Quinazoline derivatives as antitumor agents

Abstract

To provide a type I receptor tyrosine kinase inhibitor.SOLUTION: Or a pharmaceutically acceptable salt thereof. Specific examples thereof include N - (4 - ([1,2,4] triazolo [1, 5-c] pyrimidin-7-yloxy) - 3-methylphenyl) - 5 - (3 - (dimethylamino) azetidin-1-yl) - 6-methoxyquinazolin-4-amine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present application relates to novel quinazoline compounds as inhibitors of type I receptor tyrosine kinases, Pharmaceutical compositions comprising one or more of the compounds and salts thereof as components thereof, and and the use of said compounds in the treatment of hyperproliferative diseases such as cancer and inflammation in mammals, particularly humans. Concerning the use of those salts. [Background technology]

[0002] The type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and It is composed of ErbB4 (HER4) (Riese and Stern, Bioethics says(1998)20:41-48, Olayioye et al, EMBO J ournal (2000) 19:3159-3167, and Schlessinger, (Reviewed in Cell (2002) 110:669-672). These four families All members of the family have nearly identical structures, and the extracellular regions or extracellular domains or ligand binding domains It consists of a binding region, a single transmembrane domain, and an intracellular tyrosine kinase domain.

[0003] HER2 has been shown to play a role in cancer development. Overexpression of HER2 is associated with breast cancer ( BC) occurs in 20-25% of patients (Leyland-Jones B, J Clin Oncol. 2009, 5278-86). Approximately 1.7 million new cases of BC are diagnosed each year. (Cardoso F, et al. Breast 2018, 131-138) 80% of BC cases are invasive and require chemotherapy, radiation therapy, or targeted therapy in addition to surgery. (Dai X., et al. Am J Cancer Res, 2015, 2929-2943). Brain metastases occur frequently in patients with metastatic breast cancer. Breast cancer brain metastasis (BCB) The overall survival of patients with M ranges from 2 to 25.3 months (Leone JP, Exp .Hematol.Oncol.2015,4,33). Surgery, whole brain radiation therapy WBRT, stereotactic radiotherapy (SRS), and radiotherapy are the three main treatment options for BCBM. Surgery is used for solitary brain metastases or for up to three brain metastases. It can be used in patients with fewer than two intracranial lesions. WBRT is used to treat multiple brain metastases. However, it can cause significant neurocognitive decline (Venur VAe t al.Int.J.Mol.Sci.2016,1543).

[0004] Compared with other types of breast cancer, HER2-positive tumors have a higher incidence of brain metastases, and HER2 Up to 50% of patients with breast cancer who are positive for HIV will develop intracranial metastases (Leyland-Jones B, J Clin Oncol. 2009, 5278-86). In HER2-positive patients This high prevalence of BCBM is due to the inherent brain tropism of HER2-positive breast cancer cells, anti-HER2 The prolonged survival of patients treated with anti-HER2 therapy and the limited intracranial activity of anti-HER2 therapy It is believed to be due to gender (Venur VAet al. Int. J. Mol. S ci.2016,17,1543).

[0005] Several anti-HER2 drugs have been developed for clinical use, but all of them have central nervous system (CNS) penetration. The blood-brain barrier (BBB) ​​protects the CNS from potentially harmful agents in the peripheral circulation. They are essential for the growth of cells, but they also prevent potential therapeutic agents from reaching their site of action. 98% and 100% of large molecules, such as antibodies and antibody-drug conjugates, do not cross the BBB. It is estimated that (Pardridge WMNeuroRx, 2005, 2, 3 -14), which makes CNS drug discovery extremely difficult. It is a major determinant of the pharmacokinetics of some ATPs of the ABC superfamily. The endothelial cells of human brain capillaries are involved in the regulation of endothelial function. It has been discovered that (Giacomini KMet al. Nature R reviews Drug Discovery,2010,9,215-236), Pg p and BCRP play important roles in limiting the penetration of various drugs into the CNS. (Enokizono, J. et al. Drug Metabo lism and Disposition,2008,36,995-1002.,Z hou,L.et al.Drug Metabolism and Disposit ion,2009,37,946-955).

[0006] Trastuzumab does not cross the blood-brain barrier (BBB) ​​like other monoclonal antibodies. , blood-to-brain ratio (K p )<0.01 (Kabraji S. et al. Clin ical Cancer Research.2018,3351). Antibody-drug conjugates ( T-DM1, an ADC, also does not cross the BBB. p <0.01 (Askoxyl akis V.,et al.JNCI J Natl Cancer Inst,20 15,763-763). Lapatinib, an approved tyrosine kinase inhibitor (TKI), Neratinib and afatinib are potent Pgp substrates with poor brain penetration. p but These are 0.04, 0.079, and <0.08, respectively (Tanaka, Y. et al ,Scientific Reports,2018,343,Zhang,Shiro ng,et al,Acta Pharmacologica Sinica,2017 ,233-240). Tucatinib, a reversible HER2 inhibitor currently undergoing phase 1 / 2 clinical trials, is also a potent It is a good Pgp substrate, does not cross the BBB, and p is 0.02 to 0.05 (Dinke l V,et al.Cancer Research,2012,72). In addition, H It is noteworthy that the BBB is preserved in patients with ER2-positive breast cancer despite the presence of brain metastases. This was revealed by the evaluation of the brain metastasis phase after subtraction (Yonemori K, et al. Ancer, 2010, 302-308). The aforementioned non-brain-penetrating antibodies, ADCs, and TKs The use of I to treat patients with BCBM has shown limited clinical efficacy. Therefore, as a BBB-permeable HER2 inhibitor for treating HER2-positive BCBM patients, There remains a need to develop new compounds that act. Summary of the Invention

[0007] The novel quinazoline compounds disclosed herein inhibit type I receptor tyrosine kinases. It has been shown to be effective in inhibiting steroid hormones, exhibits good brain penetration in animals, and has a favorable toxicity profile (e.g., hERG As a result, the compounds of the present application have low activity against type I receptor tyrosine kinases. and is particularly useful in the treatment of diseases or conditions associated with HER2, particularly HER2-associated diseases or conditions. These diseases or conditions include cancer (e.g., metastatic cancer, such as brain metastatic cancer).

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof. (In the ceremony G is C(R5) or N; A is CH or N; B is CH or N; X1, X2, X3, X4, X5, X6, and X7 are CH or N, respectively. are each independently CH or N, provided that E is O, NH, or S; L is selected from the group consisting of O, S, and N(R6); R1 is hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, or alkenyl , alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated saturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, N(R7)(R8 ), and O(R9), wherein said cycloalkyl and heterocycloalkyl are independently selected from the group consisting of Chryl may be optionally halogenated, cyano, nitro, hydroxyl, carboxyl, carba from the group consisting of aryl, acyl, alkyl, alkenyl, alkynyl, and haloalkyl; optionally substituted with one or more independently selected groups; R2 is alkyl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heterocyclic alkyl. and wherein the alkyl, cycloalkyl, and heterocyclyl are selected from the group consisting of: In some cases, halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, Alkyl, alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl , and N(R 10 )(R 11 by one or more groups independently selected from the group consisting of may be substituted, R6 is hydrogen or alkyl, or When L is N(R6), R2 and R6 together with the nitrogen atom to which they are attached and optionally containing one or more additional heteroatoms selected from N, O, and S. and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring which may be optionally substituted, The heterocyclyl ring may optionally be substituted with halogen, cyano, nitro, carboxy, carbamo yl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially unsaturated cycloalkyl Rukill, and N(R 10 )(R 11 and one or more groups independently selected from the group consisting of may be substituted by R3 and R4 are hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, and alkoxyl, R5 is selected from the group consisting of hydrogen, halogen, and cyano; R7 and R8 are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkynyl alkynyl, heteroalkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated Unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, hetero aryl, heteroarylalkyl, or heterocyclylalkyl, respectively; and wherein the alkyl, alkenyl, alkynyl, acyl, cycloalkyl, and the like are independently selected. , heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl Heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally alkyl , alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, a alkylamino, saturated and partially unsaturated cycloalkyl, and optionally alkyl, alkenyl, saturated and partially unsaturated heteroaryls, optionally substituted by heteroaryls, and heteroaryls; substituted by one or more groups independently selected from chlorine, R7 and R8 together with the atoms bonded thereto may optionally be N, O, S, S O, SO2, and NR 12 may contain one or more additional heteroatoms selected from Forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, is optionally oxo, halogen, alkyl, alkenyl, alkynyl, saturated and partially Unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, from the group consisting of arylalkyl, heteroarylalkyl, and heterocyclylalkyl; and optionally substituted with one or more groups independently selected from R9 is alkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, Alkyl, alkynyl, acyl, cycloalkyl, and heterocyclyl are optionally substituted with hydroxyl groups. halogen, alkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, sialic No, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, aryl heteroarylalkyl, heteroarylalkyl, and heterocyclylalkyl; and optionally substituted with one or more groups selected arbitrarily, R 10 and R 11 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, hetero Alkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated Heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroaryl, heteroarylalkyl, or heterocyclylalkyl; and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, hetero Arylalkyl and heterocyclylalkyl may optionally be alkyl, alkenyl , alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated Saturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl or R 10 and R 11 together with the atoms to which they are bonded, may contain N, O, or S , SO, SO2, and NR 12 containing one or more additional heteroatoms selected from and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, The alkyl ring may optionally be oxo, halogen, alkyl, alkenyl, alkynyl, saturated and Partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl aryl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl aryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl optionally substituted with one or more groups independently selected from the group R 12 is hydrogen, alkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycle Irocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, cycloalkyl, Heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl The alkyl and heterocyclylalkyl may optionally be substituted with halogen, alkyl, alkenyl, aryl, or heterocyclyl. alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkyl chloroalkyl, alkyl, cyano, nitro, aryl, heteroaryl, arylalkyl one or more independently selected from , heteroarylalkyl, and heterocyclylalkyl; may be substituted by the above groups, n is 0, 1, or 2).

[0009] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one drug A pharmaceutical composition comprising a pharmaceutical acceptable excipient is provided.

[0010] In another aspect, the present invention provides a method for treating a type I receptor kinase-associated disease or condition in a subject in need thereof. a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, The method comprises administering to an elephant.

[0011] In another aspect, the present invention provides a method of treating a HER2-associated disease or condition in a subject in need thereof. Thus, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. The method is presented, comprising:

[0012] In other embodiments, the present invention relates to a type I receptor kinase-associated disease or condition, particularly a HER2-associated disease or condition. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition. can be.

[0013] In other embodiments, the present invention relates to a type I receptor kinase-associated disease or condition, particularly a HER2-associated disease or condition. of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition Use is suggested.

[0014] In other embodiments, the present invention relates to a type I receptor kinase-associated disease or condition, particularly a HER2-associated disease or condition. a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition wherein the compound of formula (I) is administered simultaneously, separately, or sequentially with radiation therapy. A compound or a salt thereof is presented.

[0015] In other embodiments, the one or more additional chemotherapeutic agents are administered simultaneously, separately, or sequentially. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0016] In other embodiments, the present invention relates to a type I receptor kinase-associated disease or condition, particularly a HER2-associated disease or condition. A kit for the treatment or prevention of a condition, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof the salt, a container, and optionally a package insert or label indicating a treatment method. A kit is presented, which kit does not include a second agent useful in treating the disease or disorder. The composition may further comprise a second compound or formulation. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the ORTEP diagram of 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline obtained in step 4 of Example 1 as determined by single crystal X-ray diffraction. Specific Description of the Invention

[0018] Reference will now be made in detail to certain embodiments of the present invention, the structures and formulas of which are set forth in the accompanying drawings. Examples of these embodiments are provided. The invention will be described in conjunction with the enumerated embodiments, but these It is understood that the description is not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents. , and alternatives, modifications, and equivalents thereof are within the scope of the invention as defined by the claims. Those skilled in the art will be able to develop methods and materials similar or equivalent to those described herein. By doing so, one will appreciate the many methods and materials that may be used in the practice of this invention. The present invention is in no way limited to those methods and materials described. , terms defined, term usage, techniques described, or the like, One or more of the references and similar materials cited in this application differ from or contradict this application. In this case, the present application takes priority.

[0019] Certain features of the present disclosure are described in the context of separate embodiments for clarity. However, it will be appreciated that these features may also be presented in combination in a single embodiment. Conversely, various features of the disclosure may be described in the context of a single embodiment, for the sake of brevity. Although these features are presented in the present specification, they may be presented separately or in any suitable subcombination. It can also be done as follows.

[0020] definition The definitions of certain functional groups and chemical terms are explained in more detail below. For this purpose, the chemical elements are listed in accordance with the CAS Periodic Table on the inside cover of the 75th edition of the Handbook of Chemistry and Physics. The specific functional groups are generally defined as described therein. The general principles of chemistry and specific functional moieties and reactivities are covered in Organic Chemistry , by Thomas Sorrell, University Science Book s, Sausalito, 1999, Smith and March, March's A Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, New York, 2001. Larock, Comprehens ive Organic Transformations, VCH Publishing rs, New York, 1989. Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambri University Press, Cambridge, 1987. and the entire contents of each of these documents are incorporated herein by reference.

[0021] Linking substituents are described in various parts of this disclosure. If explicitly required, the Markush variables listed for that group is understood to be a linking group. For example, if one linking group is required from the structure, and If the Markush group definition for a variable lists "alkyl," then that "alkyl" It is understood that "alkyl" represents a linking alkylene group.

[0022] As used herein, the term "substituted" when referring to a chemical group One or more hydrogen atoms of the chemical group are removed and replaced by a substituent. The term "substituent" as used herein means a group that is understood by those skilled in the art to be A chemical moiety having the ordinary meaning known in the art and covalently attached to a parent group, or As used herein, "a" refers to a chemical moiety that is fused to another in appropriate cases. "Optionally substituted" or "Optionally substituted" The term "substituent" may refer to a chemical group that has no substituents (i.e., unsubstituted) or that has one or more substituents. It means that the atom may have a substituent (i.e., be substituted). The substitution at a given atom is It is understood that the limit is based on valence.

[0023] As used herein, "C i~j The term " refers to a range of carbon atoms. , where i and j are integers, and the range of carbon atoms has endpoints (i.e., i and j). and every integer point between them, where j is greater than i. For example, C 1~6 is 1 to 6 carbon atoms A range of atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C1 ~12 " The term " refers to 1-12, especially 1-10, especially 1-8, especially 1-6, especially It refers to 1 to 5, particularly 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

[0024] As used herein, the term "alkyl" refers to a group of groups Whether used together or independently, saturated straight chain or saturated branched chain hydrocarbon radicals The carbon radical may optionally be independently substituted with one or more of the substituents described below. It may be substituted by a C i~j The term "alkyl" refers to i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In embodiments, the alkyl group may have 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, or Atom, 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms atom, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), Propyl), 1-butyl (n-butyl), 2-methyl-1-propyl (i-butyl), 2 -butyl (s-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl (n -pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2 -butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl Cyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dipentyl Methyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc. These include, but are not limited to: 1~12 Examples of "alkyl" include methyl, ethyl, Propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl Examples of hydroxypropyl methylcellulose include, but are not limited to, methylcellulose and dodecylcellulose. 1~6 An example of an "alkyl" is methyl. , ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl , n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl- 2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl xyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- Dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0025] The alkyl groups may be one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents include Cyl, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, halo haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy , alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, Alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphatase Sulfate, phosphonate, phosphinate, amino (alkylamino, dialkylamino) arylamino, diarylamino, and alkylarylamino), acyl Amino (alkylcarbonylamino, arylcarbonylamino, carbamoyl, and uranyl) including thiol, amidino, imino, sulfhydryl, alkylthio, arylthio, thio Carboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamo yl, sulfonamide, nitro, trifluoromethyl, cyano, nitro, azido, hetero These may include cyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The alkenyl group, alkynyl group, saturated or partially substituted alkyl group, as described below, are not limited to these. Unsaturated cycloalkyl groups, heteroalkyl groups, heterocyclyl groups, arylalkyl groups , heteroarylalkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, Aryl and heteroaryl groups may also be similarly substituted.

[0026] As used herein, the term "alkenyl" is used as part of another term. Whether used together or independently, they contain at least one carbon-carbon double bond. refers to a straight or branched chain hydrocarbon radical having The hydrocarbon group may be independently substituted with one or more substituents described herein. Radicals may have "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In this embodiment, the alkenyl group may have 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments Alkenyl groups contain two carbon atoms. Examples of alkenyl groups include ethylenyl (or vinyl). propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl These include, but are not limited to, thenyl and the like.

[0027] As used herein, the term "alkynyl" is used as part of another term. Whether used together or independently, they contain at least one carbon-carbon triple bond. refers to a straight or branched chain hydrocarbon radical having Optionally, each independently substituted with one or more substituents described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. Alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. 1 carbon atom, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2 ~7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2 Contains up to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc. But not limited to these.

[0028] As used herein, the term "alkoxy" or "alkoxyl" , whether used as part of another term or independently, refers to the parent molecule containing oxygen. "C" refers to the alkyl group defined above, bonded via an atom. i~j Alcoki The term "j" indicates that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 11 carbon atoms. The alkoxy group has 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, It has 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1~ 12 Examples of "alkoxyl" include methoxy, ethoxy, propoxy (e.g., n-propoxy and and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, etc. Not limited to these.

[0029] As used herein, the term "acyl" refers to a carbonyl-containing functional group, e.g., For example, -C(=O)R, where R is hydrogen or an optionally substituted alkyl group. an aliphatic group, a heteroaliphatic group, a heterocyclic group, an aryl group, a heteroaryl group, or a substituted ( For example, hydrogen or an aliphatic moiety, a heteroaliphatic moiety, an aryl moiety, or a heteroaryl moiety. Oxygen- or nitrogen-containing functional groups (e.g., carboxylic acid functional groups) substituted with a carboxylic acid moiety , ester functional groups, or amide functional groups). The formyl group, carboxyl group, C 1~6 Alkylcarbonyl group, C 2~6 Alkenylca carbonyl group (e.g., acryloyl), C 3~10 Cycloalkylcarbonyl groups (e.g. , cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, chloroheptanecarbonyl), C 3~10 Cycloalkenylcarbonyl groups (e.g., 2-cycloalkenyl cyclohexenecarbonyl), C 6~14 Arylcarbonyl group, C 7~16 Arakirka a 5- to 14-membered heteroarylcarbonyl group, a 3- to 14-membered heterocyclyl group, carbonyl groups (e.g., piperazinylcarbonyl), C 1~6 Alkoxycarbonyl group, C 6~14 Aryloxycarbonyl groups (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) oxycarbonyl), C 7~16 Aryloxycarbonyl groups (e.g., benzyloxycarbonyl groups) carbonyl, phenethyloxycarbonyl), carbamoyl group, mono or di C 1~6 Archi Carbamoyl group, mono or di C 2~6 Alkenylcarbamoyl groups (e.g., diarylcarbamoyl groups) Rubamoyl), mono or di C 3~10 Cycloalkylcarbamoyl groups (e.g., cyclopropyl propylcarbamoyl), mono or di C 6~14 Arylcarbamoyl groups (e.g., phenyl Carbamoyl), mono or di C 7~16 Aralkylcarbamoyl group, 5-14 membered aromatic aromatic heterocyclylcarbamoyl groups (e.g., pyridylcarbamoyl), thiocarbamoyl As used herein, "acyl" refers to a group such as, but not limited to, an acyl group. The term "oxy" refers to an acyl group attached to the parent molecule through an oxygen atom.

[0030] As used herein, the term "amino" or "amine" means at least It refers to a moiety in which a nitrogen atom is covalently bonded to one carbon or heteroatom. "amino" includes groups consisting of compounds in which nitrogen is attached to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, and phenethylamino. "Dialkylamino" includes at least two additional alkyl groups. The group includes a group in which a nitrogen atom is bonded to the group. An example of a dialkylamino group is dimethylamino. and diethylamino. "Arylamino" has at least one or two aryl groups attached to the nitrogen. The term "alkylarylamino," "alkylaminoaryl," or "aryl" is used interchangeably with "arylamino." "Arylaminoalkyl" refers to a group consisting of at least one alkyl group and at least one aryl group. "Alkaminoalkyl" refers to an amino group bonded to an alkyl group, an alkenyl group, Or, it refers to an alkyl group further bonded to the nitrogen atom to which the alkynyl group is bonded. "Acylamino" includes groups in which the nitrogen is attached to an acyl group. Examples of acylamino include acyl alkylcarbonylamino group, arylcarbonylamino group, carbamoyl group, and urei Examples of suitable aryl groups include, but are not limited to, aryl groups.

[0031] As used herein, the terms "amide" or "aminocarboxy" Compounds containing a nitrogen atom bonded to the carbon of a carbonyl or thiocarbonyl group, or The term refers to a moiety that is attached to the carbon of a carbonyl or thiocarbonyl group. "Alkyl" refers to an alkyl, alkenyl, or alkynyl group bonded to an amino group. The term includes "aminocarboxy" groups. "Aryl" refers to an "aryl" or "heteroaryl" moiety that is bonded to an amino group that is bonded to a nitrogen atom. Also included are "alkylaminocarboxy" and "alkenylaminocarboxy" groups. aminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" The terms "alkyl," "alkenyl," "alkynyl," and "aryl" respectively include alkyl, alkenyl, and alkynyl moieties. The nitrogen atom to which the aryl moiety is attached contains a moiety further attached to the carbon atom of a carbonyl group. Amides are used in straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, and heteroaryl groups. The substituents on the amide group may be further substituted with a substituent such as an alkyl, aryl, or heterocyclic ring. This may also be done.

[0032] As used herein, the term "aryl" refers to any group of groups that are part of another term. A single ring having a total of 5 to 20 ring members, whether used together or independently systems and polycyclic systems in which at least one ring of the system is aromatic and "Aryl" refers to the above ring systems in which each ring contains 3 to 12 ring members. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc. They may carry one or more substituents. As used herein, one or more additional Also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to an additional ring. In the case of systems, all of the rings may be aromatic (e.g., quinoline), but Only one of these rings needs to be aromatic (e.g., 2,3-dihydroindo The second ring may be fused or bridged. Examples of polycyclic aryls include benzophenone and benzophenone. Zofranil, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydrofuran The aryl group may be substituted with one or more aryl groups, such as, but not limited to, tetrahydronaphthyl, tetrahydronaphthyl, etc. The ring may be substituted at any position with the substituents described above.

[0033] As used herein, the term "arylalkyl" refers to one of the other terms Whether used as a moiety or independently, the aryl group may be substituted with one or more aryl moieties. Examples of arylalkyl radicals include benzyl, phenyl, and phenyl. Examples include, but are not limited to, ethyl and the like.

[0034] As used herein, the term "azide" is used as part of another term. Whether used together or independently, it refers to the -N3 group.

[0035] As used herein, the term "carboxy" is used as part of another term. Whether used together or independently, the group represented by the formula -COOH Point.

[0036] As used herein, the term "carbamoyl" is a part of another term Aminocarbamate as defined above, whether used together or independently It refers to the hydroxyl group. 1~12 Examples of "(alkyl)carbamoyl" include methyl Examples of aminocarbonyl include, but are not limited to, aminocarbonyl and ethylaminocarbonyl. ,N-(C 1~12 Examples of "alkyl)2carbamoyl" include dimethylaminocarbonyl and Examples include, but are not limited to, methylethylaminocarbonyl.

[0037] As used herein, "cycloalkyl," "carbocyclyl," and " The terms "carbocycle" and "carbocycle" are interchangeable and are used as part of other terms. Whether used together or independently, monovalent non-aromatic saturated or partially unsaturated monocyclic ring systems and Polycyclic ring systems, in which all ring atoms are carbon and there are at least three rings In some embodiments, the cycloalkyl has 3 to 12 ring-forming carbon atoms. ring-forming carbon atoms, 3-10 ring-forming carbon atoms, 3-9 ring-forming carbon atoms, 3-8 ring-forming carbon atoms ring-forming carbon atoms, 3-7 ring-forming carbon atoms, 3-6 ring-forming carbon atoms, 3-5 ring-forming carbon atoms carbon atoms, 4-12 ring carbon atoms, 4-10 ring carbon atoms, 4-9 ring carbon atoms ring-forming carbon atoms, 4-8 ring-forming carbon atoms, 4-7 ring-forming carbon atoms, 4-6 ring-forming carbon atoms It may contain 4 to 5 ring carbon atoms. The cycloalkyl group is saturated. The cycloalkyl group may be substituted or partially unsaturated. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. The cycloalkyl group contains at least one double or triple bond in its ring system. It may be a partially unsaturated cyclic alkyl group.

[0038] In some embodiments, the cycloalkyl group is a saturated or partially unsaturated monocyclic carbocyclic ring system. Examples of these ring systems include cyclopropyl, cyclobutyl, cyclopentyl, 1- Cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl , 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl cyclobutyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. But not limited to these.

[0039] In some embodiments, the cycloalkyl group is a saturated polycyclic or partially unsaturated polycyclic carbocyclic ring. These ring systems may be fused ring systems, spiro ring systems, or may be organized as a bridged ring system. As used herein, "fused ring" The term "spironolactone" refers to a ring system with two rings that share two adjacent atoms. The term "bicyclic" refers to a ring system with two rings connected through one common atom. The term "bridged ring" refers to a ring system having two rings that share three or more atoms. Examples of fused carbocyclyls include naphthyl, benzopyrenyl, anthracenyl, and acenaphthyl. Examples include, but are not limited to, phthalenyl, fluorenyl, and the like. Examples include spiro[5.5]undecanyl, spiropentadienyl, and spiro[3.6]deca Examples of bridged carbocyclyls include, but are not limited to, bicyclo[1 ,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptenyl butanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.2.2]octanyl Examples include, but are not limited to, chloro[3.3.3]undecanyl.

[0040] As used herein, the term "cycloalkylalkyl" means a cycloalkyl Examples of cycloalkylalkyl include, for example, For example, 5- or 6-membered cycloalkyl-C1, such as, but not limited to, cyclopropylmethyl. ~3 Examples of alkyl include:

[0041] As used herein, the term "cyano" refers to --CN.

[0042] As used herein, the term "halo" or "halogen" refers to fluorine (or is made up of fluoro, chlorine (or chloro), bromine (or bromo) and iodine (or iodo). Refers to the atom that is selected.

[0043] As used herein, the term "haloalkyl" refers to one or more halogen atoms. refers to an alkyl group substituted with an atom.

[0044] As used herein, the term "haloalkoxy" or "haloalkoxyl" refers to a The term refers to an alkoxy group substituted with one or more halogen atoms.

[0045] As used herein, the term "heteroalkyl" refers to any of the carbon atoms at least one of which is substituted with a heteroatom selected from N, O, or S; This heteroalkyl can be either a carbon radical or a heteroatom radical. (i.e., the heteroatom may be located at the center or at the end of the radical) ), optionally substituted independently with one or more substituents described herein. The term "heteroalkyl" refers to alkoxy and heteroalkoxy radicals. This includes the rule.

[0046] As used herein, the term "heteroalkenyl" refers to a heterocyclic group whose carbon atoms At least one of the groups is substituted with a heteroatom selected from N, O, or S. This heteroalkenyl can be a carbon radical or a heteroatom radical. (i.e., the heteroatom may be located in the center or at the end of the radical. ), optionally substituted independently with one or more substituents described herein. It's fine.

[0047] As used herein, the term "heteroalkynyl" refers to a heteroalkynyl group whose carbon atoms At least one of the groups is substituted with a heteroatom selected from N, O, or S. This heteroalkynyl can be a carbon radical or a heteroatom radical. (i.e., the heteroatom may be located in the center or at the end of the radical. ), optionally substituted independently with one or more substituents described herein. It's fine.

[0048] As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur. and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. .

[0049] As used herein, the term "heteroaryl" is a subset of other terms Whether used as a group or independently, a group containing one or more carbon atoms Heteroaryl refers to an aryl group containing a hetero atom. Examples of heteroaryl include thienyl and furanyl. , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, Isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyl These include, but are not limited to, thyridinyl, benzofuranyl, and pteridinyl. The heteroaryl may have one or more aryl, alicyclic, or heterocyclyl rings. (b) A group in which an aromatic ring is fused, and the radical or bonding site is not the heteroaromatic ring Non-limiting examples include indolyl, isoindolyl, benzoindolyl, and the like. Thienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, thiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl , quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, Phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinoline linyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. In some embodiments, the term "5-10 membered heteroaryl" refers to any of nitrogen, oxygen, or sulfur; an alkyl ring or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; In certain embodiments, " refers to an 8-10 membered bicyclic heteroaryl ring having the formula The term "5-12 membered heteroaryl" refers to any group independently selected from nitrogen, oxygen, or sulfur. a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, It refers to a heteroaryl ring.

[0050] As used herein, the term "heterocycle" or "heterocyclyl" refers to One or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc. , refers to a saturated or unsaturated carbocyclyl group in which the remaining ring atoms are carbon, and one or more ring atoms is optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. Cyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system In some embodiments, the heterocyclyl is any oxidized form of carbon, nitrogen, or sulfur, and and any quaternized form of basic nitrogen. The radical may be fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. This heterocyclyl radical is preferably carbon-bonded. In some embodiments, the heterocycle may be carbon- or nitrogen-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Furthermore, the group derived from imidazole may be imidazol-1-yl (nitrogen bond) or imidazo It may be aryl-3-yl (carbon bond).

[0051] In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a heterocyclyl group that is free of nitrogen, oxygen, or is a 3- to 12-membered saturated or moiety having 1 to 3 heteroatoms independently selected from sulfur; Refers to unsaturated monocyclic or polycyclic heterocyclic ring systems. Also includes fused, spiro, and bridged ring systems. Examples of monocyclic heterocyclyls included within this definition include oxetanyl, 1,1-diphenyl ether, oxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, Furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinoyl, pyrimido These include, but are not limited to, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyls include quinolinyl, isoquinolinyl, and quinoxalinyl. , quinolidinyl group, quinazolinyl group, azaindolizinyl group, pteridinyl group, chromenyl group Indolyl group, isochromenyl group, indolyl group, isoindolyl group, indolizinyl group, indyl group, Zolyl group, purinyl group, benzofuranyl group, isobenzofuranyl group, benzimidazolyl group, benzothienyl group, benzothiazolyl group, carbazolyl group, phenazinyl group, phenon Thiazinyl group, phenanthridinyl group, imidazo[1,2-a]pyridinyl group, [1,2 ,4]triazolo[4,3-a]pyridinyl group, [1,2,3]triazolo[4,3-a ]pyridinyl groups and the like. Examples of spiroheterocyclyl include spiropyranyl and spirooxazinyl. Examples of bridged heterocyclyls include, but are not limited to, morphanyl, hexamethyl, tetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3 .2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diaza-bicyclo[2.2.1]octane Examples include, but are not limited to, cyclo[2.2.2]octane (DABCO).

[0052] As used herein, the term "heteroarylalkyl" refers to a heteroaryl Heteroarylalkyl refers to an alkyl moiety substituted with an aryl moiety. Examples of heteroarylalkyl include, but are not limited to, 5- or 6-membered heteroaryl such as, but not limited to, oxazolylmethyl, pyridylethyl, etc. -C 1~3Examples of alkyl include:

[0053] As used herein, the term "heterocyclylalkyl" refers to a heterocyclyl It means an alkyl moiety substituted with an alkyl moiety. Examples of heterocyclylalkyl radicals Examples include, but are not limited to, 5- or 6-membered heterocyclyls such as tetrahydropyranylmethyl. Lu-C 1~3 Examples of alkyl include:

[0054] As used herein, the term "hydroxy" refers to an --OH group.

[0055] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0056] As used herein, the term "partially unsaturated" refers to at least one double bond. The term "partially unsaturated" refers to a radical containing multiple unsaturated sites. Although the term "aromatic ring" is intended to encompass rings having cyclic groups, it does not include aromatic (i.e., fully unsaturated) moieties. It is not intended to be inclusive.

[0057] As used herein, the term "substituted" means "optionally" Whether or not the term "" is leading, one or more hydrogen atoms in the specified moiety "Substituted" or "substituted with" means substituted with an appropriate substituent. Such substitutions are in accordance with the valence allowed for the substituted atom and do not result in stability or chemical Chemically feasible compounds, e.g., spontaneous transformations by rearrangement, cyclization, elimination, etc. It is understood that the implicit condition that compounds that do not contain As long as an "optionally substituted" group has an appropriate substituent at each substitutable position of the group, may have substituents, and may be optionally substituted by more than one substituent selected from a specific group. When substitution occurs at more than one position in a given structure, the substituents must be the same at each position. Those skilled in the art will understand that the substituents themselves can be substituted where appropriate. Unless specifically described as "unsubstituted," references herein to chemical moieties are It is understood to include substituted variants. For example, reference to an "aryl" group or moiety includes substituted Mutants and non-substituted variants are implicit.

[0058] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, Substituents such as may be attached to any atom within the ring. This is shown without showing the atoms intervening the bond when attached to the rest of the compound. When a substituent such as Combinations of substituents and / or variables are permitted, but However, such combinations are permissible only if they result in stable compounds.

[0059] Any variable (e.g., R i ) is 1 When there are more than one variable, the definition of each variable is determined by the definitions of all the other variables. Therefore, for example, R i It is shown that the If present, the group may optionally contain up to two R i may be substituted with a moiety, and Each R i is independently R i In addition, the substituents and / or variables are selected from the definitions Combinations are permissible provided that such combinations result in stable compounds. Only is permitted.

[0060] compound The present disclosure relates to novel compounds of formula (I) and pharmaceutically acceptable salts thereof, methods for making said compounds, Synthetic methods for the preparation of compounds of the present disclosure, pharmaceutical compositions containing the compounds, and various uses of the compounds of the present disclosure are also provided. Present the purpose.

[0061] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof. (In the ceremony G is C(R5) or N; A is CH or N; B is CH or N; X1, X2, X3, X4, X5, X6, and X7 are not CH. each independently being CH or N, provided that each is not N; E is O, NH, or S; L is selected from the group consisting of O, S, and N(R6); R1 is hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, or alkenyl. alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially Unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, N(R7)(R 8), and O(R9), wherein said cycloalkyl and heteroalkyl are independently selected from the group consisting of Cyclyl may optionally be substituted with halogen, cyano, nitro, hydroxyl, carboxy, or chlorine. aryl, aryl, aryloxy ... and optionally substituted with one or more groups independently selected from R2 is alkyl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heterocyclic alkyl. and wherein the alkyl, cycloalkyl, and heterocyclyl are selected from the group consisting of: In some cases, halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, Alkyl, alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl , and N(R 10 )(R 11 by one or more groups independently selected from the group consisting of may be substituted, R6 is hydrogen or alkyl, or When L is N(R6), R2 and R6 together with the nitrogen atom to which they are attached and optionally containing one or more additional heteroatoms selected from N, O, and S. and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, The membered heterocyclyl ring may optionally be substituted with halogen, cyano, nitro, carboxy, carba Moyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially unsaturated cycloalkyl Alkyl, and N(R 10 )(R 11 one or more groups independently selected from the group consisting of and optionally substituted by R3 and R4 are hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl and alkoxyl, R5 is selected from the group consisting of hydrogen, halogen, and cyano; R7 and R8 are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, alkenyl, heteroalkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated cycloalkyl Saturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, hetero heteroaryl, heteroarylalkyl, or heterocyclylalkyl; each independently selected, and aryl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaromatic Aryl, heteroarylalkyl, and heterocyclylalkyl are optionally alkyl. aryl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and partially unsaturated cycloalkyl, and optionally alkyl; Saturated and partially unsaturated heteroaryls optionally substituted with aryls and heteroaryls and optionally substituted with one or more groups independently selected from the group consisting of cyclyl , or R7 and R8 together with the atoms bonded thereto may optionally be N, O, S, SO, SO2, and NR 12 containing one or more additional heteroatoms selected from and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, The ring may optionally be oxo, halogen, alkyl, alkenyl, alkynyl, saturated and partially substituted. Partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl , cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl , arylalkyl, heteroarylalkyl, and heterocyclylalkyl and optionally substituted with one or more independently selected groups, R9 is alkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, Alkenyl, alkynyl, acyl, cycloalkyl, and heterocyclyl are optionally Halogen, alkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated Saturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cycloalkyl Ano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, azido from the group consisting of arylalkyl, heteroarylalkyl, and heterocyclylalkyl; optionally substituted with one or more independently selected groups; R 10 and R 11 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, hetero alkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated Saturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroa each selected from the group consisting of aryl, heteroarylalkyl, and heterocyclylalkyl; Independently selected from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic aryl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl The alkyl, alkenyl, and heterocyclylalkyl may optionally be alkyl, alkenyl, or heterocyclyl. alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partial Unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl or R 10 and R 11 together with the atoms bonded to them, in some cases N, O, S, SO, SO2, and NR 12 containing one or more additional heteroatoms selected from and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring which may be optionally substituted, The aryl ring may optionally be oxo, halogen, alkyl, alkenyl, alkynyl, saturated and and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkenyl alkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl alkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl and optionally substituted with one or more groups independently selected from the group consisting of: R 12 is hydrogen, alkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated hydroxyl Tetracyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl, wherein said alkyl, cycloalkyl , heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylar alkyl, and heterocyclylalkyl may optionally be halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, Cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl one independently selected from alkyl, heteroarylalkyl, and heterocyclylalkyl; may be substituted by the above groups, n is 0, 1, or 2).

[0062] In some embodiments, the formula of the compounds of the present disclosure is [ka] wherein G, A, B, X1, X6, X7, E, L, R1, R2, R3, and R4 are It is defined as above.

[0063] In some embodiments, X1 is CH.

[0064] In some embodiments, X1 is N.

[0065] In some embodiments, one of X2, X3, X4, and X5 is N.

[0066] In some embodiments, two of X2, X3, X4, and X5 are N.

[0067] In some embodiments, three of X2, X3, X4, and X5 are N.

[0068] In some embodiments, X2, X3, X4, and X5 are N.

[0069] In some embodiments, X6 is N and X7 is CH.

[0070] In some embodiments, X6 is CH and X7 is N.

[0071] In some embodiments, G is N.

[0072] In some embodiments, A is CH.

[0073] In some embodiments, A is N.

[0074] In some embodiments, B is CH.

[0075] In some embodiments, B is N.

[0076] In some embodiments, E is O.

[0077] In some embodiments, L is N(R6).

[0078] In some embodiments, L is O.

[0079] In some embodiments, R1 is hydrogen, N(R7)(R8), O(R9), or optionally and saturated or partially unsaturated heterocyclyl optionally substituted by acyl. It is selected.

[0080] In some embodiments, R1 is N(R7)(R8), and R7 and R8 are each hydrogen. , alkyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic and the alkyl, acylcycloalkyl, and heterocyclyl are independently selected from the group consisting of alkyl, acylcycloalkyl, and heterocyclyl. The alkyl group may optionally be an alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkene group. nyl, heteroalkynyl, alkylamino, saturated and partially unsaturated cycloalkyl, and Optionally substituted with alkyl, aryl, and heteroaryl substituted by one or more groups independently selected from saturated and partially unsaturated heterocyclyl; It may also be used.

[0081] In some embodiments, R1 is N(R7)(R8), where R7 is hydrogen and R8 is alkyl. and saturated or partially unsaturated cycloalkyl substituted by alkyl.

[0082] In some embodiments, R1 is N(R7)(R8), where R7 is hydrogen and R8 is 4 ,4-dimethyl-4,5-dihydrooxazol-2-yl.

[0083] In some embodiments, R1 is N(R7)(R8), where R7 is hydrogen and R8 is alkyl. acyl substituted by alkylamino or saturated alkyl substituted and partially unsaturated heterocyclyl.

[0084] In some embodiments, R1 is N(R7)(R8), where R7 is hydrogen and R8 is ( Dimethylamino)but-2-enecarbonyl or (1-methyl-pyrrolidin-2-yl) -Acryloyl.

[0085] In some embodiments, R1 is O(R9), where R9 is alkyl, acyl, saturated or substituted. partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl; The alkyl, cycloalkyl, and heterocyclyl may optionally be halogen, alkyl, or cycloalkyl. independently selected from the group consisting of aryl, alkenyl, alkynyl, acyl, and alkoxyl; The group may be substituted with one or more groups.

[0086] In some embodiments, R1 is O(R9), and R9 is C 1~6 Alkyl, C 1~6 a cycloalkyl, 3- to 6-membered saturated or partially unsaturated cycloalkyl, 3- to 6-membered saturated or partially unsaturated cycloalkyl and cycloalkyl, cyclohexyl ... Tetracyclyl is optionally independently selected from halogen, alkyl, or alkoxyl. The group may be substituted with one or more groups.

[0087] In some embodiments, R1 is O(R9), where R9 is optionally one or more full methyl, ethyl, isopropyl, each of which may be substituted by isopropyl or methyl; It is selected from piperazinylcarbonyl, cyclopropyl, or tetrahydrofuranyl.

[0088] In some embodiments, R1 is an optionally acyl-substituted moiety. In some embodiments, R1 is substituted with acryloyl. In some embodiments, R is acryloyl. and tetrahydropyridyl, wherein R is an integer from 1 to 10;

[0089] In some embodiments, L is N(R6), and R2 and R6 are the nitrogen atoms attached thereto. optionally with one or more additional atoms selected from N, O, and S; Forms a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring which may contain heteroatoms The 3- to 10-membered heterocyclyl ring may optionally be substituted with halogen, cyano, nitro, carboxyl, or the like. carboxy, carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and Partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) independently selected from the group consisting of The group may be substituted with one or more groups.

[0090] In some embodiments, L is N(R6), and R2 and R6 are the nitrogen atoms attached thereto. optionally with one or more additional atoms selected from N, O, and S; Forming a 4- to 9-membered saturated heterocyclyl ring which may contain a hetero atom, The saturated heterocyclyl ring of the formula (I) is optionally halogen, alkyl, haloalkyl, saturated and Partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) independently selected from the group consisting of The group may be substituted with one or more groups.

[0091] In some embodiments, "R2 and R6 together with the nitrogen atom to which they are attached" The phrase "forms a 4- to 9-membered saturated heterocyclyl ring" is attached to R2 and R6. It refers to the formation of a 4- to 9-membered monocyclic heterocycle from them together with the nitrogen atom. In embodiments, such terms refer to the nitrogen atoms attached to R2 and R6, along with the four atoms therefrom. In certain embodiments, such terms refer to the formation of a 9-membered spiro ring. 2 and R6 together with the nitrogen atom bound to them to form a 4- to 9-membered fused ring. Refers to...

[0092] In some embodiments, L is N(R6), and R2 and R6 are the nitrogen atoms attached thereto. Together with elementary atoms: [ka] and any of which may optionally be halogen, alkyl, and N (R 10 )(R 11 and substituted with one or more groups independently selected from the group consisting of p may be 1, 2, or 3, and q may be 1, 2, or 3.

[0093] In certain embodiments, p is 1 or 2.

[0094] In certain embodiments, p is 1.

[0095] In certain embodiments, p is 2.

[0096] In certain embodiments, q is 1 or 2.

[0097] In certain embodiments, q is 1.

[0098] In certain embodiments, q is 2.

[0099] In some embodiments, the nitrogen atom bonded to R2 and R6 is formed by them together with The heterocyclyl ring may be fluoro, methyl, 2-fluoroethyl, 2,2-difluoromethyl ... substituted with one or more groups selected from cycloethyl, cyclopropyl, or dimethylamino; In certain embodiments, the heterocyclyl ring is substituted with one or more fluoro groups. In certain embodiments, the heterocyclyl ring is substituted with one or more methyl groups. In certain embodiments, the heterocyclyl ring is substituted with one or more 2-fluoroethoxy groups. In certain embodiments, the heterocyclyl ring is substituted with one or more 2, In certain embodiments, the heterocyclyl ring is substituted with 2-difluoroethyl. is substituted with one or more cyclopropyl groups. In certain embodiments, the heteroaryl ring is substituted with one or more dimethylamino groups. The cyclocyclyl ring is substituted with fluoro and methyl.

[0100] In some embodiments, L is O and R2 is saturated or partially unsaturated cycloalkyl and saturated alkyl. and wherein the cycloalkyl and heterocyclyl are selected from unsaturated or partially unsaturated heterocyclyl. is optionally halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N(R 10 )(R 11 and substituted with one or more groups independently selected from the group consisting of That's fine.

[0101] In some embodiments, L is O and R is C 4~6 Saturated cycloalkyl or 5-6 membered wherein C is selected from saturated heterocyclyl 4~6 Saturated cycloalkyl and 5-6 membered saturated The saturated heterocyclyl may optionally be substituted with halogen, alkyl, saturated or partially unsaturated cycloalkyl. Kill and N(R 10 )(R 11 and one or more groups independently selected from the group consisting of It may be substituted by.

[0102] In some embodiments, L is O and R2 is optionally halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) independently selected from the group consisting of cyclobutyl, cyclopentyl ... The alkyl is selected from cyclohexyl, cyclohexyl, pyrrolidinyl, or piperidinyl.

[0103] In some embodiments, R2 is optionally selected from methyl, fluoro, cyclopropyl, and dihydroxybenzoates. methylamino. In embodiments, R2 is substituted with one or more methyl groups. In certain embodiments, R2 is In certain embodiments, R2 is substituted with one or more cyclohexyl groups. In certain embodiments, R2 is substituted with one or more dimethylamino groups. In certain embodiments, R2 is substituted with one or more methyl groups and one or more methyl groups. is substituted with a fluoro group.

[0104] In some embodiments, R3 is halogen.

[0105] In certain embodiments, R3 is chloro.

[0106] In some embodiments, R3 is C 1~6 It is alkyl.

[0107] In certain embodiments, R3 is methyl.

[0108] In some embodiments, R4 is hydrogen.

[0109] In other aspects, the present disclosure provides compounds of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj ... Ve), or (IVf) compounds: [ka] or a pharmaceutically acceptable salt thereof, wherein G, E, R1, R2, R3, and R4 are as defined above. It is defined as follows.

[0110] In some embodiments, L is N(R6) and R1 is halogen, cyano, nitro, hydroxyl, or the like. alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl R2 and R3 are selected from the group consisting of aryl, aryl, N(R7)(R8), and O(R9); R6 together with the nitrogen atom to which they are attached may optionally be selected from N, O, and S. A 4- to 9-membered saturated heterocycle optionally containing one or more selected additional heteroatoms. The 4- to 9-membered saturated heterocyclyl ring may optionally contain halogen, alkoxy, or the like. alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) and optionally substituted with one or more groups independently selected from the group consisting of:

[0111] In certain embodiments, L is N(R), R is N(R)(R), and R 2 and R6 together with the nitrogen atom to which they are attached may optionally represent N, O, and S, optionally containing one or more additional heteroatoms selected from The 4- to 9-membered saturated heterocyclyl ring may optionally be halogenated. , alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R 10 )(R 11 and optionally substituted with one or more groups independently selected from the group consisting of: In certain embodiments, R7 is hydrogen and R8 is a saturated alkyl substituted or partially unsaturated cycloalkyl. In certain embodiments, R7 is hydrogen and R8 is 4,4-dimethyl-4,5-dihydrooxazol-2-yl.

[0112] In certain embodiments, L is N(R), R is O(R), and R is C ~6 Alkyl, 3-6 membered saturated or partially unsaturated cycloalkyl, 3-6 membered saturated or partially unsaturated unsaturated heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are selected from the group consisting of: Tetracyclyl is optionally independently selected from halogen, alkyl, or alkoxyl. R2 and R6 may be substituted with one or more groups bonded thereto. optionally, together with the nitrogen atom, one or more additional atoms selected from N, O, and S; and forming a 4- to 9-membered saturated heterocyclyl ring optionally containing a heteroatom of the formula The 9-membered saturated heterocyclyl ring is optionally substituted with halogen, alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) independently selected from the group consisting of The group may be substituted with one or more groups selected from the group consisting of methyl, ...

[0113] In certain embodiments, L is N(R6), R1 is O(R9), and R9 is methyl, ethyl, each optionally substituted by one or more fluoro; isopropyl, cyclopropyl, or tetrahydrofuranyl; R2 and R6 together with the nitrogen atom to which they are attached, optionally selected from N, O, and S 4- to 9-membered saturated heterocyclyl optionally containing one or more additional heteroatoms The 4- to 9-membered saturated heterocyclyl ring may optionally be substituted with halogen, alkyl, or the like. , haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R 10 )(R 11 )from It may be substituted with one or more groups independently selected from the group consisting of:

[0114] In some embodiments, L is O and R2 is saturated or partially unsaturated cycloalkyl and saturated alkyl. and wherein the cycloalkyl and heterocyclyl are selected from unsaturated or partially unsaturated heterocyclyl. is optionally halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N(R 10 )(R 11 and substituted with one or more groups independently selected from the group consisting of That's fine.

[0115] In some embodiments, L is O and R is C 4~6 Saturated cycloalkyl or 5-6 membered wherein C is selected from saturated heterocyclyl 4~6 Saturated cycloalkyl and 5-6 membered saturated The saturated heterocyclyl may optionally be substituted with halogen, alkyl, saturated or partially unsaturated cycloalkyl. Kill and N(R 10 )(R 11 and one or more groups independently selected from the group consisting of It may be substituted by.

[0116] In some embodiments, L is O and R2 is optionally halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N(R 10 )(R 11 ) independently selected from the group consisting of cyclobutyl, cyclopentyl ... The alkyl is selected from cyclohexyl, cyclohexyl, pyrrolidinyl, or piperidinyl.

[0117] In other aspects, the present disclosure provides compounds of formula (Va), (Vb), (Vc), (Vd), (Ve), or is a compound of (Vf): [ka] or a pharmaceutically acceptable salt thereof, wherein G, E, R1, R2, R3, and R4 are as defined above. It is defined as follows.

[0118] In some embodiments, R1 is O(R9), and R9 is C 1~6 Alkyl, 3-6 membered Saturated or partially unsaturated cycloalkyl, 3- to 6-membered saturated or partially unsaturated heterocyclyl wherein said alkyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of: by one or more groups independently selected from halogen, alkyl, or alkoxyl. L is O, R2 is saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, wherein the cycloalkyl and heterocyclyl The alkyl group may optionally be halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N( R 10 )(R 11 and substituted with one or more groups independently selected from the group consisting of It's fine.

[0119] In certain embodiments, R1 is O(R9), and R9 is C 1~6 is alkyl, and L is O and R2 is C 4~6 From saturated cycloalkyl or 5-6 membered saturated heterocyclyl Selected C 4~6 Saturated cycloalkyl and 5- to 6-membered saturated heterocyclyl are sometimes Therefore, halogen, alkyl, saturated or partially unsaturated cycloalkyl, and N(R 10 )( R 11 and optionally substituted with one or more groups independently selected from the group consisting of .

[0120] In another aspect, the present disclosure provides: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-methylphenyl Toxicquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-morpholinoquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1-methylpiperidin-4-yl)oxy) C) quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1-methylpyrrolidin-3-yl)oxy) C) quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)cyclobutoxy)-6-methoxy quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3-(dimethylamino)cyclopentyl)oxy)-6 -methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((4-(dimethylamino)cyclohexyl)oxy)-6 -methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methylpiperazin-1-yl)quinazo Phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-ene Toxicquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-( 2-fluoroethoxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(difluoromethoxy)-5-((1S,5S)-2-methyl (2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazoline-4-amine hmm, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1R,5R)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, cis-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) (3-fluoro-1-methylpiperidin-4-yl)-3-methylphenyl )oxy)-6-methoxyquinazolin-4-amine, trans-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3-fluoro-1-methylpiperidine-4- yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-5-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1S,5S)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1R,5R)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((R)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo Phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((S)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo Phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-cyclopropoxy-5-((1S,5S)-2-methyl-2 ,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-cyclopropoxy-5-((1R,5R)-2-methyl-2 ,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-isopropoxy-5-((1S,5S)-2-methyl-2, 6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-isopropoxy-5-((1R,5R)-2-methyl-2, 6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-6-cyclopropoxy-5-((3,3-difluoro- 1-methylpiperidin-4-yl)oxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-6-cyclopropoxy-5-((3,3-difluoro- 1-methylpiperidin-4-yl)oxy)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(8-methyl-5-oxa-2,8-diaza spiro[3.5]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4S)-3-(dimethylamino)-4-fluoro pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4R)-3-(dimethylamino)-4-fluoro pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(5-methyl-8-oxa-2,5-diaza spiro[3.5]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methylhexahydropyrrolo[3,4- b][1,4]oxazin-6(2H)-yl)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (7-fluoro-5-methyl-2,5-diazaspirillum)-3-methylphenyl (b)(3.4)octan-2-yl)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (7-fluoro-5-methyl-2,5-diazaspirillum)-3-methylphenyl (b)(3.4)octan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-methyl-2,6-di azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1R,5R)-2-methyl-2,6-di azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirate (b)(3.5)nonan-2-yl)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirate (b)(3.5)nonan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(6-methyl-2,6-diazaspiro[3. 4]octan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(7-methyl-2,7-diazaspiro[3. 5]nonan-2-yl)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-7-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-7-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-7-methoxy-5-((1-methylpiperidin-4-yl)oxy) C) quinazolin-4-amine, N4-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) -3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazole- 2-yl)-5-(3-(dimethylamino)azetidin-1-yl)quinazoline-4,6 -diamines, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(8-methyl-5-oxa-2,8-diazaspiro[3.5 ]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(methoxy-d3)-5-((1S,5S)-2-methyl- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(methoxy-d3)-5-((1R,5R)-2-methyl- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]octan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]Octan-2-yl)-6-(difluoromethoxy)quinazolin-4-amine , N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]octan-2-yl)-6-(methoxy-d3)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-(7,7-difluoro-5-methyl-2,5-diacryloxy)-3-methylphenyl)- Zaspiro[3.4]octan-2-yl)-6-((tetrahydrofuran-3-yl)o hydroxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(6-methyl-2,6-diazabicyclo[3 .2.0]heptan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methyloctahydro-1H-pyrrolo[ 3,2-b]pyridin-1-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(3-methyl-3,7-diazabicyclo[4 .2.0]octan-7-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(3-methyl-3,6-diazabicyclo[3 .2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(2-cyclopropyl-2,6-diazabicyclo[3.2. 0]heptan-6-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(2-(2,2-difluoroethyl)-2,6-diazabis( chloro[3.2.0]heptan-6-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-(methyl-d3)- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1S,5S)-2-(2-fluoroethyl)-2,6- Diazabicyclo[3.2.0]heptan-6-yl)-6-methoxyquinazoline-4-a Min, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-(2,2,2-trimethylphenyl) Fluoroethyl)-2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazo Phosphorus-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoropiperidin-4-yl)-5-((3-methylphenyl)-5-((3,3-difluoropiperidin-4-yl)oxy)- ... hydroxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)pi (peridin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-((3,3-difluoro-1-isopropylpiperidyl)-3-methylphenyl)-5-((3,3-difluoro-1-isopropylpiperidyl) (di-4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-((1-cyclopropyl-3,3-difluoropiperazin-2-yl)-3-methylphenyl)- ... Lysin-4-yl)oxy)-6-methoxyquinazolin-4-amine, 1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-(methyloxy)-3-phenyl)amino)-5-(3-(dimethylamino)azetidinyl) (quinazolin-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, (R)-1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidin phenyl-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro- 1-Methylpiperidin-4-yl)oxy)quinazolin-6-yl)-3,6-dihydro pyridin-1(2H)-yl)prop-2-en-1-one, 1-(5-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-(methyloxy)-3-phenyl)amino)-5-(3-(dimethylamino)azetidinyl) (quinazolin-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-(methyloxy)-3-phenyl)amino)-5-(3-(dimethylamino)azetidinyl) (quinazolin-1-yl)quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(5-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-(methyloxy)-3-phenyl)amino)-5-(3-(dimethylamino)azetidinyl) (quinazolin-1-yl)quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(4-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -(3-(dimethylamino)-5-(3-(dimethylamino)pyrrolyl)-3-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)pyrrolyl) quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-yl En-1-on, (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl Oxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1-methylpi (peridin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile, (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl Oxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1-methylpi (peridin-4-yl)oxy)-7-methoxyquinoline-3-carbonitrile, 4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) -3-methylphenyl)amino)-5-(((R)-3,3-difluoro-1-methylpi Peridine-4-yl)oxy)quinazolin-6-yl 2,4-dimethylpiperazine-1 -carboxylate, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-3-cyano-5-((3,3-di Fluoro-1-methylpiperidin-4-yl)oxy)quinolin-6-yl)-4-(di methylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-3-cyano-5-((3,3-di Fluoro-1-methylpiperidin-4-yl)oxy)-7-ethoxyquinolin-6-yl (dimethylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1 -methylpiperidin-4-yl)oxy)-7-ethoxyquinazolin-6-yl)-4- (dimethylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1 -methylpiperidin-4-yl)oxy)quinazolin-6-yl)-4-(dimethylamino) but-2-enamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-3-cyano-5-(((R)-3,3 -difluoro-1-methylpiperidin-4-yl)oxy)quinolin-6-yl)-3- ((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-3-cyano-5-(((R)-3,3 -Difluoro-1-methylpiperidin-4-yl)oxy)-7-ethoxyquinoline-6 -yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-5-(((R)-3,3-difluoro -1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-3-((R)- 1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-5-(((R)-3,3-difluoro -1-methylpiperidin-4-yl)oxy)-7-ethoxyquinazolin-6-yl)- 3-((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azeti (Dimethylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamine Do, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)a Zetidin-1-yl)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl ) acrylamide, and (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6,7-dimethoxyquinazolin-4-amine or a pharmaceutically acceptable salt thereof.

[0121] Exemplary compounds of the present disclosure are shown in Table 1 below. [Table 1] TIFF2026009898000008.tif183136TIFF2026009898000009.tif182135TIFF2026009898000010.tif189137TIFF20260098980 00011.tif183136TIFF2026009898000012.tif192138TIFF2026009898000013.tif184137TIFF2026009898000014.tif179135 TIFF2026009898000015.tif182137TIFF2026009898000016.tif176137TIFF2026009898000017.tif181136TIFF20260098980 00018.tif181136TIFF2026009898000019.tif182135TIFF2026009898000020.tif188133TIFF2026009898000021.tif177136 TIFF2026009898000022.tif183137TIFF2026009898000023.tif191138TIFF2026009898000024.tif188135TIFF20260098980 00025.tif183135TIFF2026009898000026.tif182135TIFF2026009898000027.tif182136TIFF2026009898000028.tif181136 TIFF2026009898000029.tif191135TIFF2026009898000030.tif191134TIFF2026009898000031.tif182133TIFF20260098980 00032.tif185134TIFF2026009898000033.tif179134TIFF2026009898000034.tif187136TIFF2026009898000035.tif138135

[0122] The compounds presented herein with reference to both the general formula and the specific compounds are In addition, the compounds of the present disclosure may exist in a wide variety of forms or derivatives, and all All forms are within the scope of this disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, Regioisomers, salts, prodrugs, solvates, various crystalline forms or polymorphs, and active metabolites Contains things.

[0123] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may be present in a variety of stereoisomers. They may exist in various forms, for example as enantiomers and / or diastereomers. Thus, the compounds of the present invention and compositions thereof may be used as single enantiomers, diastereomers, or the like. or in the form of a geometric isomer, or in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the present disclosure are optically pure compounds. In some embodiments, mixtures of enantiomers or diastereomers are presented.

[0124] The term "enantiomers" refers to species that are non-superimposable mirror images of each other. The term "diastereomers" refers to two stereoisomers of a compound that are mirror images of each other. Diastereomers refer to a pair of optical isomers that are not identical. Diastereomers have different physical properties, such as melting point, It has a boiling point, spectroscopic properties, and reactivity.

[0125] Additionally, certain compounds have one or more double bonds as described herein. In some cases, they may exist as either the Z or E isomer unless otherwise indicated. The present disclosure provides the compounds as single isomers substantially free of other isomers, and alternatively The compounds may also be used as mixtures of various isomers, e.g., racemic mixtures of enantiomers. In addition to the compounds themselves, the present disclosure also encompasses compositions comprising one or more of the compounds. Contains.

[0126] As used herein, the term "isomer" refers to all geometric and isomeric isomers. For example, "isomer" includes cis and trans isomers, E and and Z isomers, R and S enantiomers, diastereomers, (D)-isomers The (L)-isomer, the (L)-isomer, racemic mixtures thereof, and other mixtures thereof are within the scope of the present invention. For example, in some embodiments, one stereoisomer is may be provided substantially free of one or more corresponding stereoisomers, The bodies are sometimes referred to as "stereochemically concentrated."

[0127] If a particular enantiomer is preferred, in some embodiments, the particular enantiomer is may be provided substantially free of the opposite enantiomer, The term "optically enriched" is sometimes used to refer to a mer that is "optically enriched." As used herein, a compound is a compound having a significantly higher proportion of one enantiomer. In certain embodiments, the compound is composed of at least about In another embodiment, the compound is made up of 90% by weight of a preferred enantiomer. at least about 95%, about 98%, or about 99% by weight of a preferred enantiomer The preferred enantiomer is isolated from the racemic mixture by chiral high pressure liquid chromatography. Any method known to those skilled in the art, including chromatographic (HPLC) and chiral salt formation and crystallization. It may be isolated by chiral synthesis or prepared by asymmetric synthesis. ques et al., Enantiomers, Racemates and Resolut ions (Wiley Interscience, New York, 1981), W Ilen, SH et al., Tetrahedron, Vol. 33, p. 2725 (1977) ), Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962), Wi len, SH, Tables of Resolving Agents and Optical Resolutions p.268 (edited by ELEliel, Un iv.of Notre Dame Press, Notre Dame, Indiana, 1 See the text of the 12th century (972).

[0128] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are Such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" , structural isomers with different energies that are interconvertible due to a low energy barrier For example, proton tautomers (also known as prototropic tautomers) Interconversions via proton transfer, such as keto-enol isomerization and amide-imino isomerization, are also possible. acid isomerization, lactam-lactim isomerization, imine-enamine isomerization, and one proton occupying more than one position on the heterocyclic ring system (e.g., 1H-imidazole and 3 H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole , and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole The valence isomers include 1H-pyrazole, 1H-pyrazole, and 2H-pyrazole. Tautomers are in equilibrium. It may be sterically fixed in one form by appropriate substitution. Compounds of the present disclosure identified as a particular tautomeric form may also include other tautomeric forms unless otherwise specified. It is intended to include.

[0129] The compounds of the present disclosure may be prodrugs, active metabolic derivatives (active metabolites), active intermediates, and pharmaceutically acceptable salts thereof.

[0130] As used herein, the term "prodrug" refers to a compound that acts as a substitute under physiological conditions. A compound or drug that, when cleaved or converted by solvolysis, yields the desired active compound. Prodrugs include esters of the active compound. , amides, carbamates, carbonates, ureides, solvates, or hydrates. Typically, the prodrug is inactive or has the activity less active than the active compounds, but with one or more advantages in terms of handling, administration, and / or metabolic properties Advantages may be offered by prodrugs. For example, some prodrugs They are esters of the active compound, and during metabolic degradation the ester group is cleaved to yield the active drug. Also, some prodrugs undergo enzymatic activation to release the active compound, or further A prodrug is a compound that undergoes a single chemical reaction to produce the active compound. They may transition from the prodrug form to the active form in the prodrug stage, or may be active themselves, or The compound may have one or more intermediate product forms that are inactive. The following references are made to T. Higuchi and V. Stella, both of which are incorporated by reference in their entireties: , “Pro-drugs as Novel Delivery Systems”, A. .CS Symposium Series Vol. 14, and Bioreversible Carr iers in Drug Design, edited by Edward B. Roche, Amer. ican Pharmaceutical Association and Perg. Discussed in: Amon Press, 1987.

[0131] As used herein, the term "metabolite" refers to, for example, an active metabolite, as defined above. These metabolites are therefore pharmacologically active compounds. or derivatives thereof produced by metabolic processes in the body of a subject. For example, such metabolites are compounds that are metabolized by the administered compound or salts or protons. Drug oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, These may be produced by enzymatic cleavage, etc. Among these, active metabolites have no such pharmacological activity. For prodrugs, the prodrug compound is generally inactive. For active metabolites, the parent compound is the active compound, or is less active than the metabolite. It may be an active or inactive prodrug.

[0132] Prodrugs and active metabolites can be identified using routine techniques known in the art. For example, Bertolini et al., 1997, J Med Chem 40:2011-2016, Shan et al., J Pharm Sci 86: 756-757, Bagshawe, 1995, Drug Dev Res 34: 2 See Wermuth, supra, at 20-230.

[0133] As used herein, the term "active intermediate" refers to an intermediate in a synthetic process. A product compound that exhibits the same or essentially the same biological activity as the final synthetic compound. It refers to.

[0134] The compounds of the present disclosure may be prepared as or in the form of pharmaceutically acceptable salts. Unless otherwise indicated, the compounds presented herein may be used in combination with other compounds. Pharmaceutically acceptable salts of such compounds are included.

[0135] As used herein, the term "pharmaceutically acceptable" refers to any The components and the substance or composition and / or the subject and the thing being treated therewith The quality or composition of the product is chemically and / or toxicologically compatible.

[0136] As used herein, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable salt unless otherwise specified. Unless otherwise indicated, the biological effectiveness of the free acid and free base of that particular compound is retained. and includes salts which are not biologically or otherwise undesirable. Possible salt forms include, but are not limited to, mono, bis, tris, tetrakis, etc. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. By preparing a suitable salt, the compound can be converted into a compound without interfering with the physiological effects of the compound. Altering the physical characteristics of a compound can facilitate its pharmacological use. Furthermore, the melting point is lowered to facilitate transmucosal administration, and the drug can be administered at a higher concentration. This includes increasing the solubility of the compound.

[0137] Pharmaceutically acceptable salts include acid addition salts, such as sulfate, chloride, hydrochloride, fumarate, phosphoric acid, Sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and Pharmaceutically acceptable salts include salts containing quinic acid, hydrochloric acid, maleic acid, sulfuric acid, lysine, thiamin ... acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid It can be obtained from acids such as quinic acid, fumaric acid, and quinic acid.

[0138] When an acidic functional group is present, such as a carboxylic acid or phenol, a pharmaceutically acceptable salt base addition salts, e.g., benzathine, chloroprocaine, choline, diethanolamine, Ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, Aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium Also included are salts containing amines, alkylamines, and zinc. 's Pharmaceutical Sciences, 19th Edition, Mack Pub Lishing Co., Easton, PA, Vol. 2, pp. 1457, 1995. “Handbook of Pharmaceutical Salts: Prope rties, Selection, and Use,” by Stahl and Wermuth , Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the corresponding bases.

[0139] Pharmaceutically acceptable salts can be prepared by standard techniques, for example by dissolving in a suitable solvent, e.g. For example, the free base form of the compound may be dissolved in an aqueous or aqueous alcoholic solution containing a suitable acid. It is possible to dissolve the compound in water and then isolate it by evaporating the solution. When a certain compound is a base, it can be reacted with any suitable method available in the art, for example with hydrochloric acid. , hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or an inorganic acid such as acetic acid, maleic acid, or succinic acid. acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, or organic acids such as salicylic acid, or pyranoside acids such as glucuronic acid or galacturonic acid or alpha-hydroxy acids such as citric acid or tartaric acid, or aspartic acid or glutamic acid amino acids such as glutamic acid, or aromatic acids such as benzoic acid or cinnamic acid, or p-toluenesulfonyl sulfonic acids such as ethanesulfonic acid or ethanesulfonic acid, or using such acids The desired pharmaceutically acceptable salt can be prepared by treatment of the free base.

[0140] Similarly, when the particular compound is an acid, it can be reacted by any suitable method, e.g., inorganic or organic. a base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkali metal nitrate; Treatment of this free acid with alkali earth metal hydroxides, or the like, produces the desired pharmaceutical Suitable salts include L-glycine, L-lysine, and amino acids such as L-arginine, ammonia, primary, secondary, and tertiary amines and cyclic groups such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine. Organic salts derived from amines, as well as sodium, calcium, potassium, magnesium, Examples of inorganic salts include inorganic salts derived from iron, copper, zinc, aluminum, and lithium.

[0141] The compounds of the present disclosure may be present in unsolvated, solvated (e.g., hydrated) and solid (e.g., crystalline) forms. The present disclosure includes all such forms. It is also to be understood that this is intended.

[0142] As used herein, the term "solvate" or "solvate" means It refers to a solvent adduct containing either stoichiometric or non-stoichiometric amounts of solvent. In the solid crystalline state, the compound traps solvent molecules in a fixed molar ratio, thus forming a solvated compound. When the solvent is water, the solvate that is formed is called a hydrate. and when the solvent is an alcohol, the solvate formed is an alcoholate. One molecule of that substance is combined with one or more molecules of water, and the water is converted into H2O. Hydrates are formed by retaining the molecular state. Examples of solvents that form solvates include water, Isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanol These include, but are not limited to, amines.

[0143] As used herein, the terms "crystalline form," "crystalline morphology," "polymorph," and "polymorph" are used interchangeably. The terms "amorph" and "amorph" can be used interchangeably and refer to the compound (or a salt or solvate thereof). The term "crystal structure" refers to a crystal structure that can crystallize in different crystal packing structures, and all of them are the same. It has a fundamental composition. Different crystalline forms have different X-ray diffraction patterns, infrared spectra, melting points, The properties of the material typically vary depending on the material, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may determine whether one crystalline form predominates. Crystalline polymorphs of the compound may be prepared by crystallization under different conditions. It is possible.

[0144] The present disclosure is also intended to include all isotopes of atoms in said compounds. 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, etc., in the compounds of this disclosure. , fluorine, chlorine, bromine, or iodine, but are not limited to 1 H, 2 H, 3 H, 11 C. 1 2 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 3 2 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I, and 131 It is intended to include isotopes thereof, such as I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon 12 C and 13 Contains C.

[0145] Synthesis of the Compound The synthesis of the compounds presented herein may involve the synthesis of pharmaceutically acceptable salts thereof. The synthesis of the compounds of the present invention is illustrated in the synthesis schemes in the Examples. The compounds can be prepared using any known method of organic synthesis and include a number of possible The compounds can be synthesized according to any of the synthetic routes, and therefore these schemes are merely illustrative. and other possible compounds that can be used to prepare the compounds presented herein. It is not intended to limit the methods that can be used. These compounds in the examples are intended to be good examples and can be modified as appropriate. Embodiments have been synthesized for research purposes and possible regulatory submissions.

[0146] The reactions for preparing the compounds of the present disclosure can be carried out in suitable solvents and can be carried out using organic synthetic compounds. Those skilled in the art can readily select such solvents. Suitable solvents are those in which the reactions are carried out. The starting material is heated at a temperature that can range from the freezing point of the solvent to the boiling point of the solvent. It can remain substantially unreacted with the reactants, intermediates, or products. A given reaction can be carried out in a variety of solvents or a mixture of more than one solvent. Depending on the particular reaction step, an appropriate solvent for that particular reaction step can be selected.

[0147] Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and the selection of appropriate protecting groups can be readily determined. TW Greene and PG Mughuts, Prot. Interactive Groups in Organic Synthesis, 3rd ed., W 1999, ...

[0148] Monitoring the reaction according to any suitable method known in the art For example, 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 liquid spectroscopy. High performance liquid chromatography (HPLC), liquid chromatography mass spectrometry ( chromatographic methods such as LCMS (liquid crystallography), or thin layer chromatography (TLC) Thus, product formation can be monitored. (HPLC) ("Preparative LC- MS Purification: Improved Compound Speci fic Method Optimization” Karl F. Blom, Bria n Glass, Richard Sparks, Andrew P. Combs, J Combi Chem., 2004, Vol. 6 (No. 6), pp. 874-883) The compounds can be purified by a variety of methods, including normal phase silica chromatography.

[0149] The structures of the compounds in the examples are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography. Characterized by mass spectrometry (LC-MS). NMR chemical shifts (δ) is 10 -6 It is presented in units of (ppm). 1 H-NMR spectra were obtained from standard materials ( Varian machine (400) using tetramethylsilane (TMS) as 0.0 ppm MHz) in CDCl3, CD3OD, or DMSO-d6 solutions. (reported in ppm).

[0150] MS measurements are performed using a range of instruments including electrospray ionization, chemical ionization, and electrospray ionization. A Shimadzu 2010 mass spectrometer or an Agilent ion beamline was used for the electron impact ionization method. Performed using a 6110A MSD or 1969A TOF mass spectrometer.

[0151] TLC measurements were performed using Yantai Huanghai HSGF254 silica gel or An The plate was used to measure the TL The silica gel plates used in C are 0.15 mm to 0.2 mm. The silica gel plates used for product separation and purification are 0.4mm to 0.5mm.

[0152] Column chromatography was performed using a Biotage system (manufactured by Biotage) with a silica gel column. Supplier: Dyax Corporation) or silica SepPak cartridges (Waters).

[0153] Known starting materials of the present disclosure can be synthesized using methods known in the art or by methods known in the art. or commercially available from Aldrich Chemical Company. Adamas-beta, TCI, Accela ChemBio, etc. These compounds are available from commercial suppliers and are used without further purification unless otherwise indicated. The starting materials used were tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane, and 1,1,2,2-Tetrachloroethane is in a sealed bottle (Sure Seal bottle). It was purchased from Aldrich and used as received.

[0154] Unless otherwise specified, all reactions in this disclosure were performed under a positive pressure of nitrogen or argon or in anhydrous solvents. The reaction is carried out using a dry tube in the reaction chamber to introduce the substrate and reagents via syringe. Glassware was typically fitted with a rubber septum. and / or heat dried.

[0155] For illustrative purposes, general methods for preparing the compounds of the present disclosure as well as key intermediates are provided. The synthesis pathway is shown below. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other synthetic routes may be used to synthesize the compounds of the present invention. It is understood that certain starting materials and reagents are shown in these schemes and are described below. Although discussed, other starting materials and reagents may be substituted to produce various derivatives and / or reaction conditions. In addition, compounds prepared by the methods described below can be easily prepared. Many of the above can be further modified using conventional chemistry well known to those skilled in the art in light of this disclosure. is.

[0156] General synthetic route In some embodiments, the compounds of formula (I) provided herein may be reacted with HCl in the presence of a suitable acid. A compound of formula (II) below: [ka] wherein X is a leaving group (e.g., a halogen atom), of formula (IIIa) or (IIIb) (where it is desired to obtain the free base from the salt, the free base is used, and the salt is then suitably a base, such as an alkali metal or alkaline earth metal carbonate or hydroxide, e.g., sodium carbonate; Treated with sodium, potassium carbonate, calcium carbonate, sodium hydroxide, or potassium hydroxide R1, R2, R3, and L may be optionally within the meaning defined herein except that any functional groups, if any, are protected. Suitable acids are organic acids such as pTSOH. In a suitable solvent, such as isopropyl alcohol, at a suitable temperature (for example, a temperature in the range of about 20 to 100°C), It is conveniently carried out in the presence of an alcohol such as propanol.

[0157] In certain embodiments, the compound of formula (II) wherein X is a halogen atom In the absence of a suitable solvent and an acid or a base, the compound of formula (IIIa) or (IIIb) is reacted with the compound of formula (IIIa). In such reactions, the halogen leaving group X is transferred in situ. The acid HX is formed and the reaction is self-catalyzed. a solvent-soluble organic solvent, such as isopropanol, dioxane, or N,N-dimethylacetamide Suitable conditions for this reaction are described above.

[0158] Protecting groups are generally described in the literature as being suitable for the protection of the group in question, or are well known in the art. The group may be selected from any of the groups known to the skilled chemist and may be introduced by conventional methods. Protecting groups are described in the literature as being suitable for the removal of the protecting group in question. or any convenient method known to the skilled chemist, e.g., by blocking a group on another part of the molecule. may be removed by a method selected to accomplish removal of the protecting group with minimal .

[0159] Scheme 1 shows several ether-linked quinazolines of formula (Ia) (compounds of formula (I) of the present disclosure). where R1 is O(R9), where PG is a suitable protecting group. (MOM, etc.). According to Scheme 1, 4-chloro-6-oxyquinone of formula (IIa) zoline (wherein X is chloro) to afford the compound of formula (I) under standard coupling conditions as described above. IIa) or (IIIb) with an appropriate aniline to provide a compound of formula (B7) After the reaction with aniline, under appropriate conditions, for example in the presence of TFA, This optional protecting group can be removed to provide a compound of formula (B8). DMF or acetone) in a suitable base, such as K2CO3, CS2CO3, or Cs The hydroxyl group of the compound of formula (B8) is converted to a suitable halogenated anhydride in the presence of (OH)2. Alternatively, R9-OH may be attached to an alkyl group R9-X to provide a compound of formula (Ia). When the alcohol has been converted to a derivatized leaving group, e.g., a tosylate, the alcohol can be reacted with R9-X In yet another approach, under standard Mitsunobu conditions, e.g. For example, the hydroxyl group of the compound of formula (B8) in the presence of DIAD / PPh3 in THF is The group can be attached to the alcohol R9-OH to provide a compound of formula (Ia). [ka]

[0160] In some embodiments, the compound of formula (II) may be obtained by conventional methods. Scheme 2 shows the synthesis of compounds of formula (II). As shown in Scheme 2, R1, As used herein, R2 and L are defined as any functional groups that may be protected if necessary. Compounds of formula (A9) having any of the defined meanings can be prepared by the addition of thionyl chloride, chloride Reaction with halogenating agents such as phosphoryl or a mixture of carbon tetrachloride and triphenylphosphine This reaction may be carried out by conventional means, after which any protecting groups present are removed. Suitable inert in the presence of an organic base, e.g., diisopropylethylamine It is conveniently carried out in a solvent such as 1,2-dichloroethane or N,N-dimethylformamide. This reaction is carried out at a temperature in the range of, for example, 0 to 150°C, preferably in the presence of a reaction solvent. It is conveniently carried out at or near reflux temperature. [ka]

[0161] Process 1 The starting materials of formula (A6) are commercially available or can be synthesized using conventional methods, for example from J. Org. .Chem.1952,17,164-176 and J.Med.Chem.1996,3 9, 1823-1835. A starting compound of formula (A6) using a suitable amino protecting group, e.g., SEM, in the presence of a suitable base The material was protected.

[0162] Process 2 The reaction is conveniently carried out in the presence of a suitable base. Suitable bases are described herein. The reaction is carried out in a suitable inert solvent, e.g. For example, this is conveniently carried out in N,N-dimethylacetamide. Scheme 1 shows the reaction of formula I where L is O. It is particularly suitable for the preparation of compounds of formula I.

[0163] Process 3 Under appropriate conditions, for example in the presence of TFA for SEM deprotection, the compound of formula (A9) can be prepared. Any protecting groups in the compound can be removed.

[0164] In some embodiments, a compound suitable for use in Scheme 1 can be prepared according to the method shown in Scheme 3. The appropriate compound of formula (IIIa) can be prepared by the addition of an appropriately dichloro-substituted pyrimidine. Reaction of hydrazinylpyrimidine with NH2NH2·H2O in EtOH to form hydrazinylpyrimidine intermediate The intermediate product 7-chloro-[1,2,4]triazolo[ 1,5-c]pyrimidines can be converted to pyrimidines using HC(OMe)3 at elevated temperatures, e.g., 90°C. This can be achieved by treating MeCN at 60°C in the presence of CS2CO3. optionally substituted 7-chloro-[1,2,4]triazolo[1,5-c]piperidin React phenol with methylimidine using standard reduction methods such as Fe / NH4Cl. Nitrogen 4-(nitrophenoxy)-[1,2,4]triazolo[1,5-c]pyrimidine The b group can be reduced to the desired aniline compound of formula (IIIa).

[0165] The present invention has been disclosed in the international application PCT, which is assigned to the same applicant as the present application. As shown in Scheme 3 of the specification of / CN2018 / 106098, HC(OM e) Cyclization of the hydrazinylpyrimidine intermediate with 3 to give 7-chloro- It was thought that [1,2,4]triazolo[4,3-c]pyrimidine would be produced. However, the present inventors have surprisingly found that the above-mentioned cyclization reaction actually affords 7-chloro-[1,2, 4]triazolo[4,3-c]pyrimidine instead of the rearrangement that occurs during this cyclization reaction results in 7-chloro-[1,2,4]triazolo[1,5-c]pyrimidine It was found that (see Scheme 3 below). [ka]

[0166] Specifically, in this case, compound a is protonated to form an anion, as shown in Scheme 3. It is believed that this produces a nitrilium salt, which promotes ring opening to give the nitrilium salt c The iminium salt b is then generated in resonance with the triazole as a result of hydrogen transfer. A linked vinyliminium salt d is formed. Nucleophilic recyclization followed by deprotonation of f yields [1,2,4]triazolo[1, 5-c]pyrimidine g is isolated. The driving force for this observed rearrangement is [1,2,4]trimethyl[1,2,4]pyrimidine g. The azolo[1,5-c]pyrimidine ring system is one of its isomers, namely [1,2,4]triazolo This is due to the fact that it is thermodynamically more stable than [4,3-c]pyrimidine.

[0167] This unexpected and sudden rearrangement led to the growth and characterization of a single crystal of the intermediate product of formula (IIIa). This confirmed the correct chemical structure (see Figure 1). HC as exemplified in Scheme 3 of PCT / CN2018 / 106098 Reaction of the hydrazinylpyrimidine intermediate with (OMe)3 invariably yields 7-chloro- It has also been confirmed that [1,2,4]triazolo[1,5-c]pyrimidines are produced. Therefore, all compounds obtained in the subsequent steps are [1 ,2,4]triazolo[4,3-c]pyrimidin-7-yl instead of [1,2,4]triazolo[4,3-c]pyrimidin-7-yl It is based on an intermediate containing riazolo[1,5-c]pyrimidin-7-yl.

[0168] In some embodiments, compounds of Formula (I) are prepared according to the method shown in Scheme 4. It is possible. [ka]

[0169] Process 1 The starting materials of formula (C1) are commercially available or can be synthesized using conventional methods, for example from J. Org. It can be prepared as described in THF or can be obtained by the reaction of formula (C1) using a suitable reducing agent, e.g., Pd / C and H2 in a solvent such as methanol. ) was subjected to selective reduction.

[0170] Process 2 The reaction of this compound of formula (C2) with DMF-DMA in a suitable solvent (e.g., THF) is For example, the reaction can be carried out at a temperature in the range of 50 to 100°C to obtain the compound of formula (C3). do.

[0171] Process 3 In the presence of an acid (AcOH, pTSOH, etc.), at a temperature of 50 to 120°C, The quinazoline ring closure reaction was carried out using compound (IIIb).

[0172] Use of the compound In one aspect, the present disclosure provides a compound of formula (I) (or formula (I'), formula (IVa), formula (IVb) , formula (IVc), formula (IVd), formula (IVe), formula (IVf), formula (Va), formula (Vb) , a compound of formula (Vc), formula (Vd), formula (Ve), or formula (Vf)) or a pharmaceutically acceptable salt thereof and acceptable salts thereof, which are effective against type I receptor tyrosine kinases, particularly HER2. Those showing high inhibitory activity are presented.

[0173] As used herein, "inhibitory activity against type I receptor tyrosine kinase" The term refers to a compound of formula (I) (or formula (I'), formula (IVa), formula (IVb), formula ( IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula ( Vc), a compound of formula (Vd), formula (Ve), or formula (Vf)) or a pharmaceutically acceptable The compound of formula (I) (or a salt thereof) as a direct or indirect response to the presence of '), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula ( IVf), formula (Va), formula (Vb), formula (Vc), formula (Vd), formula (Ve), or formula (Vf) or a pharmaceutically acceptable salt thereof It refers to a decrease in type I receptor tyrosine kinase activity compared to the activity of type I receptor tyrosine kinase. Such a decrease in activity is due to the activity of the compounds of formula (I) (or formula (I) '), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula ( IVf), formula (Va), formula (Vb), formula (Vc), formula (Vd), formula (Ve), or formula (Vf)) or a pharmaceutically acceptable salt thereof, or subsequent interaction with type I receptors. The compound of formula (I) (or formula (I)) may be combined with one or more other factors that affect the activity of tyrosine kinases. (I'), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or may result from interactions of the compound of formula (Vf) or a pharmaceutically acceptable salt thereof. , a compound of formula (I) (or formula (I'), formula (IVa), formula (IVb), formula (IVc), formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula (Vc), Formula ( (Vd), a compound of formula (Ve), or a compound of formula (Vf)) or a pharmaceutically acceptable salt thereof is I By directly binding to a type 2 receptor tyrosine kinase, it binds to another factor (directly or indirectly). by reducing type I receptor tyrosine kinase activity or by inhibiting the activity of cells or organisms By reducing (directly or indirectly) the amount of type I receptor tyrosine kinase present in The activity of this type I receptor tyrosine kinase can be reduced by

[0174] In some embodiments, compounds of the present disclosure inhibit other type I receptor tyrosine kinases, such as wild-type kinases. It is a more selective inhibitor of HER2 than wild-type EGFR (wt-EGFR).

[0175] As used herein, a "selective inhibitor of HER2" or "selective inhibitor of HER2" refers to a The term "effectively inhibits" refers to the ability of a compound to inhibit at least one of the functions described herein. Other type I receptor tyrosine kinases in assays (e.g., biochemical or cellular assays) This means that they inhibit kinases such as HER2 rather than wt-EGFR. In the embodiment, the term "selective inhibitor of HER2 over EGFR" or "selective inhibitor of HER2 over EGFR" is used. The term "selectively inhibits HER2" refers to the ability of the compound to selectively inhibit HER2. IC against HER2 as measured by assay 50 At least 10 times higher than , at least 20 times higher, at least 30 times higher, at least 40 times higher, at least 5 0 times higher, at least 60 times higher, at least 70 times higher, at least 80 times higher, at least at least 90 times higher, at least 100 times higher, at least 200 times higher, at least 30 0 times higher, at least 400 times higher, at least 500 times higher, at least 600 times higher , at least 700 times higher, at least 800 times higher, at least 900 times higher, IC against wt-EGFR is at least 1000-fold higher and at least 2000-fold higher 50 have This means that

[0176] Therefore, it is a very potent HER2 inhibitor and has a higher affinity for HER2 than EGFR. The compound of formula I (or formula (I'), formula (IVa), formula (IVb), formula ( IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula ( Vc), a compound of formula (Vd), formula (Ve), or formula (Vf)) or a pharmaceutically acceptable The present invention also provides salts thereof that can be used to treat HER2-mediated diseases. Cancers, such as those that express or overexpress HER2, can be treated relatively selectively, thereby This minimizes potential side effects associated with inhibiting other kinases such as EGFR.

[0177] In some embodiments, compounds of the present disclosure are substrates for P-glycoprotein (Pgp) and ATP. It is also not a substrate of binding cassette subfamily G member 2 (ABCG2 or BCRP). As used herein, the term "Pgp substrate" refers to a compound that binds to Pgp. Therefore, the intestinal lumen (in the case of Pgp distributed in the intestinal epithelium), the bile duct (in the case of Pgp distributed in the hepatocytes), In the case of Pgp, which is distributed in the cells of the renal proximal tubule, the urinary filter, the capillary (the blood-brain barrier and In the case of Pgp, which is distributed in the capillary endothelial cells that make up the blood-testis barrier, As used herein, the term "BCRP substrate" refers to a given The absorption of the compound is due to BCRP through the apical membrane of the intestine, the blood-testis barrier, the blood-brain barrier, and the hematopoietic This means that the cells are blocked at the cell membranes of progenitor cells and other stem cells, particularly at the blood-brain barrier. Therefore, it exhibits good brain penetration in subjects and is effective in treating extracranial cancers and metastatic cancers, e.g., brain Compounds or pharmaceutically acceptable salts thereof applicable to the treatment of both metastases are presented.

[0178] In some embodiments, the sensitivity of the compounds to Pgp and BCRP is described in more detail in the Examples section below. MDCK-MDR1 Pgp permeability assay and Ca permeability assay were performed as described in detail. In some embodiments, the present invention can be evaluated by a co-2 BCRP permeability assay. The compounds shown exhibited low Pgp sensitivity and significantly reduced MDCK-Pgp efflux rates (MDCK-Pgp E R) is less than about 5, less than about 4, less than about 3, less than about 2, or less than about 1.

[0179] In some embodiments, compounds of the present disclosure may be prepared in accordance with the methods described in detail in the Examples section below. It may be brain penetrant in vivo as determined by the mouse SOA test. In embodiments, the compounds of the present disclosure have a pH greater than about 0.1, greater than about 0.15, greater than about 0.2, greater than about 0.25, greater than about Blood-to-brain concentration ratios K of greater than 0.3, greater than approximately 0.35, greater than approximately 0.4, greater than approximately 0.45, and greater than approximately 0.5 p Shows.

[0180] Therefore, it penetrates the blood-brain barrier without the need for any drugs to facilitate blood-brain barrier penetration. The compound of formula (I) (or formula (I'), formula (IVa), formula (IVb) ), formula (IVc), formula (IVd), formula (IVe), formula (IVf), formula (Va), formula (Vb ), a compound of formula (Vc), formula (Vd), formula (Ve), or formula (Vf)) or a compound of formula (Vc), formula (Vd), formula (Ve), or formula (Vf) Acceptable salts thereof are provided. Such compounds may be used to treat metastatic cancers, e.g., brain metastases. , particularly breast cancer brain metastases are treated.

[0181] In some embodiments, the compounds of the present disclosure can be prepared in the manner described in detail in the Examples section below. In some embodiments, the compound exhibits low hERG inhibition as determined by an EGR inhibition assay. The compounds of the present disclosure may be present at concentrations greater than about 2 μM, greater than about 3 μM, greater than about 4 μM, greater than about 5 μM, greater than about 6 μM, hERG inhibition IC of greater than 7 μM, greater than about 8 μM, greater than about 9 μM, and greater than about 10 μM 50 This shows This indicates that the compounds presented herein have a low risk of cardiotoxicity in vivo. This indicates that there is

[0182] Inhibitory activity against type I receptor tyrosine kinase (and in some cases selective HER2 inhibitory activity) As a result of this property, the compounds of formula (I) and their pharmaceutically acceptable salts are useful in therapy, e.g. Diseases, including cancer, that are mediated at least in part by one or more type I receptor tyrosine kinases are useful in treating health conditions.

[0183] As used herein, the term "cancer" refers to both non-metastatic and metastatic cancers. In this context, the treatment of cancer includes the treatment of both the primary cancer and tumor metastases. do.

[0184] As used herein, the term "treatment" refers to the alleviation of one of the symptoms of a disease, for the complete or partial removal of some or all of the underlying pathology To correct or compensate for the condition by addressing it to achieve a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or Desired clinical outcomes include symptomatic relief, whether detectable or undetectable; Reduction in extent of disease, stabilization of disease state (i.e., non-worsening), delay or slowing of disease progression These include, but are not limited to, improvement or alleviation of the disease state, and remission (partial or complete). "Treatment" is the survival rate compared to the expected survival rate without that treatment. It may also mean an extension of the period. Those who need treatment include those who already have an illness or disability, It also includes those prone to have the disease or disorder, or those in whom the disease or disorder is to be prevented. Unless specifically indicated otherwise, the term "treatment" also encompasses prophylaxis. The term "therapeutically" should be construed similarly.

[0185] As used herein, the term "prophylaxis" shall have its ordinary meaning. The term includes primary prevention, which aims to prevent the onset of disease, and treatment for diseases that have already occurred. to protect the patient from the intensification or worsening of the disease or the development of new symptoms related to the disease. This includes secondary prevention for temporary or permanent protection.

[0186] The term "treatment" has the same meaning as "therapy" Similarly, "therapy" as defined herein In this case, the term "treat" is used to mean "to carry out therapy." This can be understood as "the fact that

[0187] In some embodiments, the compounds of the present disclosure have anti-cell proliferation properties, These properties are believed to result from the type I receptor tyrosine kinase inhibitory activity of the compounds of the present disclosure. Thus, the compounds of the present disclosure inhibit type I receptor tyrosine kinases, either alone or in part. These compounds are expected to be useful in the treatment of diseases or conditions mediated by The compounds exhibit anti-cell proliferation effects mediated solely or in part by inhibition of type I receptor tyrosine kinases. In some embodiments, it may be used to enhance anti-cell proliferation effects. Such diseases or conditions that are treated by administering the compound are sensitized to type I receptor tyrosine kinases. Cancer of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas, and ovary These include, but are not limited to, cancer, or other cell proliferative disorders such as psoriasis.

[0188] Thus, in one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is provided. Possible salts thereof are presented.

[0189] In some embodiments, a compound of formula (I) (or formula (I') , Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IV f), formula (Va), formula (Vb), formula (Vc), formula (Vd), formula (Ve), or formula (V f) or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the present invention relates to a disease mediated solely or in part by type I receptor tyrosine kinases. a compound of formula (I) (or formula (I'), formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va) , a compound of formula (Vb), formula (Vc), formula (Vd), formula (Ve), or formula (Vf)) or is presented as a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, a method for treating a type I receptor tyrosine kinase-associated disease or condition A compound of formula (I) (or formula (I'), formula (IVa), formula (IVb) or formula (IVc) for use in the manufacture of a medicament. IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), a compound of formula (Vc), formula (Vd), formula (Ve), or formula (Vf)) or a drug Pharmaceutically acceptable salts thereof are presented.

[0192] In some embodiments, the method comprises administering to a subject a subject, the subject being administered a therapeutically effective amount of a HER2-associated disease or condition, for use in the manufacture of a medicament for the treatment of a HER2-associated disease or condition. The compound of formula (I) (or formula (I'), formula (IVa), formula (IVb), formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), (Ve), or (Vf) or a pharmaceutically acceptable salt thereof It is presented.

[0193] In some embodiments, a compound of Formula (I) for use in the manufacture of a medicament for the treatment of cancer. Compounds (or formula (I'), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula ( IVe), Formula (IVf), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve ), or a compound of formula (Vf)) or a pharmaceutically acceptable salt thereof is presented.

[0194] Pharmaceutical Composition The present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof. Compositions are provided. In some embodiments, the pharmaceutical compositions comprise one or more compounds of the present disclosure. or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0195] "Pharmaceutical composition," as used herein, refers to the composition of the present invention in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is a bulk dosage form. Or a unit dosage form. This unit dosage form is, for example, a tablet, a capsule, a pill, a powder, a granule , sachets, cachets, lozenges, suspensions, emulsions, liquids, syrups, aerosols ( aerosols (as solids or in liquid media), sprays, ointments, pastes It is available in a variety of forms, including tablets, creams, lotions, gels, patches, inhalants, or suppositories. The active ingredient in the unit dose composition (e.g., a compound of the present disclosure, or The amount of the compound (or a formulation thereof, such as a salt, hydrate, solvate, or isomer thereof) is a therapeutically effective amount, The dosage will vary depending on the particular treatment involved. Those skilled in the art will determine the dosage depending on the age and condition of the patient. Understand that it is sometimes necessary to vary the dosage on a daily basis. The dosage also depends on the route of administration. Oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, and intravenous routes , intramuscular route, intraperitoneal route, inhalation route, buccal route, sublingual route, intrapleural route, intrathecal route A variety of routes are contemplated, including intranasal, intravenous, intradermal, etc. The compounds of the present invention may be administered topically or transdermally. Dosage forms for administration include powders, sprays, ointments, pastes, creams, lotions, and gels. In some embodiments, the compounds of the present disclosure may be administered in the form of a liquid, a patch, or an inhalant. The product is prepared under sterile conditions containing pharmaceutically acceptable excipients and any required preservatives, buffers, or is mixed with a propellant.

[0196] As used herein, the term "pharmaceutically acceptable excipient" refers to a pharmaceutical Generally safe, non-toxic, and biologically and otherwise useful in the preparation of compositions. means an excipient that is not objectionable, including excipients that are acceptable for human medical use, as well as Veterinary use is also included as an acceptable excipient. A "pharmaceutically acceptable excipient" used in a pharmaceutical product may include one such excipient and more than one The term "pharmaceutically acceptable excipient" encompasses both pharmaceutical and non-pharmaceutical excipients. The term also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0197] The particular excipient, carrier, or diluent used will depend on the means by which the compound of the disclosure is being applied. The solvent is recognized by those skilled in the art as safe for administration to mammals. Generally, solvents are selected based on what is known as a "Great Assessment of Safety" (GRAS). are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g. PEG 400, PEG 300), and mixtures thereof. Agents, diluents, carriers, and stabilizers are innocuous to the recipient at the dosages and concentrations used. These include buffers such as phosphate buffers, citrate buffers, and other organic acid buffers. Solution; Antioxidants containing ascorbic acid and methionine; Preservatives (octadecyldimethylbenzyl benzoate) Dimethylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzyl chloride ammonium, phenol, butyl alcohol or benzyl alcohol, methylparaben or Alkylparabens such as propylparaben, catechol, resorcinol, cyclohexyl alcohol, 3-pentanol, and m-cresol; low molecular weight (less than about 10 residues) Polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; poly Hydrophilic polymers such as vinylpyrrolidone; glycine, glutamine, asparagine, histidine amino acids such as sucrose, arginine, or lysine; monosaccharides, disaccharides, and sugars such as glucose, mannose, and thiamin; Other carbohydrates, including dextrin; chelating agents such as EDTA; sucrose, maize sugars such as ethanol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes), and / or TWEEN™, P nonionic surfactants such as LURONICS®; or polyethylene glycol ( The composition contains the drug (i.e., the compound of the present invention or its pharmaceutical composition). To refine the appearance of a pharmaceutical product (i.e., a pharmaceutical product) or to support the manufacture of this pharmaceutical product (i.e., a pharmaceutical product). Additives that aid in the preparation of the emulsion include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, etc. Preservatives, antioxidants, opacifying agents, lubricants, processing aids, colorants, sweeteners, flavorings, flavoring agents, and Other known additives may also be included. These pharmaceutically active ingredients are preferably used in colloidal drug delivery systems (e.g., For example, liposomes, albumin microspheres, microemulsions, nanoparticles, and Nanocapsules or macroemulsions are produced by coacervation techniques or interfacial polymerization. Microcapsules prepared by, for example, hydroxymethylcellulose microcapsules, Capsules or gelatin microcapsules and poly(methyl methacrylate) microcapsules Such technology may be used by Remington's Pharmaceuticals. In Neurological Sciences, 16th edition, Osol, A. (1980) "Liposomes" are made up of various types of lipids, phospholipids, and / or surfactants. A drug for a mammal (the compound disclosed herein, and in some cases These liposomes are useful vesicles for the delivery of drugs (e.g., chemotherapy drugs) to the body. They are commonly arranged in a bilayer formation similar to the lipid arrangement in membranes.

[0198] Pharmaceutical compositions of compounds of Formula I are available in sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. This suspension may contain suitable dispersing or wetting agents and suspending agents which have been mentioned above. This sterile injectable preparation may be formulated in accordance with known techniques for use in the manufacture of pharmaceuticals. Sterile injectable solutions or suspensions in acceptable diluents or solvents, for example 1,3-butanediol It may be prepared as a solution in water or as a lyophilized powder. Among the solvents are water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils may conventionally be employed as a solvent or suspending medium. Any brand of fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0199] Compositions suitable for parenteral administration may contain antioxidants, buffers, bacteriostats, and other additives to aid in the treatment of the intended recipient. Aqueous and non-aqueous sterile injection solutions and suspensions which may contain solutes to make them isotonic with blood and aqueous and non-aqueous sterile suspensions which may contain thickening agents.

[0200] The pharmaceutical compositions of the present disclosure may be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft tablets). solid capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs Suitable forms for topical use (e.g., creams, ointments, gels, or aqueous or or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., finely divided aerosols (powder or liquid aerosols), in a form suitable for administration by insufflation (e.g., finely divided It may also be a powder divided into

[0201] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, lactose, sodium carbonate, inert diluents such as calcium carbonate, calcium phosphate, or calcium carbonate; Granulating and disintegrating agents such as glutaric acid; binders such as starch; magnesium stearate, Lubricants such as stearic acid or talc; ethyl p-hydroxybenzoate or p-hydroxybenzoate Preservatives such as propyl hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated, depending on their disintegration in the gastrointestinal tract and subsequent release of the active ingredient. They may be coated to modify their absorption or to improve their stability or appearance. In both cases, conventional coating agents and methods well known in the art are used. do.

[0202] Formulations for oral administration may be prepared in which the active ingredient is dissolved in an inert solid diluent, such as calcium carbonate, In the form of hard gelatin capsules mixed with calcium phosphate or kaolin, The active ingredient is mixed with water or oil such as peanut oil, liquid paraffin, or olive oil. It may be in the form of a soft gelatin capsule containing the compound.

[0203] Aqueous suspensions are prepared by suspending the active ingredient in finely divided powder form in one or more suspending agents, e.g., sodium carbonate. carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, Sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, Dispersing or wetting agents, such as lecithin or condensation products of alkylene oxides with fatty acids (e.g. (e.g., polyoxyethylene stearate) or ethylene oxide with a long-chain fatty alcohol Condensation products, such as heptadecaethyleneoxycetanol, or fatty acids of ethylene oxide and condensation products with hexitol-derived partial esters, e.g., polyoxyethylene monooleate Partial esters derived from fatty acid and hexitol anhydrides of ethylene oxide Condensation products with polyethylene sorbitan monooleate, for example, These aqueous suspensions generally contain one or more preservatives (e.g., ethyl p-hydroxybenzoate). or p-hydroxybenzoic acid propyl), antioxidants (ascorbic acid, etc.), coloring agents, It may contain flavoring and / or sweetening agents (such as sucrose, saccharin, or aspartame). stomach.

[0204] Oily suspensions are prepared from vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or It can be formulated by suspending the active ingredient in mineral oil (such as liquid paraffin). These oily suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. To provide a palatable oral preparation, sweetening agents such as those set forth above, and The addition of antioxidants such as ascorbic acid may improve the flavor. These compositions may be stored.

[0205] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water contain the active ingredient. Generally, the formulation contains a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.

[0206] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, the oily phase of which may be olive oil or vegetable oil such as peanut oil, or mineral oil such as liquid paraffin, or any of these Suitable emulsifying agents are, for example, gum acacia or gum tragacanth. Natural gums such as peanuts, natural phosphatides such as soy lecithin, fatty acids and hexitol-free Water-derived esters or partial esters (e.g., sorbitan monooleate) and the partial esters condensation products of esters with ethylene oxide, e.g., polyoxyethylene monooleate sol These emulsions may also contain sweetening agents, flavoring agents, and preservatives.

[0207] Syrups and elixirs may contain glycerol, propylene glycol, sorbitol, It may be formulated with sweeteners such as aspartame or sucrose, and may contain analgesics, preservatives, flavorings, The composition may contain coloring agents and / or colorants.

[0208] Suppositories contain the active ingredient in suitable non-aqueous solutions that are solid at ordinary temperature but liquid at rectal temperature. It may be prepared by mixing with an irritating excipient, so that it dissolves in the rectum and Suitable excipients include, for example, cocoa butter and polyethylene glycols. Formulations suitable for vaginal administration are known in the art in addition to the active ingredients. Pessaries, tampons, creams, gels containing carriers such as those known in the art. The composition may be provided as a tablet, paste, foam, or spray formulation.

[0209] Topical formulations, such as creams, ointments, gels, and aqueous or oily solutions or suspensions, are also suitable. The active ingredient is made acceptable for conventional topical administration using conventional methods well known in the art. This is generally obtained by formulating the compound with a possible vehicle or diluent.

[0210] Formulations for transdermal administration may be in the form of transdermal skin patches, which are well known to those of ordinary skill in the art. stomach.

[0211] Formulations suitable for pulmonary or nasal administration may be in the range of, for example, 0.1 to 500 microns (0.5 microns). 0.1 micron, with particle size increasing in increments of 1 micron, 30 microns, 35 microns, etc. and the formulation has a particle size of 1000 μm (including particles in the range between 1000 μm and 500 μm), which penetrates into the alveolar sacs. It is administered through the nasal cavity by rapid inhalation or through the mouth by inhalation so that the Suitable formulations include aqueous or oily solutions of the active ingredient; aerosols; or dry powders. Formulations suitable for administration of may be prepared according to conventional methods and may be used to treat disorders such as those described below. may be delivered along with other therapeutic agents, such as compounds previously used in the treatment or prevention of .

[0212] The pharmaceutical composition (or formulation) in use varies depending on the method used to administer the drug. For example, the pharmaceutical composition in an appropriate form may be packaged in a container. Suitable containers are well known to those skilled in the art and include (but are not limited to) Plastic and glass bottles, sachets, ampoules, plastic bags, metal This includes items such as cylinders. A seal prevention mechanism may be included in the container. In addition, the container may include a seal prevention mechanism for preventing the contents of the container from being leaked. The label may include appropriate warnings. The compositions are packaged in single-dose or multi-dose containers, such as sealed ampoules and vials. The pharmaceutical may be packaged in a sterile injectable liquid carrier, e.g., water, which can be added immediately prior to use. It may be stored in a freeze-dried (lyophilized) form, requiring immediate injection. Suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0213] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a veterinary carrier. Also provided is a veterinary composition comprising the composition in combination with a veterinary carrier. These carriers may be solid, liquid, or gaseous materials. otherwise inactive or veterinary approved, and These veterinary compositions may be administered parenterally, orally, or may be administered by any other desired route.

[0214] As used herein, the term "therapeutically effective amount" refers to a therapeutically effective amount for treating an identified disease or The amount of a drug to treat, ameliorate, or prevent a condition, or to produce a detectable therapeutic effect or This refers to the amount of a drug that produces a suppressive or inhibitory effect, which is known in the art. The precise effective amount for the subject is detectable by any assay method known in the art. The weight, size, and health condition of the subject, the nature and extent of symptoms, frequency of administration, The effectiveness of the drug will depend on the therapeutic agent or combination of therapeutic agents used and the discretion of the prescribing physician. The therapeutically effective amount for a particular situation can be determined by routine testing and investigation methods that are within the discretion and judgment of the physician. It can be determined that:

[0215] In some embodiments, the pharmaceutical composition is administered at a dose of between 0.001 and 500 mg / kg body weight / day. Dosage, for example, 0.01 to 400 mg / kg body weight / day, 0.01 to 300 mg / kg body weight weight / day, 0.1~200mg / kg body weight / day, 0.1~150mg / kg body weight / day, 0. 1~100mg / kg body weight / day, 0.5~100mg / kg body weight / day, 0.5~80mg / kg body weight / day, 0.5-60mg / kg body weight / day, 0.5-50mg / kg body weight / day, Doses of the compounds of the present disclosure between 1 and 50 mg / kg body weight / day, 1 and 40 mg / kg body weight / day The compound or a pharmaceutically acceptable salt thereof can be formulated for administration. In some cases, dosage levels below the lower end of the aforementioned range may be appropriate; in other cases, Higher doses can be taken throughout the day without causing any harmful side effects. It is used provided that the higher dose is first divided into several smaller doses to administer the required dose. Other information regarding routes and methods of administration is specifically referenced. Comprehensive Medicinal Chemist, incorporated herein by reference. ry (Corwin Hansch, editor in chief), Vol. 5, Pergamon Press See Chapter 25.3 in the 1990 issue of the American Chemical Society.

[0216] In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure as a first active ingredient. or a pharmaceutically acceptable salt thereof, and further comprising a second active ingredient.

[0217] In some embodiments, the second active ingredients of the pharmaceutical combination or dosing regimen do not adversely affect each other. Such moieties have complementary activities to the compounds of formula I so as not to affect the function of the compounds of formula I. Suitably, they are present in combination in amounts that are effective for the purpose.

[0218] In certain embodiments, the second active ingredient is any anti-tumor agent known in the art. The antitumor agent may be one of the following categories: (i) Antiproliferative / antineoplastic agents and their combinations, such as TKIs (lapatinib, neratinib, and afatinib, etc.); DNA alkylating agents (e.g., cisplatin, oxaliplatin, Nitrogen deficiencies such as cyclophosphamide, carboplatin, cyclophosphamide, and ifosfamide Tard, bendamustine, melphalan, chlorambucil, busulfan, temozolomide nitrosoureas, such as carmustine; antimetabolites (e.g., capecitabine, gemcitabine, Cytabine, and fluoropyrimidines such as 5-fluorouracil and tegafur antifolates, raltitrexed, methotrexate, cytosine arabinoside, and hydrochloride xylourea); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin) Bicine, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, Epirubicin, idarubicin, mitomycin C, dactinomycin, amrubicin, and anthracyclines such as mithramycin and mithramycin; antimitotics (e.g., vincristine vinca alkaloids such as vinblastine, vindesine, and vinorelbine; taxoids such as taxol and taxotere, and polo-kinase inhibitors); and Topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide) cin, amsacrine, irinotecan, topotecan, and camptothecin); CHK kinase Inhibitors of DNA repair mechanisms such as enzymes; DNA-dependent protein kinase inhibitors; poly(AD P-ribose polymerase inhibitors (PARP inhibitors, including olaparib); Hsp90 inhibitors such as spimycin and retaspimycin, inhibitors of ATR kinase ( AZD6738, etc.); and WEE1 kinase inhibitors (AZD1775 / MK-1775 etc.); (ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, toremifumab) estrogen receptor antagonists; estrogen receptor antagonists anti-androgens (e.g., bicamphetamine); thamide, flutamide, nilutamide, ciproxelone acetate, and Casodex (4 '-Cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl- 3'-(trifluoromethyl)propionanilide); LHRH antagonist or L HRH agonists (e.g., goserelin, leuporlin, and buserelin); progesterone agonists (e.g., megestrol acetate); aromatase inhibitors (e.g., aspirin); trozole, letrozole, vorazole, and exemestane); finasteride, etc. 5α-reductase inhibitors; and p38 inhibitors, such as those disclosed in U.S. Patent Application Publication No. 2004 / 0 Nos. 176325, 2004 / 0180896, and 2004 / 019 Inhibitors disclosed in 2635; (iii) cancer cell invasion inhibitors (e.g., metalloprotease inhibitors such as marimastat) agents, and inhibitors of urokinase-type plasminogen activator receptor function); (iv) inhibitors of growth factor function, such as growth factor antibodies, growth factor receptor antibodies (e.g., Anti-ErbB2 antibodies such as rastuzumab [Herceptin™] and anti-ErbB1 antibodies tuximab [C225]), antibody-drug conjugates (e.g., T-DM1), farnesyltransferase enzyme inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-chlorophenyl)- N-(3-hydroxybenzoate)quinazolin-4-amine (gefitinib, ZD1839), -ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-furan) (fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 033) and other epidermal growth factor family tyrosine kinase inhibitors); platelet-derived growth factor inhibitors of the hepatocyte growth factor family; inhibitors of the hepatocyte growth factor family; and PD325901 and and compounds disclosed in U.S. Patent Application Publication No. 2004 / 0116710. MEK inhibitors such as; (v) antiangiogenic agents, e.g., agents that inhibit the effects of vascular endothelial growth factor, e.g., limited However, anti-vascular endothelial growth factor antibody bevacizumab, VEGF receptor tyrosine kinase PTK7 inhibitors, such as vandetanib (ZD6474), sorafenib, and vatalanib 87), sunitinib (SU11248), axitinib (AG-013736), pazopa NIB (GW786034) and CEDIRANIB (AZD2171); International Patent Application No. 97 / Specification No. 22596, Specification No. 97 / 30035, Specification No. 97 / 32856, and compounds disclosed in US Pat. No. 98 / 13354; and compounds that act by other mechanisms. Compounds that act on the integrin ανβ3 function and angiostatin (e.g., linomide) inhibitors), or inhibitors of angiopoietins and their receptors (Tie-1 and Tie-2) toxic agents, inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4); (vi) vascular damaging agents, such as combrestatin A4 and WO 99 / 0216 Specification No. 6, Specification No. 0 / 40529, Specification No. 00 / 41669, Specification No. 01 / Specifications No. 92224, No. 02 / 04434, and No. 02 / 08213 compounds disclosed in the document; (vii) antisense therapeutics (e.g., directed against the above targets, such as ISIS2503) antisense, and anti-ras antisense); (viii) Gene therapy approaches, such as GVAX™, aberrant p53 or Approaches to replace abnormal genes such as abnormal BRCAI or BRCA2; GDEPT (Gene-Directed Enzyme Prodrug Therapy) approach, e.g., cytosine deaminase approaches using thrombinase, thymidine kinase, or bacterial nitroreductase enzymes, and and to improve patient tolerance to chemotherapy or radiation therapy, including multidrug resistance gene therapy. including approaches to; (ix) interferon; (x) immunotherapeutic approaches, including but not limited to, enhancing the immunogenicity of tumor cells in a patient; Ex vivo and in vivo approaches for the treatment of leukemia, such as interleukin 2, forms of cytokines such as interleukin 4, or granulocyte-macrophage colony-stimulating factor transfection; an approach to reduce T cell unresponsiveness or regulatory T cell function; approaches to enhance T cell responses, such as blocking antibodies against CTLA4 (e.g. ipilimumab and tremelimumab), blocking antibodies against B7H1, blocking antibodies against PD-1 Antibody (e.g., BMS-936558 or AMP-514), blocking PD-L1 Antibodies against CD137 (e.g., MEDI4736) and agonist antibodies against CD137; transfected immunosorbent assays Approaches using immune cells, e.g., cytokine-transfected dendritic cells; Approaches using transfected tumor cell lines, antibodies against tumor-associated antigens, and depletion of target cell types antibodies that induce vasoconstriction (e.g., rituximab, radiolabeled anti-CD20 antibody Bexar, and Zeta An approach using unconjugated anti-CD20 antibodies such as Valine and anti-CD54 antibodies (Campaign) Approach using anti-idiotypic antibodies; enhancing natural killer cell function as well as antibody-toxin conjugates (e.g., anti-CD33 antibody Mylotarg) immunotoxins such as moxetumomab pasudotox; Toll-like receptor 7 or contains an agonist of Toll-like receptor 9; (xi) potency enhancers, e.g., leucovorin may be selected from:

[0219] Thus, a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one Pharmaceutical compositions comprising additional anti-tumor agents are presented.

[0220] In some embodiments, the additional anti-tumor agent is a TKI (lapatinib, neratinib, and astatinib). Fatinib, etc.), anti-HER2 drugs (e.g., monoclonal antibodies such as trastuzumab, T -DM1), and combinations thereof. In some embodiments, the additional anti-tumor agent includes capecitabine, an anti-HER2 antibody, and T-DM1. In some embodiments, one additional anti-tumor agent is present. In some embodiments, there are two additional anti-tumor agents. In some embodiments, there are three or more additional anti-tumor agents. There is an agent.

[0221] In some embodiments, the amount of additional anti-tumor agent present in the composition of the present disclosure is A smaller amount than would normally be incorporated into a composition comprising an anti-tumor agent as the only active agent. In certain embodiments, the additional anti-tumor agent in the composition of the present disclosure may not be present. The amount of anti-tumor agent is that normally present in a composition comprising that anti-tumor agent as the only therapeutically active agent. The amount will be in the range of about 50% to about 100% of the amount.

[0222] The compound of formula (I) or a pharmaceutically acceptable salt thereof and the second active ingredient may be administered in a single pharmaceutical composition. They may be administered in the form of a pharmaceutical composition or separately, and when administered separately, they may be administered simultaneously. The doses may be administered sequentially or sequentially in any order. Such sequential administration may be close in time or separated in time. The compounds of formula (I) and (II) may be used in combination to achieve the desired combined therapeutic effect. The amounts of the two drugs and their relative timing will be selected.

[0223] The appropriate dosage for any of the above co-administered medications is not currently available. The doses are based on the combination of this newly identified agent with other chemotherapy agents or treatments. It may also decrease due to synergistic effects.

[0224] As used herein, "combination" refers to simultaneous, separate, or sequential administration. In some embodiments, "in combination" refers to simultaneous administration. In some embodiments, "in combination" refers to In some embodiments, "combined" refers to sequential administration. If administered separately, delaying the administration of this second component will negate the beneficial effects of this combination. This should not be the case.

[0225] Therefore, in another embodiment, in combination with one or more active ingredients such as the antitumor agents described above. Provided are compounds of formula (I) or a pharmaceutically acceptable salt thereof:

[0226] In other embodiments, one or more of the antitumor agents described above may be administered in combination with a pharmaceutically acceptable excipient. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an active ingredient. A pharmaceutical composition is presented.

[0227] In another embodiment, a compound or agent of formula (I) in combination with one or more of the antitumor agents described above. A kit comprising a physiologically acceptable salt thereof is presented.

[0228] In other aspects (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form; (b) an anti-tumor agent selected from the anti-tumor agents described above in a second unit dosage form; and (c) a container for containing said first unit dosage form and said second unit dosage form; A kit is presented comprising:

[0229] Treatment method In another embodiment, a type I receptor tyrosine kinase-associated disease or condition is present in a subject in need thereof. The present disclosure provides a method for treating a type I receptor tyrosine kinase inhibitory activity of a compound of the present disclosure, a therapeutically effective amount of a compound of formula (I) or administering to said subject a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. The method is presented as follows:

[0230] As used herein, the term "subject in need" refers to a type I receptor tyrosine kinase inhibitor. Type I receptor agonists, as compared to subjects with a kinase-associated disease or condition (e.g., cancer), or the general population have an increased risk of developing a tyrosine kinase-associated disease or condition (e.g., cancer) In the case of cancer, the subject in question may have a precancerous condition. In some embodiments, the warm-blooded animal is a human.

[0231] In this context, the term "therapeutically effective amount" refers to an amount sufficient to effect "treatment" of a subject or to administer to a subject an I. Compounds of formula (I) useful for "treating" type 2 receptor tyrosine kinase-associated diseases or disorders In the case of cancer, the amount of a compound or a pharmaceutically acceptable salt thereof that is observable or is measurable within the definitions of "cure," "treatment," and "prevention" above. Any of the changes described in the For example, this effective amount may reduce the number of cancer or tumor cells and cause overall tumor growth. The size and number of tumors are reduced, and tumor cell invasion into peripheral tissues, including soft tissue and bone, is suppressed or prevented. The present invention also inhibits and suppresses tumor metastasis, inhibits and suppresses tumor growth, and alleviates symptoms associated with cancer. Eliminating one or more of these to some extent reduces morbidity and mortality and improves quality of life. In some cases, the effective amount of the active ingredient may improve the efficacy of the active ingredient, improve the efficacy of the active ingredient, or cause a combination of these effects. is sufficient to reduce symptoms of diseases that respond to inhibition of type I receptor tyrosine kinase activity. For cancer treatment, in vivo efficacy can be measured, for example, by survival time, time to progression (TTP), ), as determined by response rate (RR), duration of response, and / or quality of life assessment As one skilled in the art will appreciate, effective amounts will vary depending on the route of administration, excipient usage, and other drug interactions. For example, if a combination therapy is used, the amount of The compound of formula (I) or a pharmaceutically acceptable salt thereof and the amount thereof of other pharmaceutical agents as described in the specification. The pharmacoactive agents, when used in combination, are jointly effective in treating the disorder of interest in an animal patient. In this context, the combined amounts are as follows: A "therapeutically effective amount" sufficient to reduce the symptoms of a disease responsive to inhibition of rosine kinase activity. is.

[0232] Generally, a "therapeutically effective amount" is a therapeutically effective amount that one skilled in the art would recognize, e.g., as described above for a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The dosage ranges described herein for the salts thereof and the approved dosage ranges for other pharmaceutically active compounds are also included. otherwise, determined by starting from a published dose range. There are cases where this happens.

[0233] In some embodiments, the type I receptor tyrosine kinase associated disease or condition is a disorder characterized by abnormal cell proliferation. The terms "abnormal cell growth" and "hyperproliferative disorder" are used herein. "Abnormal cell growth," as used herein, generally refers to a cell that is resistant to certain types of cancer. It refers to cell growth that is not governed by normal regulatory mechanisms (e.g., contact inhibition is lost). This abnormal cell proliferation can be caused by, for example, (1) the expression of mutant tyrosine kinases or receptor tyrosine kinases; (2) Abnormal proliferation of tumor cells (tumors) due to overexpression of tyrosine kinases (3) Abnormal proliferation of benign and malignant cells in other proliferative disorders in which abnormal activation of enzymes occurs Abnormal growth of any tumor that grows due to receptor tyrosine kinase, (4) Serine / Tre (5) Abnormal growth of any tumor that grows due to abnormal activation of onion kinase, and Aberrant activation of threonine / threonine kinases occurs in benign and malignant cells of other proliferative disorders. These include abnormal proliferation of cells.

[0234] In certain embodiments, the abnormal cell growth is cancer. 20. A method of treating a disorder comprising administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of .

[0235] In some embodiments, the cancer is a HER2-expressing cancer, a HER2-overexpressing cancer, or a HER2-ligated cancer. and α-and overexpressing cancers.

[0236] "HER2-expressing cancer" refers to cancer cells or tumors that have HER2 protein present on their cell surface. HER2-overexpressing cancers are cancers that contain cells that are significantly more expressing than non-cancerous cells of the same tissue type. Cancer cells or tumor cells have very high levels of HER receptors, such as HER2, on their cell surface. Such overexpression is caused by gene amplification or increased transcription or translation. This may cause you to wake up.

[0237] HER ligand-overexpressing cancers have significantly higher levels than non-cancerous cells of the same tissue type As used herein, the term "HER2 ligand" refers to a cancer that produces a HER2 ligand. " refers to a polypeptide that binds to and / or activates a HER receptor. However, epidermal growth factor (EGF), transforming growth factor α (TGF-α), and Amphiregulin, betacellulin, heparin-binding epidermal growth factor (HB-EGF), urin, epiregulin, neuregulin-2 (NRG-2), NRG-3, NRG-4, Examples include HER2 receptor 1 (CR-1) and HER2 receptor 2 (CR-2). GF, TGF-α, amphiregulin, betacellulin, HB-EGF, and epiregulin Examples include:

[0238] Expression or overexpression of HER receptors or HER ligands can be determined (e.g., by immunohistochemical assays). (by IHC) to assess increased levels of HER proteins present on the cell surface Alternatively or in a diagnostic or prognostic assay. In addition, fluorescence in situ hybridization (FISH; published October 1998) (See International Application Publication No. WO 98 / 45479), Southern blotting PCR, or polymerase chain reaction (PCR), such as real-time quantitative PCR (RT-PCR) The level of the nucleic acid encoding HER in the cells may be measured by PCR or the like. HER receptors can be detected by measuring shed antigens (e.g., HER extracellular domains) in body fluids. Overexpression of the receptor may be considered (see, e.g., U.S. Pat. No. 6,229,629, published June 12, 1990). Publication No. 4933294, published on April 18, 1991 No. 1 / 05264, published March 28, 1995, U.S. Patent Application Publication No. 540 No. 1638, and Sias et al. J. Immunol. Methods 132: 73-80 (1990). In addition to the above assays, various other assays have been In vivo assays are available to those skilled in the art. For example, in some cases radioisotopes are used. exposing cells in the patient's body to an antibody which may be labeled with a detectable label such as In some cases, the binding of the antibody to the patient's cells can be assessed, for example, by external radioactivity scanning. Alternatively, it can be assessed by analysis of a biopsy sample taken from a patient previously exposed to the antibody.

[0239] The expression or overexpression of HER receptors or HER ligands is determined by the biological activity of the treated patient. Evaluate the increased level of HER or HER ligand in a sample (cancer cells, etc.) This may be determined in diagnostic or prognostic assays. For example, antibodies that bind to and detect the expressed HER2 protein can be used. The test biological sample may be exposed to a HER2 antibody. Alternatively, qPCR, reverse transcriptase At the nucleic acid expression level using methods such as transcriptase PCR, microarray, SAGE, and FISH HER2 may be detected. Shed antigens (e.g., HER2 extracellular domains) in body fluids such as serum may be detected. HER receptor overexpression may be assessed by measuring the expression of HER receptors (see, e.g., U.S. Pat. No. 6,223,629). Publication No. 4933294, International Application Publication No. 91 / 05264, U.S. Pat. Publication No. 5401638 and Sias et al.J.Immunol.M Methods 132: 73-80 (1990). wherein the test sample is derived from cancer cells or cancer tissue, or tumor-infiltrating immune cells.

[0240] In certain embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, or cutaneous melanoma. or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, Fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endometrial cancer secretory cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or Acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, Central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumors, brainstem glioma, ptosis body adenoma, or a combination of one or more of the foregoing cancers.

[0241] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the metastatic cancer is a central In some embodiments, the central nervous system metastases include brain metastases. In some embodiments, the central nervous system metastases include leptomeningeal metastases. This occurs when cancer spreads to the meninges, the layer of tissue that covers the tumor. Or the metastases may be transported by cerebrospinal fluid (CSF) that flows through the meninges and leave the brain. In certain embodiments, the metastatic cancer is a breast cancer brain metastasis.

[0242] Thus, in another aspect, there is provided a method of treating breast cancer brain metastasis in a subject in need thereof, comprising: , a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure The method is presented as comprising administering to the subject an amount of

[0243] The method for treating a type I receptor tyrosine kinase-associated disease or condition described herein The method may be used as a monotherapy. As used herein, "monotherapy" refers to a method for treating a patient with a condition that is a serious illness or a serious condition. The term "therapy" refers to the administration of a single active or therapeutic compound to a subject in need thereof. In some embodiments, the monotherapy comprises administering a compound of the present disclosure to a subject in need of such treatment. or a pharmaceutically acceptable salt thereof.

[0244] Depending on the particular disease or condition being treated, the type I receptor tyrosine kinases described herein may be used. The method for treating a steroid-related disease or condition comprises administering a compound of formula (I) in addition to one or more Additional treatments, such as conventional surgery, radiation therapy, chemotherapy, or other such treatments As used herein, the term "combination therapy" may include a combination of The term refers to the administration of a combination of multiple active compounds.

[0245] These additional treatments, e.g., additional anti-tumor agents, may be administered in combination with the compounds of the present disclosure as part of a multi-drug regimen. Alternatively, these additional treatments may be administered separately from the other treatments in a single composition. It may be part of a single dosage form mixed with the compounds of the present disclosure.

[0246] In some embodiments, the compounds of the present disclosure can be used to treat cancer using conventional surgery, radiation therapy, or chemotherapy. The administration of the active ingredient may be simultaneous, sequential, or separate from the active treatment.

[0247] Radiation therapy includes the following categories of treatment: (i) external beam radiation using electromagnetic radiation; (ii) interstitial or intraluminal radiotherapy; and (iii) intraoperative radiotherapy using electromagnetic radiation. Internal radiation therapy or brachytherapy, including radiotherapy; or (iii) iodine-131 and strontium-131. A category of treatments called total body radiation therapy, which includes but is not limited to thium-89 It may contain one or more of these.

[0248] Chemotherapy may include anti-tumor agents known in the art, such as those described herein. These include anti-cancer drugs, cytostatics, anti-angiogenic drugs, immunotherapeutic approaches, and efficacy enhancers. May be included.

[0249] Thus, in one embodiment, a method for treating a type I receptor tyrosine kinase-associated disease in a subject in need thereof is provided. A method for treating a disease or condition comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof The method wherein the salt is administered simultaneously, separately, or sequentially with one or more additional anti-tumor agents. It is presented.

[0250] In some embodiments, the one or more additional anti-tumor agents include capecitabine, anti-HER2 antibodies, and T-DM1.

[0251] In some embodiments, the type I receptor tyrosine kinase associated disease or condition is HER2 In some embodiments, the type I receptor tyrosine kinase-associated disease or condition is In some embodiments, the HER2-associated disease or condition is cancer. Included are breast cancer, gastric cancer, mCRC, NSCLC, or metastases thereof. wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more of the compounds of formula (I) are administered in the amount of The above additional antitumor agents are effective in synergistically exerting anticancer effects.

[0252] In another aspect, there is provided a method of treating breast cancer brain metastasis in a subject in need thereof, comprising administering to a subject a compound of formula (I) The compound or a pharmaceutically acceptable salt thereof is administered simultaneously with one or more additional antitumor agents, separately. The method is presented wherein the two or more compounds are administered simultaneously or sequentially. [Example]

[0253] The following examples are included for illustrative purposes. However, these examples are not intended to be limiting of the invention. They are not intended to be limiting, but merely to suggest a method of practicing the present disclosure. Those skilled in the art will readily appreciate that the chemical reactions described can be readily modified to prepare many other compounds of the present disclosure. Alternative methods for preparing the compounds of the present disclosure are possible and are considered to be within the scope of the present disclosure. For example, it is understood that the synthesis of compounds not exemplified in accordance with the present disclosure may be carried out in a manner that is consistent with the present disclosure. The composition may involve modifications obvious to those skilled in the art, such as appropriate protection of interfering groups, and the use of reagents other than those described. Use of other suitable reagents and / or routine modifications of reaction conditions known in the art. Alternatively, the method disclosed herein or Other reactions known in the art are applicable to the preparation of other compounds of the present disclosure. It will be understood that.

[0254] The following abbreviations are used in the examples: [Table 2] TIFF2026009898000042.tif185133TIFF2026009898000043.tif29133

[0255] Example 1 N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-methylphenyl Toxicquinazolin-4-amine [ka]

[0256] Step 1: 4-chloro-6-hydrazinylpyrimidine [ka]

[0257] 4,6-Dichloropyrimidine (100 g, 675.7 mmHg) in EtOH (900 mL) A 50 wt% aqueous solution of hydrazine (130 mL) was added to a solution of 100 ml of hydrazine at 45°C for 2 hours. The reaction mixture was then stirred at 45-50° C. for 2 hours. The crude mixture was filtered and the solid was washed with water to give the desired product (91 g, 94%) as a yellow solid. Obtained as a solid. MS (ESI) m / z: 145.1 (M+H) + .

[0258] Step 2: 7-chloro-[1,2,4]triazolo[1,5-c]pyrimidine [ka]

[0259] 4-Chloro-6-hydrazinylpyrimidine (91 g, 632 mmHg) in HCl(OMe) A solution of 1,2-diol) was stirred at 90° C. overnight. The crude mixture was concentrated and The resulting mixture was diluted with EtOAc (500 mL× The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and filtered. The residue was purified by column chromatography on silica gel (PE:Et OAc=5:1) to give the desired product (70 g, 72%) as a yellow solid Got it. MS (ESI) m / z: 155.1.

[0260] Step 3: 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1 ,5-c]pyrimidine [ka]

[0261] 2-Methyl-4-nitrophenol (30 g, 196 mmHg) in MeCN (500 mL) To a solution of 1000 ml of K2CO3 (67.6 g, 490 mmol) was added at 0 °C, and this crude mixture The mixture was stirred at room temperature for 15 minutes. 2[1,5-c]pyrimidine (33 g, 214 mmol) was added to the mixture. The reaction was stirred at 60° C. for 72 hours. The crude mixture was filtered and the filtrate The residue was triturated with MeOH (50 mL) and filtered to give the desired product. The product (13 g, 24%) was obtained as a brown solid. MS (ESI) m / z: 272.1 (M+H) + .

[0262] Step 4: 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) )-3-Methylaniline [ka]

[0263] 7-(2-methyl-4-nitrophenoxy) in propan-2-ol (200 mL) -A solution of [1,2,4]triazolo[1,5-c]pyrimidine (13 g, 48 mmol) Fe (53.7g, 960mmol), NH4Cl (25.7g, 480mmol), and water (20 mL) were added. The reaction was stirred at 120° C. for 1 hour. The crude mixture was cooled and filtered. The filtrate was concentrated and diluted with aqueous NaHCO3 (200 The resulting mixture was extracted with DCM (200 mL x 2). The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH=20:1). to give the desired product (8.3 g, 72%) as a yellow solid. MS (ESI) m / z: 242.2 (M+H) + .

[0264] 4-([1,2,4]triazolo[1,5-c]pyrimidine-7) in DCM (2 mL) Dissolve the solution of (-yloxy)-3-methylaniline (25 mg) in one clean, dry tube. The tube was then sealed with parafilm. Crystals were formed at room temperature for 3 days in a shady location. Single crystals of sufficient size were obtained.

[0265] Analysis of the single crystal of the compound shown in Figure 1 reveals that the [1,2 The presence of the [1,4]triazolo[1,5-c]pyrimidine ring is shown. The single crystal data and structure refinement parameters for the compounds are reported in Table 2. [Table 3] TIFF2026009898000050.tif58130

[0266] Step 5: 6-Bromo-2-fluoro-3-methoxybenzoic acid [ka]

[0267] 2-Fluoro-3-methoxybenzoate in CH3COOH / H2O (300 mL / 300 mL) A solution of benzoic acid (90.0 g, 529.4 mmol) was added. The mixture was stirred at 0°C. Stir, then add Br2 (41 mL, 794.12 mmol) in CH3COOH (50 mL). The reaction mixture was stirred for 1 hour from 0°C to room temperature. When LCMS showed the reaction was complete, H2O (2.5 L) was added The precipitate was filtered and the filter cake was washed with water. The crude product was dissolved in petroleum ether The mixture was precipitated to give the title compound (110 g, 84% yield) as a white solid. MS (ESI) m / z: 247.1 (M+H) + .

[0268] Step 6: 6-bromo-2-fluoro-3-methoxybenzoate methyl [ka]

[0269] 6-Bromo-2-fluoro-3-methanone in 1.05 L of MeCN / MeOH (6 / 1) To a stirred solution of benzoic acid (90 g, 361.4 mmol) at 0 °C under Ar protection, TMS -CHN2 (450 mL, 904.0 mmol) was added. The solution was then allowed to cool to room temperature. The mixture was warmed to rt and stirred for 1 h. LCMS showed the reaction was complete. H2O (1.5 L) was added to the filter, and the mixture was extracted with EtOAc (800 mL x 3). The organic layers were washed with brine, concentrated, and the residue was purified by column chromatography. (PE: EtOAc = 20:1) to give the title compound (75 g, 79% yield). Obtained as a white solid. MS (ESI) m / z: 263.0 (M+H) + .

[0270] Step 7: 6-((tert-butoxycarbonyl)amino)-2-fluoro-3-meth Methyl benzoate [ka]

[0271] 6-Bromo-2-fluoro-3-methoxybenzoate in 1,4-dioxane (2000 mL) A solution of methylbenzoate (75 g, 284.1 mmol) and tert-butyl carbamate Pd(OAc)2 (4.45 g, 19.8 mmol), Xantphos (32.84 g, 56.8 mmol), and Cs2CO3 (185.23 g, 568.2 mmol) were added. The mixture was stirred at 100 °C for 4 h under Ar2 protection. When the reaction was complete, the mixture was filtered and concentrated. The title compound ( (70 g, 82% yield) was obtained as a white solid. MS (ESI) m / z: 200.2 (M+H-100) + .

[0272] Step 8: 6-amino-2-fluoro-3-methoxybenzoic acid methyl ester hydrochloride [ka]

[0273] 6-((tert-butoxycarbonyl)amino)-2- in methanol (1.5 L) A solution of methyl fluoro-3-methoxybenzoate (70 g, 234.1 mmol) in HCl A 4M dioxane solution (200 mL) was added. The mixture was stirred at room temperature overnight. When LCMS showed the reaction was complete, the reaction mixture was dried. Concentration to give the crude product (55 g, 100% yield) as a white solid. MS (ESI) m / z: 199.9 (M+H) + .

[0274] Step 9: 5-Fluoro-6-methoxyquinazolin-4(3H)-one [ka]

[0275] 6-amino-2-fluoro-3-methoxybenzoate in 2-methoxyethanol (300 mL) A solution of methyl benzoate hydrochloride (55 g, 234 mmol) was added to formamidine acetate (36. 5 g, 351 mmol) was added, and the mixture was stirred at 100° C. overnight. When LCMS showed the reaction was complete, the reaction mixture was concentrated in vacuo and The precipitate was filtered and the filter cake was diluted with HO (100 mL). The solid was collected and dried in vacuo to give the title compound (42 g, 92% yield) as a brown solid. MS (ESI) m / z: 195.1 (M+H) + . 1 H NMR ( 400 MHz, DMSO-d6): δ 12.12 (s, 1H), 7.93 (s, 1H), 7.72-7.68 (t, J = 8.48 Hz, 1H ), 7.49-7.46 (m, 1H), 3.92(s, 3H).

[0276] Step 10: 5-Fluoro-6-methoxy-3-((2-(trimethylsilyl)ethoxy) )methyl)quinazolin-4(3H)-one [ka]

[0277] 5-Fluoro-6-methoxyquinazoline-4(3H)- in dry DMF (300 mL) A solution of 12.98 g (324.7 mmol) of 60% NaHCO3 (42 g, 216.5 mmol) The mixture was stirred at this temperature for 0.5 h. After stirring, SEMCl (54.2 g, 324.7 mmol) was added dropwise. After stirring at room temperature for 0.5 h, the mixture was diluted with water (200 mL) and The organic layer was extracted with 200 mL of EtOAc (3 times). Washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The residue was purified by column chromatography (Et0Ac:PE=1:50). This gave the title compound (40 g, 60% yield) as a white solid. MS (ESI) m / z: 32 5.1 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.51-7.42 (m, 2H), 5.40 (s, 1H), 3.98 (s, 3H), 3.71-3.67 (t, J = 8.4 Hz, 2H), 0.98-0.94 (t, J = 8.4 Hz, 2H) , 0.00 (s, 9H).

[0278] Step 11: 5-(3-(dimethylamino)azetidin-1-yl)-6-methoxy-3 -((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one [ka]

[0279] 5-Fluoro-6-methoxy-3-( (2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (3.2 A solution of Cs2CO3 (9.8 g, 30 mmol) and Cs2CO3 (9.8 g, 30 mmol) was treated with N,N-dimethylformamide. Thiazetidin-3-amine dihydrochloride (2 g, 12 mmol) was added. The resulting mixture was stirred at 90° C. for 16 hours. The crude mixture was filtered and The filtrate was poured into ice water and washed with EtOAc (100 mL). The organic phase was separated, washed with water and brine, and extracted with anhydrous Na2SO4. The residue was purified by column chromatography on silica gel. Further purification gave the desired product (1.8 g, 45% yield) as an oil. MS (ESI) m / z: 405 (M+H) + .

[0280] Step 12: 5-(3-(dimethylamino)azetidin-1-yl)-6-methoxyquina Zolin-4(3H)-one [ka]

[0281] 5-(3-(dimethylamino)azetidinyl)-2-(2-methyl-2-propanol)-1,2-diol in DCM (50 mL) stirred at room temperature methyl-1-yl)-6-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl) A solution of quinazolin-4(3H)-one (1.1 g, 2.7 mmol) was added to TFA (10 mL The resulting mixture was stirred at room temperature for 4 hours and then dried. The residue was basified with aqueous NaHCO3 to adjust the pH to 9, and DC Extract with M (100 mL), dry over anhydrous Na2SO4, filter, and concentrate to give the desired The product (0.7 g, 94% yield) was obtained as an oil. MS (ESI) m / z: 275 (M+H) + .

[0282] Step 13: 1-(4-chloro-6-methoxyquinazolin-5-yl)-N,N-dimethyl azetidin-3-amine [ka]

[0283] 5-(3-(dimethylamino)methyl)-2,4-dimethyl-1,4-dimethyl ... (amino)azetidin-1-yl)-6-methoxyquinazolin-4(3H)-one (100m g, 0.36 mmol) and triphenylphosphine (191 mg, 0.73 mmol) To the solution was added carbon tetrachloride (167 mg, 1.10 mmol). The mixture was heated to 70° C. overnight. After cooling, the solvent was evaporated to dryness to give the crude product. The product was purified by preparative TLC to give the desired product (82 mg, 75% yield) as a yellow solid. MS (ESI) m / z: 293 (M+H) + .

[0284] Step 14: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (3-(dimethylamino)azetidin-1-yl)-5-(3-(dimethylamino)azetidin-1-yl)-3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl ... (I)-6-Methoxyquinazolin-4-amine [ka]

[0285] 1-(4-chloro-6-methoxyquinazoline- in propan-2-ol (20 mL) 5-yl)-N,N-dimethylazetidin-3-amine (82 mg, 0.27 mmol) and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3 -methylaniline (66 mg, 0.27 mmol) was heated to 70 °C overnight. The crude mixture was cooled and reacted with aqueous NaHCO3 (10 mL). The reaction was stopped, and the resulting mixture was extracted with DCM (20 mL). The residue was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by preparative TLC gave the desired product (32 mg, 23% yield) as a white solid. Got it. MS (ESI) m / z: 498 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 14.40 (br, 0.5H), 14. 00 (br, 0.5H), 9.20 (d, J = 1.3 Hz, 1H), 8.56 (s, 1H), 8.26 (d, J = 44.7 Hz, 2H) , 7.97-7.63 (m, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.88 (s , 1H), 4.70-4.41 (m, 2H), 4.06 (s, 3H), 3.90-3.64 (m, 2H), 3.36-3.14 (m, 1H), 2. 44-2.20 (m, 9H).

[0286] Example 2 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-Methoxyquinazolin-4-amine [ka]

[0287] The title compound was prepared using a procedure similar to that in Example 1 to give the desired product as a white solid. MS: m / z 512 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 13.66 (d, J = 24.1 Hz, 1H ), 9.20 (dd, J = 3.6, 1.2 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 4.1 Hz, 1H), 8.06- 7.63 (m, 4H), 7.49 (dd, J = 9.2, 4.3 Hz, 1H), 7.12 (dd, J = 13.5, 8.7 Hz, 1H), 6 .88 (dd, J = 16.3, 1.3 Hz, 1H), 4.01 (d, J = 3.7 Hz, 3H), 3.69-3.24 (m, 4H), 3.0 2 (d, J = 33.0 Hz, 1H), 2.44-2.20 (m, 11H).

[0288] Example 3 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-Methoxyquinazolin-4-amine [ka]

[0289] The title compound was prepared using a procedure similar to that in Example 1 to give the desired product as a yellow solid. MS: 512 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 13.68 (d, J = 23.0 Hz, 1H), 9 .20 (d, J = 3.6 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 4.0 Hz, 1H), 8.07-7.63 (m, 4 H), 7.48 (dd, J = 9.2, 4.0 Hz, 1H), 7.11 (dd, J = 13.9, 8.7 Hz, 1H), 6.88 (d, J = 16.3 Hz, 1H), 4.01 (d, J = 2.7 Hz, 3H), 3.70-3.22 (m, 4H), 3.12-2.89 (m, 1H), 2.59-2.03 (m, 11H).

[0290] Example 4 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-Methylphenyl)-6-methoxy-5-morpholinoquinazolin-4-amine [ka]

[0291] The title compound was prepared using a procedure similar to that in Example 1 to give the desired product as a white solid. MS: m / z 485 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 13.60 (s, 1H), 9.20 (d, J = 1.3 Hz, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.86-7.68 (m, 2H), 7.49 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 1.3 Hz , 1H), 4.17-3.84 (m, 9H), 2.93 (d, J = 10.6 Hz, 2H), 2.27 (s, 3H).

[0292] Example 5 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1-methylpiperidin-4-yl)oxy) CI) Quinazoline-4-amine [ka]

[0293] The title compound was prepared using a procedure similar to that in Example 1 to give the desired product as a white solid. MS: m / z 513 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ10.26(s, 1H), 9.20(s, 1H), 8.59(s, 1H), 8.32(s, 1H), 7.85 (d, J=2.4Hz, 1H), 7.72-7.69(m, 1H) 7.66(d, J=9.2 Hz, 1H),7.51(d, J=9.2Hz, 1H), 7.12(d, J=8.8Hz, 1H), 6.90(s, 1H), 4.57-4.51(m, 1H) ), 4.00(s, 3H), 2.91-2.88(m, 2H), 2.27(s, 6H), 2.13-2.04(m, 2H), 2.01-1.94(m, 2H) ), 1.94-1.81 (m, 2H).

[0294] Using a procedure similar to that of Example 1, but using different starting materials, the following compounds were prepared: [Table 4] TIFF2026009898000066.tif63130

[0295] Example 11 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-ene Toxicquinazolin-4-amine [ka]

[0296] Step 1: 5-Fluoro-6-hydroxyquinazolin-4(3H)-one [ka]

[0297] 5-Fluoro-6-(2 ... A solution of methoxyquinazolin-4(3H)-one (1 g, 5.15 mmol) was added to BBr3( The resulting mixture was added dropwise to the flask at 0°C. The mixture was stirred at room temperature for 48 hours and then quenched with MeOH at 0°C. The solvent was evaporated to give the crude product (1 g) as a brown solid, which was carried on without further purification. Used in the next step. MS: 181 (M+H) + .

[0298] Step 2: 5-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl acetate [ka]

[0299] 5-Fluoro-6-hydroxyquinazo in AcO (10 mL) stirring at room temperature To a solution of phosphorus-4(3H)-one (1 g, 5.5 mmol) was added pyridine (1 mL). The resulting mixture was stirred at 110°C for 2 hours. After cooling, the crude mixture The mixture was poured into ice water and extracted with DCM (50 mL). The organic phase was separated and The residue was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The desired product (560 mg, in two steps) was purified by column chromatography on a tumbler. (45% yield) as a yellow solid. MS: 223 (M+H) + .

[0300] Step 3: 5-fluoro-4-oxo-3-((2-(trimethylsilyl)ethoxy)acetic acid )Methyl)-3,4-dihydroquinazolin-6-yl [ka]

[0301] 5-Fluoro-acetic acid in anhydrous DMF (10 mL) stirred at 0° C. under nitrogen 4-Oxo-3,4-dihydroquinazolin-6-yl (560 mg, 2.52 mmol) To the solution was added NaH (151 mg, 3.78 mmol) in small portions. The mixture was stirred at 0°C for 10 min, after which SEMCl (549 mg, 3.2 8 mmol) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for another 30 min. The mixture was stirred for 1 hour and then poured into ice water. (20 mL). The organic phase was separated, washed with water and brine, and extracted with anhydrous Na2SO4. Drying, filtering, and concentration gave crude 5-fluoro-4-oxo-3-((2-(trifluoromethyl)-2-propanol)-2-one acetate. (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-6-yl (1g) was obtained as a yellow solid. MS: 353 (M+H) + .

[0302] Step 4: 5-Fluoro-6-hydroxy-3-((2-(trimethylsilyl)ethoxy) )methyl)quinazolin-4(3H)-one [ka]

[0303] 5-Fluoro-4-oxo-3-acetic acid in MeOH (15 mL) stirred at room temperature ((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazoline-6- To a solution of 1 g (2.84 mmol) of methyl methylcellulose, K2CO3 (1.2 g, 8.52 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The residue was purified by column chromatography on silica gel. The desired product (500 mg, 57% yield over two steps) was purified by MS: 311 (M+H) + .

[0304] Step 5: 6-Ethoxy-5-fluoro-3-((2-(trimethylsilyl)ethoxy) Methyl)quinazolin-4(3H)-one [ka]

[0305] 5-Fluoro-6-hydroxy-3-(2-methyl-2-propanol)-2-one in MeCN (10 mL) stirred at room temperature ((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (50 0 mg, 1.61 mmol) and Cs2CO3 (1.55 g, 4.83 mmol) To the mixture was added EtI (502 mg, 3.22 mmol). The mixture was stirred for 16 h at 0° C. The crude mixture was filtered and extracted with EtOAc (10 mL). The filtrate was poured into ice water and extracted with EtOAc (30 mL). The organic phase was separated. , washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product. The product (400 mg, 54% yield) was obtained as an off-white solid. MS: 339 (M+H) + .

[0306] Step 6: 5-(3-(dimethylamino)azetidin-1-yl)-6-ethoxy-3- ((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one [ka]

[0307] N,N-Dimethylazetidin-3-amine in DMF (5 mL) stirring at room temperature dihydrochloride (264 mg, 1.53 mmol) and Cs2CO3 (1.54 g, 4 0.72 mmol) of 6-ethoxy-5-fluoro-3-((2-(trimethylsilyl) (3H)-(2-methyl-2-ethoxymethyl)quinazolin-4(3H)-one (400 mg, 1.18 mmol) l) was added, and the resulting mixture was stirred at 90°C for 16 hours. The crude mixture was filtered and washed with EtOAc (10 mL). The filtrate was poured into ice water and Extraction with EtOAc (30 mL) was performed. The organic phase was separated, washed with water and brine, and The mixture was dried over SO4, filtered, and concentrated. The residue was subjected to column chromatography on silica gel. Purification by column chromatography gave the desired product (300 mg, 61% yield) as an oil. : 419 (M+H) + .

[0308] Step 7: 5-(3-(dimethylamino)azetidin-1-yl)-6-ethoxyquinazo Phosph-4(3H)-one [ka]

[0309] 5-(3-(dimethylamino)azetidine) in DCM (4 mL) stirred at room temperature -1-yl)-6-ethoxy-3-((2-(trimethylsilyl)ethoxy)methyl) A solution of nazolin-4(3H)-one (300 mg, 0.718 mmol) was added to TFA (2 m L) was added, and the resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated to dryness, and the residue was basified with aqueous NaHCO3 to pH 9. The resulting mixture was extracted with DCM (15 mL) and washed with water over anhydrous Na2SO4 Drying, filtering, and concentration gave the desired product (200 mg crude, 98% yield). Obtained as an oil. MS: 289 (M+H) + .

[0310] Step 8: 1-(4-chloro-6-ethoxyquinazolin-5-yl)-N,N-dimethyl Azetidin-3-amine [ka]

[0311] 5-(3-(dimethylamino)methyl)-2,4-dimethyl-1,4-dimethyl ... (amino)azetidin-1-yl)-6-ethoxyquinazolin-4(3H)-one (100m g, 0.35 mmol) and triphenylphosphine (184 mg, 0.70 mmol) To the solution was added carbon tetrachloride (267 mg, 1.75 mmol). The mixture was heated to 70° C. overnight. After cooling and concentrating the reaction, the residue was separated. Purification by preparative TLC gave the desired product (82 mg, 76% yield) as a yellow solid. Obtained. LCMS: 307 (M+H) + .

[0312] Step 9: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl Oxy)-3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl )-6-ethoxyquinazolin-4-amine [ka]

[0313] 1-(4-chloro-6-ethoxyquinazoline-5) in propan-2-ol (5 mL) -yl)-N,N-dimethylazetidin-3-amine (50 mg, 0.16 mmol) and and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3- A mixture of methylaniline (39 mg, 0.16 mmol) was heated to 80°C overnight. After cooling, the crude mixture was quenched with aqueous NaHCO3 (10 mL). The organic phase was washed with water and brine, and then extracted with DCM (20 mL). The water was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC. The desired product (32 mg, 35% yield) was obtained as a white solid. MS: 511 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 9.20 (d, J = 1.2 Hz, 1H), 8.57 (s, 1H), 8.30 (d, J = 12.9 Hz, 2H), 8.20 (s, 1H), 7.77 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.89 (s, 1H), 4.56 (q, J = 11.3, 7.3 Hz, 2H), 4.35 - 4.25 (m, 2H), 3.79 (d, J = 32.2 Hz, 2H), 3.17 (s, 1H), 2.27 (s, 9H), 1.60 (d, J = 6.9 Hz, 3H) .

[0314] Example 12 N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-( 2-Fluoroethoxy)quinazolin-4-amine [ka]

[0315] Step 1: 5-fluoro-6-(2-fluoroethoxy)-3-((2-(trimethylsilyl) (aryl)ethoxy)methyl)quinazolin-4(3H)-one [ka]

[0316] 5-Fluoro-6-hydroxy-3-( (2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (140 mg, 0.45 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (19 Cs2CO3 (440 mg, 1.36 mmol) was added to a solution of Cs2CO3 (6 mg, 0.9 mmol). The resulting mixture was stirred at 60°C for 16 hours. The mixture was filtered and washed with EtOAc (10 mL). The filtrate was poured into ice water and washed with EtOAc (10 mL). The organic phase was separated, washed with brine, and dried over anhydrous Na2SO4. The residue was purified by column chromatography on silica gel to give Purification gave the desired product (140 mg, 87% yield) as an off-white solid. MS: 357 (M+H) + .

[0317] Step 2: 5-(3-(dimethylamino)azetidin-1-yl)-6-(2-fluoro Ethoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-4(3 H)-on [ka]

[0318] 5-Fluoro-6-(2-fluoroethoxy)-2-methyl-2-propanol in DMF (5 mL) stirred at room temperature 3-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-4(3H)- N,N-dimethylazetidin-3-aminedione (140 mg, 0.39 mmol) A solution of Cs2CO3 (512 mg, 2 The resulting mixture was stirred at 90°C for 16 hours. The crude mixture was then filtered and washed with EtOAc. The filtrate was added to ice water and The organic phase was separated, washed with brine, and The mixture was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel. Purification by chromatography gave the desired product (100 mg, 58% yield) as an oil. MS: 437 (M+H) + .

[0319] Step 3: 5-(3-(dimethylamino)azetidin-1-yl)-6-(2-fluoro Ethoxy)quinazolin-4(3H)-one [ka]

[0320] 5-(3-(dimethylamino)azetidin-1-yl)-6-( 2-Fluoroethoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazo To a solution of phosphorus-4(3H)-one (100 mg, 0.23 mmol) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 4 hours. The residue was concentrated to dryness and basified with aqueous NaHCO3 to adjust the pH to 9. The organic layer was dried over anhydrous Na2SO4 and filtered. Filtration and concentration gave the desired product (70 mg, 98% yield) as an oil. MS: 30 7 (M+H) + .

[0321] Step 4: 1-(4-chloro-6-(2-fluoroethoxy)quinazolin-5-yl)- N,N-Dimethylazetidin-3-amine [ka]

[0322] 5-(3-(dimethylamino)methyl)-2-(2-methyl-2-methyl-1,2-dichloroethane) in 1,2-dichloroethane (5 mL) stirred at room temperature. Amino)azetidin-1-yl)-6-(2-fluoroethoxy)quinazoline-4(3H )-one (70 mg, 0.227 mmol) and triphenylphosphine (119 mg, To a solution of 0.454 mmol of HCl was added carbon tetrachloride (174 mg, 1.14 mmol). The resulting mixture was heated to 70°C overnight. After evaporation to rt, the residue was purified by preparative TLC to give the desired product (50 mg, 65% Yield) as a yellow solid. LCMS: 325 (M+H) + .

[0323] Step 5: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl )-6-(2-fluoroethoxy)quinazolin-4-amine [ka]

[0324] 1-(4-chloro-6-(2-fluoroethoxy)methyl)propan-2-ol (5 mL) )quinazolin-5-yl)-N,N-dimethylazetidin-3-amine (50 mg, 0. 154 mmol) and 4-([1,2,4]triazolo[1,5-c]pyrimidine-7- A mixture of 1,2-dimethyl-3-methylaniline (37 mg, 0.154 mmol) and 1,2-dimethyl-3-methylaniline (37 mg, 0.154 mmol) was added overnight. The mixture was heated to 80° C. After cooling, the crude mixture was added with aqueous NaHCO3 (10 mL). The reaction was quenched with HCl and extracted with DCM (20 mL). It was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the desired product (30 mg, 35% yield) as a white solid. MS: 530 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 9.20 (d, J = 1.3 Hz, 1H ), 8.58 (s, 1H), 8.26 (d, J = 44.0 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 15.9 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.88 (s, 1H) ), 4.93 (d, J = 47.8 Hz, 2H), 4.66-4.33 (m, 4H), 3.75 (s, 2H), 3.17 (s, 1H), 2.3 0 (d, J = 20.1 Hz, 9H).

[0325] Example 17 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine

[0326] Example 18 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine [ka]

[0327] The racemic product was prepared using procedures similar to those in Examples 29 and 30 to give the desired product. was obtained as a white solid, which was subsequently separated by chiral SFC to give two isomers obtained.

[0328] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine (4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine was obtained as a white solid MS (ESI) m / z: 585(M+H) + . 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H) , 9.13 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 7.70-7.59 (m, 2H), 7.5 3 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 6.54 (t, 1H), 4.8 0-4.58 (m, 1H), 3.25-3.04 (m, 1H), 2.96-2.69 (m, 2H), 2.39- 2.22 (m, 4H), 2.18 ( s, 3H), 2.15-1.94 (m, 2H).

[0329] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine (4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine was obtained as a white solid MS (ESI) m / z: 585(M+H) + . 1 H NMR (400 MHz, CDCl3): δ9.89 (s, 1H) , 9.13 (s, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 7.71-7.61 (m, 2H), 7.5 4 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 6.54 (t, 1H), 4.8 7-4.52 (m, 1H), 3.21-3.08 (m, 1H), 2.98-2.58 (m, 2H), 2.37-2.21 (m, 4H), 2.19 (s , 3H), 2.14-2.08 (m, 2H).

[0330] Example 21 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((R)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo Phosphorus-4-amine

[0331] Example 22 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((S)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo Phosphorus-4-amine [ka]

[0332] Step 1: (S)-6-Bromo-2-fluoro-3-((tetrahydrofuran-3-yl) )Oxy)benzonitrile [ka]

[0333] 6-Bromo-2-fluoro-3-hydroxybenzonitrile (6 A solution of CsCO3 (1.82 g, 5.58 mmol) was added to the solution at 0 °C. ol) was added, followed by (R)-3-tosyltetrahydrofuran (810 mg, 3.34 After the addition, the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with water and brine, and then with anhydrous Na2 The residue was dried over SO4, filtered, and concentrated to dryness. Purification by chromatography (PE: EtOAc = 10:1) gave the desired product (60 0 mg, 75% yield) as a colorless oil.

[0334] Step 2: 4-(3-bromo-2-cyano-6-(((S)-tetrahydrofuran-3- (I)oxy)phenoxy)-3,3-difluoropiperidine-1-carboxylic acid tert -butyl [ka]

[0335] 3,3-Difluoro-4-hydroxypiperidine-1-carbohydrate in DMF (10 mL) A mixture of tert-butyl phosphate (598 mg, 2.52 mmol) and NaH , 2.95 mmol, 60% dispersion in mineral oil) was added at 0°C, and the mixture was heated at 0°C for 2 The mixture was stirred for 10 minutes. To the above mixture was added (S)-6-bromo-2-fluoro-3-(( Tetrahydrofuran-3-yl)oxy)benzonitrile (600 mg, 2.1 mmol ) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with 100 mL of ethyl acetate and extracted with 20 mL of EtOAc (30 mL x 2). The combined organic layers were washed with saturated N H4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by chromatography on silica gel (PE: EtOAc = 3:1) to give the desired product (800 mg, 76% yield) as an off-white solid. MS (ESI) m / z: 503 (M+H) + .

[0336] Step 3: 6-Bromo-2-((3,3-difluoropiperidin-4-yl)oxy)- 3-(((S)-tetrahydrofuran-3-yl)oxy)benzonitrile [ka]

[0337] 4-(3-bromo-2-cyano-6-(((S)-tetrahydro)- Furan-3-yl)oxy)phenoxy)-3,3-difluoropiperidine-1-carbo A solution of tert-butyl phosphate (800 mg, 1.59 mmol) was added to TFA (2 mL, 26 0.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude compound (800 mg ) was obtained as a viscous oil, which was used directly in the next step without further purification. (ESI) m / z: 403 (M+H) + .

[0338] Step 4: 6-Bromo-2-((3,3-difluoro-1-methylpiperidin-4-yl )oxy)-3-(((S)-tetrahydrofuran-3-yl)oxy)benzonitrile [ka]

[0339] 6-Bromo-2-((3,3-difluoropyridinium chloride)) in DCE / THF (16 / 0.8 mL) (S)-tetrahydrofuran-3-yl)oxy)-3-(((S)-tetrahydrofuran-4-yl)oxy)- (c) A solution of benzonitrile TFA salt (800 mg, 1.99 mmol) in formalin (2 0.3 mL) was added. The mixture was stirred at room temperature for 1 hour. To the mixture was added NaBH(OAc)3 (843 mg, 3.98 mmol). The mixture was stirred for an additional 2 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water (10 mL) and diluted with DCM / MeOH (10 mL x 3, 10 The combined organic layers were dried over Na2SO4, filtered, and The residue was purified by chromatography on silica gel (DCM:M The title compound (700 mg, 84% yield over two steps) was obtained by purifying the product with HCl (30:1) and HCl (30:1). Obtained as a yellow solid. MS (ESI) m / z: 417 (M+H) + .

[0340] Step 5: (2-cyano-3-((3,3-difluoro-1-methylpiperidin-4-yl) ((S)-tetrahydrofuran-3-yl)oxy)phenyl) tert-Butyl carbamate [ka]

[0341] 6-Bromo-2-((3,3-difluoro-1- Methylpiperidin-4-yl)oxy)-3-(((S)-tetrahydrofuran-3-yl) (( ... A mixture of t-butyl ether (398 mg, 3.36 mmol) and CsCO3 (1.09 g, 3 The mixture was degassed under N2 atmosphere three times and Pd(OAc)2 (19 mg, 0.08 mmol) and Xantphos (97 mg, 0. After the addition, the mixture was degassed twice under N2 atmosphere. and stirred overnight at 90° C. under a N atmosphere. c (10 mL) and washed with water and brine, dried over Na2SO4, filtered. and concentrated to give the crude product, which was purified by silica gel chromatography (DCM:Me The desired product (602 mg, 78% yield) was purified by HCl (HCl = 30:1) to give a white solid. MS (ESI) m / z: 454 (M+H) + .

[0342] Step 6: 6-amino-2-((3,3-difluoro-1-methylpiperidin-4-yl )oxy)-3-(((S)-tetrahydrofuran-3-yl)oxy)benzonitrile [ka]

[0343] (2-cyano-3-((3,3-difluoro-1-methylpiperidin)) in DCM (3 mL) ((S)-tetrahydrofuran-3-yl)oxy)-4-(((S)-tetrahydrofuran-3-yl)oxy) To a solution of tert-butyl (phenyl)carbamate (520 mg, 1.14 mmol) FA (1 mL, 13.4 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and saturated aqueous NaHCO3 was added. The residue was made alkaline to pH 8 by adding DCM (10 mL × The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The desired product (320 mg, 79% yield) was obtained as a yellow solid by filtration and concentration to dryness. Obtained as a colored oil. MS (ESI) m / z: 354 (M+H) + .

[0344] Step 7: (E)-N'-(2-cyano-3-((3,3-difluoro-1-methylpiperazin-3-yl)methyl)piperazin-3-yl) Lysin-4-yl)oxy)-4-(((S)-tetrahydrofuran-3-yl)oxy )phenyl)-N,N-dimethylformimidamide [ka]

[0345] 6-Amino-2-((3,3-difluoro-1-methylpiperidinyl) ((S)-tetrahydrofuran-3-yl)oxy)benzyl To a solution of benzonitrile (320 mg, 0.91 mmol) was added DMF-DMA (2 mL). The mixture was stirred at 70° C. for 2 h. mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=20:1 ) to give the desired product (180 mg, 49% yield) as a yellow solid. MS (ESI) m / z: 409 (M+H) + .

[0346] Step 8: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl (R)-3,3-difluoro-1-methylphenyl)-5-((oxy)-3-methylphenyl)-5-(((R)-3,3-difluoro-1-methylphenyl) (S)-tetrahydrofuran-3-yl)oxy)-6-(((S)-tetrahydrofuran-4-yl)oxy)-6-( ... Quinazolin-4-amine and N-(4-([1,2,4]triazolo[1,5-c] pyrimidin-7-yloxy)-3-methylphenyl)-5-(((S)-3,3-difluoromethylphenyl) ((S)-tetrahydro-1-methylpiperidin-4-yl)oxy)-6-( ... Lan-3-yl)oxy)quinazolin-4-amine [ka]

[0347] (E)-N'-(2-cyano-3-((3,3-difluoro- 1-Methylpiperidin-4-yl)oxy)-4-(((S)-tetrahydrofuran-3 -yl)oxy)phenyl)-N,N-dimethylformimidamide (180 mg, 0. 44 mmol) in a solution of 4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylaniline (160 mg, 0.66 mmol) was added, and The mixture was stirred at 100° C. for 5 h. The mixture was diluted with DCM (6 mL). Then, saturated aqueous NaHCO3 was added to make the mixture alkaline to a pH of 8. The mixture was extracted with DCM (5 mL x 2), and the combined organic layer was washed with brine. The residue was dried over Na2SO4, filtered, and concentrated to dryness. The racemic product was purified by chromatography (DCM:MeOH = 40:1 to 15:1). The product (90 mg, 34% yield) was obtained as a white solid, which was subsequently purified by chiral SF C to give two diastereomers.

[0348] N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((S)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo Phos-4-amine (30 mg, 67%) was obtained as a light yellow solid. 1 H-NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.42 (d, J = 3.4 Hz, 2H), 7.76 (dd, J = 13.2, 10.8 Hz, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 5.32 (s, 1H), 4.99 (s, 1H), 4.13-4.04 (m, 2H), 3.98-3.90 (m, 2H), 3.20 (s, 1H), 2.92 (d, J = 12.8 Hz, 1H), 2.50-2.31 (m, 5H), 2.30-2.20 (m, 6H), 2.08 (t, J = 12.0 Hz, 1H ). MS (ESI) m / z: 605 (M+H) + .

[0349] N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy) -3-methylphenyl)-5-(((R)-3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quina Zolin-4-amine (35 mg, 78%) was obtained as a light yellow solid. 1 H NMR (400 MH z, CD3OD) δ 9.44 (d, J = 1.2 Hz, 1H), 8.43 (d, J = 2.5 Hz, 2H), 7.83-7.71 (m, 3 H), 7.61 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H) , 5.34 (s, 1H), 4.93 (s, 1H), 4.13-4.03 (m, 2H), 4.02-3.91 (m, 2H), 3.17 (s, 1H) , 2.94 (s, 1H), 2.45-2.30 (m, 6H), 2.28-2.18 (m, 5H), 2.06-2.04 (m, 1H). MS (ESI ) m / z: 605 (M+H) + .

[0350] SFC conditions: Column: ChiralPak IA, 250 x 21.2mm inner diameter, 5μm Mobile phase A: CO2, Mobile phase B: Methanol (0.1% NH4OH); Concentration gradient: B40 %; Flow rate: 55 mL / min; Column temperature: 35°C

[0351] Example 29 (R)-N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine

[0352] Example 30 (S)-N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine [ka]

[0353] Step 1: 5-Fluoro-6-isopropoxy-3-((2-(trimethylsilyl)ethoxy)methyl) (xy)methyl)quinazolin-4(3H)-one [ka]

[0354] 5-Fluoro-6-hydroxy-3-((2-(trimethylsilyl)methyl)methyl) (450 mg, 1.45 mmol)ethoxymethyl)quinazolin-4(3H)-one To the solution of 2-(1), K2CO3 (600 mg, 4.35 mmol) was added at 0 °C, followed by 2- Iodopropane (0.43 mL, 4.35 mmol) was added. After the addition, the mixture The mixture was stirred at 90° C. for 12 hours. The reaction mixture was diluted with EtOAc (10 mL). and washed with water and brine, dried over anhydrous Na2SO4, filtered, and dried. The residue was purified by chromatography on silica gel (PE: EtOAc = 4 :1) to give the desired product (380 mg, 75% yield) as an off-white solid. LC / MS (ESI) m / z: 353 (M+H) + .

[0355] Step 2: 3,3-difluoro-4-((6-isopropoxy-4-oxo-3-((2 -(trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-5-yl) tert-Butyl oxy)piperidine-1-carboxylate [ka]

[0356] 3,3-Difluoro-4-hydroxypiperidine- in dry THF (8 mL) under N A solution of tert-butyl 1-carboxylate (307 mg, 1.29 mmol) was added to NaH(6 0 mg, 1.51 mmol, 60% dispersion in mineral oil) was added in several portions at 0°C. After the addition, the mixture was stirred at this temperature for 0.5 hours. -6-isopropoxy-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolidinyl To the above solution was added benzophenone-4(3H)-one (380 mg, 1.08 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and (10 mL x 2). The combined organic layer was washed with saturated aqueous NH4Cl and brine. The residue was extracted with HCl, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. Purification by chromatography on silica gel (PE: EtOAc = 3:1) gave the desired The product (550 mg, 89% yield) was obtained as an off-white solid. MS (ESI) m / z: 570 (M+H) + .

[0357] Step 3: 5-((3,3-difluoropiperidin-4-yl)oxy)-6-isopropyl Poxyquinazolin-4(3H)-one [ka]

[0358] 3,3-Difluoro-4-((6-isopropoxy-4-oxo)methyl)propanol in DCM (4 mL) -3-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazoline tert-Butyl (5-yl)oxy)piperidine-1-carboxylate (550 mg, 0. To a solution of 1000 mg of 1,000 sucrose (96 mmol) was added TFA (2 mL, 26.9 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to give the crude compound (500 mg) as a viscous oil, which was further It was used directly in the next step without further purification. MS (ESI) m / z: 340 (M+H) + .

[0359] Step 4: 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)- 6-Isopropoxyquinazolin-4(3H)-one [ka]

[0360] 5-((3,3-difluoropiperidine-4)-4-hydroxybenzoate in DCE / THF (10 / 0.5 mL) -yl)oxy)-6-isopropoxyquinazolin-4(3H)-one TFA salt (500 To a solution of 1.47 mg (1.47 mmol) of 1,450 mg of hydroxybenzoates was added formalin (1.45 mL). The mixture was stirred at room temperature for 1 hour. Then, NaBH(OAc)3 (62 3 mg, 2.94 mmol) was added. The mixture was stirred for an additional 2 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water (10 mL). and extracted with DCM / MeOH (10 mL x 3, 10 / 1 v / v). The organic layer was dried and filtered. The filtrate was concentrated and chromatographed on silica gel. The product was purified by column chromatography (DCM:MeOH=30:1) to give the title compound (270 mg, 2 (50% yield in 50 steps) as a yellow solid. MS (ESI) m / z: 372 (M+H) + .

[0361] Step 5: 4-chloro-5-((3,3-difluoro-1-methylpiperidin-4-yl )Oxy)-6-isopropoxyquinazoline [ka]

[0362] 5-((3,3-difluoro-1-methylpiperidin-4-yl)methyl)-2-(2-(2-methyl-3-piperidin-4-yl)methyl)- ... )oxy)-6-isopropoxyquinazolin-4(3H)-one (230 mg, 0.65 To a mixture of 100 mmol of ethanol, DIPEA (0.54 mL, 3.25 mmol) and limonene oxychloride were added. Aqueous ether (0.3 mL, 3.25 mmol) was added at 0°C. The mixture was placed under a N2 atmosphere. The mixture was stirred at 90° C. for 4 hours, and LCMS showed the reaction was complete. The resulting mixture was cooled to 0°C, poured into ice water, and added to saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (10 mL x 3). The combined organic layer was washed with water and and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The desired product (230 mg, 95% yield) was obtained as a brown solid. MS (ESI) m / z : 372 (M+H) + .

[0363] Step 6: (R)—N-(4-([1,2,4]triazolo[4,3-c]pyrimidine- 7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylphenyl) (S)-6-(2 ... -N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy) -3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl) (per)oxy)-6-isopropoxyquinazolin-4-amine [ka]

[0364] 4-chloro-5-((3,3-difluoro-1- Methylpiperidin-4-yl)oxy)-6-isopropoxyquinazoline (230 mg, 0.62 mmol) in a solution of 4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylaniline (165 mg, 0.68 mmol) was added. The reaction mixture was stirred at 90°C under N2 atmosphere. The reaction was complete by LCMS. The reaction mixture was concentrated to remove propan-2-ol. The residue was dissolved in DCM (10 mL) and basified with saturated aqueous NaHCO3 to pH 8. The mixture was extracted with DCM:MeOH = 10:1 (10 mL x 3 times). The residue was washed with water, dried over Na2SO4, filtered, and concentrated to dryness. Purify by silica gel chromatography (DCM:MeOH=40:1 to 15:1) The racemic product (190 mg, 54% yield) was obtained as a white solid, which was then The two enantiomers were separated by chiral SFC.

[0365] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine (50 mg, 53%) was obtained as a light yellow solid. 1 HNMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.2 Hz, 1H), 8.42 (d, J = 3.2 Hz, 2H), 7.84-7.71 (m, 3H), 7.58 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 5.06-4.93 (m, 1H), 4.84 (dt, J = 12.0 , 6.0 Hz, 1H), 3.26-3.15 (m, 1H), 2.94 (d, J = 12.4 Hz, 1H), 2.44 (dd, J = 29.0, 12.0 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 2.15-2.03 (m, 1H), 1.44 (dd, J = 13.6 , 6.0 Hz, 6H), 1.20 (dd, J = 30.8, 12.0 Hz, 2H). MS (ESI) m / z: 577 (M+H) + .

[0366] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-isopropoxyquinazolin-4-amine (60 mg, 63%) ) as a light yellow solid. 1 HNMR (400 MHz, CD3OD) δ 9.44 (d, J = 1.2 Hz, 1H) , 8.42 (d, J = 2.8 Hz, 2H), 7.82-7.70 (m, 3H), 7.59 (d, J = 9.2 Hz, 1H), 7.17 (d , J = 8.4 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 4.99 (dd, J = 12.4, 8.1 Hz, 1H), 4. 86-4.81 (m, 1H), 3.19 (s, 1H), 2.94 (d, J = 11.8 Hz, 1H), 2.45 (dd, J = 28.9, 12 .3 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 2.09 (d, J = 11.9 Hz, 1H), 1.44 (dd, J = 13.7, 6.0 Hz, 6H), 1.26-1.14 (m, 2H). MS (ESI) m / z: 577 (M+H) + .

[0367] SFC conditions: Column: ChiralPakIA, 250 × 21.2 mm i.d., 5 μm; Mobile phase A: CO2, Mobile phase B: methanol (0.1% NH4OH); gradient: B 40% Flow rate: 55 mL / min; Column temperature: 35°C

[0368] Example 72 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine

[0369] Example 73 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine [ka]

[0370] The racemic product was prepared using procedures similar to those in Examples 21 and 22 to give the desired product. was obtained as a yellow solid, which was subsequently separated by chiral SFC into two isomers obtained.

[0371] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine was obtained as a solid. 1 H-NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 7.91-7.73 (m, 3H), 7.69 (d, J = 9.2 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 4.87 (m, 1H), 3.20 (m, 1H), 2.93 (m, 1H), 2.49 (m, 1H), 2.34 (s, 3 H), 2.26 (s, 4H), 2.18 (m, 2H). MS (ESI) m / z: 604 (M+H) + .

[0372] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine was obtained as a solid. 1 H-NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 7.83 (m, 3H), 7.69 (d, J = 9.2 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 1.2 Hz, 1H), 4.86 (m, 1H), 3.22 (m, 1H), 2.93 (d, J = 11.8 Hz, 1H), 2.49 (dm, 1H), 2.34 (s, 3H), 2.24 (m, 4H), 2.22-2.12 (m, 2H). MS (ESI) m / z: 604 (M+H ) + .

[0373] Example 74 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine

[0374] Example 75 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0375] The racemic product was prepared using procedures similar to those in Examples 21 and 22 to give the desired product. was obtained as a yellow solid, which was subsequently separated by chiral SFC into two isomers obtained.

[0376] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((4,4-difluoro-1-methylpyrrolidine (3-yl)oxy)-6-methoxyquinazolin-4-amine as a yellow solid .1 H-NMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.0 Hz, 1H), 8.39 (t, J = 7.7 Hz, 2H), 7.85-7.76 (m, 2H), 7.74 (d, J = 9.3 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.20-7.1 3 (m, 1H), 6.92 (d, J = 1.0 Hz, 1H), 5.52 - 5.40 (m, 1H), 4.04 (s, 3H), 3.30-3.1 4 (m, 2H), 2.89-2.70 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H). MS (ESI) m / z: 535 (M+H ) + .

[0377] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((4,4-difluoro-1-methylpyrrolidine To give (3-yl)oxy)-6-methoxyquinazolin-4-amine, 1 H-NMR (400 MHz, CD3OD) δ 9.33 (d, J = 1.0 Hz, 1H), 8.30 (d, J = 8.3 Hz, 2H), 7.72-7.61 (m, 3H) , 7.49 (d, J = 9.2 Hz, 1H), 7.10-7.01 (m, 1H), 6.82 (d, J = 1.0 Hz, 1H), 5.40-5. 31 (m, 1H), 3.94 (s, 3H), 3.20-3.04 (m, 2H), 2.77-2.62 (m, 2H), 2.22 (s, 3H), 2. 15 (s, 3H). MS (ESI) m / z: 535 (M+H) + .

[0378] SFC conditions: Column: ChiralPak OD, 250 x 21.2mm inner diameter, 5μm Mobile phase A: CO2, Mobile phase B: Methanol (0.1% NH4OH); Concentration gradient: B40 %; Flow rate: 50 mL / min; Column temperature: 35°C

[0379] The following compounds were prepared according to the above method using different starting materials: [Table 5] TIFF2026009898000103.tif189130TIFF2026009898000104.tif189129TIFF2026009898000105.tif33131

[0380] Example 31 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine

[0381] Example 32 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0382] Step 1: 3,3-difluoro-4-((6-methoxy-4-oxo-3-((2-(trifluoromethyl)-2-methyl-4-oxo-3-( ... (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-5-yl)oxy ) tert-Butyl piperidine-1-carboxylate [ka]

[0383] 3,3-Difluoro-4-hydroxybenzoate under Ar2 protection in dry THF (200 mL) tert-Butyl dimethylpiperidine-1-carboxylate (11.38 g, 48.0 mmol) To the solution was added 60% NaH (2.24 g, 56.0 mmol) in several portions at 0°C. After the addition, the mixture was stirred at this temperature for 0.5 hours. -6-Methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-4 (3H)-one (13 g, 40.0 mmol) was added to the above solution. The reaction was quenched with H2O (100 mL) and stirred overnight at room temperature. The reaction mixture was extracted with CH2Cl2 (150 mL x 3). The combined organic layers were washed with brine. The mixture was washed, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and The title compound (20 g, 92% yield) as a white solid. MS (ESI) m / z: 542.2 (M+H) + .

[0384] Step 2: 5-((3,3-difluoropiperidin-4-yl)oxy)-6-methoxy Synthesis of quinazolin-4(3H)-one TFA salt [ka]

[0385] 3,3-Difluoro-4-((6-methoxy-4-oxo- 3-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazoline- tert-Butyl (5-yl)oxy)piperidine-1-carboxylate (20 g, 36.97 To a solution of 100 mmol of 1,000 sucrose was added TFA (42.1 g, 369.7 mmol). The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was then concentrated to give the crude compound (12 g) as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z: 312.1 (M+H) + .

[0386] Step 3: 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)- Synthesis of 6-methoxyquinazolin-4(3H)-one [ka]

[0387] 5-((3,3-Difluoropiperidine) in DCE / THF (200 mL / 10 mL) -4-yl)oxy)-6-methoxyquinazolin-4(3H)-one TFA salt (12 g, To a solution of 29.0 mmol of benzoyl perfluorooctanoate (29.0 mmol) was added formalin (60 mL). After stirring for 1 hour, NaBH(OAc)3 (18.4 g, 86.8 mmol) ) was added to the mixture. The mixture was stirred for an additional 2 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were washed with water (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by column chromatography (CH2Cl2:MeOH = 20:1) to give the title compound (8 g, 84% yield over two steps) as a yellow solid. MS (ESI) m / z: 326.1 (M+H)+ .

[0388] Step 4: 4-chloro-5-((3,3-difluoro-1-methylpiperidin-4-yl Synthesis of )hydroxy)-6-methoxyquinazoline [ka]

[0389] 5-((3,3-difluoro-1-methylpiperidine-4- (yl)oxy)-6-methoxyquinazolin-4(3H)-one (4.5g, 13.8mm ol) and DIEA (8.9 g, 69 mmol) was added to a solution of POCl3 (8.5 g, 55. 4 mmol) was added dropwise under Ar protection. The reaction mixture was heated at 95°C for 3 hours. The reaction mixture was then cooled to room temperature and poured into ice water. The pH of the resulting mixture was slowly adjusted to 7-8 with NaHCO3. After extraction with l2:MeOH = 20:1 (150 mL x 2), the mixture was mixed. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness. The title compound (4.3 g, 91% yield) was obtained as a brown solid. MS (ESI) m / z : 344.1 (M+H) + .

[0390] Step 5: (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidine- 7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylphenyl) (peridin-4-yl)oxy)-6-methoxyquinazolin-4-amine and (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0391] 4-chloro-5-((3,3-difluoro-1-methyl-2-methyl ... -methylpiperidin-4-yl)oxy)-6-methoxyquinazoline (410 mg, 1. 19 mmol) was added to a solution of TsOH.HO (68 mg, 0.36 mmol) and 4-([ 1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline Phosphorus (259 mg, 1.07 mmol) was added, and the resulting mixture was heated under Ar The mixture was stirred at 100°C under heating and concentrated. The residue was dissolved in H2O (100 mL). The mixture was made basic with NaHCO3 aqueous solution to pH 7-8, and the mixture was diluted with DCM:MeOH = 20:1 ( The combined organic layer was dried over anhydrous Na2SO4 and filtered. The residue was purified by column chromatography (DCM / MeOH=30 / 1). to give the product (300 mg, 46% yield) as a white solid. The racemic material was separated by chiral SFC to give two isomers.

[0392] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine (peak 1, retention time 6.2 41 min, ee: >99%) (100 mg, 67%) as a white solid. MS (ESI) m / z: 549.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 9.20 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H) 7.69 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 4.84-4.79 (m, 1H), 4.03 (s, 3H), 3.22-3.21 (m, 1H), 2.93 (d, J = 7.2 Hz, 1H), 2. 38 (s, 3H), 2.41-2.34 (m, 1H), 2.34-2.27 (m, 1H), 2.19 (s, 3H), 2.16-2.10 (m, 2H) ).

[0393] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine (peak 2, retention time 7. 573 min, ee: >99%) (105 mg, 70%) was obtained as a white solid. MS (ES I) m / z: 549.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 9.21 (s, 1H), 8. 61 (s, 1H), 8.33 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.79-7.77 (m, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.11(d, J = 8.8 Hz, 1H), 6.90 (s, 1H) , 4.86-4.79 (m, 1H), 4.03 (s, 3H), 3.24-3.19 (m, 1H), 2.93 (d, J = 7.6 Hz, 1H), 2.38 (s, 3H), 2.41-2.27 (m, 1H), 2.27 (s, 3H), 2.19-2.11 (m, 3H). SFC conditions: Column: AD 4.6 x 250, 5 μm; Mobile phase A: CO2, Mobile phase B: Methanol (0.03% DEA); gradient: B held at 30% over 25 min; flow Flow rate: 2.8 mL / min; Column temperature: 35°C

[0394] Example 33 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine

[0395] Example 34 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0396] The racemate can be synthesized according to the procedures outlined in Examples 31 and 32. This was then separated by chiral SFC to give two isomers.

[0397] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-chlorophenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine (peak 1, retention time 6. 633 min) as a white solid. MS (ESI) m / z: 569.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.69 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.33-8.32 (m, 1H), 7.86-7.84 (d, J = 9.2 Hz, 1H), 7.73-7.65 (m, 2H), 7.47-7.42 (m, 2H), 4. 92-4.84 (m, 1H), 4.01 (s, 3H), 3.18-3.13 (m, 2H), 2.82-2.79 (m, 1H), 3.23 (s, 3H) ), 2.16-2.09 (m, 2H), 1.98-1.92 (m, 1H).

[0398] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-chlorophenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine (peak 2, retention time 7. 309 min) as a white solid. MS (ESI) m / z: 569.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.70-9.69 (d, J = 1.2 Hz, 1H), 8.62 (s, 1H), 8.54 (s , 1H), 8.33-8.32 (d, J = 2.4 Hz, 1H), 7.86-7.84 (d, J = 9.2 Hz, 1H), 7.73-7.70 ( m, 1H),7.67-7.65 (d, J = 9.2 Hz, 1H), 7.47-7.45 (d, J = 8.8 Hz, 1H), 7.43-7.42 ( d, J = 0.8 Hz, 1H), 4.93-4.82 (m, 1H), 4.01 (s, 3H), 3.18-3.14 (m, 2H), 2.82-2.7 9 (d, J = 11.6 Hz, 1H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.98-1.91 (m, 1H). SFC conditions: Column: AD-H 0.46 cm i.d. x 15 cm length, 254 nm; Mobile phase: A: HEP, Mobile phase B: EtOH (0.1% DEA); Gradient: B over 15 min held at 40%; flow rate: 0.5 mL / min; column temperature: 25°C

[0399] The following compounds were prepared according to the above method using different starting materials: [Table 6]

[0400] Example 15 1 H NMR (400 MHz, DMSO-d6) δ10.04 (s, 1H), 9.65 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 7.79-7.78 (d, J = 2.4 Hz, 1H), 7.73-7.70 (d, J = 8.8 Hz, 1H), 7.20-7.18 (m, 1H), 7.14 (s, 1H), 6.96-6.95 (d, J = 2.0 Hz, 1H), 6.86-6.85 (d, J = 2.0 Hz, 1H) , 5.23-5.10 (m, 1H), 5.05-4.99 (m, 1H), 3.91 (s, 3H), 3.15-3.09 (m, 1H), 2.80-2. 77 (d, J = 10.8 Hz, 1H), 2.43-2.30 (m, 2H), 2.22 (s, 3H), 2.17 s, 3H), 2.04-2.00 (m, 2H).

[0401] Example 16 1 H NMR (400 MHz, DMSO-d6) δ9.82 (s, 1H), 9.67-9.66 (d, J = 1.2 Hz 1H), 8.58 (s, 1H), 8.47 (s, 1H), 7.79-7.78 (d, J = 2.4 Hz,1H), 7.73-7.70 (m, 1H), 7.20-7.18 ( d, J = 8.8 Hz, 1H), 7.14-7.13 (d, J = 1.2 Hz, 1H), 6.92-6.91 (d, J = 2.0 Hz, 1H) , 6.85-6.84 (d, J = 2.4 Hz, 1H), 5.16-4.99 (m, 1H), 4.89-4.83 (m, 1H), 3.91 (s, 3H), 3.19-3.14 (m, 1H), 2.76-2.73 (m, 1H), 2.35-2.30 (m, 2H), 2.27 (s, 3H), 2.24 (m, 1H), 2.19 (s, 3H). 1.91-1.83 (m, 1H).

[0402] Example 35 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0403] Step 1: 3,3-Difluoro-4-((6-methoxy-4-oxo-3,4-dihydro Quinazolin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0404] 5-((3,3-difluoropiperidin-4-yl)oxy) in DCM (20 mL) to a solution of 6-methoxyquinazolin-4(3H)-one (1.4 g, 4.50 mmol) EtN (909 mg, 9.0 mmol) and BocO (1.08 g, 4.95 mmol) l) was added at 0°C, and the resulting mixture was then stirred at room temperature for 18 hours. When LCMS showed the reaction was complete, the reaction mixture was diluted with DCM ( The organic layer was separated and washed with brine (20 mL). The residue was triturated with n-hexane at 0°C, and the precipitate was filtered to give the desired product (1 0.2 g, 64% yield) as a pale white solid. MS (ESI) m / z: 412.1 (M+H) + .

[0405] Step 2: 4-((4-chloro-6-methoxyquinazolin-5-yl)oxy)-3,3 -tert-butyl difluoropiperidine-1-carboxylate [ka]

[0406] 3,3-Difluoro-4-((6-methoxy-4-oxo-3 ,4-Dihydroquinazolin-5-yl)oxy)piperidine-1-carboxylic acid tert- A solution of butyl (1.2 g, 2.92 mmol) in EtN (3767 mg, 29.2 mmol) ol) and POCl3 (1.12 g, 7.30 mmol) were added at room temperature, and then The resulting mixture was stirred at 90°C for 4 hours under Ar protection. When S indicated the reaction was complete, the reaction mixture was cooled to 0°C and added to ice water. The aqueous phase was poured into DCM (50 mL x 3) and neutralized with saturated aqueous NaHCO3. ), and the combined organic layers were washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO and concentrated in vacuo to give the desired The product (0.8 g, 63% yield) was obtained as a brown solid. MS (ESI) m / z: 430.0 (M +H) + .

[0407] Step 3: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-5-((3,3-difluoropiperidin-4-yl) Oxy)-6-methoxyquinazolin-4-amine (Example 76) [ka]

[0408] 4-((4-chloro-6-methoxyquinazolin-5-yl)methyl)-2- ... tert-Butyl 3,3-difluoropiperidine-1-carboxylate (200mg , 0.47 mmol), 4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylaniline (112 mg, 0.47 mmol), and TsOH A mixture of 18 mg of HCl (0.09 mmol) and 1% HCl (18 mg, 0.09 mmol) was heated at 100 °C under Ar protection. The mixture was stirred for 6 hours. LCMS showed the reaction was complete. The reaction mixture was cooled to 0° C. Then, 4 M HCl in dioxane (1 mL) was added to this To the mixture was added saturated NaHCO3, and the mixture was stirred at 0°C for 2 hours. The aqueous phase was extracted with DCM (30 mL x 3). Wash with water (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (100 mg, 38% yield). Obtained as a white solid. MS (ESI) m / z: 535 (M+H) + .

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.66 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.80 (d, J = 9.2 Hz, 2H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7. 61 (d, J = 9.2 Hz, 1H), 5.04-4.91 (m, 1H), 4.00 (s, 3H), 3.16 (t, J = 11.3 Hz, 1 H), 2.94 (d, J = 12.2 Hz, 1H), 2.82 (dd, J = 32.6, 14.0 Hz, 1H), 2.56 (t, J = 12 .5 Hz, 1H), 2.19 (s, 3H), 2.09 (d, J = 12.7 Hz, 1H), 1.78 (dt, J = 11.8, 8.1 Hz, 1H).

[0410] Step 4: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3) Piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine [ka]

[0411] N-(4-([1,2,4]triazolo[1,5-c]pyrimidinyl)-2-methyl-2- ...-1-methyl-2-pyrimidinyl)-2-methyl-2-pyrimidinyl (phenyl-7-yloxy)-3-methylphenyl)-5-((3,3-difluoropiperidine (4-yl)oxy)-6-methoxyquinazolin-4-amine (100 mg, 0.18 m A solution of EtN (36 mg, 0.36 mmol) and CDI (130 mg, 0.90 mmol) was added at room temperature, and the resulting mixture was then heated under Ar at room temperature. The reaction was stirred at rt for 4 h. LCMS showed the reaction was complete. The reaction mixture was poured into ice water and neutralized with saturated aqueous NaHCO3. The aqueous phase was diluted with DCM ( The organic layer was extracted with 50 mL of water (2×50 mL) and the combined organic layer was washed with brine (20 mL). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC. The desired product (20 mg, 20% yield) was obtained as a white solid. MS (ESI) m / z: 552.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ:10.03 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H) , 8.59 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.75-7.78 (m, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 4.77-4.84 (m, 1H), 4.01 (s, 3H), 3.17-3.23 (m, 1H), 2.91-2.93 (m, 1H), 2.28 -2.39 (m, 1H), 2.25 (s, 3H), 2.13 (d, J = 6.4 Hz, 3H).

[0412] The following compounds were prepared according to the above method using different starting materials: [Table 7]

[0413] Example 78 Yellow solid. 1 HNMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.2 Hz, 1H), 8.41 (d, J = 4 .8 Hz, 2H), 7.81-7.74 (m, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H) ), 6.93 (d, J = 1.2 Hz, 1H), 4.97-4.88 (m, 1H), 4.05 (s, 3H), 3.21-3.13 (m, 1H), 2.97-2.82 (m, 2H), 2.64-2.51 (m, 1H), 2.47-2.39 (m, 1H), 2.25 (s, 4H), 2.06-1.9 5 (m, 1H), 1.05 (t, J = 6.8 Hz, 6H). MS (ESI) m / z: 577 (M+H) + .

[0414] Example 79 Yellow solid. 1HNMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.2 Hz, 1H), 8.41 (d, J = 5 .6 Hz, 2H), 7.80-7.70 (m, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H) ), 6.93 (d, J = 1.2 Hz, 1H), 5.01-4.90 (m, 1H), 4.05 (s, 3H), 3.29-3.25 (m, 1H), 3.13-3.07 (m, 1H), 2.72-2.59 (m, 1H), 2.52-2.43 (m, 1H), 2.24 (s, 3H), 2.23-2.1 8 (m, 1H), 2.03-1.92 (m, 1H), 1.81-1.75 (m, 1H), 0.52-0.39 (m, 4H). MS (ESI) m / z : 575 (M+H) + .

[0415] Example 36 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine Example 37 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine [ka]

[0416] Step 1: 4-Bromo-2-fluoro-1-(methoxy-d3)-benzene [ka]

[0417] 4-Bromo-2-fluorophenol (6 g, 31.6 mmHg) in acetone (60 mL) To a solution of 1000 ml of KCO (8.72 g, 63.2 mmol) was added KCO (8.72 g, 63.2 mmol) at 0 °C, followed by C D3I (5.5 g, 37.9 mmol) was added. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (100 mL) and added water and Washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness The residue was purified by chromatography on silica gel (PE: EtOAc = 50:1). Purification gave the desired product (6 g, 92% yield) as a colorless oil.

[0418] Step 2: 6-Bromo-2-fluoro-3-(methoxy-d3)-benzaldehyde [ka]

[0419] 4-Bromo-2-fluoro-1-(methoxy-d3)-benzene in THF (60 mL) A solution of ethanol (6 g, 29.1 mmol) was added to LDA (18.9 mL, 37.83 mmol, T HF) was added dropwise at −78° C. under N2 atmosphere, and the mixture was heated to −78° C. The mixture was stirred at -70 °C for 0.5 h. DMF (4.14 g, 56.7 mmol) was added to the mixture. C. to this mixture, and the resulting mixture was heated to room temperature under a N2 atmosphere. The mixture was stirred at RT for 1 h. A saturated aqueous solution of NH4Cl (10 mL) was added to the mixture at 0 °C. The reaction was quenched using HCl and extracted with EtOAc (30 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (PE: EtOAc = 30:1). Further purification gave the desired product (2.8 g, 41% yield) as a yellow solid. 1 HN MR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.42 (t, J = 8 .8 Hz, 1H).

[0420] Step 3: (E)-6-Bromo-2-fluoro-3-(methoxy-d3)-benzaldehyde Hydroxime [ka]

[0421] 6-Bromo-2-fluoro-3-(methoxy-d3)-benz in EtOH (3 mL) A mixture of aldehyde (2.65 g, 11.2 mmol) was added to pyridine (1.15 g, 14.6 mmol) was added, followed by hydroxylamine hydrochloride (938 mg, 13.5 After the addition, the mixture was stirred at 80° C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and evaporated. Concentration to give the desired product (2.5 g, 89% yield) as a white solid. Ta. MS (ESI) m / z: 251 / 253 (M+H) + .

[0422] Step 4: 6-Bromo-2-fluoro-3-(methoxy-d3)-benzonitrile [ka]

[0423] (E)-6-Bromo-2-fluoro-3-(methoxy-d3) in MeCN (30 mL) )-benzaldehyde oxime (2.5 g, 10.0 mmol) was added to a mixture of Cu(OAc )2 (200 mg, 1.0 mmol) was added and the reaction was heated at 85 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and The residue was purified by chromatography on silica gel (PE:Et OAc=20:1) to give the desired product (2.2 g, 96% yield) as a yellow solid. Obtained as a physical object.

[0424] Step 5: 4-(3-bromo-2-cyano-6-(methoxy-d3)-phenoxy)-3 ,3-Difluoropiperidine-1-carboxylic acid tert-butyl ester [ka]

[0425] 3,3-Difluoro-4-hydroxypiperidine-1-carbohydrate in DMF (20 mL) A mixture of tert-butyl phosphate (1.02 g, 4.3 mmol) and NaH (224 mg, 5.59 mmol, 60% dispersion in mineral oil) was added at 0°C, and the mixture was heated at 0°C for 10 The mixture was stirred for 1 minute. 6-Bromo-2-fluoro-3-(methoxy-d 3)-Benzonitrile (1 g, 4.3 mmol) was added, and the resulting mixture was heated at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and EtOAc (30 mL The combined organic layers were washed with saturated aqueous NH4Cl and brine, and then extracted with anhydrous N The residue was dried over Na2SO4, filtered, and concentrated to dryness. The desired product was purified by chromatography on ice (eluting with PE: EtOAc = 10:1). The product (1.3 g, 67% yield) was obtained as a yellow solid. MS (ESI) m / z: 450 / 452 (M +H) + .

[0426] Step 6: 6-Bromo-2-((3,3-difluoropiperidin-4-yl)oxy)- 3-Methoxybenzonitrile hydrochloride [ka]

[0427] 4-(3-bromo-2-cyano)-HCl in 1,4-dioxane (10 mL, 4 M) 6-(Methoxy-d3)-phenoxy)-3,3-difluoropiperidine-1-carvone A solution of tert-butyl acetate (1.3 g, 2.9 mmol) was stirred at room temperature for 1 h. The mixture was concentrated to dryness to give 6-bromo-2-((3,3-difluoro Piperidin-4-yl)oxy)-3-methoxybenzonitrile hydrochloride (1.3 g, 10 0% yield) as a white solid, which was used directly in the next step without purification. . MS (ESI) m / z: 350 / 352 (M+H) + .

[0428] Step 7: 6-Bromo-2-((3,3-difluoro-1-methylpiperidin-4-yl )oxy)-3-(methoxy-d3)-benzonitrile [ka]

[0429] 6-Bromo-2-((3,3-difluoropiperidine-4- (yl)oxy)-3-methoxybenzonitrile hydrochloride (650 mg, 1.43 mmol) Paraformaldehyde (429 mg, 14.3 mmol) was added to the mixture at 0°C, followed by AcOH (26 mg, 0.43 mmol) and sodium cyanoborohydride (27 After the addition, the mixture was heated at 70° C. overnight. The mixture was diluted with water and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by chromatography on silica gel (PE: EtOAc = 6:1) to give the desired product (500 mg, 96% yield) as a yellow solid. MS (ESI) m / z: 364 / 366 (M+H) + .

[0430] Step 8: (2-cyano-3-((3,3-difluoro-1-methylpiperidin-4-yl) tert-Butyl)4-((4-(methoxy-d3)-phenyl)oxy)-4-(methoxy-d3)-phenyl)carbamate [ka]

[0431] 6-Bromo-2-((3,3-difluoro-1-methyl) ... (ethylpiperidin-4-yl)oxy)-3-(methoxy-d3)-benzonitrile (50 0 mg, 1.38 mmol) and tert-butyl carbamate (71 mg, 2.75 mmol) To the mixture of 1.35 g (4.14 mmol) of Cs2CO3 was added. The mixture was degassed three times under N2 atmosphere and Pd(OAc)2 (31.4 mg, 0.14 mmol) and Xantphos (133.3 mg, 0.28 mmol) were added. After the addition, the mixture was degassed under N2 atmosphere three times and heated at 90 °C overnight. The mixture was diluted with EtOAc (10 mL) and washed with water and brine. The mixture was washed, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was then purified by filtration. Purification by silica gel chromatography (PE: EtOAc = 5:1) gave the desired product (380 mg, 69% yield) was obtained as a yellow solid. MS (ESI) m / z: 401 (M+H) + .

[0432] Step 9: 6-amino-2-((3,3-difluoro-1-methylpiperidin-4-yl )oxy)-3-(methoxy-d3)-benzonitrile [ka]

[0433] (2-cyano-3-((3,3-dihydro-HCl)) in HCl / 1,4-dioxane (5 mL, 4 M) Fluoro-1-methylpiperidin-4-yl)oxy)-4-(methoxy-d3)-phenyl A solution of tert-butyl (nyl)carbamate (380 mg, 0.95 mmol) at room temperature After stirring for 1 hour, the mixture was concentrated to dryness and saturated NaHC1 The residue was made alkaline by adding aqueous O3 to a pH of 8. This mixture was then treated with DC The mixture was extracted with MgCl (10 mL x 2), and the combined organic layers were washed with brine and anhydrous Na2S Drying over O4, filtering, and concentrating to dryness gave the desired product (280 mg, 98% yield) as a yellow oil. MS (ESI) m / z: 301 (M+H) + .

[0434] Step 10: (E)-N'-(2-cyano-3-((3,3-difluoro-1-methylpiperidinyl) (4-(methoxy-d3)-phenyl)-N,N-dimethylamino-4-(oxy)-4-(methoxy-d3)-phenyl Fluorimidamide [ka]

[0435] 6-Amino-2-((3,3-difluoro-1-methylpiperidinyl) (4-(4-yl)oxy)-3-(methoxy-d3)-benzonitrile (280 mg, 0. To a solution of 93 mmol of dimethylformamide (DMF) was added 3 mL of DMF-DMA, and the mixture was heated at 70 °C for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with water and brine. The mixture was washed, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was then purified by filtration. Purification by silica gel chromatography (PE: EtOAc = 2:1) gave the desired product (300 mg, 91% yield) was obtained as a yellow oil. MS (ESI) m / z: 356 (M+H) + .

[0436] Step 11: (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidine) -7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methyl Piperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine and (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine [ka]

[0437] (E)-N'-(2-cyano-3-((3,3-difluoro- 1-Methylpiperidin-4-yl)oxy)-4-(methoxy-d3)-phenyl)-N ,N-dimethylformimidamide (150 mg, 0.42 mmol) solution with 4-([ 1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline Phosphorus (152 mg, 0.63 mmol) was added and the mixture was heated at 100°C for 5 hours. The mixture was diluted with EtOAc (10 mL) and saturated NaHCO3 The mixture was made alkaline to pH 8 by adding aqueous EtOAc (2 The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography ( The racemic product (90 mg, 38 0.9% yield) as a white solid, which was then separated by chiral SFC to give Two enantiomers were obtained.

[0438] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine (peak 1, retention Time: 5.41 min) (28 mg, 12% yield) as a light yellow solid. 1 H-NMR ( 400 MHz, CD3OD) δ 9.43 (s, 1H), 8.41 (d, J = 4.5 Hz, 2H), 7.77 (dd, J = 9.6, 4. 6 Hz, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 1.0 Hz, 1H), 5.00-4.91 (m, 1H), 3.21-3.12 (m, 1H), 2.99-2.85 (m, 1H), 2.46 (dd, J = 29.6, 13.0 Hz, 1H), 2.33 (s, 3H), 2.32-2.27 (m, 1H), 2.25 (s, 4H), 2.14-2.06 (m, 1H). MS (ESI) m / z: 552 (M+H) + .

[0439] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine (peak 2, Retention time: 6.32 min) (30 mg, 13% yield) was obtained as a light yellow solid. 1 H-NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.41 (d, J = 4.6 Hz, 2H), 7.77 (dd, J = 9.6, 4.4 Hz, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 5 .05- 4.89 (m, 1H), 3.16 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 11.3 Hz, 1H), 2.46 (d d, J = 29.5, 12.7 Hz, 1H), 2.33 (s, 3H), 2.29 (d, J= 13.1 Hz, 2H), 2.25 (s, 3H), 2.08 (t, J = 14.1 Hz, 1H). MS (ESI) m / z: 552 (M+H) + . SFC conditions: Column: ChiralPak AS, 250 x 21.2 mm inner diameter, 5 μm Mobile phase A: CO2, Mobile phase B: Methanol (0.1% NH4OH); Concentration gradient: B40 %; Flow rate: 50 mL / min; Column temperature: 35°C

[0440] Example 77 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)pi (Peridine-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine [ka]

[0441] The title compound was obtained as a white solid following the procedures outlined in Examples 36 and 37. 1HNMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.41 (d, J = 3.8 Hz, 2H) , 7.77 (m, 3H), 7.62 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H) , 5.01 -4.90 (m, 1H), 3.17 (m, 1H), 2.92 (d, J = 12.4 Hz, 1H), 2.46 (m, 1H), 2.3 6-2.16 (m, 5H), 2.07 (m, 1H). MS (ESI) m / z: 555 (M+H) + .

[0442] Example 38 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(8-methyl-5-oxa-2,8-diaza Spiro[3.5]nonan-2-yl)quinazolin-4-amine [ka]

[0443] Step 1: 3-Hydroxy-3-(nitromethyl)azetidine-1-carboxylic acid tert -butyl [ka]

[0444] tert-Butyl 3-oxoazetidine-1-carboxylate in EtOH (150 mL) (16.0 g, 0.09 mol) was added to a solution of EtN (0.95 g, 9.40 mmol) and and nitromethane (21.7 g, 0.36 mol) were added. The mixture was stirred at room temperature for 16 hours. Stir for 1 hour and concentrate to dryness to give the desired product (20 g crude). was obtained as a yellow oil, which was used directly in the next step without further purification. MS (ESI) m / z: 233 (M+H) + .

[0445] Step 2: 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylic acid tert -butyl [ka]

[0446] 3-Hydroxy-3-(nitromethyl)azetidine-1- in EtOH (200 mL) A solution of tert-butyl carboxylate (20 g, 0.09 mol) was added to Pd / C (2 g, 10 % wt) was added, the reaction mixture was degassed three times under N2 atmosphere, and The mixture was stirred at 50°C for 16 hours under reduced pressure. The mixture was filtered, and the filtrate was dried. The residue was purified by silica gel chromatography (DCM:MeOH=50:1). The desired product (13.0 g, 75% yield) was obtained as a colorless oil. ESI) m / z: 103 (M+H-100) + .

[0447] Step 3: 3-((2-chloroacetamido)methyl)-3-hydroxyazetidine-1 -tert-butyl carboxylate [ka]

[0448] 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate in DCM (150 mL) A solution of tert-butyl carboxylate (13.0 g, 0.06 mol) in Et3N(8 0.5g, 0.08mol) was added, followed by 2-chloroacetyl chloride (8.7g, 0 The mixture was stirred at room temperature for 2 hours, and then The reaction was quenched with water and the resulting mixture was extracted with DCM (150 mL). HCl and brine, dried over anhydrous NaSO, filtered, and The residue was purified by silica gel chromatography (DCM:MeOH= 50:1) to give the desired product (14.0 g, 79% yield) as a yellow oil Got it. MS (ESI) m / z: 279 (M+H) + .

[0449] Step 4: 7-oxo-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide tert-Butyl carboxylate [ka]

[0450] 3-((2-chloroacetamido)methyl)- in 1,4-dioxane (100 mL) tert-Butyl 3-hydroxyazetidine-1-carboxylate (7.0 g, 25.2 mm ol) was added NaH (1.76 g, 44.1 mmol, 60% dispersion in mineral oil) to The mixture was stirred at 80°C for 16 hours and then cooled to 80°C. The reaction was quenched with water, and the mixture was extracted with EtOAc (50 mL) and saturated NH 4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (DCM:MeOH=100: 1) to give the desired product (2.7 g, 44% yield) as a yellow oil. (ESI) m / z: 243 (M+H) + .

[0451] Step 5: 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylic acid tert- Synthesis of t-butyl [ka]

[0452] 7-Oxo-5-oxa-2,8-diazaspiro[3.5]no in THF (30 mL) A solution of tert-butyl naphthalene-2-carboxylate (2.7 g, 11.2 mmol) was added to borane. -tetrahydrofuran complex (33.6 mL, 33.6 mmol) was added dropwise at 0 °C. The mixture was stirred at 25° C. for 16 hours. To the mixture was added MeOH( The reaction was quenched with 10 mL of HCl, and the mixture was stirred at 70° C. for 5 h. The resulting mixture was concentrated to dryness and the residue was purified by silica gel chromatography. The desired product (2.3 g) was purified by chromatography (DCM:MeOH=25:1) to give the desired product (2.3 g , 90% yield) was obtained as a yellow oil. MS (ESI) m / z: 229 (M+H) + .

[0453] Step 6: 8-Methyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide Synthesis of tert-butyl benzoate [ka]

[0454] 5-Oxa-2,8-diazaspiro[3.5]nonane-2- in MeOH (25 mL) tert-Butyl carboxylate (2.3 g, 10.1 mmol) and paraformaldehyde To a degassed mixture of Pd / C (150 mg, 10 w t) was added, the mixture was degassed three times under N2 atmosphere and The mixture was stirred at 25°C for 16 hours. The mixture was filtered and the filtrate was dried. Concentration to give the desired product (2.0 g, 82% yield) as a colorless oil. (ESI) m / z: 243 (M+H) + .

[0455] Step 7: Synthesis of 8-methyl-5-oxa-2,8-diazaspiro[3.5]nonane hydrochloride Growth [ka]

[0456] 8-Methyl-5-oxa-2,8 in HCl / 1,4-dioxane (10 mL, 4 M) -tert-butyl diazaspiro[3.5]nonane-2-carboxylate (1.3 g, 5.3 A solution of 100 mmol of HCl was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The desired product (1.1 g, 100% yield) was obtained as a light yellow solid, which was Used directly in the next step without purification. MS (ESI) m / z: 143 (M+H) + .

[0457] Step 8: 3-Methoxy-6-((4-methoxybenzyl)amino)-2-nitrobenzo Nitrile [ka]

[0458] 6-Fluoro-3-methoxy-2-nitrobenzonitrile ( A solution of 4-methoxybenzylamine (4.5 g, 27.5 mmol) was added at 0°C. 33 mmol) was added followed by the addition of DBU (5.86 g, 38.5 mmol). After the addition, the mixture was stirred at room temperature for 16 hours. 00 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and The residue was purified by silica gel chromatography (PE: EtOAc = 5:1 to 3:1) to give the desired product (4.5 g, 52% yield) as an orange solid. MS (ESI) m / z: 314 (M+H) + . 1H-NMR (400 MHz, CDCl3) δ 7.25-7.27 ( d, J= 8.4 Hz, 2H), 7.17-7.19 (d, J= 9.2 Hz, 1H), 6.91-6.93 (d, J= 8.8 Hz, 2H), 6 .79-6.82 (d, J= 9.6 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

[0459] Step 9: 2-amino-3-methoxy-6-((4-methoxybenzyl)amino)benzo Nitrile [ka]

[0460] 3-Methoxy-6-((4-methoxybenzyl)amino)-2 in THF (50 mL) A solution of 3.5 g (11.2 mmol) of nitrobenzonitrile was added to Pd / C (500 mg , 10 wt) was added, the mixture was degassed under N2 three times, and H2 The mixture was stirred under atmospheric pressure at room temperature for 5 hours, filtered, and the filtrate was dried. Concentration to dryness gave the desired product (2.3 g, 73% yield) as a brown solid. which was used directly in the next step without further purification. MS (ESI) m / z: 284 (M+H) + .

[0461] Step 10: 2-Bromo-3-methoxy-6-((4-methoxybenzyl)amino)benzyl Zonitrile [ka]

[0462] 2-amino-3-methoxy-6-((4-methyl- A solution of (2.2 g, 7.77 mmol) benzonitrile (2.2 g, 7.77 mmol) in water ( NaNO2 (805 mg, 11.7 mmol) in 2 mL of HCl was added at 0 °C. After stirring for 1 hour, the mixture was added to a solution of CuBr( The resulting mixture was added dropwise to a solution of 2.2 g of acetic acid (15.55 mmol) at 10°C. The mixture was stirred at room temperature for 1 hour. The mixture was made basic with NH4OH and The mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine and anhydrous Na The mixture was dried over 2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography. The desired product (7 00 mg, 26% yield) as a yellow solid. MS (ESI) m / z: 347 / 349 (M+H) + .

[0463] Step 11: 6-amino-2-bromo-3-methoxybenzonitrile [ka]

[0464] 2-Bromo-3-methoxy-6-((4-methoxybenzyl)a)a in DCM (3 mL) To a solution of (amino)benzonitrile (700 mg, 2.02 mmol) was added 0 mL of TFA. C. and the reaction was stirred at room temperature for 1 hour. Concentration was carried out and the residue was dissolved in DCM (10 mL) and saturated aqueous NaHCO3 and Wash with brine, dry over anhydrous Na2SO4, filter, and evaporate to dryness. The desired product (500 mg crude) was obtained as a red solid, which was purified without further purification. This was used directly in the next reaction. MS (ESI) m / z: 227 / 229 (M+H) + .

[0465] Step 12: (E)-N'-(3-bromo-2-cyano-4-methoxyphenyl)-N, N-dimethylformimidamide [ka]

[0466] 6-Amino-2-bromo-3-methoxybenzonitrile (500 mL) in THF (5 mL) To a solution of 100 mg of dimethylformamide (2.02 mmol) was added DMF-DMA (5 mL), and the mixture was stirred for 7 The mixture was stirred at 0° C. for 16 h. The mixture was diluted with EtOAc (10 mL) and The mixture was washed successively with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE:acetone=5:1). and purification to give the desired product (390 mg, 69% yield over two steps) as a yellow oil. MS (ESI) m / z: 282 / 284 (M+H) + .

[0467] Step 13: (E)-N'-(2-cyano-4-methoxy-3-(8-methyl-5-oxo)methyl) (2,8-diazaspiro[3.5]nonan-2-yl)phenyl)-N,N-dimethyl Formimidamide [ka]

[0468] (E)-N'-(3-bromo-2-cyano-4- (Methoxyphenyl)-N,N-dimethylformimidamide (300 mg, 1.07 mm ol) and 8-methyl-5-oxa-2,8-diazaspiro[3.5]nonane (227m g, 1.60 mmol) was added to a mixture of Cs2CO3 (1.04 g, 3.20 mmol), P d2(dba)3 (98 mg, 0.11 mmol), and Ru-phos (100 mg, After the addition, the mixture was degassed three times under N2 atmosphere. The mixture was degassed and stirred at 100°C under a N2 atmosphere for 16 hours. was diluted with EtOAc (10 mL) and washed with water and brine, and then added over anhydrous Na2SO4 The residue was purified by silica gel chromatography. Purification with PE:acetone=1:1 gave the desired product (260 mg, 71% yield). ) was obtained as a yellow solid. MS (ESI) m / z: 344 (M+H) + .

[0469] Step 14: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (3-methylphenyl)-6-methoxy-5-(8-methyl-5-oxa-2 ,8-diazaspiro[3.5]nonan-2-yl)quinazolin-4-amine [ka]

[0470] (E)-N'-(2-cyano-4-methoxy-3-(8-methyl- 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)phenyl)-N A solution of N-dimethylformimidamide (260 mg, 0.76 mmol) in AcOH (3 mL) and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylaniline (183 mg, 0.76 mmol) was added. The mixture was stirred under N2 atmosphere at 100 °C for 8 hours. The residue was dissolved in DCM (10 mL) and saturated aqueous NaHCO3 The mixture was washed with HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (10% to 100% acetonitrile in water containing 0.1% formic acid). Purification by HCl (HCl) afforded the desired product (37 mg, 9.1% yield) as a white solid. Got it. MS (ESI) m / z: 540 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ9.66 (s, 1H), 8.57 ( s, 1H), 8.45 (s, 1H), 8.10 (s, 1H),7.89 (s, 1H), 7.75-7.70 (m, 2H), 7.22-7.20 (m , 1H), 7.11 (s, 1H), 4.18 (m, 2H), 4.06 (s, 3H), 3.82-3.80 (m, 4H), 2.62 (s, 2H) , 2.35 (s, 2H), 2.25 (s, 3H), 2.19 (s, 3H).

[0471] Example 39 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4S)-3-(dimethylamino)-4-fluoro Pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine [ka]

[0472] Step 1: (3R,4S)-3-(dimethylamino)-4-hydroxypyrrolidine-1- tert-Butyl carboxylate [ka]

[0473] (3R,4S)-3-amino-4-hydroxypyrrolidine- in MeOH (25 mL) 1-tert-Butyl carboxylate (1 g, 4.95 mmol) and paraformaldehyde (1.49 g, 49.5 mmol) was added to a degassed mixture of Pd(OH)2 (500 mg, 10 wt) was added and the mixture was degassed three times under N2 atmosphere and then re-degassed under H2 atmosphere. The mixture was stirred under atmosphere at 25° C. for 16 hours. The mixture was filtered and the filtrate was Concentration to dryness afforded the desired product (950 mg, 84% yield) as a colorless oil. Got it. MS (ESI) m / z: 231 (M+H) + .

[0474] Step 2: (3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylate tert-Butyl carboxylate [ka]

[0475] (3R,4S)-3-(dimethylamino)-4-hydroxypyrrolidine in DCM (3 mL) To a mixture of tert-butyl lysine-1-carboxylate (500 mg, 2.17 mmol) DAST (83 mg, 3.26 mmol) was added dropwise at −78° C. After the addition, The mixture was stirred at room temperature for 16 hours and saturated aqueous NaHCO3 (10 mL) The reaction was quenched by adding 10 mL of HCl and the resulting mixture was extracted with DCM (10 mL x 2). The organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and The residue was purified by column chromatography on silica gel (DCM Purification with HCl (MeOH = 60:1) gave the desired product (460 mg, 92% yield). Obtained as a yellow oil. MS (ESI) m / z: 233 (M+H) + .

[0476] Step 3: (3R,4S)-4-Fluoro-N,N-dimethylpyrrolidin-3-amine salt Acid salts [ka]

[0477] (3R,4S)-3-(dimethylamino)methylpropional in HCl / 1,4-dioxane (10 mL, 4 M) tert-Butyl amino)-4-fluoropyrrolidine-1-carboxylate (460 mg, 1 A solution of 1,2-dimethyl-3,4-dichloro-2 ... Concentration gave the desired product (430 mg, 100% yield) as a white solid. This was used directly in the next reaction without further purification. MS (ESI) m / z: 133 (M+H) + .

[0478] Step 4: 2-Bromo-3-methyl-4-nitrophenol [ka]

[0479] 3-Methyl-4-nitrophenol (25 g, 0.149 mL) in AcOH (200 mL) mol) in AcOH (50 mL) The solution was added dropwise at 15° C. After addition, the mixture was stirred at room temperature for 16 hours. After TLC (PE:DCM=1:1) showed that the reaction was complete, The reaction mixture was poured into ice water and the slurry was filtered. The filter cake was washed twice with water. and dried under vacuum to obtain 2-bromo-3-methyl-4-nitrophenol and 2- The mixture of bromo-5-methyl-4-nitrophenols (28 g, 76% yield) was dissolved in a brown Obtained as a solid which was used directly in the next reaction without further purification.

[0480] Step 5: 2-Bromo-1-methoxy-3-methyl-4-nitrobenzene (3) [ka]

[0481] 2-Bromo-3-methyl-4-nitrophenol and 2- A mixture of bromo-5-methyl-4-nitrophenol (28 g, 0.114 mol) At 20°C, KCO (23.6 g, 0.171 mol) was added, followed by MeI (19.4 g After the addition, the reaction was stirred at 35° C. for 3 hours. The mixture was filtered, and the filtrate was diluted with EtOAc and washed with water and brine. The residue was purified by silica gel chromatography (PE:EtO Ac=15:1 to 5:1) and purified by 2-bromo-1-methoxy-3-methyl-4- Mixture of nitrobenzene and 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (12.3 g, 44% yield) was obtained as a yellow solid.

[0482] Step 6: (E)-2-(2-bromo-3-methoxy-6-nitrophenyl)-N,N- Dimethylethenamine [ka]

[0483] 2-Bromo-1-methoxy-3-methyl-4-nitrobenzene in DMF (100 mL) and 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (12 g, 48.8 To the mixture (2.5 mmol) was added pyrrolidine (3.5 g, 48.8 mmol), followed by DM F-DMA (17.4 g, 0.15 mol) was added and the resulting mixture was placed under a N2 atmosphere. The mixture was stirred at 100° C. under atmosphere for 16 hours. The mixture was concentrated to dryness. The residue was diluted with EtOAc, washed with water and brine, and dried to dryness. Drying and concentration gave (E)-2-(2-bromo-3-methoxy-6-nitrophenyl)-N, N-Dimethylethenamine and (E)-2-(4-bromo-5-methoxy-2-nitrophenyl) The mixture of N,N-dimethylethen-1-amine (15.5 g crude) was added to a dark Obtained as an oil which was used directly in the next reaction without purification.

[0484] Step 7: 2-Bromo-3-methoxy-6-nitrobenzaldehyde [ka]

[0485] NaIO4 (31.2 g, 0.146 mo) in water / DMF (300 mL / 100 mL) To a stirred solution of (E)-2-(2-bromo-3-methoxy-6-methyl-2-methylpropional) in DMF (50 mL) -nitrophenyl)-N,N-dimethylethenamine and (E)-2-(4-bromo-5 -Methoxy-2-nitrophenyl)-N,N-dimethylethen-1-amine (1 5.5 g, 48.8 mmol) was added dropwise at 0° C. After the addition, the mixture was Stirred for 3 hours. The mixture was diluted with EtOAc and washed with water and brine. The residue was extracted with HCl, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The product was purified by silica gel chromatography (PE: EtOAc = 10:1 to 5:1). The desired product (4.6 g, 36% yield) was obtained as a yellow solid.

[0486] Step 8: (E / Z)-2-Bromo-3-methoxy-6-nitrobenzaldehydeoxy M [ka]

[0487] 2-Bromo-3-methoxy-6-nitrobenzaldehyde ( A solution of hydroxylamine hydrochloride (1.28 g, 18.4 mmol) mol) and AcONa (1.64 g, 20 mmol) were added. The mixture was stirred at 5° C. for 2 hours and then concentrated to dryness. The residue was dissolved in EtOAc. Dissolved, washed with water and brine, and dried and concentrated to dryness to give the desired product (4. 3 g, 100% yield) as a yellow oil. MS (ESI) m / z: 275 / 277 (M+H) + .

[0488] Step 9: 2-Bromo-3-methoxy-6-nitrobenzonitrile [ka]

[0489] (E / Z)-2-Bromo-3-methoxy-6-nitrobenzyl alcohol in DMSO (100 mL) A solution of benzoyl oxime (4.3 g, 15.4 mmol) in K2CO3 (4.25 g , 30.8 mmol) was added, followed by the addition of AcO (3.1 g, 30.8 mmol). The mixture was stirred at 60°C under a N2 atmosphere for 16 hours. The material was diluted with EtOAc, washed with water and brine, and dried and concentrated to dryness. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1 to 3:1). Purification gave the desired product (3.8 g, 91% yield) as a yellow solid.

[0490] Step 10: 2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine -1-yl)-3-methoxy-6-nitrobenzonitrile [ka]

[0491] 2-Bromo-3-methoxy-6-nitrobenzonate in 1,4-dioxane (5 mL) (150 mg, 0.59 mmol) and (3R,4S)-4-fluoro-N,N-diphenylmethane A mixture of methylpyrrolidin-3-amine hydrochloride (178 mg, 0.77 mmol) and Cs CO3 (587 mg, 1.77 mmol) was added, followed by Pd2(dba)3 (54 0.9mg, 0.06mmol) and Ru-phos (55.9mg, 0.12mmol) was added under N2 atmosphere. After the addition, the mixture was cooled three times under N2 atmosphere. The mixture was degassed and stirred overnight at 90°C under a N2 atmosphere. Diluted with tOAc (20 mL) and washed with water and brine, dried over anhydrous Na2SO4 The crude product was purified by silica gel chromatography (P Purification by HCl (3:1) gave the desired product (160 mg, 88% yield). Obtained as a yellow oil. MS (ESI) m / z: 309 (M+H) + .

[0492] Step 11: 6-amino-2-((3R,4S)-3-(dimethylamino)-4-fluoro (1-hydroxypyrrolidin-1-yl)-3-methoxybenzonitrile [ka]

[0493] 2-((3R,4S)-3-(dimethylamino)methyl)-2-(2-(4-methyl-2-propanol)-2-one in MeOH (3 mL) and EtOAc (3 mL) (ethylamino)-4-fluoropyrrolidin-1-yl)-3-methoxy-6-nitrobenzo A mixture of nitrile (160 mg, 0.52 mmol) and Pd / C (30 mg, 10 wt) The mixture was degassed three times under N2 atmosphere and then degassed under H2 atmosphere. The mixture was stirred at 25° C. for 2 hours. The mixture was filtered and the filtrate was dried. Concentration gave the desired product (100 mg, 69% yield) as a yellow oil. MS (ESI) m / z: 279 (M+H) + .

[0494] Step 12: (E)-N'-(2-cyano-3-((3R,4S)-3-(dimethylamine) (4-fluoropyrrolidin-1-yl)-4-methoxyphenyl)-N,N-dimethyl Fluorimidamide [ka]

[0495] 6-amino-2-((3R,4S)-3-(dimethylamino)- in THF (2 mL) 4-fluoropyrrolidin-1-yl)-3-methoxybenzonitrile (100 mg, 0. To a solution of 36 mmol of dimethylformamide (DMF) was added 2 mL of DMF-DMA, and the mixture was heated at 70 °C for 2 hours. The mixture was diluted with EtOAc (20 mL) and washed with water and brine. The mixture was washed, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was then purified by filtration. Purification by silica gel chromatography (PE: EtOAc = 1:1) gave the desired product (100 mg, 83% yield) was obtained as a yellow oil. MS (ESI) m / z: 334 (M+H) + .

[0496] Step 13: N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (3R,4S)-3-(dimethylamino)- 4-Fluoropyrrolidin-1-yl)-6-methoxyquinazolin-4-amine [ka]

[0497] (E)-N'-(2-cyano-3-((3R,4S)-3-( Dimethylamino)-4-fluoropyrrolidin-1-yl)-4-methoxyphenyl)-N ,N-dimethylformimidamide (100 mg, 0.30 mmol) solution with 4-([ 1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline Phosphorus (108 mg, 0.45 mmol) was added, and the mixture was heated at 100°C for 16 hours. The mixture was diluted with EtOAc (10 mL) and saturated NaHCO The mixture was made alkaline to pH 8 by adding aqueous 3. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The residue was purified by column chromatography on silica gel. The desired product ( 30 mg, 19% yield) as a white solid. MS (ESI) m / z: 530 (M+H) + . 1 HN MR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.43 (d, J= 1.2 Hz, 1H), 8.58 (s, 1H), 8 .46 (s, 1H), 7.81-7.87 (m, 2H), 7.75-7.77 (m, 2H), 7.18-7.20 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 1.2 Hz, 1H),5.32-5.56 (m, 1H), 3.94-4.04 (m, 1H), 4.00 (s, 3H), 3.3 8-3.53 (m, 4H), 2.26-2.29 (br, 6H), 2.17 (s, 3H).

[0498] Example 40 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4R)-3-(dimethylamino)-4-fluoro Pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine [ka]

[0499] This material was synthesized according to the procedure outlined in Example 39 to give the desired product as a white solid. MS (ESI) m / z: 530 (M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.66 (d, J= 1.1 Hz, 1H), 8.58 (s, 1H), 8.45 (d, J= 5.4 Hz, 1H) , 7.87 (d, J= 2.0 Hz, 1H), 7.85-7.78 (m, 1H), 7.76 (d, J= 5.9 Hz, 2H), 7.20-7.06 (m, 2H), 5.50-5.35 (m, 1H), 4.12-3.90 (m, 4H), 3.57 -3.39 (m, 2H), 3.28-3.09 (m , 1H), 2.30 (t, J= 13.0 Hz, 6H), 2.17 (s, 3H).

[0500] Example 41 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(5-methyl-8-oxa-2,5-diaza Spiro[3.5]nonan-2-yl)quinazolin-4-amine [ka]

[0501] This material was synthesized according to the procedure outlined in Example 39 to give the desired product as a bright yellow It can be obtained as a solid. MS (ESI) m / z: 540 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6 ) δ 13.29 (s, 1H), 9.67 (d, J= 1.2 Hz, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.79 (d , J= 9.3 Hz, 1H), 7.72-7.67 (m, 3H), 7.21-7.18 (m, 1H), 7.16 (d, J= 1.1 Hz, 1H), 4.59-4.21 (m, 2H), 4.05 (s, 3H), 3.86-3.83 (m, 2H), 3.82-3.65 (m, 2H), 3.65-3.6 1 (m, 2H), 2.58 (s, 3H), 2.54-2.51 (m, 2H), 2.18 (s, 3H).

[0502] Example 42 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methylhexahydropyrrolo[3,4- b][1,4]oxazin-6(2H)-yl)quinazolin-4-amine [ka]

[0503] This material was synthesized according to the procedure outlined in Example 39 to give the desired product as a yellow solid. MS (ESI) m / z: 540 (M+H) + . 1 H-NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.39-8.41 (d, J= 8.0 Hz, 2H), 7.99-8.02 (dd, J= 8.4, 2.4 Hz, 1H), 7.94-7.95 (d, J= 2.4 Hz, 1H), 7.73 (s, 2H), 7.14-7.16 (d, J= 8.4 Hz, 1H), 6.89 (s, 1H), 4.31-4.33 (m, 1H), 4.06 (s, 3H), 3.98-4.01 (m, 1H), 3.76-3.81 (m, 2H), 3.67-3.72 (m, 1H), 3.60-3.66 (m, 2H), 3.25-3.27 (m, 1H), 2.80-2.87 (m, 1H), 2.54 -2.57 (m, 1H), 2.40 (s, 3H), 2.24 (s, 3H).

[0504] Example 43 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (7-fluoro-5-methyl-2,5-diazaspirillum)-3-methylphenyl (2-[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine

[0505] Example 44 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (7-fluoro-5-methyl-2,5-diazaspirillum)-3-methylphenyl (2-[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine [ka]

[0506] Step 1: (2S)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2 -dicarboxylic acids [ka]

[0507] 1-(tert-butyl) 2-methyl(2S)-4-hydrogen nitrite in DCE (100 mL) A solution of 1,2-pyrrolidine-1,2-dicarboxylic acid (8 g, 32.7 mmol) was added to DAST ( 7.89 g, 48.9 mmol) was added dropwise at 0°C, and the mixture was heated at 25°C for 5 hours. The mixture was quenched with ice-cold saturated aqueous NaHCO3 solution, and The organic phase was washed with water and brine, and extracted with anhydrous NaCl. The residue was dried over 2SO4, filtered, and concentrated to dryness. The desired product was obtained by column chromatography (DCM:MeOH=60:1). The product (6.0 g, 74% yield) was obtained as a light yellow oil. MS (ESI) m / z: 248 (M+H) + .

[0508] Step 2: 2-(benzylamino)acetonitrile [ka]

[0509] A solution of 2-chloroacetonitrile (15 g, 0.2 mol) in EtOAc (60 ml) Benzylamine (43.9 g, 0.4 mol) was added to the solution, and the mixture was heated at 45°C for 0. The mixture was stirred for 5 hours, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1). and purified to give 2-(benzylamino)acetonitrile (29 g, 99% yield). Obtained as an oil. MS (ESI) m / z: 147 (M+H) + .

[0510] Step 3: 2-benzyl-7-fluoro-1-oxo-2,5-diazaspiro[3.4] tert-Butyl octane-5-carboxylate [ka]

[0511] 2-(benzylamino)acetonitrile (2 g, 13.7 mL) in anhydrous THF (20 mL) To a solution of 100 mmol of 1,000 sachets of LDA (23.9 mL, 47.9 mmol, 1 M) was added dropwise at -78 °C. After the addition, the reaction mixture was stirred at this temperature for 60 minutes. followed by 1-(tert-butyl)-2-methyl(2S)-4 in THF (20 mL). -solution of fluoropyrrolidine-1,2-dicarboxylic acid (6.76 g, 27.4 mmol) The reaction mixture was stirred and allowed to warm from -78°C to room temperature overnight. The resulting mixture was quenched with saturated aqueous NH4Cl (40 mL). The combined organic layer was washed with brine. The mixture was then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was by flash chromatography (silica gel, 0–20% EtOAc in PE). Purification gave the desired product (2.4 g, 53% yield) as a yellow solid. MS (ESI) m / z 335 (M+H) + .

[0512] Step 4: 2-benzyl-7-fluoro-5-methyl-2,5-diazaspiro[3.4] Octane [ka]

[0513] Suspension of LiAlH4 (816 mg, 21.5 mmol) in anhydrous THF (50 mL) Aluminum trichloride (2.83 g, 21.5 mmol) was added in several portions at 0°C. After the addition, the mixture was stirred at this temperature for 30 minutes, followed by addition of 2-benzyl-7 -Fluoro-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylic acid ert-Butyl ether (2.4 g, 7.16 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was stirred overnight. The slurry was filtered and the filter cake was quenched with 1 mL of ethanol (wt) and water (1 mL, 3 mL). The combined filtrate was dried over anhydrous Na2SO4, filtered, and The mixture was concentrated to give the desired product (700 mg, 42% yield) as a yellow oil. I) m / z: 235 (M+1) + .

[0514] Step 5: 2-benzyl-7-fluoro-5-methyl-2,5-diazaspiro[3.4] Octane [ka]

[0515] 2-Benzyl-7-fluoro-5-methyl-2,5-diazonium nitrate in methanol (20 mL) Zaspiro[3.4]octane (700 mg, 2.97 mmol) and HOAc catalyst (0. The solution of 1 mL of Pd(OH)2 ( The mixture was again degassed and heated under an H2 atmosphere. The reaction was filtered and the filtrate was concentrated to dryness. The desired product (350 mg, 81% yield) was obtained as a light yellow oil. MS (ESI) m / z: 145 (M+1) + .

[0516] Steps 6 to 9: (S)-N-(4-([1,2,4]triazolo[1,5-c]pyridine) 5-(7-fluoro-5-methyl-)-3-methylphenyl-5-((2-fluoro-3-methylphenyl)-2- ... 2,5-Diazaspiro[3.4]octan-2-yl)-6-methoxyquinazoline-4- Amines and (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidine- 7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-methyl-2,5- Diazaspiro[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine [ka]

[0517] Racemic N-(4-([1,2,4]triazolo[1,5-c])) as a white solid pyrimidin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-methyl (2,5-diazaspiro[3.4]octan-2-yl)-6-methoxyquinazoline The 4-amine (60 mg) was prepared as in Example 39 and separated by chiral SFC. The following were randomly assigned: (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-(7-fluoro-5-methyl-2,5-diazas Pyrro[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine (Peak 1 , retention time: 4.02 min) (22 mg, 9.4% yield) as a light yellow solid. MS (ESI) m / z: 542 (M+H) + . 1 H-NMR (400 MHz, CD3OD) δ 9.42 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.67-7.74 (m, 5H), 7.18-7.20 (d, J= 8.8 Hz, 1H), 5.14-5.28 (m, 1H ), 4.09-4.29 (m, 2H), 4.11 (s, 3H), 3.41-3.69 (m, 2H), 2.91-3.16 (m, 2H), 2.56-2 .71 (m, 2H), 2.70 (s, 3H), 2.25 (s, 3H).

[0518] (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-(7-fluoro-5-methyl-2,5-diazas Pyrro[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine (Peak 2 , retention time: 4.51 min) (9 mg, 3.8% yield) was obtained as a light yellow solid. MS (ESI) m / z: 542 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.67-7.74 (m, 4H), 7.21-7.23 (d, J= 8.8 Hz, 1H), 6.96 (s, 1H), 5. 14-5.28 (m, 1H), 4.10-4.31 (m, 2H), 4.13 (s, 3H), 3.42-3.70 (m, 2H), 2.91-3.12 ( m, 2H), 2.56-2.71 (m, 2H), 2.72 (s, 3H), 2.26 (s, 3H).

[0519] SFC conditions: Column: ChiralPak AS, 250 x 21.2 mm inner diameter, 5 μm Mobile phase A: CO2, Mobile phase B: Methanol (0.1% NH4OH); Concentration gradient: B30 %; Flow rate: 55 mL / min; Column temperature: 35°C

[0520] Example 45 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-methyl-2,6-di Azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine Example 46 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1R,5R)-2-methyl-2,6-di Azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine [ka]

[0521] Step 1: 6-(2-cyano-6-methoxy-3-nitrophenyl)-2,6-diazabiphenyl tert-Butyl cyclo[3.2.0]heptane-2-carboxylate [ka]

[0522] 2-Bromo-3-methoxy-6-nitrobenzoate in degassed 1,4-dioxane (30 mL) Isobenzonitrile (1.5 g, 5.83 mmol) and 2,6-diazabicyclo[3.2 .0] Mixture of tert-butyl heptane-2-carboxylate (1.3 g, 6.55 mmol) Cs2CO3 (3.3 g, 10 mmol) was added to the mixture, followed by Pd2(dba)3 ( 320 mg, 0.35 mmol) and RuPhos (196 mg, 0.52 mmol) After the addition, the mixture was degassed three times under N2 atmosphere. The mixture was evaporated and stirred at 100°C under N2 atmosphere for 16 hours. The reaction was complete after 2 min (EtO: EtOAc = 2:1). Diluted with Ac (50 mL) and washed with water (30 mL) and brine (20 mL), Drying over Na2SO4, filtering, and concentrating in vacuo gave the crude product, which was then purified by silica gel. Purify the desired product by column chromatography (PE: EtOAc = 5:1 to 3:1). The product (1.6 g, 73% yield) was obtained as an orange solid. MS (ESI) m / z: 375 (M+H) + .

[0523] Step 2: 2-(2,6-diazabicyclo[3.2.0]heptan-6-yl)-3-methyl Toxo-6-nitrobenzonitrile TFA salt [ka]

[0524] 6-(2-cyano-6-methoxy-3-nitrophenyl)-2 in DCM (10 mL) ,6-diazabicyclo[3.2.0]heptane-2-carboxylate tert-butyl (1. To a solution of 6 g (4.27 mmol) of TFA (10 mL) was added at 0° C., and the reaction mixture The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, and the residue was The residue was dried in vacuo to give the desired product (2 0.4 g) as a brown oil, which was used directly in the next reaction without purification. MS (ES I) m / z: 275 (M+H) + .

[0525] Step 3: 3-Methoxy-2-(2-methyl-2,6-diazabicyclo[3.2.0]heptyl) (6-butan-6-yl)-6-nitrobenzonitrile [ka]

[0526] 2-(2,6-diazabicyclo[3.2.0]heptane-6- (yl)-3-methoxy-6-nitrobenzonitrile TFA salt (1.6 g, 2.84 mmol) Paraformaldehyde (430 mg, 14.2 mmol) was added to the solution of (I) at 0°C. NaBH3CN (536 mg, 8.52 mmol) was then added and the mixture was heated at 50°C. The reaction was quenched with 1N aqueous HCl (10 mL). and diluted with EtOAc (30 mL). This mixture was diluted with water (20 mL) and brine (2 0 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH=40:1). This gave the desired product (760 mg, 93% yield) as a yellow syrup. MS (ESI) m / z: 289 (M+H) + .

[0527] Steps 4 to 6: N-(4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (1S,5S)-2-methyl-6-methoxy-5-((1S,5S)-2-methyl-2-methyl-3-methylphenyl) ... (2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazoline-4-amine and N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) (1R,5R)-2-methyl-2-(3-methylphenyl)-6-methoxy-5-((1R,5R)-2-methyl-2, 6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine [ka]

[0528] Racemic N-(4-([1,2,4]triazolo[1,5-c])) as a yellow solid Pyrimidin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(2-methyl (2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazoline-4-amine The enantiomers (95 mg) were prepared as in Example 39 and separated by chiral SFC to give the enantiomers. Thiomers were obtained. N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-methyl-2,6-di Azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine (peak 1, Retention time: 6.86 min) (35 mg, 4.8% yield) was obtained as a light yellow solid. MS (ESI) m / z: 510 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 9.67 (s, 1H) , 8.58 (s, 1H), 8.39 (s, 1H), 7.82-7.84 (m, 2H), 7.78-7.80 (d, J= 9.2 Hz, 1H), 7 .69-7.72 (d, J= 9.2 Hz, 1H), 7.20-7.22 (d, J= 9.2 Hz, 1H), 7.16 (s, 1H), 4.90-4. 93 (t, 1H), 4.10-4.11 (m, 1H), 4.09 (s, 3H), 3.98-4.01 (m, 1H), 3.83-3.88 (m, 2H) ), 3.07-3.13 (m, 1H), 2.96-3.01 (m, 1H), 2.42 (s, 3H), 2.22 (s, 3H), 1.90-1.94 ( m, 1H), 1.71-1.75 (m, 1H).

[0529] N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) -3-methylphenyl)-6-methoxy-5-((1R,5R)-2-methyl-2,6- Diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine (Peak 2 , retention time: 8.31 min) (35 mg, 4.8% yield) as a light yellow solid. MS (ESI) m / z: 510 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 9.67 (s, 1 H), 8.58 (s, 1H), 8.39 (s, 1H), 7.81-7.84 (m, 2H), 7.78-7.80 (d, J= 9.2 Hz, 1H), 7.69-7.72 (d, J= 9.2 Hz, 1H), 7.20-7.22 (d, J= 9.2 Hz, 1H), 7.16 (s, 1H), 4.90- 4.93 (t, 1H), 4.10-4.11 (m, 1H), 4.09 (s, 3H), 3.98-4.01 (m, 1H), 3.84-3.88 (m, 2H), 3.07-3.11 (m, 1H), 2.97-3.01 (m, 1H), 2.42 (s, 3H), 2.22 (s, 3H), 1.90-1.94 (m, 1H), 1.71-1.75 (m, 1H). SFC conditions: Column: ChiralPak AS, 250 x 21.2 mm inner diameter, 5 μm Mobile phase A: CO2, Mobile phase B: Methanol (0.1% NH4OH); Concentration gradient: B40 %; Flow rate: 50 mL / min; Column temperature: 35°C

[0530] Example 47 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirate (3.5)nonan-2-yl)-6-methoxyquinazolin-4-amine Example 48 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirate (3.5)nonan-2-yl)-6-methoxyquinazolin-4-amine [ka]

[0531] Step 1: 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylic acid ert-butyl [ka]

[0532] tert-Butyl 3-oxoazetidine-1-carboxylate in toluene (300 mL) (15 g, 87.6 mmol) in a solution of 2-(triphenyl-λ-phosphanylidene)acetic acid Ethyl acetate (33.5 g, 96.4 mmol) was added and the resulting mixture was stirred at 110 The mixture was stirred at 5° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted to approximately 50 mL. The filtrate was concentrated to dryness and the residue was purified by flash chromatography. Purification by chromatography (silica gel, 0-30% EtOAc in PE) gave the desired product. The product (20 g, 95% yield) was obtained as a colorless liquid. MS (ESI) m / z: 242 (M+H) + .

[0533] Step 2: 3-amino-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate tert-Butyl carboxylate [ka]

[0534] 3-(2-ethoxy-2-oxoethylidene)azetidine in EtOH (130 mL) A solution of tert-butyl 1-carboxylate (20 g, 82.9 mmol) was added to NH4OH ( 130 mL, 30 wt) was added and the mixture was stirred at 60° C. for 16 hours. The mixture was concentrated to dryness and the residue was extracted with EtOAc (2 x 100 mL). Dilute, wash with water (100 mL) and brine (100 mL), and dry over anhydrous Na2SO4 The residue was purified by flash chromatography ( Purification by silica gel, 50% to 100% EtOAc in PE gave the desired product (1 5 g, 70% yield) as a light yellow liquid. MS (ESI) m / z: 259 (M+H) + .

[0535] Step 3: 3-(2-ethoxy-2-oxoethyl)-3-(3-ethoxy-3-oxo Propanamido)azetidine-1-carboxylic acid tert-butyl ester [ka]

[0536] 3-Amino-3-(2-ethoxy-2-oxoethyl) in anhydrous DCM (300 mL) A solution of tert-butyl azetidine-1-carboxylate (18.6 g, 72 mmol) was added to T EA (15 mL, 110 mmol) was added, followed by 3-chloro- A solution of ethyl 3-oxopropionate (14.4 g, 95.62 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with aqueous NaHCO3 (100 mL) and the layers were separated. The layer was extracted with DCM (100 mL x 2), and the combined organic layer was washed with brine and anhydrous Na Drying over 2SO4, filtering, and concentrating to dryness gave the desired product (26 g, 97% yield) as a light yellow oil, which was used directly in the next step without purification. MS (ESI) m / z: 373 (M+H) + .

[0537] Step 4: 2-(tert-butyl)7-methyl(S)-6,8-dioxo-2,5-di Azaspiro[3.5]nonane-2,7-dicarboxylic acid [ka]

[0538] 3-(2-ethoxy-2-oxoethyl)-3-(3-ethoxy-2-oxoethyl)- ... tert-Butyl azetidine-1-carboxylate (2-oxo-3-propanamido) A solution of sodium methanolate (6 g, 69.86 mmol) in 100 mL of MeOH (5.4 M) was added and the reaction mixture was stirred at 80° C. for 4 hours. The mixture was concentrated to dryness, and the residue was poured into ice-cold saturated aqueous NH4Cl solution, and The combined organic layer was washed with brine and extracted with EtOAc (150 mL x 2). The residue was dried over Na2SO4, filtered, and concentrated to dryness. Purification was performed by chromatography (silica gel, 0-70% EtOAc in PE). The desired product (18.6 g, 85% yield) was obtained as a light yellow oil. MS (ESI) m / z: 313 (M+H) + .

[0539] Step 5: 6,8-Dioxo-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl [ka]

[0540] (S)-2-tert-butyl 7-methylpropional in MeCN (304 mL) and water (34 mL) 6,8-dioxo-2,5-diazaspiro[3.5]nonane-2,7-dicarboxylic acid (18.6 g, 59.59 mmol) was stirred at 100°C for 4 hours. The mixture was concentrated under vacuum to give the desired product (14.5 g, 96% yield) as a light yellow oil. MS (ESI) m / z: 255 (M+H) + .

[0541] Step 6: 8-Hydroxy-2,5-diazaspiro[3.5]nonane-2-carboxylic acid ert-butyl [ka]

[0542] 6,8-Dioxo-2,5-diazaspiro[3.5]nonitrile in anhydrous THF (150 mL) A solution of tert-butyl naphthalene-2-carboxylate (14.5 g, 57 mmol) was added to borane- Tetrahydrofuran complex (228 mL, 1 M in THF) was added dropwise at 0°C, The resulting mixture was stirred at room temperature overnight. The reaction was quenched using HCl and the mixture was concentrated to dryness. Purification by chromatography (silica gel, 0-30% MeOH in DCM) gave the desired The product (4.5 g, 33% yield) was obtained as a light yellow oil. MS (ESI) m / z: 243 (M+H ) + .

[0543] Step 7: 5-benzyl 2-(tert-butyl) 8-hydroxy-2,5-diazaspirillum b[3.5]nonane-2,5-dicarboxylic acid [ka]

[0544] 8-Hydroxy-2,5-diazaspiro[3.5]nona in anhydrous DCM (120 mL) A solution of tert-butyl benzoate (2.7 g, 11.14 mmol) in TEA (3.1 mL, 22.28 mmol) was added, followed by benzyl chloroformate (2. 85 g, 16.71 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was diluted with DCM (10 The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The residue was purified by flash chromatography ( Purification by silica gel, 0-100% EtOAc in PE) gave the desired product (1.5 g, 36% yield) as a colorless oil. MS (ESI) m / z: 377 (M+H) + .

[0545] Step 8: 5-benzyl 2-(tert-butyl) 8-fluoro-2,5-diazaspiro [3.5]nonane-2,5-dicarboxylic acid [ka]

[0546] 5-Benzyl 2-(tert-butyl) 8-hydroxybenzoate in anhydrous DCM (150 mL) -2,5-diazaspiro[3.5]nonane 2,5-dicarboxylic acid (1.5 g, 3.98 m mol) in anhydrous DCM (7 mL) was added dropwise at 0°C and the mixture was stirred at 0°C for 1 hour. The reaction was quenched with aqueous aHCO3 (100 mL) and the layers were separated. The mixture was extracted with DCM (50 mL x 2), and the combined organic layer was washed with brine and anhydrous Na2S The mixture was dried over O4, filtered, and concentrated to dryness. The residue was purified by flash chromatography. Purify by chromatography (silica gel, 0-40% EtOAc in PE) to obtain the desired product. The product (600 mg, 40% yield) was obtained as a colorless oil. MS (ESI) m / z: 379 (M+H) + .

[0547] Step 9: 8-Fluoro-5-methyl-2,5-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl carboxylate [ka]

[0548] 5-benzyl 2-(tert-butyl) 8-fluoro-2, in MeOH (50 mL) 5-diazaspiro[3.5]nonane-2,5-dicarboxylic acid (590 mg, 1.56 mm A mixture of Pd / C ( The mixture was degassed three times under N2 atmosphere and The mixture was then stirred at room temperature under an H atmosphere for 16 hours. The filtrate was concentrated to dryness, and the residue was purified by flash chromatography (silica gel). Purification by ethanol (0-15% MeOH in DCM) afforded the desired product (300 mg, 75 % yield) as a colorless oil. MS (ESI) m / z: 259 (M+H) + .

[0549] Step 10: 8-Fluoro-5-methyl-2,5-diazaspiro[3.5]nonane triflate Fluoroacetate [ka]

[0550] 8-Fluoro-5-methyl-2,5-diazaspiro[3.5 ] A solution of tert-butyl nonane-2-carboxylate (258 mg, 1 mmol) was added to TFA (1 mL) was added and the mixture was stirred for 2 hours at 0° C. The mixture was dried The mixture was concentrated to 100°C, and the residue was coevaporated twice with toluene and dried in vacuo. Drying gave the desired product (380 mg, 98% yield) as a yellow solid. LC-MS (E SI) m / z: 159 (M+H) + .

[0551] Step 11-14: (R)-N-(4-([1,2,4]triazolo[1,5-c]pyridine) 5-(8-fluoro-5-methyl-)-3-methylphenyl-5-((2-fluoro-3-methylphenyl)-2-(4-methyl-2-pyridin-7-yloxy)-3-methylphenyl)-5-(8-fluoro-5-methyl- 2,5-diazaspiro[3.5]nonan-2-yl)-6-methoxyquinazoline-4-a Min and (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirate (3.5)nonan-2-yl)-6-methoxyquinazolin-4-amine [ka]

[0552] Racemic N-(4-([1,2,4]triazolo[1,5-c ]pyrimidin-7-yloxy)-3-methylphenyl)-5-(8-fluoro-5-methylphenyl) thyl-2,5-diazaspiro[3.5]nonan-2-yl)-6-methoxyquinazoline- The 4-amine (49 mg) was prepared as in Example 39 and separated by chiral SFC. The following were randomly assigned: (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazas Pyro[3.5]nonan-2-yl)-6-methoxyquinazolin-4-amine (peak 1, Retention time: 15.71 min) (11 mg, 22% yield) was obtained as a light yellow solid. MS (ESI) m / z: 556 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 8.07-8.08 (m, 1H), 7.77-7.79 (m, 1H), 7.75-7.77 (d, J= 9.2 Hz, 1H ), 7.69-7.71 (d, J= 9.2 Hz, 1H), 7.17-7.20 (d, J= 8.8 Hz, 1H), 7.11 (s, 1H), 4.7 5-4.80 (br, 1H), 4.01-4.14 (m, 4H), 4.06 (s, 3H), 2.91-2.95 (m, 1H), 2.66-2.71 ( m, 1H), 2.28-2.33 (m, 1H), 2.18 (s, 3H), 2.09-2.14 (m, 1H), 1.66-1.88 (m, 2H).

[0553] (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) Oxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazas pyro[3.5]nonan-2-yl)-6-methoxyquinazolin-4-amine (peak 2, Retention time: 18.43 min) (12 mg, 24% yield) was obtained as a light yellow solid. MS (ESI) m / z: 556 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.58 (s, 1H), 8.41 (s, 1H), 8.07-8.08 (m, 1H), 7.77-7.79 (m, 1H), 7.76-7.78 (d, J= 9.2 Hz, 1H ), 7.69-7.71 (d, J= 9.2 Hz, 1H), 7.18-7.20 (d, J= 8.8 Hz, 1H), 7.11 (s, 1H), 4.7 5-4.80 (br, 1H), 4.02-4.13 (m, 4H), 4.06 (s, 3H), 2.91-2.95 (m, 1H), 2.66-2.71 ( m, 1H), 2.28-2.33 (m, 1H), 2.18 (s, 3H), 2.09-2.14 (m, 1H), 1.84-1.91 (m, 1H), 1 .68-1.73 (m, 1H). SFC conditions: Column: ChiralPak AS, 250 x 21.2 mm inner diameter, 5 μm Mobile phase A: CO2, Mobil...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the ceremony G is C(R ５ ) or N, A is CH or N; B is CH or N; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ is X ６ and X ７ But each is not CH each independently being CH or N, provided that each is not N; E is O, NH, or S; L is O, S, and N (R ６ ) selected from the group consisting of R １ are hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, and alkenyl groups, respectively. alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially Unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, N(R ７ ) (R ８ ), and O(R ９ wherein said cycloalkyl and heteroalkyl are independently selected from the group consisting of Cyclyl may optionally be substituted with halogen, cyano, nitro, hydroxyl, carboxy, or chlorine. aryl, aryl, aryloxy ... and optionally substituted with one or more groups independently selected from R ２ is alkyl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heteroalkyl. cyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl is optionally halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl , alkyl, alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl ru, and N(R １０ ) (R １１ and one or more groups independently selected from the group consisting of and optionally substituted with R ６ is hydrogen or alkyl, or L is N (R ６ ) when R ２ and R ６ together with the nitrogen atoms attached to them. and optionally containing one or more additional heteroatoms selected from N, O, and S. and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, The membered heterocyclyl ring may optionally be substituted with halogen, cyano, nitro, carboxy, carba Moyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially unsaturated cycloalkyl Alkyl, and N(R １０ ) (R １１ one or more groups independently selected from the group consisting of and optionally substituted by R ３ and R ４ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl and alkoxyl, R ５ is selected from the group consisting of hydrogen, halogen, and cyano; R ７ and R ８ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaromatic alkenyl, heteroalkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated cycloalkyl Saturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, hetero heteroaryl, heteroarylalkyl, or heterocyclylalkyl; each independently selected, and aryl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaromatic Aryl, heteroarylalkyl, and heterocyclylalkyl are optionally alkyl. aryl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and partially unsaturated cycloalkyl, and optionally alkyl; Saturated and partially unsaturated heteroaryls optionally substituted with aryls and heteroaryls and optionally substituted with one or more groups independently selected from the group consisting of cyclyl , or R ７ and R ８ together with the atoms bonded to them may be N, O, S, SO, SO ２ , and N.R. １２ containing one or more additional heteroatoms selected from and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, The ring may optionally be oxo, halogen, alkyl, alkenyl, alkynyl, saturated and partially substituted. Partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl , cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl , arylalkyl, heteroarylalkyl, and heterocyclylalkyl and optionally substituted with one or more independently selected groups, R ９ is alkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, Alkenyl, alkynyl, acyl, cycloalkyl, and heterocyclyl are optionally Halogen, alkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated Saturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cycloalkyl Ano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, azido from the group consisting of arylalkyl, heteroarylalkyl, and heterocyclylalkyl; optionally substituted with one or more independently selected groups; R １０ and R １１ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, hetero alkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated Saturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroa each selected from the group consisting of aryl, heteroarylalkyl, and heterocyclylalkyl; Independently selected from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic aryl, cycloalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroaryl The alkyl, alkenyl, and heterocyclylalkyl may optionally be alkyl, alkenyl, or heterocyclyl. alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partial Unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl or R １０ and R １１ together with the atoms bonded to them, may be N, O, S, SO, SO ２ , and N.R. １２ containing one or more additional heteroatoms selected from and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring which may be optionally substituted, The aryl ring may optionally be oxo, halogen, alkyl, alkenyl, alkynyl, saturated and and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkenyl alkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl alkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl and optionally substituted with one or more groups independently selected from the group consisting of: R １２ is hydrogen, alkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated hydroxyl Tetracyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl, wherein said alkyl, cycloalkyl , heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylar alkyl, and heterocyclylalkyl may optionally be halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, Cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl one independently selected from alkyl, heteroarylalkyl, and heterocyclylalkyl; may be substituted by the above groups, n is 0, 1, or 2).

2. The formula of said compound is 【Chemistry 2】 2. The compound of claim 1, wherein:

3. X １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is CH.

4. X ２ , X ３ , X ４ , and X ５ 10. The compound or drug of claim 1, wherein one of and biologically acceptable salts thereof.

5. X ２ , X ３ , X ４ , and X ５ 2. The compound or drug of claim 1, wherein two of and biologically acceptable salts thereof.

6. X ６ is N and X ７ is CH or a pharmaceutically acceptable That salt.

7. X ６ is CH and X ７ is N or a pharmaceutically acceptable That salt.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein G is N. Salt.

9. A compound or pharmaceutical composition according to any one of claims 1 to 8, wherein A is CH and B is N. and commercially acceptable salts thereof.

10. A compound according to any one of claims 1 to 9, wherein E is O, or a pharmaceutically acceptable salt thereof. Salt.

11. R １ is hydrogen, N(R ７ ) (R ８ ), O(R ９ ), or in some cases substituted by acyl Optionally substituted saturated or partially unsaturated heterocyclyl.

11. The compound according to any one of claims 10 or a pharmaceutically acceptable salt thereof.

12. L is N (R ６ ) and R ２ and R ６ together with the nitrogen atoms bonded to them and optionally containing one or more additional heteroatoms selected from N, O, and S. and forming a 3- to 10-membered saturated or partially unsaturated heterocyclyl ring, which may be substituted with any of the 3- to 10-membered saturated or partially unsaturated heterocyclyl rings. The 0-membered heterocyclyl ring is optionally halogen, alkyl, haloalkyl, saturated and Partially unsaturated cycloalkyl, and N(R １０ ) (R １１ ) independently selected from the group consisting of 12. The compound according to claim 1, wherein the compound is optionally substituted with one or more groups selected from the group consisting of methyl, ... or a pharmaceutically acceptable salt thereof.

13. R ２ and R ６ together with the nitrogen atom to which they are bonded, may be N, O, and S, forming a heterocyclyl ring, said 4- to 9-membered saturated heterocyclyl ring optionally containing halo alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R １０ ) (R １１ and optionally substituted with one or more groups independently selected from the group consisting of 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof.

14. R ２ and R ６ together with the nitrogen atom to which they are attached: 【Transformation 3】 and any of these may optionally be halogen, alkyl, haloa, alkyl, saturated and partially unsaturated cycloalkyl, and N(R １０ ) (R １１ ) group consisting of and p is 1, 2, or 3 and q is 1, 2, or 3. and biologically acceptable salts thereof.

15. L is O and R ２ saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated and heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally selected from: is halogen, alkyl, and N(R １０ ) (R １１ ) independently selected from the group consisting of The compound according to any one of claims 1 to 11, which may be substituted by one or more groups. or a pharmaceutically acceptable salt thereof.

16. R ２ is C ４～６ selected from saturated cycloalkyl or saturated 5- to 6-membered heterocyclyl; Said C ４～６ Saturated cycloalkyl and 5- to 6-membered saturated heterocyclyl are optionally halogen, alkyl, and N(R １０ ) (R １１ ) one independently selected from the group consisting of 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, optionally substituted by the above groups. That salt is useful.

17. R ３ is selected from halogen or alkyl. The compound or a pharmaceutically acceptable salt thereof.

18. R ４ is hydrogen, or a pharmaceutically acceptable salt thereof That salt is useful.

19. G is N, A is CH; B is N, X １ is CH, X ６ is N, X ７ is CH, E is O, L is O or N(R ６ ) are selected from R １ is O(R ９ ), N(R ７ ) (R ８ ), or optionally substituted by acyl optionally partially unsaturated heterocyclyl; R ２ is C ４～６ selected from saturated cycloalkyl or saturated 5- to 6-membered heterocyclyl; Said C ４～６ Saturated cycloalkyl and 5- to 6-membered saturated heterocyclyl are optionally halogen, alkyl, and N(R １０ ) (R １１ ) one independently selected from the group consisting of may be substituted by the above groups, or R ２ and R ６ together with the nitrogen atom to which they are bonded, may be N, O, and S, forming a heterocyclyl ring, said 4- to 9-membered saturated heterocyclyl ring optionally containing halo alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R １０ ) (R １１ and optionally substituted with one or more groups independently selected from the group consisting of Ku, R ３ is selected from halogen or alkyl; R ４ and R ５ is hydrogen, R ７ and R ８ are selected from hydrogen, acyl, and saturated or partially unsaturated heterocyclyl, respectively. and the acyl and heterocyclyl are optionally selected from alkyl, alkyl group, and and one or more groups selected from saturated and partially unsaturated heterocyclyl. and optionally substituted with R ９ is alkyl, acyl, C ３～７ Saturated or partially unsaturated cycloalkyl, and 4- to 6-membered and the alkyl, acyl, Cycloalkyl and heterocyclyl are optionally substituted with halogen, alkyl, acyl, and and alkoxyl, R １０ and R １１ is alkyl, and n is 1; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

20. The compound is: 【Chemistry 4】 3. The compound of claim 1 or 2, having a formula selected from the group consisting of: Possible salt.

21. L is N (R ６ ) and R １ is halogen, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl , heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkenyl alkyl, saturated or partially unsaturated heterocyclyl, aryl, N(R ７ ) (R ８ ), and O( R ９ and R ２ and R ６ together with the nitrogen atom to which they are bonded, may be N, O, and S, forming a heterocyclyl ring, said 4- to 9-membered saturated heterocyclyl ring optionally containing halo alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, and N(R １０ ) (R １１ and optionally substituted with one or more groups independently selected from the group consisting of stomach, 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof.

22. The compound is: 【Transformation 5】 3. The compound of claim 1 or 2, having a formula selected from the group consisting of: Possible salt.

23. The compound N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-methylphenyl Toxicquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3-(dimethylamino)pyrrolidin-1-yl)-5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl)-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3-(dimethylamino)pyrrolidin-1-yl)-5-(3-(dimethylamino)pyrrolidin-1-yl)-3-methylphenyl)-5-(3-(dimethylamino)pyrrolidin-1-yl) -6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-morpholinoquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1-methylpiperidin-4-yl)oxy) l) quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1-methylpyrrolidin-3-yl)oxy) l) quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)cyclobutoxy)-6-methoxy quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3-(dimethylamino)cyclopentyl)oxy)-6 -methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((4-(dimethylamino)cyclohexyl)oxy)-6 -methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methylpiperazin-1-yl)quinazo phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-en Toxicquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-6-( 2-fluoroethoxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(difluoromethoxy)-5-((1S,5S)-2-methyl (2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazoline-4-amine hmm, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1R,5R)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, cis-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) (3-fluoro-1-methylpiperidin-4-yl)-3-methylphenyl )oxy)-6-methoxyquinazolin-4-amine, trans-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) oxy)-3-methylphenyl)-5-((3-fluoro-1-methylpiperidine-4- yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(difluoromethoxy)quinazolin-5-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1S,5S)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1R,5R)-2-methyl-2,6-diazabicyclo[ 3.2.0]heptan-6-yl)-6-(((S)-tetrahydrofuran-3-yl) hydroxy)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((R)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(((S)-3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazo phosphorus-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-cyclopropoxy-5-((1S,5S)-2-methyl-2 ,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-cyclopropoxy-5-((1R,5R)-2-methyl-2 ,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-isopropoxy-5-((1S,5S)-2-methyl-2, 6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-isopropoxy-5-((1R,5R)-2-methyl-2, 6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro- 1-methylpiperidin-4-yl)oxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro- 1-methylpiperidin-4-yl)oxy)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-isopropoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3,3-difluoro-1-(methyl-d3)piperidine -4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(8-methyl-5-oxa-2,8-diaza spiro[3.5]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4S)-3-(dimethylamino)-4-fluoro pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((3R,4R)-3-(dimethylamino)-4-fluoro pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(5-methyl-8-oxa-2,5-diaza spiro[3.5]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methylhexahydropyrrolo[3,4- b] [1,4]oxazin-6(2H)-yl)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) hydroxy)-3-methylphenyl)-5-(7-fluoro-5-methyl-2,5-diazaspirate b[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) hydroxy)-3-methylphenyl)-5-(7-fluoro-5-methyl-2,5-diazaspirate b[3.4]octan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-methyl-2,6-di azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1R,5R)-2-methyl-2,6-di azabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 2,5-diazaspirillum hydroxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirillum b[3.5]nonan-2-yl)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 2,5-diazaspirillum hydroxy)-3-methylphenyl)-5-(8-fluoro-5-methyl-2,5-diazaspirillum b[3.5]nonan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(6-methyl-2,6-diazaspiro[3. 4]octan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(7-methyl-2,7-diazaspiro[3. 5]nonan-2-yl)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-7-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-7-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-7-methoxy-5-((1-methylpiperidin-4-yl)oxy) l) quinazolin-4-amine, N4-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) -3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazole- 2-yl)-5-(3-(dimethylamino)azetidin-1-yl)quinazoline-4,6 -diamine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(8-methyl-5-oxa-2,8-diazaspiro[3.5 ]nonan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(methoxy-d3)-5-((1S,5S)-2-methyl- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-(methoxy-d3)-5-((1R,5R)-2-methyl- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]octan-2-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]Octan-2-yl)-6-(difluoromethoxy)quinazolin-4-amine 、 N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazaspiro [3.4]octan-2-yl)-6-(methoxy-d3)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) hydroxy)-3-methylphenyl)-5-(7,7-difluoro-5-methyl-2,5-diazo zaspiro[3.4]octan-2-yl)-6-((tetrahydrofuran-3-yl)o quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(6-methyl-2,6-diazabicyclo[3 .2.0]heptan-2-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(4-methyloctahydro-1H-pyrrolo[ 3,2-b]pyridin-1-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(3-methyl-3,7-diazabicyclo[4 .2.0]octan-7-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-(3-methyl-3,6-diazabicyclo[3 .2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(2-cyclopropyl-2,6-diazabicyclo[3.

2. 0]heptan-6-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-(2-(2,2-difluoroethyl)-2,6-diazabis( chloro[3.2.0]heptan-6-yl)-6-methoxyquinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-(methyl-d3)- 2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazolin-4-amine, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-5-((1S,5S)-2-(2-fluoroethyl)-2,6- Diazabicyclo[3.2.0]heptan-6-yl)-6-methoxyquinazoline-4-a Min, N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)- 3-methylphenyl)-6-methoxy-5-((1S,5S)-2-(2,2,2-trimethylphenyl) fluoroethyl)-2,6-diazabicyclo[3.2.0]heptan-6-yl)quinazo phosphorus-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6-(trifluoromethoxy)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine, (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 4,4-difluoro-1-methylpyrrolidine- 3-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoropiperidin-4-yl)-5-((3,3-difluoro-4-yl)-2-(2-methyl-2-phenyl ... hydroxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) (3,3-difluoro-1-(methyl-d3)pi (peridin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-isopropylpiperidyl)-5-((3,3-difluoro-1-isopropylpiperidyl)-3-methylphenyl)-5-((3,3-difluoro-1-isopropylpiperidyl)- (di-4-yl)oxy)-6-methoxyquinazolin-4-amine, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 1-cyclopropyl-3,3-difluoropiperidine Lysin-4-yl)oxy)-6-methoxyquinazolin-4-amine, 1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azetidinyl (quinazolin-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, (R)-1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidinyl) phenyl-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro- 1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-3,6-dihydro pyridin-1(2H)-yl)prop-2-en-1-one, 1-(5-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azetidinyl (quinazolin-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(4-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azetidinyl (quinazolin-1-yl)quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(5-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7- (3-(dimethylamino)-5-(3-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azetidinyl (quinazolin-1-yl)quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl ) prop-2-en-1-one, 1-(4-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -(3-(dimethylamino)-5-(3-(methyloxy)-3-phenyl)amino)-5-(3-(dimethylamino)pyrrolidine quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-yl En-1-on, (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl oxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1-methylpi (peridin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile, (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl oxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1-methylpi (peridin-4-yl)oxy)-7-methoxyquinoline-3-carbonitrile, 4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy) -3-methylphenyl)amino)-5-(((R)-3,3-difluoro-1-methylphenyl)amino) 2,4-dimethylpiperazine-1,4-diol -carboxylate, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-3-cyano-5-((3,3-di Fluoro-1-methylpiperidin-4-yl)oxy)quinolin-6-yl)-4-(di methylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-3-cyano-5-((3,3-di Fluoro-1-methylpiperidin-4-yl)oxy)-7-ethoxyquinolin-6-yl (dimethylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1 -methylpiperidin-4-yl)oxy)-7-ethoxyquinazolin-6-yl)-4- (dimethylamino)but-2-enamide, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluoro-1 (-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-4-(dimethylamino) n) but-2-enamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-3-cyano-5-(((R)-3,3 -difluoro-1-methylpiperidin-4-yl)oxy)quinolin-6-yl)-3- ((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -yloxy)-3-methylphenyl)amino)-3-cyano-5-(((R)-3,3 -difluoro-1-methylpiperidin-4-yl)oxy)-7-ethoxyquinoline-6 -yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -3,3-difluoro-3-methylphenyl)amino)-5-(((R)-3,3-difluoro-2 ... -1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-3-((R)- 1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -3,3-difluoro-3-methylphenyl)amino)-5-(((R)-3,3-difluoro-2 ... -1-methylpiperidin-4-yl)oxy)-7-ethoxyquinazolin-6-yl)- 3-((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine-7 -(3-(dimethylamino)azetiyloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)azetiyl (Dimethylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamine Do, (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidine -7-yloxy)-3-methylphenyl)amino)-5-(3-(dimethylamino)a Zetidin-1-yl)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl ) acrylamide, and (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl) 3,3-difluoro-1-methylpiperidine- 4-yl)oxy)-6,7-dimethoxyquinazolin-4-amine A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, selected from the group consisting of Acceptable its salt.

24. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and at least 1. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

25. The medicament of claim 24, which does not contain an agent for promoting blood-brain barrier (BBB) ​​crossing. composition.

26. A method of treating a HER2-associated disease or condition in a subject in need thereof, comprising administering to a subject a compound of claim 1 to a subject in need thereof a compound of claim 2 to a subject in need thereof a compound of claim 3 to a subject in need thereof a compound of claim 4 to a subject in need thereof a compound of claim 5 to a subject in need thereof a compound of claim 6 to a subject in need thereof a compound of claim 7 to a subject in need thereof a compound of claim 8 to a subject in need thereof a compound of 23 or a pharmaceutically acceptable salt thereof, The method comprising administering to an elephant.

27. The HER2-associated disease or condition is breast cancer, gastric cancer, mCRC, NSCLC, or any of their 27. The method of claim 26, wherein the cancer is a metastasis.

28. 28. The method of claim 27, wherein the metastasis is in the brain.

29. The compound or a pharmaceutically acceptable salt thereof is used to promote blood-brain barrier (BBB) ​​crossing.

29. The method of claim 28, wherein the compound is capable of crossing the blood-brain barrier (BBB) ​​in the absence of an agent for the treatment of the disease. method.

30. A compound according to any one of claims 1 to 23 for use in the treatment of a HER2-associated disease or condition. or a pharmaceutically acceptable salt thereof.

31. Any of claims 1 to 23 in the manufacture of a medicament for the treatment of a HER2-associated disease or condition.

10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

32. A compound according to any one of claims 1 to 23 for use in the treatment of a HER2-associated disease or condition. or a pharmaceutically acceptable salt thereof, wherein said compound is a compound such as capecitabine Simultaneously with one or more chemotherapeutic agents, T-DM1, radiation therapy, and anti-HER2 antibody, or separately or sequentially administered said compound or a pharmaceutically acceptable salt thereof.

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