject an effective amount of one or more compounds of formula (I), pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, or one or more pharmaceutical compositions as described above.

[0012] In a further aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof in combination with a second therapeutic agent, preferably an anti-tumor agent, such as a chemotherapeutic drug (capecitabine, docetaxel, vinorelbine), or a HER2-targeting antibody (trastuzumab (Herceptin), trastuzumab emtansine (T-DM1), pertuzumab (Perjeta)).

[0013] In another aspect, the disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof in the manufacture of a medicament for treating a disease associated with ErbB (e.g., HER2) in a subject. DETAILED DESCRIPTION OF THE INVENTION

[0014] compound In one aspect, the present disclosure provides a compound of formula (I):

[0015] [ka]

[0016] or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, During the ceremony, R1 is hydrogen; R2 is hydrogen, halogen, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; G is N or C-CN; W is O, C(=O), S, SO or SO2; Y is a bond or C 1~12 is alkylene, R3 is a 3- to 10-membered saturated or unsaturated carbocyclyl or a 3- to 10-membered saturated or unsaturated heterocyclyl, which may be substituted with halogen, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl, substituted C 1~12 may be optionally mono- or independently polysubstituted by alkyl; i is 0, 1, 2 or 3; Each R4 is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; j is 0, 1, 2 or 3; Each R5 is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 haloalkyl or OR6, where R6 is a 3- to 10-membered saturated or unsaturated carbocyclyl or a 3- to 10-membered saturated or unsaturated heterocyclyl, which are hydroxyl, halogen, cyano, C 1~12 Alkyl or C 1~12 optionally mono- or independently polysubstituted by haloalkyl; A is O, C(=O), S, SO or SO2; E is

[0017] [ka]

[0018] and X1, X2, X3 and X4 are each independently N or CR8; X5 and X6 are each independently N or CR8, and X7 is O, S, NR9 or CR 10 R11 wherein at least one of X5 and X6 is N; R8, R9, R 10 and R 11 are each independently hydrogen, halogen, or C 1~12 Alkyl, cyano, amino, hydroxyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; p is 0, 1, 2 or 3; Each R7 is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 It is haloalkyl.

[0019] In some embodiments, R in Formula (I) is halogen, hydroxyl, C 1~12 Alkyl or C 1~12 It is alkoxyl. In some embodiments, i = 0. In some embodiments, i = 1 and R4 in Formula (I) is halogen.

[0020] In some embodiments, j=1 or 2 and each R5 is independently selected from amino, C 1~12 alkoxyl or OR6; where R6 is a 3- to 10-membered saturated or unsaturated carbocyclyl or a 3- to 10-membered saturated or unsaturated heterocyclyl, which may be substituted with hydroxyl, halogen, cyano, C 1~12 Alkyl or C 1~12 Optionally mono- or independently polysubstituted with haloalkyl.

[0021] In some embodiments, R5 in Formula (I) is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12haloalkyl or OR6, which is mono- or polysubstituted with deuterium.

[0022] In some embodiments, W in formula (I) is O. In some embodiments, A in formula (I) is O. In some embodiments, R3 in Formula (I) is a 3-10 membered saturated or unsaturated heterocyclyl mono- or polysubstituted with deuterium.

[0023] In some embodiments, R3 in Formula (I) is a 3-10 membered saturated heterocyclyl, which is selected from the group consisting of halogen, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl, C 1~12 It may be optionally mono- or independently polysubstituted by alkyl.

[0024] In some embodiments, R in Formula (I) is a deuterium-substituted C 1~12 It is a 3-10 membered saturated heterocyclyl mono- or polysubstituted independently by alkyl. In some embodiments, R3 in Formula (I) is a 5-10 membered saturated heterocyclyl containing 1 or 2 N atoms, which is selected from the group consisting of halogen, deuterium, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl or deuterium substituted C 1~12 It may be optionally mono- or independently polysubstituted with alkyl. In certain embodiments, R in formula (I) contains at least one halogen substituent, preferably the halogen is F. In certain embodiments, R in formula (I) contains two, three or more halogen substituents, preferably the halogen is F.

[0025] In some embodiments, R3 in Formula (I) is

[0026] [ka]

[0027] which includes halogens, deuterium, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl or deuterium substituted C 1~12 It may be optionally mono- or independently polysubstituted by alkyl.

[0028] In some embodiments, R3 in Formula (I) is

[0029] [ka]

[0030] which includes halogens, deuterium, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl or deuterium substituted C 1~12 It may be optionally mono- or independently polysubstituted by alkyl.

[0031] In some embodiments, Y in formula (I) is a bond or C 1~3 It is alkylene. In some embodiments, E in formula (I) is

[0032] [ka]

[0033] and During the ceremony, X2 and X3 are each independently N or CR8; X6 is N or CR8, and X7 is O, S, NR9 or CR 10 R 11 and; p is 0, 1, 2 or 3; Each R7 is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; R8, R9, R 10 and R 11 are each independently hydrogen, halogen, or C 1~12 Alkyl, cyano, amino, hydroxyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 It is haloalkyl.

[0034] In some embodiments, E in formula (I) is

[0035] [ka]

[0036] wherein X2 is N or CR8. In some embodiments, compounds of the present disclosure have formula (Ia):

[0037] [ka]

[0038] or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof; During the ceremony, R2 is hydrogen, halogen, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; R 12、 R 13 , R 14 and R 15 are each independently hydrogen, halogen, deuterium, hydroxyl, amino, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 Haloalkyl, deuterium-substituted C 1~12 is alkyl; R 16 and R 17 are each independently hydrogen, halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH, C 1~12 haloalkyl or OR6; where R6 is a 3- to 10-membered saturated or unsaturated carbocyclyl or a 3- to 10-membered saturated or unsaturated heterocyclyl, which may be hydroxyl, halogen, cyano, C 1~12 Alkyl or C 1~12 optionally mono- or independently polysubstituted with haloalkyl; In the formula, E is

[0039] [ka]

[0040] and During the ceremony, X2 and X3 are each independently N or CR8; X6 is, independently at each occurrence, N or CR8; and X7 is O, S, NR9, or CR 10 R 11 and; p is 0, 1, 2 or 3; Each R7 is independently selected from halogen, amino, hydroxyl, C 1~12 Alkyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 is haloalkyl; R8, R9, R 10 and R 11 are each independently hydrogen, halogen, or C 1~12 Alkyl, cyano, amino, hydroxyl, C 1~12 Alkoxyl, C 1~12 Alkyl-OH or C 1~12 It is haloalkyl.

[0041] In some embodiments, R2 in Formula (Ia) is halogen, hydroxyl, C 1~12 Alkyl or C 1~12 It is alkoxyl. In some embodiments, R in Formula (Ia) 12、 R 13 , R 14 and R 15 are each independently hydrogen, halogen, deuterium, hydroxyl, amino, C 1~12 Alkyl or C 1~12 It is alkoxyl.

[0042] In some embodiments, R in Formula (Ia) 13 and R 14 In some embodiments, at least one of R in Formula (Ia) is halogen. 13 and R 14 In some embodiments, both of R in Formula (Ia) are halogen. 13 and R 14 At least one of is F. In some embodiments, R in Formula (Ia) 13 and R 14 and R are F. In some embodiments, R in Formula (Ia) 15 is hydrogen. In some embodiments, R in Formula (Ia) 15 is a halogen.

[0043] In some embodiments, R in Formula (Ia) 16 and R 17 are each independently hydrogen, halogen, amino, C 1~12alkoxyl or OR6, which may be optionally mono- or independently polysubstituted by deuterium; where R6 is a 3- to 10-membered saturated or unsaturated carbocyclyl or a 3- to 10-membered saturated or unsaturated heterocyclyl, which may be substituted with hydroxyl, halogen, cyano, C 1~12 Alkyl or C 1~12 In some embodiments, R in Formula (Ia) is optionally mono- or polysubstituted with independently haloalkyl. 16 and R 17 are each independently hydrogen, amino or C 1~12 It is alkoxyl.

[0044] In some embodiments, E in Formula (Ia) contains at least 2 or 3 N atoms. In some embodiments, E in Formula (Ia) is

[0045] [ka]

[0046] wherein X2 is CR8, and R8 is hydrogen, halogen, C 1~12 Alkyl, cyano, amino, hydroxyl or C 1~12 It is alkoxyl. In some embodiments, E in Formula (Ia) is

[0047] [ka]

[0048] wherein X2 is CR8, and R8 is hydrogen, halogen, C 1~12 Alkyl, cyano, amino, hydroxyl or C 1~12 In some embodiments, E in Formula (Ia) is

[0049] [ka]

[0050] wherein X2 and X3 are each independently CR8, and R8 is hydrogen, halogen, C 1~12 Alkyl, cyano, amino, hydroxyl or C 1~12 It is alkoxyl.

[0051] Illustrative compounds 1-46 of formula (I) are set forth in Table 1 below.

[0052] [Table 1-1]

[0053] [Table 1-2]

[0054] [Table 1-3]

[0055] [Table 1-4]

[0056] [Table 1-5]

[0057] [Table 1-6]

[0058] [Table 1-7]

[0059] [Table 1-8]

[0060] [Table 1-9]

[0061] [Table 1-10]

[0062] [Table 1-11]

[0063] [Table 1-12]

[0064] [Table 1-13]

[0065] [Table 1-14]

[0066] [Table 1-15]

[0067] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0068] In various places in this disclosure, linking substituents are described. When a structure clearly requires a linking group, it is understood that the Markush variable listed for that group is the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl," it is understood that "alkyl" represents the linking alkylene group.

[0069] 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 and refers to a chemical moiety that is covalently attached to, or fused, where appropriate, to, a parent group. As used herein, the terms "optionally substituted" or "optionally...substituted" mean that a chemical group can have no substituents (i.e., unsubstituted) or can have one or more substituents (i.e., substituted). It should be understood that substitution at a given atom is limited by valence.

[0070] 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 every integer point therebetween, where j is greater than i when i∈{1, 2, 3, 4, 5, 6, 7, 8, 9, or 10}, and j∈{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.

[0071] As used herein, the term "alkyl" whether used as part of another term or independently means an unsaturated alkyl group. Japanese charcoal Hydrogen chain vinegar. The hydrocarbon chains mentioned above may be straight or branched. i~j The 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. a Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. do.

[0072] 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 formula -CN.

[0073] As used herein, the term "hydroxyl" refers to a group of formula -OH. As used herein, the term "alkoxy," whether used as part of another term or independently, refers to a group of formula -O-alkyl. i~j The term "alkoxy" means that 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), t-butoxy, and the like.

[0074] As used herein, "Ci~j The term "alkyl-OH" refers to a group of the formula "-C 1~12 "alkyl-OH" refers to the group "alkyl-OH," where the alkyl portion of the group has i to j carbon atoms, and the hydroxyl group can be attached to any carbon atom in the alkyl portion. 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.

[0075] As used herein, "C i~j The term "haloalkyl" refers to halogen-substituted (mono- or poly-substituted) C i~j Refers to an alkyl group. 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 9 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.

[0076] Carbocyclyl groups can include monocyclic or polycyclic rings (e.g., 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 (having one to four 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 having two rings connected through a single common atom; the term "fused ring" refers to a ring system having two rings sharing two adjacent atoms; and the term "bridged ring" refers to a ring system having two rings sharing 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, nene, and the like. Examples of bridged carbocyclyls include, but are not limited to, bicyclo[1,1,1]pentenyl, 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, and the like.

[0077] As used herein, the term "heterocyclyl" refers to a carbocyclyl group in which one or more (e.g., one, two, or three) ring atoms are replaced by heteroatoms, including, but not limited to, oxygen, sulfur, nitrogen, phosphorus, etc. In some embodiments, a heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, an unsaturated heterocyclyl group can contain one or more aromatic rings.

[0078] Heterocyclyl groups can contain monocyclic or polycyclic rings (e.g., having 2, 3, or 4 fused, bridged, or spiro rings). Illustrative monocyclic heterocyclyl groups include, but are not limited to, piperidyl, 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, and the like. Examples of bridged heterocyclyls include, but are not limited to, morphane, hexamethylenetetramine, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0079] As used herein, the term "i- to j-membered" refers to a carbocyclyl or heterocyclyl group having i to j ring-forming atoms. For example, a "3- to 8-membered carbocyclyl" refers to a carbocyclyl group having 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) ring-forming members; a "3- to 10-membered heterocyclyl" refers to a heterocyclyl having 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) ring-forming 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.

[0080] As used herein, the term "aromatic group" or "aromatic ring" means at least "Carbocyclyl" refers to a monocyclic or polycyclic carbocyclyl or heterocyclyl moiety having alternating double and single bonds between ring-forming atoms in 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, idenyl, and the like. In some embodiments, the heteroaromatic group is 5 or 6 members. 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.

[0081] "Compounds" of the present disclosure, unless otherwise specified, are intended to encompass all stereoisomers, geometric isomers, and tautomers of the structures depicted. The term "stereoisomer" refers to any of the various stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of asymmetric compounds (e.g., those having one or more asymmetrically substituted carbon atoms—"chiral centers"). Compounds of the present disclosure containing chiral centers can be isolated in optically active (enantiomers and diastereomers) or optically inactive (racemic) forms. 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 that can be defined in terms of absolute configuration at each chiral center as (R)- or (S)- according to the Cahn-Ingold-Prelog R-S system. Resolved compounds of unknown absolute configuration 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 by resolution by HPLC or stereoselective synthesis.

[0082] "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 "tautomer" includes prototropic tautomers, which are isomeric protonation states of compounds with the same formula and total charge. Examples of prototropic 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 protons can occupy more than one position in a heterocyclic ring 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 can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0083] The "compounds" of the present disclosure are intended to encompass all isotopes of atoms in the compound. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the "compounds" of the present disclosure include, but are not limited to: 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, the term "substituted by deuterium" or "deuterium substitution" refers to the replacement of other isoforms of hydrogen (e.g., protium) with deuterium in a chemical group. In some embodiments, carbon is 12 C and 13 Contains C.

[0084] It is to be understood that the "compounds" of the present disclosure can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, solid forms, etc., and the present disclosure is intended to encompass all such solvated and unsolvated forms.

[0085] It should be understood that the "compounds" of the present disclosure can further exist in the form of pharmaceutically acceptable salts or esters. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms are those approved by a regulatory authority (such as the U.S. Food and Drug Administration, the China Food and Drug Administration, or the European Medicines Agency) for use in animals, and more particularly in humans, or that are listed in a generally recognized pharmacopoeia (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia).

[0086] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an acidic (e.g., carboxyl, etc.) or basic (e.g., amine, alkali, etc.) moiety present therein 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. Pharmaceutically acceptable salts are typically acid and / or base salts that retain the biological effectiveness and properties of the parent compound, which are not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts that can be derived from inorganic 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, napadisylic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.). In some embodiments, the pharmaceutically acceptable salt of the compounds of the present disclosure is a formic acid salt. In some embodiments, the pharmaceutically acceptable salt of the compounds of the present disclosure is a TFA salt.

[0087] 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, and hydroxide, carbonate, and bicarbonate salts of metals from Groups I to XII of the periodic table, such as calcium, magnesium, iron, silver, zinc, and copper) or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, basic ion exchange resins, and the like). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. Those skilled in the art will recognize that acids or bases can be added to form acid / base addition salts other than those shown in the examples. It will be appreciated that it may be possible to add additional salts. Listings of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0088] As used herein, "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Such esters can act as prodrugs, as defined herein. Esters can be formed at amine, hydroxyl, or carboxyl side chains on the compounds described herein. For example, if the disclosed compounds contain 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, a carboxylic acid group, a phosphate group, a phosphinic acid group, a sulfinic acid group, a sulfonic acid group, and a boronic acid group. Procedures and specific groups for making such esters are known to those skilled in the art and can be readily found in reference resources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999, which are incorporated herein by reference in their entirety.

[0089] The present disclosure also includes active intermediates, active metabolites, and prodrugs of the disclosed compounds. As used herein, "active intermediate" refers to an intermediate compound in a synthetic process that exhibits the same or essentially the same biological activity as the final synthetic compound.

[0090] As used herein, "active metabolite" refers to a breakdown or end product of a compound of the present disclosure, or a salt or prodrug thereof, produced via metabolism or biotransformation in the animal or human body, that exhibits the same or essentially the same biological activity as the specified compound. Such metabolites may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound or salt or prodrug.

[0091] As used herein, a "prodrug" refers to any compound or conjugate that releases an active parent drug upon administration to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in the compound such that the modification is cleaved from the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, or carboxyl group is bonded to any group that cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively, upon administration to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in compounds of the present disclosure. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entireties.

[0092] Unless otherwise specified, "wild-type ErbB" refers to a normal ErbB family member present in a natural environment that performs the normal function of ErbB. 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 more than one ErbB family kinase. In some other embodiments, the compounds of the present disclosure selectively inhibit ErbB2 (i.e., HER2) but do not inhibit other ErbB family kinases (e.g., EGFR).

[0093] In some embodiments, the compounds of the present disclosure can inhibit both wild-type (WT) and mutant forms of ErbB family kinases.As used herein, the term "mutation" refers to any mutation in ErbB protein; "mutant" or "mutant form" refers to the protein containing said mutation.Illustrative mutations of ErbB include, but are not limited to, L858R, T790M, G719S, G719X, delE746-A750, A763_Y764insFQEA, V769_D770insASV, H773_V774insNPH, etc. in EGFR, and Exon 20 insYVMA in HER2.In some embodiments, the compounds of the present disclosure can inhibit both wild-type (WT) HER2 and mutant forms of HER2 (for example, Exon 20 insYVMA).

[0094] In some embodiments, the compounds of the present disclosure are administered in a concentration of 0.1 to 200 nM, preferably 0.1 to 150 nM, 0.1 to 130 nM, 0.1 to 120 nM, 0.1 to 100 nM, 0.1 to 50 nM, 0.1 to 40 nM, 0.1 to 30 nM, 0.1 to 25 nM, 0.1 to 20 nM, 0.1 to 10 nM, 0.5 to 200 nM, 0.5 to 150 nM, 0.5 to 130 nM, 0.5 to 120 nM, 0.5 to 100 nM, 0.5 to 50 nM, 0.5 to 40 nM, 0.5 to 30 nM, 0.5 to 25 nM, 0.5 to 20 nM, 0.5 to 10 nM IC50 of 0.1 to 150 nM, 1 to 130 nM, 1 to 120 nM, 1 to 100 nM, 1 to 50 nM, 1 to 40 nM, 1 to 30 nM, 1 to 25 nM, 1 to 20 nM, 1 to 10 nM, 2 to 200 nM, 2 to 150 nM, 2 to 130 nM, 2 to 120 nM, 2 to 100 nM, 2 to 50 nM, 2 to 40 nM, 2 to 30 nM, 2 to 25 nM, 2 to 20 nM, or 2 to 10 nM, more preferably 0.1 to 150 nM, 0.1 to 130 nM, 1 to 150 nM, 1 to 130 nM, 2 to 130 nM, or 2 to 150 nM 50 values, inhibiting the phosphorylation of WT HER2.

[0095] The growth inhibitory effect is measured using the "50% growth inhibitory concentration" (GI), which refers to the concentration of a compound at which 50% of its maximum growth inhibitory effect is observed. 50 ) value. 50The value can be measured by methods known in the art, such as MTS, casein, and any other methods. In some embodiments, the compound of the present disclosure has a concentration of 0.1 to 200 nM, preferably 0.1 to 150 nM, 0.1 to 130 nM, 0.1 to 120 nM, 0.1 to 100 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, 1 to 200 nM, 1 to 150 nM, 1 to 130 nM, 1 to 120 nM, 1 to 100 nM, 1 to 50 nM, 1 to 40 nM, 1 to 30 nM, 1 to 20 nM, 1 to 10 nM, 2 to 200 nM, 2 to 30 nM, 3 to 40 nM, 4 to 50 nM, 5 to 60 nM, 6 to 70 nM, 7 to 80 nM, 8 to 90 nM, 9 to 100 nM, 10 to 200 nM, 11 to 200 nM, 12 to 100 nM, 13 to 200 nM, 14 to 200 nM, 15 to 100 nM, 15 to 100 nM, 16 to 200 nM, 16 to 200 nM, 17 to 200 nM, 18 to 200 nM, 19 to 210 nM, 19 to 220 nM, 23 to 240 nM, 24 to 250 nM, 25 to 260 nM, 2 GI of 150nM, 2 to 130nM, 2 to 120nM, 2 to 100nM, 2 to 50nM, 2 to 40nM, 2 to 30nM, 2 to 25nM, 2 to 20nM, or 2 to 10nM, 4 to 200nM, 4 to 150nM, 4 to 130nM, 4 to 120nM, 4 to 50nM, 4 to 40nM, 4 to 30nM, 4 to 20nM, 4 to 10nM, more preferably 0.1 to 150nM, 0.1 to 130nM, 1 to 150nM, 1 to 130nM, 2 to 150nM, 2 to 130nM, 4 to 150nM, or 4 to 130nM 50 values, inhibiting proliferation of WT HER2- and / or mutant HER2-bearing cells.

[0096] As used herein, "selectively inhibiting" HER2 means that provided compounds are at least 1000-fold, at least 500-fold, at least 200-fold, 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, or at least 10-fold more potent as inhibitors of WT HER2 (and / or mutant forms of HER2) compared to other types of ErbB kinases (e.g., EGFR). In some embodiments, "selectively inhibiting" HER2 means that 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, or up to 50-fold more potent as inhibitors of HER2 (WT and / or mutant forms) compared to other types of ErbB kinases (e.g., EGFR).

[0097] In some embodiments, the term "does not inhibit" other types of ErbB kinase (e.g., EGFR) refers to a compound that has an IC50 of at least 500 nM. 50 In some embodiments, such compounds have an IC50 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 and inhibits other forms of ErbB kinase.

[0098] In some embodiments, the IC of the compound against WT-EGFR 50 and / or G.I. 50 is the IC of the compound against WT HER2 50 and / or G.I. 50 at least 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold, preferably 50-fold, 100-fold, 200-fold, 500-fold, or 1000-fold higher than

[0099] The compounds or their pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers exhibit certain improved properties compared to other clinically available ErbB inhibitors, such as higher blood-brain barrier (BBB) ​​penetration (thus making them potentially useful for treating cancers that have metastasized to the central nervous system (CNS), particularly brain and leptomeningeal metastases); and exhibit better selectivity for certain types of ErbB (e.g., HER2), while maintaining comparable or improved inhibitory activity compared to existing drugs for said certain types of ErbB. Therefore, these compounds or their pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers may be particularly useful in treating these HER2-related disease states, for example, in the treatment of cancer, particularly cancers with CNS (e.g., brain and leptomeningeal) metastases. Synthesis method The synthesis of the compounds provided herein, including their salts, esters, hydrates or solvates or stereoisomers, is illustrated in the synthetic schemes in Examples.The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a large number of possible synthetic routes; therefore, these schemes are merely illustrative and are not intended to limit the other possible methods that can be used to prepare the compounds provided herein.In addition, the steps in the schemes are for better illustration and can be appropriately changed.The compound embodiments in Examples are synthesized for the purpose of research investigation and potential submission to regulatory authorities.

[0100] The reactions to prepare compounds of the present disclosure can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents are those which are compatible with the starting materials at the temperatures at which the reactions are carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. The solvent may be substantially non-reactive with the reactants, intermediates, or products. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, an appropriate solvent for a particular reaction step can be selected by one skilled in the art.

[0101] The preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0102] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal-phase silica chromatography.

[0103] As used herein, abbreviations are defined as follows: "1x" or "x1" means 1x, "2x" or "x2" means 2x, "3x" or "x3" means 3x, "4x" or "x4" means 4x, "5x" or "x5" means 5x, "°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" is milliliter(s), "μL" is microliter(s), "Nor" is normal, "m" is mole, "mmol" is millimole(s), "min" is minute(s), "h" or "hr" is hour(s), "rt" or "rt" is room temperature, "atm" is atmosphere, "psi" is pounds per square inch, "conc." is concentrated, "sat" or "sat'd" is saturated, "MS" or "Mass Spec" is mass spectroscopy, "ESI" is electrospray ionization mass spectroscopy, "LCMS" is liquid chromatography mass spectroscopy, "HPLC" is high pressure 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" is proton, "δ" is delta, "S" is singlet, "d" 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.

[0104] Abbreviations for chemicals used in the synthesis of the compounds provided herein are listed below:

[0105] [Table 2-1]

[0106] [Table 2-2]

[0107] [Table 2-3]

[0108] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure.In some embodiments, pharmaceutical compositions comprise more than one compound of the present disclosure.In some embodiments, pharmaceutical compositions comprise one or more compounds of the present disclosure and pharmaceutically acceptable carriers.

[0109] Pharmaceutically acceptable carriers are conventional pharmaceutical carriers in the art that 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.

[0110] The term "pharmaceutically acceptable carrier," as used herein, refers to a pharmaceutically acceptable material, 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 location, body fluid, tissue, organ (internal or external), or part of the body to another location, body fluid, tissue, organ, or part of the body. A pharmaceutically acceptable carrier can be a vehicle, diluent, excipient, or other material that can be used to contact the tissue of an animal without undue toxicity or adverse effects. Exemplary pharmaceutically acceptable carriers include: Examples of suitable carriers include sugars, starches, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginic acid, isotonic saline, buffers, etc. Pharmaceutically acceptable carriers that can be used in the present disclosure include those generally known in the art, such as those disclosed in "Remington Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0111] Some examples of materials 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, ethyl cellulose, 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, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycolic acid; (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-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols, such as ethyl alcohol and propane alcohol; (20) phosphate buffer solutions; and (21) other non-toxic, compatible substances used in pharmaceutical formulations, such as acetone.

[0112] The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances as needed 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.

[0113] The form of the pharmaceutical composition will depend on a number of criteria, including but not limited to the route of administration, the extent of the disease, or the dosage to be administered. The pharmaceutical composition can be formulated for oral, nasal, rectal, transdermal, intravenous or intramuscular administration.Depending on the desired administration route, 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.

[0114] The pharmaceutical composition can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. In some embodiments, the pharmaceutical composition is formulated in a sustained-release form. As used herein, the term "sustained-release form" refers to the release of an active agent from a pharmaceutical composition over a long period of time (extended release) or at a specific location (controlled release) so that the active agent becomes available for bioabsorption in the subject, primarily in the subject's gastrointestinal tract. In some embodiments, a long period of time can be about 1 to 24 hours, 2 to 12 hours, 3 to 8 hours, 4 to 6 hours, 1 to 2 days, or more. In certain embodiments, a long period of time 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 the form of a tablet. For example, the release rate of an active agent can be controlled not only by the dissolution of the active agent in gastrointestinal fluid and the subsequent diffusion from the tablet or pill, which is independent of pH, but also by the physical process of tablet disintegration and erosion. In some embodiments, "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Pres., Boca Raton, Polymeric materials can be used for sustained release, as disclosed in Florida (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105. The above references are incorporated herein by reference in their entireties.

[0115] In certain embodiments, the pharmaceutical composition comprises from about 0.0001 mg to about 5000 mg of a compound of the present disclosure (e.g., 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 500 mg, 0 mg to 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 dosage per subject may be from about 5 mg to about 500 mg, preferably from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, or from about 50 mg to about 500 mg.

[0116] In certain embodiments, the pharmaceutical compositions can be formulated in a unit dosage form, each dosage being from about 0.0001 mg to about 10 mg, from about 0.001 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 400 mg 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 of a compound of the present disclosure.

[0117] The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of an active ingredient 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 any anti-cancer agent known in the art, such as a chemotherapeutic agent, a cell signaling inhibitor, a cell signaling inhibitor, an alkylating agent, or the like. , topoisomerase inhibitors, immunotherapeutic agents, antimitotic agents, antihormonal agents, chemotherapeutic agents, EGFR inhibitors, CTLA-4 inhibitors, MEK inhibitors, PD-L1 inhibitors; OX40 agonists, and the like. Representative examples of anti-cancer agents for treating cancer or tumors include, but are not limited to, trastuzumab, trastuzumab emtansine, pertuzumab, ONT380, neratinib, lapatinib, sorafenib, sunitinib, dasatinib, vorinostat, temsirolimus, everolimus, pazopanib, trastuzumab, ado-trastuzumab emtansine, pertuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, tremelimumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, and durvalumab. , crizotinib, ruxolitinib, capecitabine, docetaxel, vinorelbine, paclitaxel, vincristine, vinblastine, cisplatin, carboplatin, gemcitabine, tamoxifen, raloxifene, cyclophosphamide, chromabucil, carmustine, methotrexate, fluorouracil, actinomycin, doxorubicin, epirubicin, anthracyclines, bleomycin, mitomycin C, irinotecan, topotecan, teniposide, interleukins, interferons, etc. In some embodiments, the second active agent is one or more of a chemotherapeutic agent (capecitabine, docetaxel, vinorelbine) or a HER2-targeting antibody (trastuzumab, trastuzumab emtansine, pertuzumab). Methods for Treatment The present disclosure provides methods for treating diseases associated with ErbB (including, for example, HER2), comprising administering to a subject a therapeutically effective amount of one or more compounds, pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof, or pharmaceutical compositions of the present disclosure.

[0118] As used herein, the term "ErbB-associated disease" refers to a disease whose occurrence or development, or both, is associated with genomic alterations, expression, overexpression, or activity of ErbB. Examples include, but are not limited to, immune-related diseases, proliferative disorders, cancer, and other diseases.

[0119] As used herein, the term "HER2-associated disease" refers to a disease or disorder whose occurrence or development, or both, as the case may be, is associated with genomic alterations, expression, overexpression, or activity of HER2. Examples include, but are not limited to, immune-related diseases, proliferative disorders, cancer, and other diseases.

[0120] In some embodiments, the ErbB-related disease is cancer, preferably ErbB-expressing cancer or ErbB-overexpressing cancer. "ErbB-expressing cancer" refers to cancer cells or tumor cells that have ErbB proteins, such as HER2, present on the cell surface. "ErbB-overexpressing cancer" refers to cancer or tumor cells that have significantly higher levels of ErbB proteins, such as HER2, on the cell surface compared to non-cancer cells of the same tissue type. Such overexpression can be caused by gene amplification or increased transcription or translation. ErbB receptor expression or overexpression can be determined in diagnostic or prognostic assays by evaluating the increased level of ErbB proteins present on the cell surface (e.g., via immunohistochemistry; IHC). Alternatively, or in addition, the level of ErbB-encoding nucleic acid in cells can be measured, for example, by fluorescence in situ hybridization (FISH; see WO98 / 45479, published October 1998), Southern blotting, or polymerase chain reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR). (Methods 132:73-80 (1990)). In addition to the above assays, various in vivo assays are available to those skilled in the art. For example, cells within a patient's body can be exposed to an antibody that is optionally labeled with a detectable label, such as a radioisotope. and binding of the antibody to cells in the patient can be assessed, for example, by external scanning for radioactivity or by analyzing a biopsy taken from the patient that has been pre-exposed to the antibody.

[0121] In particular, cancers include, but are not limited to, leukemia, glioblastoma, melanoma, chondrosarcoma, bile duct adenocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, stomach 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 cancer, 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 breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, ovarian cancer, or 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 disease associated with ErbB (eg, HER2) is a cancer that has metastasized to the central nervous system (CNS), particularly a cancer with brain and leptomeningeal metastases.

[0122] As used herein, the terms "treatment" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment can be performed after one or more symptoms have developed. In other embodiments, treatment can be performed in the absence of symptoms. For example, treatment can be performed in a susceptible individual 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 can also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0123] The therapeutically effective amount of the compounds as provided herein depends on various factors known in the art, such as body weight, age, medical history, current medications, the subject's health status, and the potential for cross-reactivity, allergies, sensitivities and adverse side effects, as well as the route of administration and the extent of disease development. Dosages can be proportionally reduced or increased by a skilled artisan (e.g., a physician or veterinarian) as indicated by these and other circumstances or requirements.

[0124] As used herein, the terms "subject" and "individual" are used interchangeably and refer to a warm-blooded animal, including humans or any non-human animals (e.g., mice, rats, rabbits, dogs, cats, cows, pigs, sheep, horses, or primates). Humans include pre- and post-natal forms. In some embodiments, the subject is a human. The subject is a subject suspected of suffering from a disease associated with ErbB (preferably HER2), but may or may not exhibit symptoms of the disease.

[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, one or more compounds, their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers, or pharmaceutical compositions are administered orally, enterally, buccal, nasal, intranasal, transmucosal, epidermal, transdermal, subdermal, ocular, pulmonary, sublingual, rectal, vaginal, topical, subcutaneous, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intraarticular, subcapsular, subarachnoid, intrathecal, intrathecal or intrasternal.

[0126] The compounds provided herein may be used in pure form, in combination with other active ingredients, or in combination with other active ingredients. In some embodiments, the compounds provided herein can be administered to a subject in need thereof in combination with one or more anti-cancer agents (single or multiple) known in the art, either simultaneously or sequentially. In some embodiments, administration is performed once a day, twice a day, three times a day, or 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, pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, or pharmaceutical compositions are orally administered. For oral administration, any dose that achieves the desired goal is appropriate. In some embodiments, an appropriate 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, and is administered once a day, twice a day, three times a day, daily, or 3 to 5 days a 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] In some embodiments, one or more compounds provided herein, pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof, or pharmaceutical compositions can cross the blood-brain barrier (BBB) ​​of a subject after being administered to the subject. 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., HER2).

[0129] The compounds and pharmaceutical compositions thereof disclosed herein can be used to inhibit ErbB (expression or activity), particularly HER2 (expression or activity) both in vivo and in vitro. In some embodiments, the compounds and pharmaceutical compositions disclosed herein can be used to inhibit ErbB (expression or activity), particularly HER2 (expression or activity) in non-diagnostic, non-treatment methods (e.g., for research purposes).

[0130] The compounds of the present disclosure and pharmaceutical compositions thereof can be used in preventing or treating the occurrence or development of any of the diseases associated with ErbB (eg, HER2) in warm-blooded animals, particularly humans.

[0131] In this context, the present disclosure also provides a method for screening patients suitable for treatment with the compounds or pharmaceutical compositions of the present disclosure, alone or in combination with other components (e.g., second active components, e.g., anticancer agents), comprising sequencing a tumor sample from the patient and detecting accumulation of ErbB (e.g., HER2) in the patient. [Example]

[0132] The general methods of the present disclosure are further described below. The compounds of the present disclosure can be prepared by methods known in the art. The following are examples of detailed methods for preparing preferred compounds of the present disclosure. However, they in no way limit the methods for preparing the compounds of this disclosure. Synthesis Examples The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) were 10-6 The units are shown in ppm. 1 H-NMR spectra were recorded in dimethyl sulfoxide-d6 (DMSO-d6) or CDCl3 or CD3OD or DO (from Aldrich or Cambridge Isotope Lab., Inc.) on a Bruker AVANCE NMR (400 MHz) spectrometer using ICON-NMR (under TopSpin program control) or on a Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (under VnmrJ program control) using tetramethylsilane as an internal standard.

[0133] 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 methods from a range of instruments.

[0134] High-performance liquid chromatography (HPLC) measurements were performed on a Shimadzu LC-20A system or Shimadzu LC-2010HT series, or an Agilent 1200 LC or Agilent 1100 series, using an Ultimate XB-C18 column (3.0 × 50 mm, 3 μm or 3.0 × 150 mm, 3 μm), an Xbridge shield RP18 column (5 μm, 50 mm × 2.1 mm), an Xtimate C18 column (3 μm, 2.1 × 30 mm), a Merck RP18 2.5-2 mm, or an Agilent Zorbax Eclipse Plus C18 column (4.6 mm × 150 mm, 5 μm).

[0135] 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 thin-layer chromatography (TLC) ranged from 0.15 mm to 0.2 mm. The silica gel plates used for separating and purifying the products by TLC ranged from 0.4 mm to 0.5 mm.

[0136] The chromatography columns used for purification were either silica gel (100-200, 200-300, or 300-400 mesh, such as those manufactured by Yantai Huanghai Co. or Anhui Liang Chen Gui Yuan Co.) or flash columns (silica-CS flash columns, 40-60 μm, or reversed-phase C18 columns, 20-35 μm, such as those manufactured by Agela Technologies) on a Teledyne ISCO Combi-Flash or Biotage Flash system. Column sizes were adjusted depending on the amount of compound.

[0137] Known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased commercially from Alfa Aesar, Langcaster, TCI, Aldrich, Bepharm, and Scochem (or PharmaBlock, Bide, Amatek, Stru Chem, Firster Pharmaceutical, Titan (Adamas), etc.).

[0138] Unless otherwise specified, all reactions in the examples were carried out under an argon or nitrogen atmosphere. The argon or nitrogen atmosphere was determined by filling the reaction flask with argon having a volume of approximately 1 L. or connected to a nitrogen balloon. Hydrogenation was usually carried out under pressure. Unless otherwise specified, the reaction temperature in the examples was ambient temperature, which was 20°C to 30°C.

[0139] The progress of the reaction 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 different polarity of the compounds.

[0140] The eluent systems used for column chromatography and TLC purification 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 reagent (0.1%-1%), such as formic acid, acetic acid, TFA, or ammonia, can be added for adjustment.

[0141] Example 1 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)quinazolin-4-amine

[0142] [ka]

[0143] Procedure for the preparation of compound 1b: To a solution of 4-methoxy-pyridin-2-ylamine (5.0 g, 40.3 mmol) in ethanol (150 mL) was added dimethoxymethyl-dimethyl-amine (4.8 g, 40.3 mmol). The mixture was then stirred at reflux for 10 hours. The mixture was concentrated to give the crude product (7.8 g), which was used directly in the next step without purification. LCMS: Rt = 0.898 min on 0-60AB_220&254 cm chromatography (Xtimate C18, 2.1 x 30 mm, 3 um), MS (ESI) m / z = 179.9 [M+H + ]. Procedure for the preparation of compound 1c: To a solution of 1b (7.8 g crude) in methanol, hydroxylamine-o-sulfonic acid (5.42 g, 47.9 mmol) and pyridine (7 g, 88.5 mmol) were added, and the resulting solution was stirred at reflux for 10 h. The solution was concentrated, and the residue was purified by silica gel (CHCl:MeOH, 100:1 to 50:1) to give product 1c (4.0 g). (61.5% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.76 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 7.6 Hz, 1H), 3.89 (s, 3H). Procedure for the preparation of compound 1d: A mixture of compound 1c (900 mg, 6.03 mmol) and pyridine hydrochloride (6 g, 51.9 mmol) in a flask was stirred at 160 °C for 4 h. The mixture was cooled to 25 °C, and the solution was neutralized with sodium hydroxide solution (1 M) to adjust the pH to 5-7. The resulting mixture was filtered to obtain the product as a white solid. The filtrate was extracted with EtOAc (200 mL × 5), and the organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product as a white solid (700 mg, 85.9% yield). 1 H NMR (400MHz, DMSO-d6) δ 10.87 (s, 1H), 8.70 (dd, J = 7.4 Hz, 1H), 8.24 (s, 1H), 6.89 (dd, J = 2.8 Hz, 1H), 6.75-72 (m, 1H). Procedure for the preparation of compound 1e: To a stirred solution of 1d (1.0 g, 7.4 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.4 g, 8.9 mmol) in DMF (10 mL), CsCO (4.8 g, 14.8 mmol) was added, and the mixture was heated to 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (50 mL). The solution was washed with water and brine. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel (eluted with 5% to 20% ethyl acetate in petroleum ether) to give compound 1e (1.5 g, 75.0% yield) as a white solid. Procedure for the preparation of compound 1f: A solution of 1e (1.5 g, 5.6 mmol) and 10% Pd / C (150 mg) in methanol (15 mL) was heated under a hydrogen atmosphere (40 psi) at 45° C. for 3 h. The hot solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give compound 1f (1.2 g, crude) as a pale gray solid, which was used directly in the next step. Procedure for the preparation of compound 1g:

[0144] [ka]

[0145] A stirred solution of compound 1g1 (100 g, 734.5 mmol) in concentrated HSO (700 mL) was stirred at 65° C. for 3 hours. The mixture was then poured into ice and adjusted to pH=9 with 20% aqueous NaOH. The mixture was extracted with EtOAc (1000 mL×3), and the organic layers were combined, washed with brine, dried over NaSO, and then concentrated in vacuo to give compound 1g2 (100 g, 88% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 7.52 (d, J = 12.4 Hz, 2H), 7.10-7.04 (m, 1H), 6.50 (d, J = 8.0 Hz, 2H), 6.33-6.28 (m, 1H), 6.16 (s, 1g2(2H).CH(OEt)3 in 300mL A solution of 1g3 (30 g, 19.5 mmol) was stirred at 140° C. for 72 hours. The resulting mixture was then concentrated to give a crude residue, which was recrystallized from ethyl acetate / PE=1:2 (v / v) to give compound 1g3 (28 g, yield: 87.8%) as a white solid. 1 H NMR (400 MHz, DMSO-d) δ 12.28 (s, 1H), 8.08 (s, 1H), 7.81–7.75 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.29–7.24 (m, 1H). A solution of compound 1g3 (20 g, 12.2 mmol) in SOCl2 (400 mL) and anhydrous DMF (5 mL) was stirred at reflux for 24 h. The mixture was then concentrated to give compound 1g (24 g, 99% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ 9.23 ( s, 1H), 8.49 (d, J = 8.4, 1H), 8.15-8.21 (m, 1H), 7.62-7.66 (m, 1H). Procedure for the preparation of compound 1h: A mixture of compound 1g (3 g, 6.48 mmol) and compound 1f (3.95 g, 16.48 mmol) in anhydrous CH3CN (30 mL) was stirred at reflux for 2 hours. A solid precipitated from the mixture. The mixture was cooled to room temperature (25-30 °C) and filtered to give the desired compound 1h (5 g, 78.1% yield) as a yellow solid. LCMS: 0-60 AB_4 min. Chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) showed R t =2.144min, MS(ESI)m / z=387.0[M+H] + . 1H NMR (400MHz, methanol-d4) δ 9.13-9.10 (m, 2H), 8.84 (s, 1H), 8.20-8.15 (m, 1H), 7.78-7.77 (m, 2H), 7.73-7.68 (m, 2H), 7.50 (dd, J1= 2.4 Hz, J2= 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 2.32 (s, 3H). Procedure for the preparation of compound 1i:

[0146] [ka]

[0147] To a solution of compound 1i1 (130 g, 0.948 mol) in an ice-salt bath was added 98% HCOOH (200 mL, 4.47 mol). The resulting mixture was warmed to 25 °C, and 40% HCHO (137 mL, 1.896 mol) was added. A large amount of gas was released during heating to 40 °C. Upon completion, the solution was adjusted to pH 9-10 by adding concentrated NaOH, extracted with EtOAc (1.5 L × 3), and washed with water and brine (1.6 L). The organic layer was dried over NaSO and concentrated to give compound 1i (116.8 g, crude) as a white solid. Procedure for the preparation of Compound 1 and Compound 1': A solution of compound 1h (100 mg, 0.259 mmol), compound 1i (118 mg, 0.778 mmol), and t-BuOK (146 mg, 1.3 mmol) in DMF (2 mL) was stirred at 100 °C for 16 h. The mixture was purified by reverse-phase preparative HPLC (Sunfire C8 30 × 100 mm × 5 μm column, gradient: 0–20% B (A = 47% ethanol / 0.05% HCl, B = acetonitrile), flow rate: 30 mL / min) to give 1j, which was separated by SFC separation to give the enantiomers compound 1' (28.6 mg) and compound 1 (26.0 mg).

[0148] Compound 1: LCMS: 0-60AB_4 min chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) t =1.931 min, MS(ESI)m / z=518.4[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.74 (d, J = 7.6 Hz, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 7.85 (m, 2H), 7.78 (t, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 5.17-5.08 (m, 1H), 3.27 (m, 1H), 2.98-2.95 (m, 1H), 2.68-2.58 (m, 1H), 2.48-2.41 (m, 2H), 2.41 (s, 3H), 2.12 (s, 3H), 2.10-2.03 (m, 1H). Example 2 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((1R,3r,5S)-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)quinazolin-4-amine

[0149] [ka]

[0150] Procedure for the preparation of compound 2: To a solution of compound 1h (100 mg, 0.26 mmol) in THF (3 mL) and DMF (3 mL) was added compound 2a (99 mg, 0.52 mmol) and t-BuOK (88 mg, 0.78 mmol). After the addition, the mixture was stirred at 90 °C for 5 days. The mixture was filtered, concentrated, and purified by HPLC (column: ASB 150 × 25 mm × 5 μm, gradient: 5 to 30% B (HCl, B = acetonitrile), flow rate: 30 mL / min) to give compound 2 (10 mg, 6.9%).

[0151] Compound 2: LCMS: 10-80AB_4 min chromatography (Xtimate C18, 2.1 x 30 mm, 3 um) t =1.865min, MS(ESI)m / z=558.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 9.07 (d, J = 7.6 Hz, 1 H), 9.01 (d, J = 6.4 Hz, 1 H), 8.79 (s, 1 H), 8.09 (t, J = 8.4 Hz, 1 H), 7.87 (s, 1 H), 7.76-7.69 (m, 1 H), 7.51-7.40 (m, 3 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 6.55 (tt, J1= 53.6 Hz, J2= 3.2 Hz, 1 H), 5.29 (s, 1 H), 4.25 (s, 2 H), 3.73-3.60 (m, 2 H), 2.90-2.86 (m, 2H), 2.70-2.67 (m, 2 H), 2.41 (s, 2 H), 2.32-2.28 (m, 5 H). Example 3 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine

[0152] [ka]

[0153] Procedure for the preparation of compound 3b: To a solution of compound 3a (5.0 g, 26.44 mmol) in DMF (50 mL) was added NaCN (1.43 g, 29.08 mmol). The reaction mixture was stirred at 20° C. for 12 hours. The mixture was concentrated to give a residue. The residue was dissolved in EtOAc (80 mL) and washed with water (20 mL×2) and saturated brine (20 mL×2). The organic layer was extracted with Na2S Drying over O4, filtration, and evaporation gave the crude product, which was purified by flash silica chromatography (PE / EtOAc = 20:1 to 5:1 (v / v)) and concentrated to give compound 3b (2.5 g, 48.1% yield) as a yellow solid. LCMS: 10-80AB_2.0 min_R in E chromatography (Merck RP-18e 25-2 mm, SN: UM9504 / 198). t =0.845min, MS(ESI)m / z=197.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.22 (br d, J=8.80 Hz, 1 H), 7.24 - 7.33 (m, 1 H), 4.09 (s, 3 H). Procedure for the preparation of compound 3c: To a solution of compound 3b (2.3 g, 11.73 mmol) in AcOH (25 mL) and water (0.3 mL) at 0 °C, Fe (3.27 g, 58.63 mmol) was added. The resulting mixture was stirred at 20 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (50 mL) and adjusted to pH = 8-9 with saturated NaHCO3. The organic phase was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated to give compound 3c (2 g, crude) as a yellow solid. LCMS: 10-80AB_2 min_E chromatography (Merck RP-18e 25-2 mm, SN: UM9504 / 198) t =0.689min, MS(ESI)m / z=167.1[M+H]+ . 1 H NMR (400MHz, CDCl3) δ 7.06 (t, J=9.00 Hz, 1 H), 6.46 (dd, J=9.00, 1.76 Hz, 1 H), 4.21 (br s, 2 H), 3.71 - 3.91 (m, 3 H). Procedure for the preparation of compound 3d: A mixture of compound 3c (1 g, 6.02 mmol) in DMF-DMA (15 mL) was stirred at 100° C. for 12 h. The mixture was concentrated to give crude compound 3d (1.5 g, crude) as a yellow solid. LCMS: 0-60 AB_2 min_E chromatography (Merck RP-18e 25-2mm, SN:UM9504 / 198) t =0.577min, MS(ESI)m / z=222.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 7.73 (s, 1 H), 7.27 (t, J=9.26 Hz, 1 H), 6.82 (dd, J=9.04, 1.76 Hz, 1 H), 3.72 - 3.98 (m, 3 H), 3.01 - 3.14 (m, 6 H). Procedure for the preparation of compound 3e: A mixture of compound 3d (1.5 g, 6.78 mmol) and compound 1f (2.44 g, 10.17 mmol) in AcOH (20 mL) was stirred at 50 °C for 12 h. The mixture was concentrated in vacuo. The residue was suspended in EtOAc (15 mL), the pH was adjusted to 8-9 with saturated K2CO3 (aq), filtered, and the cake was washed with ethyl acetate (5 mL) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-fluoro-6-methoxyquinazolin-4-amine (Y02, 2 g, 4.81 mmol, 90.0% wt, 70.9% yield) as a brown solid. LCMS: 0-60 AB_2 min_E chromatography (Merck RP-18e 25-2 mm, SN: UM9504 / 198) yield: R t =1.022min, MS(ESI)m / z=417.2[M+H]+ . 1 H NMR (400MHz, methanol-d4) δ 8.71 - 8.77 (m, 1 H), 8.44 (s, 1 H), 8.27 - 8.31 (m, 1 H), 7.79 - 7.88 (m, 1 H), 7.70 - 7.77 (m, 2 H), 7.66 (dd, J=9.26, 1.76 Hz, 1 H), 7.19 (d, J=8.60 Hz, 1 H), 7.05 - 7.11 (m, 1 H), 6.85 (d, J=2.43 Hz, 1 H), 4.05 (s, 3 H), 2.25 (s, 3 H). Procedure for the preparation of compound 3: A mixture of compound 3e (400 mg, 537.9 µmol, 56% purity), compound 3f (214.9 mg, 1.61 mmol, 3.0 equiv.), and t-BuOK (211.3 mg, 1.88 mmol, 3.5 equiv.) in DMF (5 mL) was stirred at 130 °C for 16 h. The mixture was adjusted to pH 7–8, filtered, and the filtrate was purified by neutral preparative HPLC (Phenomenex Gemini C18 200 × 25 mm × 10 µm column, gradient: 28–58% B (A: HO, B: CHCN), flow rate: 25 mL / min) followed by SFC separation to give the cis isomer of compound 3 (40 mg, 14% yield) as a white solid.

[0154] Compound 3: LCMS: 0-60AB_4 min chromatography (Xtimate C18, 2.1 x 30 mm, 3 um) t =1.906 min, MS(ESI)m / z=530.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.74 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.84-7.81 (m, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.06 (dd, J = 2.4 Hz and 7.6 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 5.20-5.07 (m, 1H), 4.98-4.89 (m, 1H), 4.04 (s, 3H), 3.25-3.23 (m, 1H), 2.91 (d, J = 8.0 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 2.49-2.15 (m, 3H). Example 4 (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro-1-methylpiperidin-2-yl)methoxy)-6-methoxyquinazolin-4-amine

[0155] [ka]

[0156] To a solution of compound 3e (100 mg, 0.24 mmol) in THF (6 mL) and DMF (4 mL) was added compound 4a (119 mg, 0.72 mmol) and t-BuOK (94 mg, 0.84 mmol). After the addition, the mixture was stirred at 80° C. for 24 hours. The mixture was filtered, concentrated, and purified by HPLC (column: Agella Venusil ASB C18 Purification was performed using a column (150 × 21.2 mm × 5 μm, gradient: 10-40% B (HCl, B = acetonitrile), flow rate: 25 mL / min) to obtain compound 4 (80 mg, yield 59.3%).

[0157] Compound 4: LCMS: 10-80AB_4 min chromatography (Xtimate C18, 2.1 x 30 mm, 3 um) t =2.079min, MS(ESI)m / z=562.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 9.08 (d, J = 7.6 Hz, 1 H), 9.04 (s, 1 H), 8.71 (s, 1 H), 8.07 (d, J = 9.2 Hz, 1 H), 7.91-7.88 (m, 2 H), 7.76 (d, J = 9.2 Hz, 1 H), 7.45 (dd, J1= 7.6 Hz, J2= 2.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 4.87 (m, 1 H), 4.58-4.55 (m, 1 H), 4.17 (s, 3 H), 4.09-4.05 (m, 1 H), 3.77 (m, 1 H), 3.51-3.48 (m, 1 H), 3.26 (s, 3H), 2.86-2.69 (m, 3H), 2.47-2.44 (m, 1H), 2.30 (s, 3H). Example 5 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro-1-methylpiperidin-3-yl)oxy)-6-methoxyquinazolin-4-amine

[0158] [ka]

[0159] The synthesis followed the same experimental procedure as for compound 3, and enantiomeric compound 5 was obtained as a solid after SFC separation. Compound 5: LCMS: 0-60AB_4 min chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) t =2.065min, MS(ESI)m / z=548.3[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.69-12.04 (m, 1H), 10.86-10.49 (m, 1H), 8.98 (d, J =7.2 Hz, 1H), 8.81 (s, 1H), 8.42 (s, 1H), 8.06 (d, J =9.6 Hz, 1H), 7.86 (d, J =8.8 Hz, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.31 (d, J =6.0 Hz, 1H), 7.06 (dd, J1=2.8 Hz, J2=7.6 Hz, 1H), 6.83 (s, 1H), 5.56-4.88 (m, 1H), 4.27-4.23 (m, 6H), 4.12 (brs, 1H), 3.31 (brs, 3H), 2.91 (s, 3H), 2.58 (brs, 1H), 2.23 (s, 3H) Example 6 Enantiomer-1: (S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine and Enantiomer-2: (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine

[0160] [ka]

[0161] Procedure for the preparation of compound 6b: A mixture of compound 6a (2.5 g, 11.2 mmol) and CuCN (2.9 g, 22.4 mmol) in NMP (25 mL) was stirred at 160° C. for 5 h. After cooling to room temperature, filtration, and concentration, the crude product 6b was used directly in the next step without further purification. Procedure for the preparation of compound 6c: NH gas was pumped into 100 mL of EtOH at 0° C. for 15 min, compound 6b (3 g crude) was dissolved in 30 mL of MeOH, and the mixture was stirred in a sealed tube at 120° C. overnight. The solution was concentrated, and the residue was purified by column chromatography on silica gel (PE / EtOAc=1 / 1) to give compound 6c (450 mg, 24% yield for two steps) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 6.38 (s, 2H), 6.17 (d, J = 2 Hz, 1H), 6.13 (dd, J1= 2.0 Hz, J2= 9.2 Hz, 1H), 3.73 (s, 3H). Procedure for the preparation of compound 6d: A mixture of compound 6c (2 g crude) in DMF-DMA (8 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the precipitate was washed with ethyl acetate to give compound 6d (800 mg crude) as a yellow solid, which was used directly in the next step. Procedure for the preparation of compound 6e: A mixture of compound 6d (800 mg, 3.62 mmol) and compound 1f (1.303 g, 5.43 mmol) in AcOH (15 mL) was stirred at 40-60 °C overnight. Concentration, adjustment of pH to 8-9 with KCO (aq), filtration, and washing of the cake with ethyl acetate gave compound 6e (1.6 g, crude) as a brown solid. LCMS: 5-95AB_R in 1.5 min. Chromatography (Xtimate C18 2.1 × 30 mm) t =0.702 min, MS(ESI)m / z417.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.74 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 7.71 (s, 1H), 7.67 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.09-7.00 (m, 3H), 6.85 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 2.25 (s, 3H). Procedure for the preparation of compound 6: Compound 6e (1.1 g, 2.64 mmol), compound 1i (991 mg, 5.28 mmol) and t-BuOK (889 mg, 7.92 mmol) in THF / DMF (15 mL / 6 mL) A mixture of (2,2'-dichloro- ...

[0162] Compound 6 (enantiomer-1): LCMS: 0-60AB_4 min. Chromatography (Xtimate C18, 2.1 x 30 mm, 3 um) t =2.001 min, MS(ESI)m / z=548.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.89 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 8.58 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.77 (dd, J1= 9.2 Hz, J2= 2.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (dd, J1= 13.6 Hz, J2= 2.0 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.92 (s, 1H), 5.67-5.59 (m, 1H), 4.28 (brs, 1H), 4.08 (s, 3H), 3.91-3.76 (m, 2H), 3.53-3.47 (m, 1H), 3.07 (s, 3H), 2.88 (d, J = 13.2 Hz, 1H), 2.43-2.40 (m, 1H), 2.29 (s, 3H). Compound 6' (enantiomer-2): LCMS: 0-60AB_4 min. Chromatography (Xtimate C18, 2.1 x 30 mm, 3 um) t =2.009min, MS(ESI)m / z=548.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.89 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H), 8.57 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.77 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.22 (dd, J1= 7.6 Hz, J2= 2.4 Hz, 2H), 6.96 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.72-5.63 (m, 1H), 4.26-4.24 (m, 1H), 4.08 (s, 3H), 3.94-3.76 (m, 2H), 3.57-3.51 (m, 1H), 3.07 (s, 3H), 2.87 (d, J = 14.4 Hz, 1H), 2.48-2.42 (m, 1H), 2.29 (s, 3H). Example 7 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)quinazolin-4-amine

[0163] [ka]

[0164] Procedure for the preparation of compound 7b: To a solution of compound 7a (5.0 g, 29.76 mmol) in DMF (50 mL), NaH (1.3 g, 32.74 mmol) was added at 0° C. and stirred for 10 min. MeI (6.34 g, 44.64 mmol) was added and stirred at 35° C. for 1.5 h. TLC showed that compound 1 was completely consumed. Water (50 mL) was added to the solution, and EtOAc (1 The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered, and concentrated to give compound 7b (6.2 g, 100%) as a red solid. 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.8 Hz, 1 H), 7.18 (dd, J = 9.6 Hz, 3.2 Hz, 1 H), 6.82 (d, J = 9.6 Hz, 1 H), 3.80 (s, 3 H), 3.02 (d, J = 5.2 Hz, 3H). Procedure for the preparation of compound 7c: To a solution of compound 7b (6.2 g, 34.06 mmol) in EtOH (147 mL) and THF (27 mL), Pd / C (1.0 g) was added, and the solution was stirred at room temperature under a H balloon for 4 h. After completion, the solution was filtered, concentrated, and purified by column chromatography (PE: EtOAc = 3:1 (v / v)) to give compound 7c (3.5 g, 69%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.60 (d, J = 8.4 Hz, 1 H), 6.39-6.35 (m, 2 H), 3.74 (s, 3 H), 2.82 (s, 3 H). Procedure for the preparation of compound 7d: A solution of compound 7c (3.5 g, 23.03 mmol) and formamidine acetate (4.8 g, 46.06 mmol) in 2-methoxy-ethanol (60 mL) was stirred at 120 °C for 20 hours. The mixture was then concentrated, HO (60 mL) was added, and extracted with CHCl (150 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over NaSO, filtered, and concentrated to give compound 7d (3.6 g, 97%) as a solid.1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1 H), 7.29-7.26 (m, 2 H), 6.97 (dd, J1= 2.4 Hz, J2= 8.8 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H). Procedure for the preparation of compound 7e: A solution of compound 7d (1.0 g, 6.17 mmol) in 38% HBr (30 mL) and AcOH (30 mL) was stirred at 110° C. for 48 hours. After completion, the mixture was concentrated and neutralized with Na2CO3 to pH=7. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered, and concentrated to give compound 7e (0.2 g, 22%) as a solid. 1 H NMR (400 MHz, Methanol-d4) δ 7.97 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1 H), 6.87 (dd, J1= 2.4 Hz, J2= 8.8 Hz, 1 H), 3.84 (s, 3 H). Procedure for the preparation of compound 7g: To a solution of compound 7e (209.0 mg, 1.35 mmol) and compound 7f (200.0 mg, 1.35 mmol) in DMF (5 mL) was added KCO (209.0 mg, 1.35 mmol) and stirred at 80° C. for 20 h. After completion, water (10 mL) was added to the mixture, extracted with EtOAc (50 mL×3), and the combined organic layer was washed with brine (50 mL×3), dried over NaSO, filtered, and concentrated to give compound 7g (0.4 g, crude) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1 H), 7.95 (d, J = 2.8 Hz, 1 H), 7.93 (d, J = 2.8 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.26 (s, 1 H), 7.07 (dd, J1= 2.4 Hz, J2= 8.8 Hz, 1 H), 6.67 (d, J = 9.2 Hz, 1 H), 3.89 (s, 2 H), 2.46 (s, 3 H). Procedure for the preparation of compound 7h: To a solution of compound 7g (400.0 mg, 1.41 mmol) in MeOH (50 mL), Pd / C (0.5 g) was added and stirred at room temperature under a H balloon for 2 h. After completion, the mixture was filtered and concentrated to give compound 7h (340 mg, 69% yield) as a red solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.89-6.85 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.42 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H), 4.88 (s, 2H), 3.79 (s, 3H), 1.99 (s, 3H). Procedure for the preparation of compound 7i: A solution of compound 7h (340.0 mg, 1.344 mmol) and compound 1g (244.0 mg, 1.344 mmol) in CHCN (40 mL) was stirred at 80 °C for 20 h. Upon completion, the mixture was concentrated to give compound 7i (530.0 mg, 98.0% yield) as a yellow solid. LCMS: 10-80AB_4 min chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) yielded R t =1.351 min, MS(ESI)m / z=400.1[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.49 (s, 1H), 8.10 (s, 1 H), 7.85-7.79 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.55-7.48 (m, 2H), 7.35 (dd, J1= 8.0 Hz, J2= 12.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1 H), 7.08 (dd, J1= 2.4 Hz, J2= 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1 H), 3.90 (s, 3H), 2.30 (s, 3H). Procedure for the preparation of compound 7: A solution of compound 7i (430.0 mg, 1.08 mmol), compound 1i (325.0 mg, 2.16 mmol), and t-BuOK (362.0 mg, 3.24 mmol) in DMF (5 mL) and THF (5 mL) was stirred at 100 °C for 20 h. The mixture was filtered and concentrated, and the crude was purified by HPLC (column: Phenomenex Gemini C18 200 × 25 mm × 10 μm, gradient: 10–20% B (A = water / 0.05% TFA, B = acetonitrile) followed by SFC separation to give enantiomeric compound 7 (140 mg, 24% yield) as a white solid.

[0165] Compound 7: LCMS: 10-80AB_4 min chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) t =1.166 min, MS(ESI)m / z=531.1[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 9.37 (s, 1 H), 8.83 (s, 1 H), 8.10 (t, J = 8.4 Hz, 1 H), 7.95 (d, J = 9.2 Hz, 1 H), 7.77-7.73 (m, 2 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.40 (dd, J1= 2.0 Hz, J2= 8.8 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 1 H), 5.81-5.73 (m, 1 H), 4.32-4.27 (m, 1H), 4.17 (s, 3H), 4.06-3.95 (m, 1 H), 3.81 (d, J = 12.8 Hz, 1 H), 3.69-3.62 (m, 1H), 3.10 (s, 3 H), 2.92-2.88 (m, 1 H), 2.51-2.47 (m, 1 H), 2.32 (s, 3 H). Example 8 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-7-methoxyquinazolin-4-amine

[0166] [ka]

[0167] Procedure for the preparation of compound 8c: A solution of compound 8a (12.68 g, 1.0 equiv.), compound 8b (9.0 g, 1.0 equiv.), and CsCO (53.26 g, 2.0 equiv.) in DMF (135 mL) was stirred at 80° C. for 16 h. After completion, the mixture was poured into water, extracted with ethyl acetate (150 mL×3), washed with brine (150 mL×3), then dried over NaSO, filtered, concentrated, and the crude was purified by column chromatography on silica gel (PE:EA=1:1 (v / v)) to give compound 8c (10 g, 49% yield) as a yellow solid. .1 H NMR (400MHz, DMSO-d6) δ 8.28 (d, J = 2.4 Hz, 1H), 8.13 (dd, J1= 8.8 Hz, J2= 2.4 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.19 (dd, J1= 6.0 Hz, J2= 2.0 Hz, 1H), 6.04 (s, 2H), 5.89 (d, J = 2.4 Hz, 1H), 2.27 (s, 3H). Procedure for the preparation of compound 8d: A solution of compound 8c (10.0 g, 1.0 equiv.) in 2-chloroacetaldehyde (137.9 g, 43.1 equiv.) was stirred at 80° C. for 16 hours. The mixture was quenched with saturated aqueous NaOH (50 mL), concentrated, and purified by silica column chromatography (CHCl / CHOH=10:1 (v / v)) to give compound 8d as a brown solid (9.0 g, 91.9% yield). LCMS: 5-95AB_4 min. Chromatography (Xtimate C18, 2.1×30 mm, 3 μm) showed R t =0.640min, MS(ESI)m / z=269.9[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.21 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.09 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.75 (dd, J1= 7.6 Hz, J2= 2.4 Hz, 1H), 2.37 (s, 3H). Procedure for the preparation of compound 8e: To a solution of compound 8d (9.0 g, 1.0 equiv.) and NH4Cl (17.88 g, 10.0 equiv.) in MeOH / HO = 3:1 (v / v) (100 mL) was added Fe (9.33 g, 5.0 equiv.), and the mixture was stirred at 60 °C for 6 h. The suspension was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give crude product 8e, which was used in the next step without further purification. Procedure for the preparation of compound 8f: A mixture of compound 6d (203.4 mg, 0.919 mmol) and compound 8e (200 mg, 0.836 mmol) in AcOH (5 mL) was stirred at 40-60 °C for 3 days. The AcOH was removed in vacuo, and the residue was basified to pH 8-9 with aqueous NaCO and filtered. The filtrate was dried to give compound 8f (250 mg, crude) as a red oil, which was used directly in the next step without further purification. LCMS: 0-60 AB_4 min. Chromatography (Xtimate C18, 2.1 × 30 mm) yielded R t =1.901 min, MS(ESI)m / z=416.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.77 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.36-7.28 (m, 3H), 7.08 (s, 1H), 7.04 (s, 1H), 4.06 (s, 3H), 2.29 (s, 3H). Procedure for the preparation of compound 8: A mixture of compound 8f (250 mg, 0.6 mmol), compound 1i (136.4 mg, 0.9 mmol), and t-BuOK (134.4 mg, 1.2 mmol) in THF (5 mL) and DMF (2 mL) was stirred at 80-100 °C overnight. The mixture was concentrated, and the crude was purified by reverse-phase preparative HPLC (Sunfire C8 30 × 100 mm × 5 μm column, gradient: 0-20% B (A = water / 0.05% HCl, B = acetonitrile), flow rate: 30 mL / min), followed by SFC separation to give enantiomeric compound 8 (18.2 mg, 5.6% yield in two steps) as a yellow solid.

[0168] Compound 8: LCMS: 0-60AB_4 min chromatography (Xtimate C18 2.1 x 30 mm) t =1.81 min, MS(ESI)m / z=547.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.79 (d, J = 7.2 Hz, 1H), 8.77 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.89-7.79 (m, 3H), 7.35-7.31 (m, 3H), 7.02 (d, J = 2.4 Hz, 1H), 6.98 (s, 1H), 5.73 (brs, 1H), 4.29-4.26 (m, 1H), 4.08 (s, 3H), 4.01-3.89 (m, 1H), 3.79 (d, J = 12.8 Hz, 1H), 3.63-3.57 (m, 1H), 3.09 (s, 3H), 2.87 (s, 1H), 2.49-2.46 (m, 1H), 2.29 (s, 3H). Example 9 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(3- Methyl-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)quinazolin-4-amine

[0169] [ka]

[0170] Procedure for the preparation of compound 9b: A mixture of 2-fluoro-1-methyl-5-nitrobenzene (0.301 g, 1.0 equiv.), CsCO (1.26 g, 2.0 equiv.), and compound 9a (0.26 g, 1.0 equiv.) in DMF (10 mL) was stirred at 80 °C for 2 h. After completion, water (50 mL) was added to the mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with brine, dried over NaSO, filtered, and concentrated to give crude compound 9b, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give a yellow solid (0.45 g, yield: 86%). LCMS: 5-95AB_1.5 min, R in chromatography (XMK RP-18e 25-2 mm). t =0.866 min, MS(ESI)m / z=269.9[M+H] + . 1 H NMR: (400MHz, CDCl3) δ 8.37 (dd, J1= 1.2 Hz, J2= 2.4 Hz, 1H), 8.17 (dd, J1= 0.8 Hz, J2= 2.8 Hz, 1H), 8.02-7.99 (m, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.61 (dd, J1= 4.8 Hz, J2= 9.6 Hz, 1H), 6.96 (dd, J1= 2.0 Hz, J2= 9.6 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 6.61 (dd, J1= 0.8 Hz, J2= 2.4 Hz, 1H), 2.46 (s, 3H). Procedure for the preparation of compound 9c: To a solution of compound 9b (0.45 g, 1.0 equiv.) and Zn powder (0.874 g, 8.0 equiv.) in MeOH (20 mL) was added NH4Cl (0.715 g, 8.0 equiv.) in portions over 5 minutes. The mixture was stirred at 30°C for 5 hours. Upon completion, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography to give a foamy solid (0.36 g, 90% yield). LCMS: 5-95AB_1.5 min, R t =0.656 min, MS(ESI)m / z239.9[M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.93 (t, J = 1.2 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 9.6 Hz, 1H), 7.02 (dd, J1= 2.4 Hz, J2= 9.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.52 (dd, J1= 2.8 Hz, J2= 8.8 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H). Procedure for the preparation of compound 9d: A mixture of compound 9c (0.2 g, 1.0 equiv.) and compound 1g (0.4152 g, 1.0 equiv.) in MeCN (10 mL) was stirred at reflux for 2 hours. After completion, the mixture was concentrated to give compound 9d (0.32 g, 99% yield) as a yellow solid. LCMS: 10-80AB_4 min. R t =1.874 min, MS(ESI)m / z=385.9[M+H] + . 1H NMR (400MHz, CDCl3) δ 8.71 (s, 1H), 8.44 (d, J = 19.6 Hz, 1H), 8.14 (t, J =1.2 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.79-7.71 (m, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.27-7.22 (m, 1H), 7.04 (dd, J1= 9.6 Hz, J2= 2.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 1.6 Hz, 1H), 2.36 (s, 3H). Procedure for the preparation of compound 9e: To a solution of compound 9d (270 mg, 1.0 equiv.) and B (116 mg, 1.10 equiv.) in THF / DMF (20 mL, v / v=1:1) was added t-BuOK (326 mg, 4.1 equiv.). The mixture was stirred at 100° C. for 12 h. After completion, the mixture was concentrated to give the crude product, which was pre-purified by column chromatography on silica gel (dichloromethane:MeOH=20:1). The crude was then purified by reverse-phase preparative HPLC to give 70 mg of compound 9e as a pale solid (100 mg, 27.6% yield). LCMS: 10-80AB_4 min. R in chromatography (Xtimate C18 2.1×30 mm SN: 3U411201583). t =1.614 min, MS(ESI)m / z=517.3[M+H] + . 1H NMR (400MHz, CDCl3) δ 10.01 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H), 8.13 (t, J = 1.2 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.69-7.60 (m, 3H), 7.51 (d, J = 9.2 Hz, 1H), 7.04 (dd, J1= 2.4 Hz, J2= 9.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 4.74-4.645 (m, 1H), 3.27-3.20 (m, 1H), 2.60-2.50 (m, 1H), 2.43 (s, 3H), 2.40-2.33 (m, 2H), 2.29 (s, 3H), 2.21-2.13 (m, 1H). Procedure for the preparation of compound 9: Compound 9e (85 mg) was separated by SFC to give compound 9 (39 mg) and compound 9' (41 mg).

[0171] Compound 9 (enantiomer-1): LCMS: 10-80AB_4 min, R in chromatography (Xtimate C18, 2.1 x 30 mm, 3 um SN: 3U411201579) t =1.583min, MS(ESI)m / z=517.1[M+H] + . 1H NMR (400MHz, methanol-d4) δ 8.49 (s, 1H), 8.12 (t, J = 1.2 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.78-7.67 (m, 4H), 7.42 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.14 (dd, J1= 2.0 Hz, J2= 9.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 5.15-5.05 (m, 1H), 3.29-3.23 (m, 1H), 2.95 (d, J = 12.0 Hz, 1H), 2.68-2.58 (m, 1H), 2.49-2.40 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.10-2.02 (m, 1H). Example 10 N 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)quinazoline-4,7-diamine

[0172] [ka]

[0173] Procedure for the preparation of compound 10b: To a mixture of compound 10a (20 g) in an autoclave, NH3 / EtOH (200 mL) was added. The mixture was stirred at 100 °C overnight. The mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (100 mL). The organic layer was concentrated to give a gray solid, which was washed with petroleum ether (3 × 100 mL) and dried to give compound 10b (19.5 g, 98% yield). 1 H NMR (400MHz, CDCl3) δ 6.72 (t, J = 1.2 Hz, 1H), 6.67 (dd, J1= 8.8 Hz, J2=1.2 Hz. 1H), 4.63 (s, 2H). Procedure for the preparation of compound 10c: A solution of compound 10b (10.0 g) and DMF-DMA (11.0 g, 2.0 equiv.) in toluene was stirred at 120° C. for 2 hours. The mixture was concentrated in vacuo to give compound 10c (15.2 g, crude) as a grey solid, which was used directly in the next step. LCMS: 5-95AB_1.5 min. R chromatographically (Welch Xtimate C18, 2.1×30 mm, 3 um) t =0.718 min, MS(ESI)m / z=271.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.63 (s, 1H), 6.93-6.91 (m, 2H), 3.11 (d, J = 2.0 Hz, 6H). Procedure for the preparation of compound 10d: A mixture of compound 10c (15.2 g) and compound 1f (11.1 g, 1.0 equiv.) in acetic acid (150 mL) was stirred at 120° C. for 2 hours. A strong desired M peak (466.9) was detected by LCMS. The mixture was cooled and then poured into water (100 mL). The mixture was filtered, concentrated, and purified by chromatography (DCM:MeOH=20:1 (v / v)) to give compound 10d (8.0 g, 38%) as a brown solid. LCMS: 5-95AB_R in 1.5 min chromatography (Welch Xtimate C18, 2.1×30 mm, 3 um). t =0.787min, MS(ESI)m / z=466.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.28 (d, J = 11.6 Hz, 1H), 8.93 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 7.85-7.67 (m, 4H), 7.21 (d, J = 8.4 Hz, 1H), 7.02 (dd, J1= 7.6 Hz, J2= 2.8 Hz, 1H), 6.78 (d, J = 2.8 Hz, 1H), 2.18 (s, 3H). Procedure for the preparation of compound 10e: A mixture of compound 10d (4.6 g), compound 1i (1.5 g, 1.0 equivalent), and t-BuOK (2.2 g, 2.0 equivalents) in THF (50 mL) and DMF (20 mL) was stirred at 70° C. overnight. The mixture was poured into water (50 mL) and then filtered. The solid was dried to give compound 10e (4.74 g, 80% yield) as a gray solid. LCMS :5-95AB_1.5 min Chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 μm) t =0.737min, MS(ESI)m / z=597.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.95 (s, 1H), 8.92 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.73 (dd, J1= 8.8 Hz, J2= 2.4 Hz, 1H), 7.64 (s, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.02 (dd, J1= 7.6 Hz, J2=2.4 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 5.43-5.35 (m, 1H), 3.27-3.23 (m, 2H), 2.86-2.82 (m, 1H), 2.38-2.32 (m, 2H), 2.29 (s, 3H), 2.19 (s, 3H), 1.97-1.89 (m, 1H). Procedure for the preparation of compound 10f: A mixture of compound 10e (200 mg), Pd(OAc) (8 mg, 0.1 equiv.), dppf (18 mg, 0.1 equiv.), and EtN (67 mg, 2.0 equiv.) in methanol (10 mL) was stirred overnight at 70 °C under a carbon monoxide atmosphere (45 Psi). The mixture was then filtered, and the filtrate was concentrated to give compound 10f (223 mg, crude) as a brown oil. LCMS: 5-95AB_1.5 min. R chromatograph (Welch Xtimate C18, 2.1 x 30 mm, 3 um) t =0.730min, MS(ESI)m / z=576.1[M+H] + . Procedure for the preparation of compound 10g: A solution of compound 10f (223 mg) and LiOH-HO (70 mg, 5.0 equiv.) in THF / HO (5 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by 1N distillation. Acidified with a solution of HCl. The precipitate was collected and dried to give compound 10g (140 mg, crude) as a grey solid. LCMS: 5-95AB_1.5 min. R on chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um). t =0.643min, MS(ESI)m / z=562.1[M+H] + . Procedure for the preparation of compound 10: A solution of compound 10g (70 mg), DPPA (42 mg, 1.2 equiv.), and EtN (25 mg, 2.0 equiv.) in t-BuOH (3 mL) was stirred at 80 °C overnight. The mixture was concentrated in vacuo, and the residue was treated with HCl / dioxane (4 M, 1 mL). The reaction was stirred at room temperature for 10 minutes. The mixture was concentrated, and the residue was purified by preparative HPLC (Column: Sunfire C8 30 x 100 mm x 5 um, Gradient: 15-25% B (A = water / 0.05% HCl, B = acetonitrile), Flow Rate: 30 mL / min) followed by SFC separation to give enantiomeric compound 10 (7.9 mg, 10% yield). LCMS: 10-80AB_4 min chromatography (Welch Xtimate C18, 2.1 x 30 mm, 3 um) yielded R t=1.427min, MS(ESI)m / z=533.0[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 9.06 (d, J = 7.6 Hz, 1H), 9.00 (s, 1H), 8.51 (s, 1H), 7.79-7.74 (m, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H), 6.49 (d, J = 1.2 Hz, 1H), 5.65-5.58 (m, 1H), 4.27 (m, 2H), 4.06-3.94 (m,1H), 3.80-3.65 (m, 2H), 3.09 (s, 3H), 2.88-2.86 (m, 2H), 2.44-2.41 (m, 2H), 2.27 (s, 3H). Example 11 5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazolin-4-amine

[0174] [ka]

[0175] Procedure for the preparation of compound 11b: DMF-DMA (3.93 mL, 29.38 mmol, 2.0 equiv) was added to a solution of compound 11a (2 g, 14.69 mmol) in toluene (20 mL). The resulting suspension was stirred at 120° C. for 1.5 hours. LCMS analysis indicated the reaction was complete. The solution was concentrated to give compound 11b (3.0 g, crude, 93% purity) as a yellow solid. LCMS: 5-95AB_220&254 chromatographically showed R t =0.135min, MS(ESI)m / z=191.9[M+H] + . Procedure for the preparation of compound 11c: To a solution of compound 11b (1.5 g, 93% pure, 7.30 mmol, 1.0 equiv.) in acetic acid (30 mL) was added compound 8e (2.62 g, 10.94 mmol, 1.5 equiv.), and the reaction mixture was heated to 120° C. for 2 h. LCMS showed the reaction was complete. The acetic acid was removed in vacuo, and the crude product was dissolved in acetonitrile (20 mL) and diluted with water (50 mL). The solution was basified to pH=8 with sodium carbonate solution. The precipitate was filtered, and the filter cake was washed with ethyl acetate, dried over sodium sulfate, and concentrated to give compound 11c (1.5 g, crude). LCMS: 5-95AB_1.5 min R t =0.609 min, MS(ESI)m / z=386.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.20 (3H, s), 6.55 (1H, d, J = 2.4 Hz), 6.82 (1H, dd, J1= 7.2 Hz, J2=2.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.40-7.48 (2H, m), 7.61-7.74 (3H, m), 7.81-7.89 (2H, m), 8.56 (1H, d, J = 7.6 Hz), 8.58 (1H, s), 9.20 (1H, br.s) Procedure for the preparation of compound 11 cis isomer: To a solution of compound 11c (300 mg, 1.0 equiv.) and compound cis-11d (207 mg, 2.0 equiv.) in THF / DMF (20 mL, v / v 1:1) was added t-BuOK (306 mg, 3.5 equiv.). The mixture was stirred at 100° C. for 72 h. Upon completion, the reaction was concentrated, and the residue was purified by column chromatography on silica gel using DCM / MeOH (10:1) to give the crude product, which was further purified by preparative HPLC followed by SFC separation to give the enantiomerically pure cis isomer, compound 11, as a white solid (35 mg, 9% yield). LCMS: 0-60 AB_4 min. R chromatographically (Xtimate C18, 2.1×30 mm, 3 um SN: 3U411201579) t=1.560 min, MS(ESI)m / z=499.0[M+H] + . 1 H NMR (400MHz, D2O) δ 8.65 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.05 (t, J = 8.4 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.70 (d, J =2.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 7.6 Hz, 2.4 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 5.65-5.53 (m, 1H), 5.44-5.30 (m, 1H), 4.11-4.04 (m, 1H), 3.78-3.74 (m, 1H), 3.71-7.57 (m, 1H), 3.45-3.38 (m, 1H), 3.01 (s, 3H), 2.67-2.64 (m, 1H), 2.49-2.37 (m, 1H), 2.24 (s, 3H). Example 12 (S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((1-ethyl-3,3-difluoropiperidin-4-yl)oxy)quinazolin-4-amine and (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((1-ethyl-3,3-difluoropiperidin-4-yl)oxy)quinazolin-4-amine

[0176] [ka]

[0177] Procedure for the preparation of compound 12a: To a solution of compound 1i1 (0.2 g, 1.46 mmol) in MeOH (8 mL) was added sodium cyanoborohydride (0.092 g, 1.46 mmol) and acetaldehyde (0.099 mL, 1.75 mmol). The resulting mixture was stirred at 12–23 °C for 16 h. The reaction was then poured into water (15 mL) and extracted with chloroform / isopropanol (v / v = 3 / 1, 10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude compound 12a (0.22 g) as a yellow oil. The product was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ 1.09 (3H, t, J = 7.2 Hz), 1.75-2.04 (4H, m), 2.75-2.85 (1H, m), 2.45-2.05 (2H, m), 2.53-2.67 (2.5H, m), 2.75-2.92 (2H, m), 3.69-3.85 (2H, m), 4.02-4.05 (1H, m). Procedure for the preparation of compound 12b: To a solution of compound 1h (300 mg, 0.776 mmol) in DMF (10 mL) and THF (4 mL) was added potassium tert-butoxide (305 mg, 2.72 mmol) and compound 12a (154 mg, 0.931 mmol). The resulting mixture was stirred at 100° C. for 16 hours. The reaction was then poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, and concentrated to give a residue, which was purified by preparative HPLC (column: YMC-Actus Triart C18 150×30 5 u, gradient: 5-35% B (A=water / 0.05% HCl, B=acetonitrile), flow rate: 25 mL / min) and lyophilized to give compound 12b (110 mg, crude) as a yellow solid. LCMS: R 4.0 min chromatographic t =1.972min, MS(ESI)m / z=532.3[M+H] + . Compounds 12 / 12': Procedure for the preparation of enantiomers-1 / -2 Compound 12b (110 mg) was separated by preparative chiral HPLC on an AD (250 mm x 30 mm, 5 μm) column, mobile phase: A: CO₂, B: ethanol (0.05% DEA), conditions: base - ETOH, starting B 40% and ending B 40%, flow rate (mL / min) = 50. Fractions containing the desired compound were evaporated to dryness to give enantiomer 1 and enantiomer 2, which were then repurified by preparative HPLC (DuraShell 150 x 25 mm x 5 μm, 35%-65% B (A = water / 10 mM NH₄Ac, B = MeCN)). Most of the MeCN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give compound 12' (24.6 mg, yield: 5.96%) as a white solid and compound 12 (27.6 mg, yield: 6.69%) as a white solid.

[0178] Compound 12' (enantiomer-2): LCMS: 4.0 min chromatographic TeR t =1.903 min, MS(ESI)m / z532.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 1.14 (3H, t, J = 7.2 Hz), 2.07-2.09 (1H, m), 2.25 (3H, s), 2.44-2.65 (5H, m), 3.04 (1H, d, J = 12.4 Hz), 3.34-3.39 (1H, m), 5.07-5.16 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 7.06 (1H, dd, J = 7.6, 2.4 Hz), 7.18 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.76-7.88 (3H, m), 8.28 (1H, s), 8.54 (1H, s),8.73 (1H, d, J = 8.0 Hz). Compound 12 (Enantiomer-1): LCMS: 4.0 min. R t =1.905 min, MS(ESI)m / z532.2[M+H] + .1 H NMR (400MHz, methanol-d4) δ 1.14 (3H, t, J = 7.2 Hz), 2.04-2.07 (1H, m), 2.25 (3H, s), 2.40-2.65 (5H, m), 3.04 (1H, d, J = 12.4 Hz), 3.34-3.39 (1H, m), 5.07-5.16 (1H, m). 6.81 (1H, d, J = 2.4 Hz), 7.06 (1H, dd, J = 10.0, 2.4 Hz), 7.18 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 7.6 Hz), 7.76-7.88 (3H, m), 8.28 (1H, s), 8.54 (1H, s),8.73 (1H, d, J = 7.6 Hz). Example 13 N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-5-(quinuclidin-4-yloxy)quinazolin-4-amine

[0179] [ka]

[0180] Procedure for the preparation of compound 13c: NaH (87 mg, 60% wt, 2.17 mmol) was added in portions to compound 13b (230 mg, 1.81 mmol) and compound 13a (300 mg, 1.81 mmol) in THF (5 mL) at 0 °C under nitrogen over 5 min. The resulting mixture was stirred at 17-27 °C for 3 h. The reaction mixture was then poured into saturated NH4Cl (75 mL) and extracted with EtOAc (50 mL x 2). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by flash silica chromatography (PE:EA = 3:1 to 100% methanol). Pure fractions were evaporated to dryness to give compound 13b (320 mg, crude) as a yellow solid. LCMS: R 1.5 min chromatographically.t =0.579min, MS(ESI)m / z=274.0[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.95-2.01 (6H, m), 3.08-3.12 (6H, m), 7.49 (1H, d, J = 8.4 Hz), 7.67 (1H, t, J = 8.4 Hz), 7.99 (1H, d, J = 8.4 Hz). Procedure for the preparation of compound 13d: Compound 13c (320 mg, 1.17 mmol) and Pd-C (120 mg, 10 wt%, 0.11 mmol) in methanol (30 mL) were stirred under a hydrogen balloon atmosphere at 17-24 °C for 1 h. The reaction mixture was then filtered, and the filtrate was evaporated to dryness to give compound 13d (280 mg, 98% yield) as a pale yellow oil that solidified upon standing. LCMS: R t =0.279min, MS(ESI)m / z=244.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.90-1.94 (6H, m), 3.02-3.06 (6H, m), 4.42 (2H, br.s.), 6.39 (1H, d, J = 8.0 Hz), 6.43 (1H, d, J = 8.4 Hz), 7.18 (1H, t, J = 8.0 Hz). Procedure for the preparation of compound 13e: 1,1-Dimethoxy-N,N-dimethylmethanamine (0.339 mL, 2.53 mmol) was added to compound 13d (280 mg, 1.15 mmol) in toluene (10 mL) at 20° C. The resulting mixture was stirred at 110° C. for 90 minutes. The reaction mixture was concentrated to give the crude product, which was used directly in the next step without further purification. LCMS: R t =0.128min, MS(ESI)m / z=299.1[M+H] + . Procedure for the preparation of compound 13: Compound 8e (164 mg, 0.68 mmol) was added to compound 13e (170 mg, 0.57 mmol) in AcOH (5 mL) at 20 °C. The resulting mixture was stirred at 120 °C for 90 min. The reaction mixture was then concentrated to give the crude product, which was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 30 5 μm, 25-55% B (A = water / 0.05% ammonia, B = acetonitrile), Flow rate: 25 mL / min). The fractions containing the desired compound were dried by lyophilization to give compound 13 (95.3 mg, 33.9% yield) as a white solid. LCMS: 1.5 min chromatographic analysis revealed that the t R =0.578 min, MS(ESI)m / z=493.2[M+H] + LCMS: 4.0 min chromatographic R =2.740min, MS(ESI)m / z=493.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 2.01-2.05 (6H, m), 2.26 (3H, s), 3.07-3.11 (6H, m), 6.72-6.76 (2H, m), 7.08 (1H, d, J = 8.4 Hz), 7.16 (1H, d, J = 7.2 Hz), 7.49 (1H, d, J = 10.4 Hz), 7.58-7.65 (3H, m), 7.80 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 7.2 Hz), 8.66 (1H, s), 10.22 (1H, s). Example 14 (S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine and (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine

[0181] [ka]

[0182] Procedure for the preparation of compound 14b: To a solution of benzyl alcohol (10 g, 76 mmol) in dioxane (150 mL), NaH (3.3 g, 1.1 equivalents) was added, and the solution was stirred at 60 °C for 2.0 hours. Compound 14a (8.2 g, 76 mmol) was then added to the reaction mixture, and the mixture was refluxed for 3.0 hours. After completion, the reaction solution was quenched with NH Cl and extracted with EtOAc. The combined organic layers were concentrated, and the residue was recrystallized with PE / EtOAc = 10 / 1 (20 ml) to give the product (14 g, 84.1% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.20 (d, J = 6.0 Hz, 1H), 7.44-7.37 (m, 5H), 6.92 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 5.11 (s, 2H). Procedure for the preparation of compound 14c: To a mixture of compound 14b (12 g, 5.01 mmol), Pd2(dba)3 (550 mg, 0.5 mmol), and Xphos (525 mg, 1.1 mmol) in THF (120 mL) was added LiHMDS (66.0 mL, 66 mmol). After heating to 65 °C for 60 min, the mixture was cooled to room temperature. Upon completion, the reaction was quenched with aqueous HCl (2.0 mL, 1.0 mol / L) and extracted with ethyl acetate. The liquid solution was adjusted to pH > 8 with aqueous NaHCO3 and extracted with EtOAc (200 mL × 2). The combined organic layers were concentrated to give compound 14c (10.5 g, 88% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.91 (d, J = 6.0 Hz, 1H), 7.41-7.33 (m, 5H), 6.34 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 6.05 (d, J = 2.4 Hz, 1H), 5.05 (s, 2H), 4.38 (s, 2H). Procedure for the preparation of compound 14d: To a mixture of compound 14c (10.5 g, 52.5 mmol) in t-BuOH (50 mL) was added BocO (12.6 g, 1.1 equiv.), and the solution was then stirred at 50° C. for 2.0 h. After completion, EtOH (300 mL) was added to the reaction solution. The mixture was cooled to room temperature, filtered, and concentrated to give the product (16 g, 95.2% yield). LCMS 10-80AB_2.0 min chromatography (Welch Xtimate C18 2.1×30 mm) R t =0.946min, MS(ESI)m / z=300.9[M +H] + . Procedure for the preparation of compound 14e: To a solution of compound 14d (15 g, 50 mmol) in MeOH (300 mL) was added Pd / C (3.0 g). The solution was stirred at room temperature for 3.0 hours. The reaction solution was then filtered, and the filtrate was concentrated to give compound 14e (8.5 g, 80.9% yield) as a white solid without further purification. Procedure for the preparation of compound 14f: To a solution of compound 14e (5.0 g, 28.9 mmol) and 1,5-difluoro-2-methyl-4-nitrobenzene (6.06 g, 28.9 mmol) in DMF (100 mL), KCO (5.9 g, 43.4 mmol) was added, and the solution was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 1 / 2) to give compound 14f (6.5 g, 61.9% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 8.24 (d, J = 5.6 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 6.79-6.82 (d, J=11.6 Hz, 1H), 6.57 (m, 1H), 2.30 (s, 3H), 1.50 (s, 9H). Procedure for the preparation of compound 14g: To a solution of compound 14f (6.5 g, 17.9 mmol) in DCM (40 mL) was added TFA (15 mL), and the solution was stirred at reflux for 3.0 hours. TLC showed that the starting material was consumed. LCMS showed that the product was found. The mixture was concentrated, and the residue was washed with aqueous NaHCO3 and extracted with DCM. The combined organic layers were concentrated to give compound 14g (4.5 g, 95%) as a yellow oil, which was used directly in the next step. Procedure for the preparation of compound 14h: A solution of compound 14g (4.5 g, 13.8 mmol) in DMF-DMA (20.0 mL) was stirred at reflux for 3.0 h. The mixture was concentrated to give compound 14h (6.2 g, crude) as a yellow oil, which was used directly in the next step. LCMS: 0-60 AB_4 min chromatography, R on (Welch Xtimate C18 2.1 x 30 mm) t =2.579min, MS(ESI)m / z=319.0[M+H] + . Procedure for the preparation of compound 14i: To a solution of compound 14h (6.3 g, 13.8 mmol) in i-PrOH (50.0 mL) was added NHOH.HCl (1.3 g, 13.8 mmol), and the solution was stirred at room temperature for 4.0 h. The mixture was filtered to give compound 14i (5.5 g, crude) as a yellow solid, which was used directly in the next step. LCMS: 5-95AB_1.5 min chromatography, R on (Welch Xtimate C18 2.1 x 30 mm). t =0.767min, MS(ESI)m / z=307.0[M+H] + . Procedure for the preparation of compound 14j: To a solution of compound 14i (5.0 g, 13.0 mmol) in THF (50.0 mL) was added TFAA (4.5 g, 16.9 mmol), and the solution was stirred at 50 °C overnight. The mixture was adjusted to pH > 8 with NaHCO and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica gel column to give compound 14j (2.1 g, crude) as a yellow solid. Procedure for the preparation of compound 14k: To a solution of compound 14j (3.0 g, 10.4 mmol) in EtOH (100 mL) and HO (50 mL), Fe (2.9 g, 52 mmol) and NH4Cl (3.2 g, 63 mmol) were added, and the solution was stirred at reflux for 3.0 h. The reaction solution was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC (column: AD (250 × 30 mm, 5 μm): 5-25% B (A = 45% MeOH NH3HO water, B = acetonitrile), flow rate: 50 mL / min, UV detector 220 nm) to give compound 14k (700 mg, 19.7% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.47 (d, J = 7.6 Hz, 1H), 8.21 (s, 1H), 6.85-6.83 (m, 1H), 6.79-6.71 (m, 3H), 3.71 (s, 2H), 2.06 (s, 3H). Procedure for the preparation of compound 14l: To a solution of compound 14k (400 mg, 1.55 mmol) in i-PrOH (5.0 mL) was added triethoxymethane (690 mg, 4.65 mmol). The solution was stirred at 100° C. for 1.0 h, and then 2-amino-6-fluoro-4-methoxybenzonitrile (260 mg, 1.55 mmol) and TFA (0.2 mL) were added to the reaction solution, and the solution was stirred at reflux for 2.0 h. The reaction solution was concentrated, and the residue was washed with PE / EtOAc (v / v=10 / 1, 3.0 mL) to give compound 14l (400 mg, crude) as a yellow solid, which was used directly in the next step. LCMS: 5-95AB_1.5 min chromatography, R on (Welch Xtimate C18 2.1×30 mm) t =0.753min, MS(ESI)m / z=434.9[M+H] + . Procedure for the preparation of compound 14m: To a solution of compound 14l (400 mg, 0.92 mmol) in DMF (5.0 mL), t-BuONa (260 mg, 2.76 mmol) and compound 1i (280 mg, 1.84 mmol) were added, and the solution was stirred at 120 °C for 2.0 h. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: YMC-Triat, 10-30% B (A = TFA water, B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 14m (202 mg, 38.7% yield) as a white solid. LCMS: 0-60 AB_2.0 min chromatography (Welch MK RP-18e, 25-2 mm SN: UM8505 / 155). t =1.004 min, MS(ESI)m / z=566.1[M+H] + . 1 H NMR (400MHz, MeOH-d4) δ 9.15 (d, J = 10.0 Hz,1H), 9.13 (s, 1H), 8.83 (s, 1H), 8.27 (d, J = 8.4Hz, 1H), 7.51 (dd, J = 7.6 Hz, 2.8 Hz, 1H), 7.40-7.33 (m, 3H), 7.03 (s, 1H), 5.78 (m, 1H), 4.27 (m, 1H), 4.11 (s, 3H), 4.02-3.91 (m, 1H), 3.83-3.80 (m, 1H), 3.63-3.57 (m, 1H), 3.11 (s, 3H), 2.83 (m, 1H), 2.52 (m, 1H), 2.30 (s, 3H). Procedure for the preparation of compound 14: Compound 14m (150 mg, 0.265 mmol) was separated by SFC to give the product compound 14' (55 mg, 36.7% yield) as a white solid and compound 14 (54 mg, 36% yield) as a white solid. Compound 14' (Enantiomer-2): LCMS 5-95AB_1.5 min chromatography (Welch MK RP-18e, 25-2 mm SN: UM8505 / 155) t =0.672 min, MS(ESI)m / z=566.2[M+H] + . 1 H NMR (400MHz, MeOH-d4) δ 8.78 (d, J = 7.2 Hz,1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 11.2 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 6.99 (s, 1H), 6.94 (s, 1H), 6.90 (s, 1H), 5.21-5.13 (m, 1H), 3.99 (s, 3H), 3.22-3.17 (m, 1H), 2.96-2.93 (m, 1H), 2.72-2.62 (m, 1H), 2.52-2.46 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.17-2.13 (m, 1H). Compound 14 (Enantiomer-1): LCMS: 5-95AB_1.5 min chromatography, (Welch MK RP-18e, 25-2 mm SN: UM8505 / 155) t =0.675min, MS(ESI)m / z=566.2[M+H] + . 1 H NMR (400MHz, MeOH-d4) δ 8.78 (d, J = 7.2 Hz,1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 10.4 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 6.97 (s, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 5.17-5.09 (m, 1H), 3.99 (s, 3H), 3.20-3.15 (m, 1H), 2.94-2.91 (m, 1H), 2.69-2.59 (m, 1H), 2.49-2.43 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 2.17-2.13 (m, 1H). Example 15 (±)-(5-(((2S,4S)-2-(difluoromethyl)piperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methyl (phenyl)quinazolin-4-amine and (±)-(5-(((2R,4S)-2-(difluoromethyl)piperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazolin-4-amine

[0183] [ka]

[0184] Procedure for the preparation of compound 15b: To a solution of compound 15a (0.271 g, 1.44 mmol) in THF (10 mL) was added NaH (0.241 g, 6.02 mmol, 60% in mineral oil). The resulting mixture was stirred at 20-27 °C for 0.5 h. Then, 2-fluoro-6-nitrobenzonitrile (0.2 g, 1.20 mmol) was added to the above mixture. The resulting mixture was stirred at 20-27 °C for 20 h. The reaction mixture was then poured into water (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give product 15b (0.28 g, 78.2% yield) as a yellow oil. LCMS: R 1.5 min. t =0.389min, MS(ESI)m / z=298.0[M+H] + The product is a mixture of cis and trans isomers. Procedure for the preparation of compound 15c: To a solution of compound 15b (0.28 g, 0.94 mmol) in MeOH (10 mL) was added Pd-C (0.1 g, 50% HO and 10% Pd). The resulting mixture was stirred under a H balloon at 20-25 °C for 1 h. After completion, the reaction mixture was filtered and washed with MeOH (10 mL × 3). The filtrate was concentrated under reduced pressure to give crude product 15c (0.2 g) as a colorless oil, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ 1.97-2.13 (0.3H, m), 2.13-2.24 (1H, m), 2.25-2.28 (1H, m), 2.97-2.98 (1H, m), 3.24-3.30 (1H, m), 4.34-4.48 (2H, m), 5.70 (td, J1 = 56.4 Hz, J2 = 4.8 Hz), 6.24 (0.6H, t, J = 8.0 Hz), 6.32 (1H, d, J = 8.0 Hz), 6.79 (0.7H, t, J = 8.8 Hz), 7.18-7.23 (0.6H, m), 7.47-7.51 (0.3H, m). Procedure for the preparation of compound 15d: To a solution of compound 15c (0.05 g, 0.19 mmol) in toluene (5 mL) was added DMF-DMA (0.075 mL, 0.56 mmol). The resulting mixture was stirred at 110° C. for 2 hours. The reaction was concentrated under reduced pressure to give crude compound 15d (0.06 g) as a yellow oil, which was used directly in the next step without further purification. LCMS: R t = 0.123 min, MS (ESI) m / z = 323.1[M+H] + . Procedure for the preparation of compound 15: To a solution of compound 15d (0.054 g, 0.17 mmol) in AcOH (5 mL) was added compound 8e (0.04 g, 0.17 mmol). The resulting mixture was stirred at 110 °C for 2 h. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 × 30 5 μl, 33% to 63% B, A = water / 0.05% ammonia hydroxide, B = MeCN). Most of the MeCN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give isomer-1, compound 15 (2.5 mg, yield: 2.9%) as a white solid and isomer-2, compound 15' (1.4 mg, yield: 1.6%) as a yellow solid.

[0185] Compound 15 (±) Isomer-1: LCMS: 4.0 min. R t =1.654 min, MS(ESI)m / z=517.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 1.91-1.99 (2H, m), 2.22-2.25 (4H, m), 2.35 (1H, d, J = 12.4 Hz), 3.01-3.05 (2H, m), 3.35 (1H, m), 5.28 (1H, s), 5.78 (1H, t, d, J = 56.0, 4.4 Hz). 6.62 (1H, d, J = 2.4 Hz), 6.82 (1H, d, J = 7.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.39 (1H, d, J = 8.0 Hz),7.43 (1H, s), 7.70-7.79 (4H, m), 8.41 (1H, d, J = 7.6 Hz), 8.48 (1H, s). Compound 15': (±) Isomer-2 LCMS: 4.0 min. R t =1.691 min, MS(ESI)m / z517.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 2.19-2.39 (5H, m), 2.72 (1H, d, J = 12.4 Hz), 2.37 (1H, t, d, J = 14.4 Hz), 3.48 (1H, t, J = 13.2 Hz), 3.74 (1H, d, J = 12.0 Hz), 4.09-4.14 (1H, m), 5.36 (1H, s), 6.33 (1H, t, J = 53.6 Hz), 7.04 (1H, d, J = 1.6 Hz),7.35 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 8.4 Hz), 7.83-7.91 (3H, m), 8.09-8.12 (2H, m), 8.80-8.82 (2H, m). Example 16 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoropiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine

[0186] [ka]

[0187] Procedure for the preparation of compound 16b: To a solution of compound 16a (10 g, 72.92 mmol) in CHCl (200 mL) was added BocO (15.92 g, 72.92 mmol), and the reaction mixture was stirred at 10° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (20% EtOAc:80% petroleum ether, 120 g silica column) to give compound 16b (13 g, 75.1% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 4.03- 3.90 (m, 1H), 3.84-3.62 (m, 2H), 3.61-3.40 (m, 2H), 2.13 (br. s., 1H), 1.95 (br. s., 1H), 1.86-1.74 (m, 1H), 1.46 (s, 9H). Procedure for the preparation of compound 16c: To a solution of compound 16b (569.74 mg, 0.24 mmol) in THF / DMF (20 mL / 8 mL) was added t-BuOK (404.21 mg, 0.36 mmol). The mixture was stirred at 20 °C for 20 minutes. Compound 6e (500 mg, 0.12 mmol) was then added. The reaction mixture was stirred at 90 °C for 5 hours and then concentrated in vacuo. After completion, the residue was partitioned between ethyl acetate (100 mL) and water (500 mL). The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (10% MeOH:90% DCM, 40 g silica column) to give the crude product, which was separated by SFC to give enantiomer-1, compound 16c (300 mg, 16.43% yield). LCMS: 10-80AB_2.0 min A: Xtimate, 2.1×30mm, 3um 3U411201577 B: XBrige Shield 2.1×50mm, SN: 01193135614705 t=1.028 min, MS(ESI)m / z=634.4[M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.62 (s, 1H), 8.61 (s, 1H), 8.53-8.46 (m, 1H), 8.22 (s, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.97-6.84 (m, 3H), 6.51 (s, 1H), 4.74 (dt, J=5.3, 10.6 Hz, 1H), 4.21 (br. s., 1H), 4.00-3.91 (m, 3H), 3.72 (q, J=7.1 Hz, 1H), 3.34 (br. s., 1H), 3.12 (br. s., 1H), 2.41 (d, J=12.8 Hz, 1H), 2.27-2.20 (m, 3H), 2.09 (d, J=5.3 Hz, 1H), 1.57-1.32 (m, 9H). Procedure for the preparation of compound 16: To a solution of compound 16c (300 mg, 0.47 mmol) in EtOAc (10 mL) was added HCl / EtOAc (3 mL). The mixture was stirred at 10° C. for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give compound 16 (217.0 mg, 85.9% yield) as a white solid in the form of the HCl salt. LCMS: 10-80AB_2.0 min_220&254 chromatograph (Xtimate ODS 2.1×30 mm, 3 um) R t =0.746min, MS(ESI)m / z=534.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 9.06 (d, J=7.5 Hz, 1H), 8.99 (s, 1H), 8.77 (s, 1H), 7.89-7.76 (m, 2H), 7.42 (dd, J=2.4, 7.7 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.29 (d, J=1.3 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 5.78-5.63 (m, 1H), 4.16-4.03 (m, 4H), 3.90-3.75 (m, 1H), 3.66 (d, J=12.8 Hz, 1H), 3.56-3.44 (m, 1H), 2.85 (d, J=14.1 Hz, 1H), 2.47-2.32 (m, 1H), 2.29 (s, 3H). Example 17 (S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-fluoroquinazolin-4-amine and (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-fluoroquinazolin-4-amine

[0188] [ka]

[0189] Procedure for the preparation of compound 17b: A solution of compound 17a (5 g, 31.8 mmol) in acetonitrile (128 mL) and ammonia (64 mL) was analyzed by TLC (R f The mixture was stirred at room temperature for 3 days while monitoring with a 2:1 (petroleum ether:ethyl acetate = 2:1) mixture. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried and concentrated to give the crude product, which was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate = 10:1 to 2:1 (v / v) to give Compound 17b (1.5 g, yield: 30%).1 H NMR (400MHz, CDCl3) δ 6.28-6.23 (m, 2H), 4.70 (br, 2H). Procedure for the preparation of compound 17c: A solution of compound 17b (500 mg, 3.24 mmol) and DMF-DMA (580 mg, 4.86 mmol) in toluene (20 mL) was analyzed by TLC (R f The mixture was stirred at 120° C. for 2 hours while monitoring with an aqueous solution of 17c (petroleum ether:ethyl acetate=2:1, ethanol = 0.5). The solvent was removed in vacuo to give compound 17c (690 mg, crude), which was used directly in the next step. Procedure for the preparation of compound 17d: A solution of compound 17c (690 mg, 3.24 mmol) and compound 1f (780 mg, 3.24 mmol) in acetic acid (15 mL) was stirred at 120 °C for 2 h. The solvent was removed in vacuo, and the residue was diluted with NaHCO solution to adjust the pH to 7-8. The mixture was then filtered, and the filter cake was dried in vacuo to give compound 17d (720 mg, 55% yield). 1 H NMR (400MHz, DMSO-d6) δ 9.25 (br, 1H), 8.93 (d, J = 7.6 Hz, 1H ), 8.56 (s, 1H), 8.37 (s, 1H), 7.70-7.65 (m, 3H), 7.57 (d, J = 9.6 Hz, 1H ), 7.20 (d, J = 9.2 Hz, 1H ), 7.02 (dd, J1= 2.4 Hz, J2= 7.2 Hz, 1H ), 6.78 (d, J = 2.8 Hz, 1H ), 2.18 (s, 3H). Procedure for the preparation of compound 17: A solution of compound 17d (720 mg, 1.78 mmol), compound 1i (335 mg, 1.78 mmol), and potassium t-butoxide (700 mg, 6.23 mmol) in DMF-THF (40 mL, 2:5) was stirred at 100° C. overnight while monitoring by LCMS. The solution was filtered, and the filtrate was dried and concentrated to give crude product 17e (900 mg). 300 mg of the crude product was purified by preparative HPLC (column: Waters Xbridge Purification by C18 150 × 20 mm × 5 μm, gradient: 34–54% B (A = water / 0.05% ammonia, B = acetonitrile), flow rate: 25 mL / min) and SFC (column: OD (250 mm × 50 mm, 5 μm), condition: 40% EtOH in NH₃·H₂O 50 mL / min) gave compound 17 (64.9 mg) and compound 17′ (12.2 mg).

[0190] Compound 17 (Enantiomer-1): LCMS: R in 4 min chromatography t =1.487min, MS(ESI)m / z=536.3[M+H] + . 1 H NMR (400MHz, Tanol-d4) δ 8.78-8.73 (m, 2H ), 8.31 (s, 1H), 7.82-7.77 (m, 2H), 7.52 (dd, J1= 2.4 Hz, J2= 10.8 Hz, 1H ), 7.23-7.10 (m, 3H), 6.80 (d, J = 2.4 Hz, 1H), 5.45 (br, 1H), 3.81 (br, 1H), 3.39-3.31 (m, 2H), 3.04-3.01 (m, 1H), 2.77-2.69 (m, 4H), 2.32-2.21 (m, 4H). Compound 17' (enantiomer-2): R in LCMS 4 min chromatography t =1.421 min, MS(ESI)m / z536.1[M+H] + . 1H NMR (400MHz, methanol-d4) δ 8.79-8.76 (m, 2H ), 8.33 (s, 1H), 7.82-7.56 (m, 3H), 7.27-7.22 (m, 2H), 7.10 (dd, J1= 2.4 Hz, J2= 7.2 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 75.56-5.49 (m, 1H), 3.94 (br, 1H), 3.54-3.43 (m, 2H), 3.22-3.15 (m, 1H), 2.86-2.74 (m, 4H), 2.34-2.28 (m, 4H). Example 18 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine

[0191] [ka]

[0192] Procedure for the preparation of compound 18: A solution of compound 17e (70 mg, 0.2 mmol), tetrahydrofuran-3-ol (35 mg, 0.4 mmol), and potassium tert-butoxide (68 mg, 0.6 mmol) in DMF-THF (5 mL, 2:5) was stirred at 100 °C overnight while monitoring by LCMS. The solution was purified by preparative HPLC (column: Phenomenex Gemini C18 200 × 25 mm × 10 μm, gradient: 37–67% B (A = water, B = acetonitrile), flow rate: 25 mL / min), followed by purification by SFC separation to give compound 18 (7.2 mg, yield 9.1%).

[0193] LCMS: R in 4 min chromatography t =1.540min, MS(ESI)m / z=604.1[M+H] + .1 H NMR (400MHz, methanol-d4) δ 8.72 (d, J = 7.6 Hz, 1H ), 8.44 (s, 1H), 8.27 (s, 1H), 7.79-7.77 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H ), 7.04 (d, J = 9.6 Hz, 1H ), 6.88 (d, J = 2.0 Hz, 1H ), 6.79 (dd, J1= 2.4 Hz, J2= 7.2 Hz, 1H ), 5.15-5.05 (m, 2H), 4.06-3.90 (m, 4H), 3.27 (brs, 1H), 2.95-2.92 (m, 1H), 2.47-2.35 (m, 7H), 2.22-2.18 (m, 4H), 2.06-2.06 (m, 1H). Example 19 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((2S,4S)-5,5-difluoro-1,2-dimethylpiperidin-4-yl)oxy)quinazolin-4-amine and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((2R,4R)-5,5-difluoro-1,2-dimethylpiperidin-4-yl)oxy)quinazolin-4-amine

[0194] [ka]

[0195] Procedure for the preparation of compound 19b: To a solution of compound 19a (30 g) in MeOH (400 mL) was added ethyl (E)-but-2-enoate (31.96 g, 0.28 mol). The resulting mixture was stirred at 75 °C for 48 h. The reaction mixture was concentrated under reduced pressure to give crude compound 19b (62 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. Procedure for the preparation of compound 19d: To a solution of compound 19b (30 g, 0.136 mol) in MeOH (300 mL) was added compound 19c (16.2 g, 0.136 mol) and (CHO) n (4.9 g, 0.163 mol) was added. The mixture was stirred under N protection at 15-20 °C for 18 h. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica chromatography using PE / EA = 1 / 0 to 9 / 1 to 4 / 1. Pure fractions were evaporated to dryness to give compound 19d (25.6 g, 55.7% yield) as a yellow oil. Procedure for the preparation of compound 19f: To a suspension of zinc dust (9.89 g, 151.3 mmol) in dry THF (200 mL) was added TMSCl (16.44 g, 151.3 mmol) under N2 at 12-20 °C. After 10 min, compound 19e (16.89 g, 83.22 mmol) was added dropwise, maintaining the temperature at 12-20 °C. The mixture was stirred for an additional 10 min. Then, a solution of compound 19d (25.6 g, 75.65 mmol) in THF (100 mL) was added to the above mixture and stirred at 12-20 °C for 18 h. Upon completion, the reaction was quenched by the addition of 5% aqueous NaHCO3 (500 mL). The mixture was then filtered, and the filtrate was extracted with EtOAc (200 mL × 2). The combined layers were washed with brine (600 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography using petroleum ether:ethyl acetate (0 / 1 to 97:3 to 95:5) to give compound 19f (11.0 g, 42.3% yield) as a colorless oil. LCMS: R t =0.905min, MS(ESI)m / z=344.1[M+H] +. 1 H NMR (400MHz, CDCl3) δ 1.04 (3H, d, J = 6.8 Hz), 1.30 (3H, t, J = 6.8 Hz), 2.04-2.24 (1H, m), 2.48-2.54 (1H, m), 3.11 (2H, t, J = 13.2 Hz), 3.28-3.30 (1H, m), 3.61 (3H, s), 3.70 (2H, dd, J = 14.0, 34.4 Hz), 4.22-4.27 (2H, m), 7.24-7.29 (5H, m). Procedure for the preparation of compound 19g: LDA (70.5 mL, 2 M in n-heptane and THF) in THF (100 mL) To a solution of compound 19f (32.4 g, 4.08 mmol) in THF (100 mL) was added at −65° C. under N2. The cooling bath was removed, and the reaction mixture was slowly warmed to 15–23° C. and stirred for an additional 20 h. The reaction mixture was poured into NH4Cl (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 19g (31.0 g, crude) as a brown oil. LCMS: R 1.5 min chromatographically. t =0.866 min, MS(ESI)m / z=298.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ 1.21-1.28 (3H, m), 3.06-3.10 (1H, m), 3.21-3.33 (2H, m), 3.69-3.84 (6H, m), 7.28-7.36 (5H, m). Procedure for the preparation of compound 19h: A solution of compound 19g (30.0 g, 100.9 mmol) in 3 M HCl (400 mL) was heated to reflux and stirred for 18 h. The reaction mixture was cooled to room temperature, and then the pH was adjusted to 7-8 with solid NaHCO. The aqueous phase was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (700 mL), dried over NaSO, and concentrated in vacuo to give compound 19h (17.6 g, crude), which was used in the next step without further purification. Procedure for the preparation of compound 19i: To a solution of compound 19h (17.6 g, 0.068 mol) in EtOH (200 mL) was added NaBH4 (3.86 g, 0.102 mol) at 0 °C. The resulting mixture was stirred at 16-25 °C for 20 h. Upon completion, the reaction was quenched by adding HCl solution (3 M, 10 mL). The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were concentrated in vacuo to give compound 19i (16.8 g, crude), which was used in the next step without further purification. LCMS: R t =0.173min, MS(ESI)m / z=242.0[M+H] + . Procedure for the preparation of compound 19j: To a solution of compound 19i (2.0 g, 8.29 mmol) and Pd / C (250 mg, 50% HO and 10% Pd) in MeOH (50 mL) was added (CHO)n (1.24 g, 41.45 mmol). The resulting mixture was stirred under a hydrogen atmosphere at 50 psi and 50 °C for 18 h. The reaction mixture was filtered and washed with MeOH (20 mL × 3). The filtrate was concentrated under reduced pressure to give compound 19j (1.3 g, crude) as a yellow oil, which was used in the next step without further purification. Procedure for the preparation of compound 19k: To a solution of compound 1h (1.0 g, 2.59 mmol) in DMF (20 mL) / THF (8 mL) was added compound 19j (1.28 g, 7.77 mmol) and potassium tert-butoxide (1.02 g, 9.07 mmol). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250 × 50 mm × 10 μm, 30–60% B (A = water / 0.05% ammonia hydroxide, B = acetonitrile), flow rate: 90 mL / min) to give a trans and cis mixture of 19k (0.7 g, crude) as a pale red solid. LCMS: 4.0 min chromatographic t =1.960 min, MS(ESI)m / z=532.3[M+H] + . Procedure for the preparation of compound 19: Compound 19k (0.7 g, crude) was separated by preparative chiral HPLC on an AD (250 mm x 30 mm, 5 μm) column, mobile phase: A:CO₂B:ethanol (0.05% DEA); conditions: base - EtOH, start B 40% and end B 40%, flow rate (ml / min) = 50. Fractions containing the desired compound were evaporated to dryness to give four isomers, which were then purified by preparative HPLC (Waters Xbridge Prep OBD C18 150× Repurification with 30 ml of 5 ml of 35% to 65% B (A = water / 0.05% ammonium hydroxide, B = MeCN) afforded trans enantiomer-1, compound 19' (16.3 mg, 2.3% yield) as a white solid, and trans enantiomer-2, compound 19 (10.7 mg, 1.5% yield, trans, peak 2) as a white solid. Compound 19' (trans enantiomer-1): LCMS: 4.0 min. R t =1.946 min, MS(ESI)m / z532.3[M+H] + . 1H NMR (400MHz, methanol-d4) δ 1.19 (3H, d, J = 6.8 Hz), 2.11-2.16 (1H, m), 2.26 (3H, s), 2.31-2.38 (4H, m), 2.82 (1H, s), 2.91-2.97 (1H, m), 3.20-3.22 (1H, m), 5.22-5.24 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 7.06 (1H, dd, J = 4.8, 7.2 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 7.6 Hz), 7.77-7.82 (3H, m), 8.29 (1H, s), 8.52 (1H, s), 8.74 (1H, d, J = 7.6 Hz). Compound 19 (trans enantiomer) Mer-2): LCMS: 4.0 min. R t =1.902 min, MS(ESI)m / z532.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 1.18 (3H, d, J = 6.4 Hz), 2.08-2.13 (1H, m), 2.23 (3H, s), 2.29-2.37 (4H, m), 2.80 (1H, s), 2.89-2.92 (1H, m), 3.18-3.20 (1H, m), 5.17-5.24 (1H, m), 6.80 (1H, d, J = 2.4 Hz), 7.03 (1H, d, J = 7.6 Hz), 7.16 (1H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.74-7.79 (3H, m), 8.27 (1H, s), 8.49 (1H, s), 8.71 (1H, d, J = 7.2 Hz). Example 20 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)quinazolin-4-amine

[0196] [ka]

[0197] Procedure for the preparation of compound 20: To a solution of compound 1h (100 mg, 0.26 mmol) in DMF (5 mL) was added potassium tert-butoxide (58 mg, 0.52 mmol) at 25°C. The resulting mixture was stirred at 90°C for 5 days. The reaction mixture was cooled to 25°C and filtered. The filtrate was purified by preparative HPLC (column: Phenomenex Gemini C18 250 x 21.2 mm x 5 um, 65-95% B (A = water / 0.05% ammonia, B = methanol), flow rate: 25 mL / min) to give compound 20 (9.1 mg, yield: 6.93%) as a white solid. LCMS: R t =2.842min, MS(ESI)m / z=508.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.74 (2H, d, J = 7.6 Hz), 2.03-2.08 (2H, m), 2.18-2.33 (7H, m), 2.39 (3H, s), 3.33-3.43 (2H, m), 4.80-4.89 (1H, m), 6.88-6.95 (3H, m), 7.09 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.61-7.65 (2H, m), 7.77 (1H, s), 8.23 (1H, s), 8.49 (1H, d, J = 7.6 Hz), 8.65 (1H, s), 10.13 (1H, br.s.) Example 21 5-((5,5-difluoro-1-methylazepan-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline -4-amine

[0198] [ka]

[0199] Procedure for the preparation of compound 21: The synthesis followed the same experimental procedure as for compound 11, and compound 21 was obtained as a solid after SFC separation. LCMS: 4.0 min chromatographic t =1.459 minutes. MS(ESI)m / z=531.3[M+H] + . 1 HNMR (400MHz, methanol-d4) δ 8.64 (d, J = 7.6 Hz, 1H), 8.53 (s, 1H), 7.95 (s, 1H), 7.86-7.85 (m, 2H), 7.83 (t, J = 8.4 Hz, 1H), 7.78-7.75 (m, 1H), 7.71-7.69 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25-7.19 (m, 2H), 7.17-7.15 (m, 1H), 6.83 (s, 1H), 5.37-5.27 (m, 1H), 3.36-3.31 (m, 2H), 3.23-3.20 (m, 2H), 2.75 (s, 3H), 2.72-2.59 (m,2H), 2.49-2.40 (m, 2H), 2.26 (s, 3H). Example 22 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)-7-methoxyquinazolin-4-amine

[0200] [ka]

[0201] The synthesis followed the same experimental procedure as for compound 6, affording compound 22 as a solid. The crude product 22a was purified by preparative SFC on a CHIRALPAK AD-H SFC 5 x 25 cm, 5 um Chiral-P(AD-H)006S90ADHSCY-QH001 column, eluting isocratically with 50% CO in IPA as the eluent. Fractions containing the desired compound were evaporated to dryness to afford compound 22 (enantiomer-1): (350 mg, 33.3% yield) as an off-white solid. LCMS: MS(ESI) m / z = 566.2 [M+H] + ;HPLC R t =1.911 minutes. 1 H NMR (300 MHz, CDCl3) δ 1.22 (d, 1H), 2.27 (s, 5H), 2.32 - 2.65 (m, 6H), 2.97 (d, 1H), 3.18 - 3.34 (m, 1H), 3.95 (s, 3H), 4.63 (td, 1H), 6.52 (d, 1H), 6.86 (d, 1H), 6.94 (d, 1H), 7.10 (d, 1H), 7.78 (dd, 1H), 7.85 (d, 1H), 8.23 ​​(s, 1H), 8.55 - 8.67 (m, 2H), 9.80 (s, 1H). 19 F NMR (282 MHz, CDCl3) δ -154.2, -116.6, -109.7. Example 23 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)-6-methoxyquinazolin-4-amine

[0202] [ka]

[0203] The synthesis followed the same experimental procedure as for compound 3, and compound 23a was obtained as a solid. The crude product 23a was purified by preparative SFC on a CHIRALPAK IF 2 x 25 cm, 5 um 86445S90IF0SCJ-RA002 column, eluting isocratically with 50% CO2 in EtOH (modified with 2 mM NH3) as the eluent. The fractions containing the desired compound were evaporated to dryness to give compound 23 (enantiomer-1): (25.00 mg, 25.0% yield) as an off-white solid. Compound 23 (enantiomer-1): LCMS: MS (ESI) m / z = 566.2 [M+H] + ;HPLC:R t =1.193 minutes. 1 H NMR (CRO-HER2_P-1-202-011-01, 300 MHz, methanol-d4) δ 2.04 - 2.16 (m, 1H), 2.32 (d, 8H), 2.48 (dd, 1H), 2.94 (d, 1H), 3.19 (s, 1H), 4.07 (s, 3H), 4.89 - 5.06 (m, 1H), 6.86 (d, 1H), 7.23 (d, 1H), 7.63 (d, 1H), 7.79 (d, 1H), 7.85 (d, 2H), 8.30 (s, 1H), 8.44 (s, 1H), 9.07 (d, 1H). 19 F NMR (282 MHz, methanol-d4) δ -156.2, -118.2, -111.7. Example 24 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)quinazolin-4-amine

[0204] [ka]

[0205] Procedure for the preparation of compound 24a: To a solution of compound 1h (0.5 g, 1.29 mmol) in DMF (20 mL) and THF (8 mL) was added compound 27a (0.307 g, 1.29 mmol) and t-BuOK (0.508 g, 4.53 mmol). The resulting mixture was stirred at 100 °C for 16 h. LCMS showed the reaction was complete. Water (20 mL) was added and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by flash silica chromatography. The mixture was purified by ethyl acetate / MeOH (1 / 0 to 9 / 1). The pure fractions were evaporated to dryness to give compound 24a (760 mg, 92.2% yield) as a yellow oil. LCMS: 4.0 min. R t =2.794 min, MS(ESI)m / z604.1[M+H] + SFC analysis method: Column: Chiralcel OD-3 100 x 4.6 mm ID, 3 μm; Mobile phase: A:CO2, B:ethanol (0.05% DEA); Gradient: 5% to 40% B in 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40°C Procedure for the preparation of compound 24b: Compound 24a was separated by preparative chiral HPLC on an OD (250 mm x 30 mm, 5 μm) column, mobile phase: A = CO2, B = ethanol (0.05% DEA); conditions: base - EtOH, flow rate: 50 ml / min. Fractions containing the desired compound were evaporated to dryness to give compound 24b' (0.340 g, 44.7% yield) (isomer-1) and compound 24b (0.310 g, 40.8% yield) (isomer-2), both as pale yellow solids. Compound 24b': Enantiomer-1 LCMS: R t =0.760 min, MS(ESI)m / z626.1[M+Na] + Compound 24b: Enantiomer-2 LCMS: 1.5 min. Chromatographically R t =0.762 min, MS(ESI)m / z626.1[M+Na] + . Procedure for the preparation of compound 24c: To a solution of compound 24b (0.15 g, 0.25 mmol, enantiomer-2) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The resulting mixture was stirred at 16-18 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (3 mL), the pH was adjusted to 8-9 with ammonia, and then purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 30 5 μl, 30%-60% B (A = water / 0.05% ammonia hydroxide, B = MeCN)] to give compound 24c (0.069 g, 55.1% yield) as a white solid. LCMS: R 4.0 min chromatographically. t =1.946min, MS(ESI)m / z=504.2[M+H] + . 1 HNMR (400MHz, DMSO-d6) δ 1.77-1.81 (1H, m), 2.20 (3H, s), 2.36 (1H, d, J = 10.8 Hz), 2.65 (1H, s), 2.74 (1H, t, J = 12.4 Hz), 2.88-2.99 (2H, m), 3.29-3.32 (1H, m), 5.30-5.39 (1H, m), 6.81 (1H, d, J = 7.6 Hz), 7.02 (1H, d, J = 7.6 Hz), 7.24 (1H, d, J = 8.8 Hz), 7.40 (2H, dd, J = 8.0, 17.6 Hz), 7.76-7.78 (2H, m), 7.87 (1H, s), 8.38 (1H, s), 8.59 (1H, s), 8.92 (1H, d, J = 7.6 Hz), 10.15 (1H, s). Procedure for the preparation of compound 24: To a solution of compound 24c (300 mg, 0.596 mmol) in DMF (5 mL) were added CDI3 (69 mg, 0.894 mmol) and K2CO3 (124 mg, 0.894 mmol). The resulting mixture was stirred at 27-31 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by HPLC (Waters Xbridge Prep OBD C18 150 × 30 5 μl, 42-42% B, A = water (0.05% ammonium hydroxide), B = MeCN, flow rate (mL / min) = 25 mL / min). Most of the MeCN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give compound 24 (25.1 mg, 8.1% yield) as a white solid. LCMS: R t =2.026min, MS(ESI)m / z=521.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 2.06-2.10 (1H, m), 2.25 (3H, s), 2.42-2.48 (2H, m), 2.64 (1H, dd, J = 11.6, 28.8 Hz), 2.96 (1H, d, J = 12.0 Hz), 3.24-3.27 (1H, m), 5.08-5.16 (1H, m), 6.81 (1H, d, J = 2.8 Hz), 7.06 (1H, dd, J = 2.4, 7.6 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.4 Hz),7.76-7.86 (3H, m), 8.28 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.73 (1H, d, J = 7.6 Hz). Example 25 (±)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(((2R,4S)-1-(methyl-d3)-2-(trifluoromethyl)piperidin-4-yl)oxy)quinazolin-4-amine

[0206] [ka]

[0207] Procedure for the preparation of compound 25b: To a solution of compound 25a (15.0 g, 1.0 equiv.) in methanol (200 mL) was added hydrochloric acid (12 M, 3 mL) and PtO (1.2 g). The mixture was stirred at 50 °C under a hydrogen atmosphere (50 psi) for 3 days. The solid was dissolved in methanol (200 mL), and hydrochloric acid (12 M, 3 mL) and PtO (1.2 g) were added to the mixture, which was then stirred at 50 °C under a hydrogen atmosphere (50 psi) for 20 hours. The mixture was filtered and concentrated to give the hydrochloride salt of compound 25b (18.2 g, 96% yield) as a colorless solid. 1 H NMR (400 MHz, methanol-d4) δ 1.60-1.86 (2H, m), 1.91-2.07 (1H, m), 2.17-2.27 (1H, m), 2.32-2.45 (0.5H, m), 3.10-3.30 (1H, m), 3.46-3.64 (1H, m), 3.90-4.00 (0.5H, m), 4.15-4.40 (1H, m). Procedure for the preparation of compound 25c: The HCl salt of compound 25b was dissolved in methanol, basified with ammonia, and concentrated. The residue was diluted with dichloromethane, filtered, and the filtrate was concentrated to give compound 25b (3.8 g, free base), which was used in the next step. To a solution of compound 25b (300 mg, 1.2 equiv.) in THF (10 mL) was added NaH (180 mg, 3.0 equiv., 60%) under stirring. After 0.5 h, 2-fluoro-6-nitrobenzonitrile (250 mg, 1.0 equiv.) was added to the reaction mixture, which was stirred at 21–29 °C for 2 days. LCMS analysis indicated that the reaction was nearly complete. The mixture was poured into a saturated solution of NH4Cl (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-50% EA in PE) to give compound 25c (230 mg, 48% yield) as a yellow oil. LCMS: 5-95AB_220&254 chromatographically showed R t =0.641 min, MS(ESI)m / z=315.9[M+H] + . 1 H NMR (400MHz, CDCl3) δ 1.79-1.86 (2H, m), 2.18-2.29 (1H, m), 2.35-2.44 (1H, m), 2.78-2.83 (1H, m), 3.25-3.37 (1H, m), 3.38-3.45 (1H, m), 4.48-4.57 (1H, m), 7.37 (1H, d, J = 8.0 Hz), 7.73 (1H, t, J = 8.4 Hz), 7.90 (1H, d, J = 8.4 Hz). Procedure for the preparation of compound 25d: To a mixture of compound 25c (180 mg, 1.0 equiv.) and potassium carbonate (118 mg, 1.5 equiv.) in DMF (10 mL) was added CD3I (66 mg, 0.8 equiv.). The mixture was stirred at 23-26 °C for 6 h. The reaction was poured into brine (50 mL) and extracted with EA (20 mL × 3). The combined organic layer was dried over sodium sulfate and filtered. The residue was purified by column chromatography on silica gel (0-30% EA in PE) to give compound 25d (140 mg, crude) as a brown oil. LCMS: 5-95AB_220&254 chromatographically t =0.684 min, MS(ESI)m / z=333.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ 1.94-2.05 (2H, m), 2.10-2.18 (1H, m), 2.35-2.51 (2H, m), 2.74-2.85 (1H, m), 3.05-3.15 (1H, m), 4.40-4.53 (1H, m), 7.35 (1H, d, J = 8.4 Hz), 7.72 (1H, t, J = 8.4 Hz), 7.89 (1H, d, J = 8.4 Hz). Procedure for the preparation of compound 25e: To a solution of compound 25d (140 mg, 1.0 equiv.) in methanol (10 mL) was added Pd / C (50 mg, 10%) under argon. The suspension was stirred under hydrogen (balloon) at 24-30°C for 17 hours. LCMS analysis indicated the reaction was complete. The mixture was filtered and concentrated to give compound 25e (60 mg, 68% yield) as a yellow oil. LCMS: 5-95AB_220&254 chromatographically showed R t =0.620 min, MS(ESI)m / z=303.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ 1.83-1.93 (2H, m), 2.08-2.14 (1H, m), 2.31-2.49 (2H, m), 2.71-2.79 (1H, m), 3.03-3.09 (1H, m), 4.25-4.35 (1H, m), 4.44 (2H, br. s), 6.25 (1H, d, J = 8.4 Hz), 6.34 (1H, d, J = 7.6 Hz), 7.22 (1H, t, J = 8.4 Hz). Procedure for the preparation of compound 25f: To a mixture of compound 25e (60 mg, 1.0 equiv.) in anhydrous toluene (10 mL) was added DMF-DMA (54 uL, 2.0 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS analysis showed the reaction was complete. The solution was concentrated to give compound 25f (0.2 mmol, crude). LCMS: 5-95AB_220&254 chromatographically showed R t =0.222min, MS(ESI)m / z=358.1[M+H] + . Procedure for the preparation of compound 25: To a mixture of compound 25f (0.20 mmol, 1.0 equiv.) in AcOH (10 mL) was added compound 1f (57 mg, 1.2 equiv.). The mixture was stirred at 120° C. for 1.5 hours. LCMS analysis indicated the reaction was complete. The solution was concentrated. The residue was purified by preparative HPLC (column: DuraShell 150×25 mm×5 μm, gradient: 50% to 80% B (A=water / 0.05% ammonia hydroxide, B=acetonitrile), flow rate: 25 mL / min) to give compound 25 (13.1 mg, 12% yield) as a white solid. LCMS: 0-60 AB_4 min_220&254 R in chromatography. t =2.307min, MS(ESI)m / z=553.3[M+H] + HPLC: 0-60 AB 1.2 ml R t =4.31 minutes. 1H NMR (400MHz, CDCl3) δ 1.90-1.96 (1H, m), 2.01-2.08 (1H, m), 2.25 (3H, s), 2.35-2.43 (1H, m), 2.49-2.55 (1H, m), 2.62-2.69 (1H, m), 2.79-2.89 (1H, m), 3.12-3.19 (1H, m), 4.59-4.69 (1H, m), 6.87-6.91 (2H, m), 6.95 (1H, d, J = 8.0 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.62-7.74 (3H, m), 8.23 ​​(1H, s), 8.50 (1H, dd, J1= 7.2 Hz, J2= 1.2 Hz), 8.68 (1H, s), 10.03 (1H, s). Example 26 (±)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine

[0208] [ka]

[0209] Procedure for the preparation of compound 26a: A mixture of compound 3e (200 mg, 0.48 mmol) and pyridine hydrochloride (277.52 mg, 2.40 mmol) was stirred at 170 °C for 2 h. The mixture was cooled to room temperature. The pH was adjusted to 8-9 with saturated NaHCO3. The mixture was vigorously stirred, filtered, and the precipitate was washed with ethyl acetate (5 mL) to give compound 26a (120 mg, 62.1% yield) as a brown solid. LCMS: 0-60 AB_2 min_E chromatography (Merck RP-18e 25-2mm, SN:UM9504 / 198) t =0.956 min, MS(ESI)m / z=403.2[M+H]+ . 1 H NMR (400MHz, methanol-d4) δ 8.73 (br d, J=7.50 Hz, 1 H), 8.09 - 8.39 (m, 2 H), 7.69 - 7.87 (m, 2 H), 7.30 - 7.49 (m, 2 H), 7.03 - 7.25 (m, 2 H), 6.87 (s, 1 H), 2.24 (s, 3 H). Procedure for the preparation of compound 26b: To a solution of compound 26a (120 mg, 0.30 mmol) and KCO (49.46 mg, 0.36 mmol) in DMF (8 mL) was added CDI (51.88 mg, 0.36 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was filtered and concentrated to give the product, which was identified by preparative TLC (CHCl / MeOH = 10:1, R f =0.6) to give compound 26b (60 mg, 48% yield) as a yellow solid. LCMS: 0-60 AB_2 min_E chromatography (Merck RP-18e 25-2 mm, SN: UM9504 / 198) yielded R t =1.016 min, MS(ESI)m / z=420.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (dd, J=7.50, 0.66 Hz, 1 H), 8.44 (s, 1 H), 8.28 (s, 1 H), 7.78 - 7.87 (m, 1 H), 7.70 - 7.76 (m, 2 H), 7.66 (dd, J=9.15, 1.87 Hz, 1 H), 7.19 (d, J=8.38 Hz, 1 H), 7.07 (dd, J=7.50, 2.43 Hz, 1 H), 6.84 (d, J=2.20 Hz, 1 H), 2.25 (s, 3 H). Procedure for the preparation of compound 26: To a solution of compound 26c (60.6 mg, 0.39 mmol) in THF (5 mL) and DMF (2 mL) was added tBuOK (44.1 mg, 0.39 mmol). The mixture was stirred at 20 °C for 30 minutes, and then compound 26b (60 mg, 0.13 mmol) was added. The mixture was stirred at 90 °C for 12 hours. The reaction mixture was filtered and concentrated in vacuo to give the crude product, which was analyzed by preparative TLC (CHCl / MeOH = 10:1, R f =0.5) to give compound 26 (16.37 mg, 22.57% yield) as a yellow solid. LCMS: 0-60AB_2.0 min. R t =1.034min, MS(ESI)m / z=554.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (d, J=7.72 Hz, 1 H), 8.41 (s, 1 H), 8.28 (s, 1 H), 7.73 - 7.84 (m, 3 H), 7.62 (d, J=9.26 Hz, 1 H), 7.17 (d, J=8.38 Hz, 1 H), 7.06 (dd, J=7.50, 2.65 Hz, 1 H), 6.83 (d, J=2.65 Hz, 1 H), 4.90 - 5.01 (m, 1 H), 3.12 - 3.23 (m, 1 H), 2.86 - 2.97 (m, 1 H), 2.38 - 2.53 (m, 1 H), 2.23 - 2.28 (m, 5 H), 2.03 - 2.14 (m, 1 H). Example 27 (±)N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl-4-d)oxy)-7-methoxyquinazolin-4-amine

[0210] [ka]

[0211] Procedure for the preparation of compound 27b: To a solution of compound 27a (1.0 g, 4.22 mmol) in dry CHCl (50 mL) was slowly added Dess-Martin reagent (3.58 g, 8.44 mmol). The mixture was stirred at 20 °C for 2 h, then quenched with saturated NaSO / NaHCO (v / v = 3 / 1, 100 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give compound 27b (700 mg, 65.5% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 3.94 (br t, J=12.0 Hz, 1H), 3.79 (br t, J=6.1 Hz, 2H), 3.61-3.52 (m, 1H), 3.11 (br s, 1H), 2.76 (br t, J=6.0 Hz, 1H), 1.93 (br s, 1H), 1.49 (d, J=14.5 Hz, 9H). Procedure for the preparation of compound 27c: To a solution of compound 27b (700 mg, 2.76 mmol) in dry CD3OD (5 mL) was added NaBD4 (231.07 mg, 5.52 mmol) slowly at 0 °C under N2. The mixture was stirred at 20 °C for 1 h, then quenched with DO (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give crude compound 27c (500 mg, 76.1% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 3.88-3.62 (m, 2H), 3.60-3.40 (m, 2H), 2.24 (br s, 1H), 2.00-1.88 (m, 1H), 1.86-1.73 (m, 1H), 1.53-1.44 (m, 9H). Procedure for the preparation of compound 27d: To a solution of compound 27c (300 mg, 1.26 mmol) in dry THF / DMF (10 mL / 4 mL) was added t-BuOK (212.06 mg, 1.89 mmol) under N2 at 20 °C and stirred at this temperature for 30 min. Compound 6e (262.55 mg, 0.63 mmol) was added and then heated at 90 °C for 12 h. The reaction mixture was diluted with 30 mL of water and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl / MeOH = 100 / 1 to 20 / 1, R f =0.4) to give compound 27d (320 mg, 80% yield) as a yellow solid. LCMS: 0-60 AB_2.0 min_220&254 R t =1.254 min, MS(ESI)m / z634.9[M+H] + . 1 H NMR (400MHz, CDCl3) δ 9.63 (s, 1H), 8.62 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.80 (s, 1H), 7.68 (br d, J=8.6 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.93 (d, J=1.4 Hz, 1H), 6.91-6.83 (m, 2H), 6.52 (d, J=1.8 Hz, 1H), 4.45 (br s, 1H), 4.25-4.10 (m, 1H), 3.95 (s, 3H), 3.35 (br s, 1H), 3.13 (br s, 1H), 2.41 (br d, J=10.2 Hz, 1H), 2.25 (s, 3H), 2.14-2.00 (m, 1H), 1.50 (s, 9H). Procedure for the preparation of compound 27e: Compound 27d (320 mg, 0.5 mmol) was dissolved in a solution of TFA in CHCl (20%, 10 mL) and stirred at 20 °C for 3 h. The reaction mixture was adjusted to pH 7-8 with NaHCO (saturated) and extracted with CHCl (30 mL × 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give compound 27e (280 mg, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 9.75 (s, 1H), 8.51 (s, 1H), 8.43 (d, J=7.4 Hz, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.66 (br d, J=8.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.88-6.76 (m, 3H), 6.52 (d, J=2.2 Hz, 1H), 6.55-6.50 (m, 1H), 3.86 (s, 3H), 3.42-3.31 (m, 1H), 3.13 (br d, J=13.5 Hz, 1H), 3.02-2.88 (m, 1H), 2.77 (br t, J=12.8 Hz, 1H), 2.43-2.35 (m, 1H), 2.17 (s, 3H), 1.93-1.90 (m, 2H). Procedure for the preparation of compound 27: To a solution of compound 27e (140 mg, 0.26 mmol) in dry CH2Cl2 / MeOH (4 mL / 4 mL) was added (HCHO) n (23.4 mg, 0.26 mmol), followed by 5 drops of HCOOH (1 drop of pure HCOOH diluted with 1 mL of CHCl) was added. The mixture was stirred at 20°C for 12 h, and then NaCNBH (163.4 mg, 2.6 mmol) was added. The resulting mixture was stirred at 20°C for 30 min, quenched with 10 mL of saturated NHCl, and extracted with CHCl (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl / MeOH = 100 / 1 to 15 / 1, R f=0.3) to give compound 27 (40.32 mg, 28.3% yield) as a yellow solid. LCMS: 5-95AB_1.5 min_220&254 R t =0.690min, MS(ESI)m / z549.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 (d, J=7.5 Hz, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 7.87-7.70 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.08-6.97 (m, 1H), 6.92-6.76 (m, 3H), 3.95 (s, 3H), 3.31 (br s, 2H), 3.29-3.19 (m, 1H), 2.94 (br d, J=11.9 Hz, 1H), 2.70-2.54 (m, 1H), 2.52-2.35 (m, 5H), 2.22 (s, 3H), 2.12-1.97 (m, 1H). Example 28 (S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl-4-d)oxy)-7-methoxyquinazolin-4-amine and (R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl-4-d)oxy)-7-methoxyquinazolin-4-amine

[0212] [ka]

[0213] Procedure for the preparation of compound 28a: To a solution of compound 27e (140 mg, 0.262 mmol) and KCO (145 mg, 0.275 mmol) in dry DMF (5 mL) was added dropwise CD3I (37.97 mg, 0.262 mmol) under N2 at 20 °C and stirred at this temperature for 2 h. The reaction mixture was diluted with 20 mL of water, extracted with EtOAc (30 mL × 3), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by preparative HPLC (instrument: AA / Boston Green ODS 150 × 30 5 μl, conditions: water (0.05% HCl)-ACN, start B5, end B30, gradient time (min): 12, 100% B, retention time (min): 2.2, flow rate (ml / min): 25) to give compound 28a (48.3 mg, 27.9% yield) as a yellow solid in the form of the HCl salt. LCMS: 0-60 AB_2.0 min_220&254 Chromatography (Xtimate 3um, C18, 2.1 x 30mm S / N3U411201576) t =1.204 min, MS(ESI)m / z552.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.96 (br d, J=7.1 Hz, 1H), 8.81-8.59 (m, 2H), 7.98-.71 (m, 2H), 7.45-7.24 (m, 3H), 6.99 (br d, J=17.4 Hz, 2H), 4.28 (br s, 1H), 4.08 (s, 3H), 4.01-3.85 (m, 1H), 3.79 (br d, J=11.9 Hz, 1H), 3.66-3.52 (m, 1H), 2.87 (br d, J=14.8 Hz, 1H), 2.46 (br t, J=12.3 Hz, 1H), 2.29 (s, 3H). Procedure for the preparation of compound 28: Compound 28a (45 mg, 0.068 mmol) was purified by chiral SFC (SFC method: Instrument: SFC-MS; Column: Chiralcel AD (250 mm × 30 mm, 10 μm); Conditions: 0.1% NH₃H₂O IPA; Start B: 45%, End B: 45%, Flow rate: 80 mL / min) and lyophilized to give compound 28 (18.9 mg, 50.4% yield) and compound 28′ (18.1 mg, 48.3% yield) as yellow solids.

[0214] Compound 28 (enantiomer-1): SFC:R t =5.868 min (220 nm) OD-H_EtOH(DEA)_5_40_2.5M (Column: ChiralCel OD-H 150 x 4.6 mm ID, 5 μm Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min Flow rate: 2.5 mL / min Column temperature: 40 °C). 1 H NMR (400MHz, methanol-d4) δ 9.87 (s, 1H), 8.92 (d, J=7.7 Hz, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.73 (dd, J=2.1, 8.7 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.04-6.99 (m, 2H), 6.88 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 3.92 (s, 3H), 3.26-3.16 (m, 1H), 2.82 (br d, J=11.5 Hz, 1H), 2.56 (br s, 1H), 2.40-2.29 (m, 2H), 2.18 (s, 3H), 1.96-1.85 (m, 1H). Compound 28' (enantiomer-2): SFC:R t =6.789min(220nm) OD H_EtOH(DEA)_5_40_2.5M (Column: ChiralCel OD-H 150 x 4.6 mm ID, 5 μm Mobile phase: A:CO2 B:Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min Flow rate: 2.5 mL / min Column temperature: 40 °C). 1 H NMR (400MHz, methanol-d4) δ 9.87 (s, 1H), 8.92 (d, J=7.5 Hz, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.82 (br s, 1H), 7.74 (br d, J=8.8 Hz, 1H), 7.23 (br d, J=8.8 Hz, 1H), 7.02 (br s, 2H), 6.89 (s, 1H), 6.81 (d, J=2.0 Hz, 1H), 3.92 (s, 3H), 3.24 (br d, J=10.8 Hz, 1H), 2.82 (br d, J=11.0 Hz, 1H), 2.56 (br s, 1H), 2.41-2.29 (m, 2H), 2.18 (s, 3H), 1.96-1.79 (m, 1H). Biological Examples: Example 29: Efficacy assessment against WT EGFR The inhibitory activity of compounds for EGFR WT can be assessed using NCI-H838 (ATCC® CRL-5844™), which expresses the wild-type EGFR protein, as a count screening to define compound selectivity.

[0215] Compound inhibition of target modulation was determined as follows: NCI-H838 cells were sorted overnight into 96-well plates (20,000 cells / well) with DMEM medium containing 1% FBS, and then treated with test compounds at a range of concentrations (3 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, 0.0001 μM). The plates were incubated at 37°C with 5% CO for 4 hours, followed by stimulation with recombinant hEGF (100 ng / ml, 10 minutes, RD, Cat. No. 236-EG). The cellular EGFR (Y1068) phosphorylation level in each well was then measured using an MSD kit (MULTI-SPOT® 96 4-Spot HB Prototype EGFR Triplex Analytes: pEGFR (Tyr1068), pEGFR (Tyr1173), total EGFR (Cat. No. N45ZB-1). The assay was performed using an MSD SECTOR® Imager with an electrochemiluminescence method (MESO SCALE) to determine both cellular phosphorylated and total EGFR. DISCOVERY), and then the ratio of p-EGFR / total EGFR can be generated by the machine. The percentage of inhibition was obtained from the formula: % inhibition = 100 x [1 - (ratio of sample well - ratio of Min control well) / (ratio of Max - ratio of Min control well)]. IC was calculated using Prism GraphPad 7.0 or Microsoft Xlfit software. 50 Values ​​were further calculated as the compound concentration required for 50% inhibition in the best fit curve.

[0216] Example 30: Efficacy assessment against WT HER2 The activity of compounds in selectively inhibiting HER2 wild-type amplification can be evaluated using the BT474 cell line (ATCC® HTB-20™), which expresses phosphorylated HER2 protein and whose proliferation is dependent on the amplified gene, and can be used for in vitro PD and antiproliferative assays.

[0217] Compound inhibition of target modulation was determined as follows: BT474 cells were sorted overnight into 96-well plates (20,000 cells / well) with DMEM medium containing 10% FBS, and then treated with test compounds at a range of concentrations (3 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, 0.0001 μM). The plates were incubated at 37°C with 5% CO for 4 hours, and then the HER2 (Y1248) phosphorylation level of cells in each well was measured using an MSD kit (phospho-ErbB2 (Tyr1248) Assay Whole Cell). The assay was performed using an MSD SECTOR® Imager to measure phosphorylated HER2 and The electrochemiluminescence method (MESO SCALE DISCOVERY) was used to determine both p-HER2 and total HER2, and then the ratio of p-HER2 / total HER2 could be generated by the machine. The percentage of inhibition was obtained from the formula: % inhibition = 100 × [1 - (ratio of sample well - ratio of Min control well) / (ratio of Max - ratio of Min control well)]. IC was calculated using Prism GraphPad 7.0 or Microsoft Xlfit software. 50 Values ​​were further calculated as the compound concentration required for 50% inhibition in the best fit curve.

[0218] The antiproliferative activity of the compounds was determined as follows: BT474 cells were sorted into 384-well plates with DMEM medium containing 10% FBS and 1M OAA overnight, and then the test compounds were dosed at a series of concentrations (30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.001 μM) the next day. Meanwhile, another cell plate was prepared to measure the G value the next day. The dosed plate was incubated at 37°C with 5% CO2 for 72 hours, and the number of viable cells in each well of the G or dosed plate was determined using MTS (CellTiter 96 (AQueous®)). The cell proliferation rate was measured by One Solution Cell Proliferation Assay (Promega) endpoint. This assay is a colorimetric method for determining the number of viable cells in a proliferation assay. 5 μl of detection reagent was dispensed per well, and the plate was incubated at room temperature for 2 hours. The absorbance at 490 nm and 650 nm (reference wavelength) in each well was then measured using a safile II (Tecan). The percentage of proliferation was obtained from the formula: % proliferation = 100 × (G3 value - G0 value of sample well) / (G3 value - G0 value of DMSO control). The GI50 value was further calculated using Genedata Screener® software as the compound concentration required for 50% proliferation in the optimal curve.

[0219] [Table 3]

[0220] Example 31: Blood-brain barrier permeation assay in rats In vitro blood, plasma, and brain binding assays were performed using an equilibrium dialysis apparatus. Diluted blood (1:1 with DPBS pH 7.4), EDTA-anticoagulated plasma, and brain homogenate (1:3 with DPBS pH 7.4) were spiked with 5 μM test compound (in triplicate) and dialyzed against an equal volume of 150 μL of 100 mM PBS buffer (pH 7.4) at 37°C for the appropriate equilibration time in a slowly rotating plate. At the end of the incubation, 50 μL aliquots were taken from the receiver chamber and 5 μL from the donor chamber. 5 μL samples were further diluted with 45 μL of blank blood, plasma, or brain homogenate. Paired samples were matrix-matched with either buffer or blank matrix, mixed for 2 minutes, and then precipitated with 150 μL of cold acetonitrile with 100 ng / mL tolbutamide as an internal standard. After centrifugation at 4000 rpm for 20 min, the supernatant was diluted with 0.1% formic acid aqueous solution and analyzed by LC / MS / MS (API 4000, Applied Pharma The unbound fraction (fu) of the test compound was calculated by the ratio of the response in the buffer solution to the response in the brain homogenate / plasma / blood solution, and the unbound fractions of the test compound in undiluted blood and tissues (fu,bl, fu,pl, and fu,br) were calculated from the measured fu in the homogenate and diluted blood using the following equation: fu,bl(fu,br)=(1 / D) / [(1 / fu-1)+1 / D)], where D is the dilution factor. (D is equal to 1 for plasma, 2 for blood, and 4 for brain.) The Short Oral Absorption (SOA) model is an in vivo screening model for identifying the brain penetration of compounds. Six male Han Wistar rats purchased from Vital River were orally administered with the compound.At predetermined post-dose time points, cerebrospinal fluid (CSF) was collected from the cisterna magna, and blood samples (>60 μL / time point / each site) were collected via cardiac puncture into separate EDTA anticoagulation tubes.The blood samples were then immediately diluted with 3 times the volume of water or centrifuged at 4000 g for 10 minutes to obtain plasma.Brain tissue was collected and homogenized in 3 times the volume of 100 mM phosphate buffered saline (pH 7.4).All samples were stored at approximately -70 ° C before LC / MS / MS analysis.

[0221] Standards were prepared by spiking blank plasma, blood, brain homogenate, and artificial CSF. Homogenized brain tissue was precipitated together with the blood / plasma samples by adding three volumes of cold acetonitrile containing the internal standard, and 10 μL of CSF samples was precipitated with 100 μL of cold acetonitrile containing the internal standard. After vortexing for 2 minutes and centrifugation at 14,000 rpm for 5 minutes, the supernatant was analyzed by LC / MS / MS (API 4000, Applied Biosystems, Foster City). Two sets of standard curves were run at the beginning and end of each batch from the blood sample analysis. For brain and CSF samples, one standard curve was analyzed together with the test samples.

[0222] Brain / blood ratio (K p,brain Total brain levels, expressed as AUC (brain) / AUC (blood or plasma), were measured in rodents after oral administration. Similarly, the ratio of CSF / blood exposure (K p,CSF CSF levels, expressed as AUC(CSF) / AUC(blood or plasma), were determined by AUC(CSF) / AUC(blood or plasma). The free fraction of test compound in the biological matrix was determined by in vitro blood and brain binding assays.

[0223] K p,uubrain and K. p,uuCSF was calculated by the following equation: K p,uubrain = AUC(brain) / AUC(blood or plasma) × (fu brain / fu blood / plasma ) and K p,uuCSF = AUC(CSF) / AUC(blood or plasma) × (1 / fu blood / plasma ).

[0224] [Table 4]

[0225] K p,uubrain and K. p,uuCSF Both should be key parameters measured and optimized in CNS drug discovery (Di L et al., Journal of Medicinal Chemistry

[2013] , 56:2-12). p,uubrain The relationship between the concentrations of unbound drug in the brain and blood predicts drug activity against metastatic tumors in the brain. Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, resulting in central nervous system dysfunction. p,uuCSF represents the distribution of drug in the CSF compared to the distribution of drug in the blood, which drives drug response during treatment of leptomeningeal metastases. The assay data in Table 3 for the compounds of this application, as well as the data obtained for neratinib, demonstrate the superior brain barrier and CSF barrier penetration properties of the compounds of the present invention compared to neratinib.

[0226] While the present disclosure has been particularly shown and described with reference to certain embodiments, some of which are preferred embodiments, it should be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof. (In the formula, R １ is hydrogen; R ２ is hydrogen or C １～１２ is alkyl; G is N; W is O; Y is a bond or C １～１２ alkylene; R ３ is a 6- to 8-membered saturated heterocyclyl, which is substituted with halogen, deuterium, C １～１２ Alkyl, C １～１２ Haloalkyl or deuterium-substituted C １～１２ may be optionally mono- or independently polysubstituted by alkyl; i is 0, 1, 2 or 3; Each R ４ are independently halogen or C １～１２ is alkyl; j is 0, 1, 2 or 3; Each R ５ are independently selected from halogen, amino, C １～１２ Alkoxyl, or OR ６ which is optionally mono- or independently polysubstituted with deuterium; R ６ is a 5-membered saturated heterocyclyl; A is O; E is a compound having the following chemical structure: 【Chemistry 2】 and X １ , X ２ , X ３ and X ４ are each independently N or CR ８ and X ５ and X ６ are each independently N or CR ８ and X ７ is NR ９ where X ５ and X ６ at least one of is N; ８ and R ９ are each independently hydrogen or C １～１２ is alkyl; p is 0, 1, 2 or 3; Each R ７ are independently halogen), However, it is not a compound represented by formula (Ia) below. 【Transformation 3】 (In the formula, R ２ is C １～１２ is alkyl, R １２ is hydrogen, C １～１２ Alkyl or deuterium-substituted C １～１２ is alkyl, Each R １３ and R １４ is a halogen, R １５ is hydrogen, Each R １６ and R １７ are each independently hydrogen or C １～１２ is alkoxyl, E is a group of the following structure: 【Chemistry 4】 X ２ is CH).

2. R ３ The chemical structure of 【Transformation 5】 which is a halogen, deuterium, C １～１２ Alkyl, C １～１２ Haloalkyl, Deuterium-substituted C １～１２ 10. The compound of claim 1, which is optionally mono- or independently polysubstituted with alkyl.

3. R ３ The chemical structure of 【Transformation 6】 which is a halogen, deuterium, C １～１２ Alkyl, C １～１２ Haloalkyl, Deuterium-substituted C １～１２ 10. The compound of claim 1, which is optionally mono- or independently polysubstituted with alkyl.

4. Y is a bond or C １～３ The compound of claim 1 which is an alkylene.

5. E is a chemical structure of the following formula: 【Transformation 7】 The compound of claim 1, (In the ceremony X ２ and X ３ are each independently N or CR ８ and X ６ are each independently N or CR ８ and X ７ is NR ９ and p is 0, 1, 2 or 3; Each R ７ are independently halogen; R ８ and R ９ are each independently hydrogen or C １～１２ alkyl).

6. Formula (Ia): 【Transformation 8】 or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof. (In the formula, R ２ is hydrogen or C １～１２ is alkyl; R １２、 R １３ , and R １４ are each independently hydrogen, halogen, deuterium, C １～１２ Alkyl, C １～１２ Haloalkyl or deuterium-substituted C １～１２ is alkyl; R １５ is hydrogen, halogen, or C １～１２ is alkyl; R １６ and R １７ are each independently hydrogen, halogen, amino, C １～１２ Alkoxyl, or OR ６ which may be optionally mono- or independently polysubstituted by deuterium; R ６ is a 5-membered saturated heterocyclyl; E is a compound having the following chemical structure: 【Chemistry 9】 and During the ceremony, X ２ and X ３ are each independently N or CR ８ and X ６ are each independently N or CR ８ and X ７ is NR ９ and p is 0, 1, 2 or 3; Each R ７ are independently halogen; R ８ and R ９ are each independently hydrogen or C １～１２ alkyl).

7. R ２ But C １～１２ The compound of claim 6, wherein the compound is alkyl.

8. R １２、 R １３ , and R １４ are each independently hydrogen, halogen, deuterium, or C １～１２ is alkyl, The compound of claim 6, wherein R 15 is hydrogen, halogen, or C 1-12 alkyl.

9. R １３ and R １４ The compound of claim 6, wherein at least one of is a halogen.

10. The compound of claim 9 wherein the halogen is F.

11. R １６ and R １７ are each independently hydrogen, halogen, amino, or C １～１２ The compound of claim 6 which is an alkoxyl.

12. R １５ is hydrogen, and R １６ is halogen, amino, or C １～１２ The compound of claim 11 which is alkoxyl.

13. 7. The compound of claim 6, wherein E contains 3 or 2 N atoms.

14. E is a chemical structure of the following formula: 【Chemistry 10】 and X ２ is CR ８ and R ８ is hydrogen, or C １～１２ The compound of claim 6, wherein the compound is alkyl.

15. A compound of the formula 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 is selected from the group consisting of Here, * in the chemical formula represents an asymmetric center. The compound of claim 1.

16. 16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, in crystalline form.

17. 16. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 15, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.

18. 18. The pharmaceutical composition of claim 17 for use as a medicament for inhibiting HER2.

19. 19. The pharmaceutical composition of claim 18, for use in treating a disease associated with HER2 in a subject, wherein the disease associated with HER2 is cancer.

20. 20. The pharmaceutical composition of claim 19, wherein the disease associated with HER2 is cancer such as breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, ovarian cancer, lung cancer including non-small cell lung cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the disease associated with HER2 is cancer with brain and leptomeningeal metastasis.

22. 20. The pharmaceutical composition of claim 19, wherein the subject is a warm-blooded animal such as a human.

23. 23. The pharmaceutical composition of any one of claims 18 to 22, wherein the HER2 is a mutant HER2.

24. 24. The pharmaceutical composition of any one of claims 18 to 23, wherein the one or more compounds, pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof cross the blood-brain barrier (BBB) ​​of a subject.

25. 16. A combination of a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, and a second therapeutic agent.

26. 20. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof in the manufacture of a medicament for treating a disease associated with HER2 in a subject, wherein the disease associated with HER2 is cancer.

27. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, for use as a medicament for inhibiting HER2.

28. 26. The combination of claim 25, wherein the second therapeutic agent is an anti-tumor agent.

29. 29. The combination of claim 28, wherein the anti-tumor agent is a chemotherapeutic agent or a HER2-targeting antibody.

30. 30. The combination of claim 29, wherein the chemotherapeutic agent is capecitabine, docetaxel, or vinorelbine.

31. 30. The combination of claim 29, wherein the HER2-targeting antibody is trastuzumab, trastuzumab emtansine, or pertuzumab.

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