WO2024249642A1 - Egfr inhibitors - Google Patents

Abstract

Compounds of Formula (I): a pharmaceutically acceptable salt, a stereoisomer, or a racemate thereof. Each of R₄, R₅, R₆, R₇, R₈, X, and Y is defined herein. Also disclosed are pharmaceutical compositions containing such a compound, methods of treating cancer or inhibiting EGFR using the compound.

Description

EGFR INHIBITORS CROSS REFERENCES TO RELATED APPLICATONS This application claims the benefit of priority based on US Application Series No. 63/470,633 filed on June 2, 2023, the content and disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present invention provides quinazoline compounds, pharmaceutical compositions thereof, their preparation methods, and use as EGFR inhibitors for treating cancer. BACKGROUND Epidermal growth factor receptor (EGFR) belongs to the HER family of receptors which comprise four related proteins EGFR, HER2, HER3, and HER4. The HER receptors are known to be activated by binding to different ligands including EGF (see Duggirala et.al., Biomol Ther, 2022, 30, 19). After binding to a ligand, the receptor forms functionally active dimers including EGFR-EGFR, EGFR-HER2, EGFR-HER3, and EGFR-HER4. Dimerization induces the activation of the tyrosine kinase domain of EGFR, leading to a series of downstream signaling pathways for cell proliferation, survival, and anti- apoptosis (see Uribe et al., Cancers 2021, 13, 2748). Dysregulations of EGFR signal transduction pathways, including EGFR gene mutations, can promote malignant transformation of normal cells into tumor cells and subsequently assist tumor cell proliferation, invasion, metastasis, and angiogenesis. In non-small cell lung cancer (NSCLC) patients, the two most common EGFR gene mutations are del19 (i.e., a short in-frame deletion in exon 19) and L858R (i.e., a single missense mutation in exon 21). See Konduri et.al., Cancer Discov, 2016, 6, 601. These two mutations trigger ligand independent EGFR activation, driving cancerous growth and metastasis of NSCLC (see Uribe et al., Cancers 2021, 13, 2748). Given the prominent importance of EGFR signaling in cancer development, several small-molecule EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and the like, have been developed to inhibit oncogenic EGFR activity for treating NSCLC patients harboring del19 and L858R mutations. Nevertheless, almost all cancer patients developed resistance to EGFR-TKIs (erlotinib and gefitinib) after 10–14 months of treatment. The TKI resistance has been associated with a secondary mutation (T790M) in the EGFR’s kinase domain in 50%–60% of the cases (see Pao et al., PLoS Med.2005, 2, e73 and Leonetti et al., British Journal of Cancer, 2019, 121, 725). To overcome T790M mutation resistance, osimertinib as a third-generation EGFR inhibitor was developed for treating patients carrying the EGFR T790M mutation. Unfortunately, acquired resistance to osimertinib inevitably occurs, relating to EGFR C797X mutations (wherein "X" can be an S, G, N, Y, T, or D), which occurs in exon 20 (see Papadimitrakopoulou et al., Annals of Oncology, 2018, 29, LBA51 and Bertoli et al., Int. J. Mol. Sci. 2022, 23, 6936). Tumors harboring double mutants, e.g., Del19/C797X and L858R/C797X, are no longer sensitive to osimertinib or other third-generation EGFR inhibitors. There is no approved medicine to treat patients carrying double mutants. Further, current EGFR inhibitors such as gefitinib and erlotinib are not effective in treating brain cancer due to their low ability to cross the blood-brain barrier. It is critical that EGFR inhibitors are capable of crossing the blood-brain barrier, as about 70% of NSCLC patients bearing mutant-EGFR develop brain metastases (see Subramaniam et al, Front Oncol.2018, 8, 208). Thus, there is an unmet medical need for effective EGFR inhibitors to penetrate blood- brain barrier and treat NSCLC patients having double EGFR mutants and brain metastasis. SUMMARY The present invention is based on an unexpected discovery that certain quinazoline compounds show promising anti-tumor activities. In one aspect, this invention relates to quinazoline compounds of Formula I:

I, in which one of X and Y is H, deuterium, or halo; the other of X and Y is

, in which R₁ is F, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 4-6 membered heterocyclyl, R₂ is H, deuterium, F, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 4-6 membered heterocyclyl, or R₁ and R₂, together with the carbon atom they bond to, are C₃-C₆ cycloalkyl or 4-6 membered heterocyclyl; R3 is 5-10 membered heteroaryl orC₆-C₁₀ aryl; and n is 1, 2, or 3; R₄ is H, halo, cyano, C₃-C₆ cycloalkyl, ORa, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, in which Ra is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl; R₅ is H or deuterium; R₆ is H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; R₇ is 6-10 membered aryl or 5-10 membered heteroaryl; R₈ is H, deuterium, halo, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; alkyl is optionally substituted with one or more groups selected from the group consisting of deuterium, halo, cyano, C₁-C₄ alkoxy, NR_1aR_1b, C₃-C₆ cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-6 membered heterocyclyl, in which R_1a and R_1b, independently, is H, deuterium, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl, or R₁a and R₁b, together with the nitrogen atom they bond to, are C4-C₆ heterocyclyl; and each of cycloalkyl, heterocyclyl, aryl, and heteroaryl, independently, is optionally substituted with one or more groups selected from the group consisting of deuterium, halo, cyano, acetylenyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, 4-6 membered heterocyclyl, and NR_1aR_1b. Preferably, the above-described compounds have one or more of the following features: (i) n is 1; (ii) R₁ is F, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃, and more preferably, methyl; or R₁ and R₂, together with the carbon atom they bond to, are C₃-C₆ cycloalkyl, preferably cyclopropyl; (iii) R₂ is H, F, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃; (iv) R₃ is

; preferably, R₃ is pyrimidinyl, imidazolyl,

;

(vi) R₇ is phenyl optionally substituted with one or more groups selected from the group consisting of F, Cl, Br and acetylenyl, preferably R₇ is

. Further, R₇ can also be 9- or 10- membered bicyclic heteroaryl optionally substitutes with halo (e.g., F). Examples include quinolinyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, benzo[c]isothiazolyl, and benzo[d]isothiazolyl such as

(vii) R₆ is H, CH₃, CD₃, or CHF₂, preferably H or CHF₂; (viii) R₈ is H or deuterium, preferably H. Subsets of the compounds of Formula I are represented by Formulas IA and IB:

. Each of R₁-R₇ and n is defined above including any combinations of features (i) to (vii) as shown above. In addition, in Formula IA, R₄ can be

Preferred compounds of Formula IA have the following features: (i) n is 1; (ii) R₅ is H or deuterium; (iii) R₁ is F, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃, and R₂ is H, F, CH₃, D, CD₃, cyclopropyl, CF₃, CHF₂; or R₁ and R₂, together with the carbon atom they are bonded to, is cyclopropyl;

In Formula IB above, preferably n is 1, 2, or 3 and R₁ is F, CH₃, CD₃, CF₃, CHF₂, cyclopropyl. Further in Formula IB, R₄ can be

. Preferred compounds of Formula IB include the following features: (i) n is 1; (ii) R₅ is H or deuterium; (iii) R₁ is F, CH₃, CD₃, CF₃, CHF₂, cyclopropyl; (iv) R₂ is H, CH₃, D, CD₃, F, cyclopropyl, CF₃, or CHF₂; (v) R₃ is

(vii) R₆ is H, CH₃ or CHF₂; and (viii) R₇ is

. Another aspect of this invention is a method of treating cancer comprising administering to a subject in need thereof an effective amount of any one of the compounds described above. Nonlimiting examples of cancer treatable by the compounds of this invention include lung cancer (e.g., non-small cell lung cancer) and brain cancer. The current invention further includes use of such a compound (e.g., a pharmaceutical composition containing one of the compounds of Formula I described above) for treating cancer or for the manufacture of a medicament for treating cancer. Also within the scope of this invention is a method of inhibiting EGFR by administering to a subject in need thereof an effective amount of any one of the compounds described above. Still within the scope of this invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. As described above, the pharmaceutical composition is particularly useful in treating cancer. Table 1 below shows 65 exemplary compounds of the present invention, i.e., Compounds 1-65. Table 1

Preferred compounds include Compounds 1-4, 6-8, 10, 15-17, 20-24, 27, 28, 31-33, 35, and 43-65. The term “halo” herein refers to a fluoro, chloro, bromo, or iodo radical. Examples include a fluoro radical (F) and a bromo radical (Br). The term “alkyl” refers to a straight or branched hydrocarbon group, containing 1-20 carbon atoms (e.g., C_1-6) and a monovalent radical center derived by the removal of a hydrogen atom from a carbon atom of a parent alkane. Exemplary alkyl groups are methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. The term “haloalkyl” refers to alkyl substituted with one or more halo atoms. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl (e.g., 1-fluoroetyl and 2-fluoroethyl), difluoroethyl (e.g., 1,1-, 1,2-, and 2,2-difluoroethyl), and trifluoroethyl (e.g., 2,2,2- trifluoroethyl). The term “alkyl” as used herein includes haloalkyl. The term “alkoxy” refers to an –O–alkyl group. Examples are methoxy, ethoxy, propoxy, and isopropoxy. Alkoxy also includes haloalkoxy, namely, alkoxy substituted with one or more halogens, e.g., –O-CH₂Cl and –O-CHClCH₂Cl. The term “cycloalkyl” refers to a nonaromatic, saturated or unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group containing 3 to 12 carbons (e.g., C_3-6 and C_3-10). Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term “heterocyclyl” refers to a nonaromatic, saturated or unsaturated, 3–8 membered monocyclic, 8–12 membered bicyclic, or 11–14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include aziridinyl, azetidinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydro-2-H-thiopyran-1,1-dioxidyl, piperazinyl, piperidinyl, morpholinyl, imidazolidinyl, azepanyl, dihydrothiadiazolyl, dioxanyl, and quinuclidinyl. Both “cycloalkyl” and “heterocyclyl” also include fused, bridged, and spiro ring systems. They further include substituted groups such as halocycloalkyl and haloheterocyclyl. The term “aryl” refers a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system wherein each ring can have one or more (e.g., 1 to 10, 1 to 5, and 1 to 3) substituents. Examples include phenyl, biphenyl, 1‑ or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, and indanyl. The term “aralkyl” refers to alkyl substituted with an aryl group. The term "heteroaryl" refers to an aromatic 5–8 membered monocyclic, 8–12 membered bicyclic, or 11–14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, pyrazolyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isoxazolyl, carbazolyl, furyl, imidazolyl, thienyl, thiazolyl, and benzothiazolyl. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl or heteroaryl group. Alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heterocyclylalkyl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise. Examples of a substituent include deuterium (D), hydroxyl (OH), halo (e.g., F and Cl), amino (NH₂), cyano (CN), nitro (NO₂), alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acylamino, alkylamino, aminoalkyl, haloalkyl (e.g., trifluoromethyl), heterocyclyl, alkoxycarbonyl, amido, carboxy (COOH), alkanesulfonyl, alkylcarbonyl, alkenylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, aryl, arylamino, aralkyl, and heteroaryl. All substitutes can be further substituted. The term “compound”, when referring to a compound of this invention, also includes its salts, solvates, and prodrugs. The pharmaceutically acceptable salts include those listed in Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2^nd Revised Edition, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, New York, (2011). In addition to pharmaceutically acceptable salts, other salts are contemplated in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or are useful for identification, characterization or purification of compounds of the invention. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of a pharmaceutically acceptable solvent include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. A prodrug refers to a compound that, after administration, is metabolized into a pharmaceutically active drug. Examples of a prodrug include esters and other pharmaceutically acceptable derivatives. The compounds of the present invention may contain one or more non-aromatic double bonds or asymmetric centers. Each of them occurs as a racemate or a racemic mixture, a single R enantiomer, a single S enantiomer, an individual diastereomer, a diastereometric mixture, a cis-isomer, or a trans-isomer. Compounds of such isomeric forms are within the scope of this invention. They can be present as a mixture or can be isolated using chiral synthesis or chiral separation technologies. The term “treating” or “treatment” refers to administering one or more of the compounds to a subject with the purpose to confer a therapeutic effect, e.g., to slow, interrupt, arrest, control, or stop of the progression of an existing disorder and/or symptoms thereof, but does not necessarily indicate a total elimination of all symptoms. “An effective amount” refers to the amount of a compound that is required to confer the therapeutic effect. Effective doses will vary, as recognized by those skilled in the art, depending on the types of symptoms treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment. Cancer treatable with a compound of this invention includes those caused by KRAS mutation, SOS1 oncogenic mutation, or oncogenic mutation/overexpression of receptor tyrosine kinases such as EGFR, FGFR, etc. Nonlimiting examples include pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma, and brain metastasis. The compounds of this invention are particularly effective in treating cancer associated with EGFR such as brain cancer, lung cancer (e.g., non-small cell lung cancer, and non-small cell lung cancer with brain metastasis or leptomeningeal). The term “subject” refers to an animal including human or non-human, such as a mammal. A human is a preferred subject. A compound of this invention may be administered alone or in the form of a pharmaceutical composition with pharmaceutically acceptable carriers, diluents or excipients. Such pharmaceutical compositions and processes for making the same are known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition., Academic Press, 2020). To practice the method of the present invention, a composition or a kit containing one or more of the above-described compounds can be administered alone or co-administered with at least one other pharmacologically active substance simultaneously, concurrently, sequentially, successively, alternately, or separately. Simultaneous administration, also referring to as concomitant administration, includes administration at substantially the same time. Concurrent administration includes administering the active agents within the same general time period, for example on the same day(s) but not necessarily at the same time. Alternate administration includes administration of one agent during a time period, for example over the course of a few days or a week, followed by administration of the other agent(s) during a subsequent period of time, for example over the course of a few days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administration of one agent during a first time period (for example over the course of a few days or a week) using one or more doses, followed by administration of the other agent(s) during a second and/or additional time period (for example over the course of a few days or a week) using one or more doses. An overlapping schedule may also be employed, which includes administration of the active agents on different days over the treatment period, not necessarily according to a regular sequence. Variations on these general guidelines may also be employed, e.g., according to the agents used and the condition of the subject. The elements of the combinations of this invention may be administered (whether dependently or independently) by methods customary to the skilled person, e.g., by oral, enteral, parenteral, nasal, vaginal, rectal, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and/or vehicles appropriate for each route of administration. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique. A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents. A composition having one or more of the above-described compounds can also be administered in the form of suppositories for rectal administration. The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound. Examples include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION The present invention is based on a surprising discovery that the compounds of Formula I reproduced below are effective in inhibiting EGFR and treating cancer.

I Variables R₁-R₇, X, and Y are defined above. Further, in a subset of the compounds of formula I, R₃ is

Preferably, R₃ is

. In another subset of the compounds of formula I, R₄ is

. In a third subset of the compounds of formula I, R₇ is phenyl, and R₇ is optionally substituted with one or more groups selected from the groups consisting of F, Cl, Br and acetylenyl; Preferably, R₇ is

. More preferably, R₇ is

. In another subset of the compounds of formula I, R₇ is 9- or 10- membered bicyclic heteroaryl, preferably quinolinyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2- a]pyridinyl, benzo[c]isothiazolyl or benzo[d]isothiazolyl; and R₇ is optionally substituted with halo (for example F); Preferably, R₇ is .

. In a preferred subset of the compounds of formula IA:

. In a preferred subset of the compounds of formula IB:

R₃ is

. The compounds of the invention are useful in treating mutant EGFR mediated cancer that has metastasized to brain and central nervous system. They are also suitable for treating mutant EGFR mediated local or metathesized lung cancer. The compound can be a compound of Formula I, IA, or IB. The compounds of Formula I can be prepared by synthetic methods well known in the art. See, e.g., R. Larock, Comprehensive Organic Transformations (3^rd Ed., John Wiley and Sons 2018); P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups in Organic Synthesis (4^th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (John Wiley and Sons 1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2^nd ed., John Wiley and Sons 2009) and subsequent editions thereof. The compounds thus prepared can be purified following conventional methods such as crystallization, distillation/vacuum distillation, flash chromatography over silica, and preparative liquid chromatography. Efficacy of the compounds of this invention can be initially determined using cellular pERK potency assay or 2D cell proliferation assay, all described below. The selected compounds can be further tested to verify their efficacy, e.g., by administering it to an animal. Based on the results, an appropriate dosage range and administration route can be determined. A compound of this invention is preferably formulated into a pharmaceutical composition containing a pharmaceutical carrier. The pharmaceutical composition is then given to a subject in need thereof to inhibit mutant EGFR (e.g. del19, L858R, del19/C797S, del19/L858R, amplification) thus treating cancer. Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following examples are to be construed as merely illustrative and not limitative in any way whatsoever. All publications cited herein are hereby incorporated by reference in their entirety. Set forth below are examples illustrating preparation and efficacy evaluation of compounds of this invention. The abbreviations as used herein are provided in Table 2 below with their definitions, which are used conventionally in the art. Table 2

Schemes I to V depict five exemplary routes for preparing a compound of the invention (In the following schemes, Ar is R₇). Scheme I

Scheme III

The compounds of the invention can be prepared by combining the reactions in these general synthetic schemes or additional reaction schemes specifically depicted herein or reactions known in the art and not limited to the general schemes described herein. General Synthetic Procedures Provided below are exemplary processes for preparing compounds of Formula I (e.g., IA and IB). These processes provide further features of the invention and are illustrated below. Generally, compounds of formula IA and IB can be synthesized using the procedures illustrated in Schemes I to V above. As shown in Scheme I, quinazolinone IA-2 can be prepared by reacting benzonitrile derivative IA-1 with formic acid in the presence of H₂SO₄. Quinazolinone IA-2 is then converted to chloride IA-3 using oxalyl chloride, thionyl chloride, or POCl₃ in a suitable solvent such as chloroform. The chlorine atom in IA-3 is displaced by IA-4 (i.e., H₂N-Ar) to yield IA-5 in a suitable solvent such as isopropanol. The fluorine atom in IA-5 is displaced by chiral or achiral alcohol IA-6 in the presence of a base, such as NaH or t-BuOK, in a suitable solvent such as THF to yield ether IA-7. Finally, R₄ is introduced using palladium mediated coupling with borate, boronic acid, or boronate ester derivatives such as IA-8a or IA-8b in a suitable solvent (e.g., dioxane and water) to provide a compound of formula IA-9. Furthermore, reduction of the halide of IA-7 with Et₃SiH in the presence of a palladium catalyst or catalytic hydrogen reduction in a suitable solvent such as dioxane can provide a compound of Formula IA-10. Compounds of formula IA can also be prepared following Scheme II, starting with a reaction between benzonitrile derivative IA-1 and DMF-DMA to generate imine IA-11, which undergoes ring formation in the presence of H₂N-Ar (IA-4) in acetic acid to form quinazoline derivative IA-12. The fluorine atom in IA-12 is displaced with chiral or achiral alcohol IA-6 in the presence of a base (e.g., NaH and t-BuOK) in a suitable solvent such as THF to generate ether IA-13. Finally, R₄ is introduced using palladium mediated coupling with borate, boronic acid or boronate ester derivatives (e.g., IA-8a and IA-8b) in a suitable solvent such as dioxane and water to provide a compound of formula IA-9. Alternatively, nucleophilic displacement reaction with an amine or heteroaryl R₄ (e.g., pyrazole and imidazole or their derivatives) in a suitable solvent such as dioxane provides a compound of formula IA-9. Furthermore, the bromine atom in intermediate IA-13 can be displaced using metal halide (e.g., cuprous iodide) mediated coupling with heteroaryl-OH derivatives (IA-8d) such as 1-methyl-1H-pyrazol-4-ol, in the presence of a suitable ligand such as 3,4,7,8-tetramethyl-1,10-phenanthroline in a suitable solvent such as toluene to generate compound of formula 1A-9. The bromine atom in intermediate IA-13 can also be displaced by HO-alkyl (IA-8d) group via palladium mediated C-O bond formation using RockPhos Pd G3 (CAS# 2009020-38-4) catalyst. Compounds of formula IB can be synthesized following Scheme III. The fluorine atom in nitrobenzene derivative IB-1 is displaced by chiral or achiral alcohol IA-6 in the presence of a base (e.g., NaH and tBuOK) in a suitable solvent such as THF and DMF to yield nitrobenzene derivative IB-2. The nitro group in IB-2 is selectively reduced with Fe or Zn and NH₄Cl in a suitable solvent such as ethanol and water, to provide intermediate amino IB-3, which reacts with formamidine acetate in the presence of pTSA in a suitable solvent such as ethanol, to generate quinazolinone derivative IB-4. Quinazolinone derivative IB-4 is converted to chloride IB-5 using oxalyl chloride, thionyl chloride or POCl₃ in a suitable solvent such as CHCl₃. The chlorine atom in IB-5 is displaced by IA-4 (i.e., H₂N-Ar) to provide intermediate IB-6. Finally, R₄ is introduced using palladium mediated coupling with borate, boronic acid or boronate ester derivatives (e.g., IA-8a or IA-8b) in a suitable solvent such as dioxane and water to yield the final product of formula IB-7. Some of the compounds of formula IB can be synthesized following scheme IV. IB-8 is etherified using a Mitsunobu reaction using reagents such as diethyl azodicarboxylate/Ph₃P or 1,1′-(azodicarbonyl)dipiperidine/n-Bu3P with chiral or achiral alcohol IA-6 to yield a compound of formula IB-9. Compounds of formula IB can also be synthesized following scheme V. Phenol derivative IB-10 is converted to a corresponding carbonate IB-11 using ethyl carbonochloridate in a suitable solvent such as dichloromethane. Nitration of the carbonate IB-11 in a mixture of H₂SO₄ and HNO₃ affords nitro derivative IB-12, which is hydrolyzed using a base such as NaHCO₃ in a suitable solvent such as methanol to from phenol IB-13. The phenol IB-13 is converted to vinyl ether using di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium mediated vinylation using vinyl acetate in a suitable solvent such as toluene to form intermediate IB-14. The vinyl group in IB-14 is converted to cyclopropyl derivative IB-15 using diiodomethane and diethyl zinc in a suitable solvent such as DCM. The bromo group in IB-15 is displaced with CuCN in a suitable solvent such as NMP to form the cyano intermediate IB-16. The fluorine atom in IB-16 is displaced with chiral or achiral alcohol IA-6 in the presence of a base (e.g., NaH and t-BuOK) in a suitable solvent such as THF to generate ether IB-17. The nitro group in IB-17 is selectively reduced with sodium dithionite in a suitable solvent such as tetrahydrofuran and water, to provide intermediate amino IB-18, which reacts with (E)-N,N'-bis(3-chloro-2-fluorophenyl)formimidamide (IB-19) in the presence of acetic acid in a suitable solvent such as 2-methyl tetrahydrofuran, to generate quinazolinone derivative of formula IB-20. All chemicals, reagents, and solvents were purchased from commercial sources when available and were used as received without further purification. Air- and moisture-sensitive reactions were carried out under an inert atmosphere of argon or nitrogen in oven-dried glassware. The reactions were monitored using analytical thin layer chromatography (TLC). The developed TLC plates were visualized by UV light (λ = 254, 365 nm) or immersion in alkaline potassium permanganate solution followed by heating on a hot plate. All reactions were stirred magnetically at ambient temperature unless otherwise indicated.¹H NMR spectra were recorded on Agilent Technologies or VARIAN, 400 MHz NMR spectrometer.¹H NMR spectra were reported in parts per million (δ) relative to TMS (0.0), DMSO-d₆ (2.50) or CD₃OD (4.80) as an internal reference. ¹H NMR data are reported as follows: chemical shift in ppm; multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet/complex pattern, td = triplet of doublets, ddd = doublet of doublet of doublets, br = broad signal); coupling constants (J) in Hz, integration. Mass spectral data was collected on SHIMADZU, LCMS-2020. Column chromatography is performed with regular gravity or flash chromatography, or pre-packed silica gel cartridges using a medium pressure chromatography apparatus (SANTAI Technologies, SepaBean machine U200), eluting with the solvent or solvent mixture indicated in the respective experiment. Preparative high performance liquid chromatography (HPLC) is performed using a reverse phase column (SHIMADZU, Column, Boston Analytics, Inc, Green ODS C18, 21.2 x 250 mm) of a size appropriate to the quantity of material being separated, generally eluting with a gradient of increasing concentration of methanol or acetonitrile in water, containing 0.1% trifluoroacetic acid or 0.1% formic acid or 0.04% ammonium bicarbonate in water/MeCN at a rate of elution suitable to the column size and separation to be achieved. Chemical names are generated using ChemDraw Professional version 19.1. EXAMPLES The following intermediates may be used to prepare compounds of the present invention. Synthesis of 5-fluoroquinolin-6-amine (1A-4-1)

To a solution of quinolin-6-amine (4 g, 27.76 mmol, 1 eq) in dioxane (120 mL) was added NaHCO₃ (7 g, 83.24 mmol, 3 eq). Under stirring at 40 °C, SelectFluor^TM (1-chloro- methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 12.8 g, 36 mmol, 1.3 eq) was added to the above solution in one portion. The resultant mixture was stirred at 40 °C for 4 h under nitrogen, cooled to room temperature, and filtered thought celite® with washing by EtOAc (50 mL x 3). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/DCM (1:1) to afford the title compound (1.95 g, 43% yield) as a brown solid. LCMS: m/z = 163.25 [M+1]⁺. Synthesis of 7-fluorobenzo[d]isothiazol-6-amine (1A-4-2)

Step 1. Synthesis of 6-bromo-7-fluorobenzo[d]isothiazole To a solution of 4-bromo-2,3-difluorobenzaldehyde (7 g, 32 mmol, 1 eq) in DMF (70 mL) was added S₈ (1.12 g, 35 mmol, 1.1 eq) and ammonium hydroxide (3.5 mL). The mixture was stirred at 100 °C for 16 h. After cooling to rt, it was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA (20:1)) to afford the title compound (2 g, 27.3% yield) as a yellow solid. LCMS: m/z = 231.85/233.85 [M+1]⁺. Step 2. Synthesis of tert-butyl (7-fluorobenzo[d]isothiazol-6-yl)carbamate A mixture of 6-bromo-7-fluorobenzo[d]isothiazole (1.5 g, 6.5 mmol, 1 eq), tert-butyl carbamate (838 mg, 7.1 mmol, 1.1 eq), Cs₂CO₃ (6.35 g, 19 mmol, 3 eq), Xantphos (564 mg, 0.97 mmol, 0.15 eq) and Pd2(dba)3 (297 mg, 0.32 mmol, 0.05 eq) in toluene (20 mL) was degassed and purged with nitrogen and the mixture was stirred at 100 °C for 14 h. After cooling to rt, the mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA (15:1)) to afford the title compound (820 mg, 47.7% yield) as a yellow solid. LCMS: m/z = 268.95 [M+1]⁺. Step 3. Synthesis of 7-fluorobenzo[d]isothiazol-6-amine To a solution of tert-butyl (7-fluorobenzo[d]isothiazol-6-yl)carbamate (1.1 g, 4 mmol, 1 eq) in dioxane (25 mL) was added HCl/dioxane (15 mL). The mixture was stirred at 40 °C for 5 h under nitrogen. The reaction mixture was concentrated under vacuum to afford the title compound (700 mg, 99% yield) as a yellow solid. LCMS: m/z = 169.05 [M+1]⁺. Synthesis of 4-fluoropyrazolo[1,5-a] pyridin-5-amine (1A-4-3)

Step 1. Synthesis of tert-(3-fluoropyridin-4-yl) carbamate To a solution of 3-fluoropyridin-4-amine (4 g, 36 mmol, 1 eq) in THF (40 mL) was added di-tert-butyl dicarbonate (9.37 g, 43 mmol, 1.2 eq). After being stirred at rt for 6 h, the reaction mixture was condensed to dryness. The residue was suspended in petroleum ether (60 ml) and then stirred for 1 h, filtered to give the title compound (7.6 g, 98 % yield) as a white solid. LCMS: m/z = 213.2 [M+1] ⁺. Step 2. Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoropyrazolo[1,5-a]pyridine-3- carboxylate To a solution of tert-butyl (3-fluoropyridin-4-yl)carbamate (1 g, 4.7 mmol, 1 eq) in MeCN (20 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (938 mg, 4.7 mmol, 1 eq) at room temperature, the mixture was stirred at 40 °C for 12 h under N2. The solvent was removed under vacuum to afford the crude residue. To the crude residue was added dry DMF (20 mL), K₂CO₃ (1.95 g, 14.13 mmol, 3 eq) and ethyl propiolate (693.4 mg, 7 mmol, 1.5 eq). The suspension was stirred at room temperature for 12 h. The reaction was quenched with water and extracted with EtOAc (100 mL x 3). The organic phases were washed with water (50 mL x 3) and brine (50 mL), dried over Na₂SO₄, concentrated under reduced pressure. The residue was purified by FCC (eluted with 0%~20% EA in PE) to afford ethyl 5-((tert-butoxycarbonyl) amino)-4-fluoropyrazolo[1,5-a] pyridine-3-carboxylate (400 mg, 22 % yield) as a white solid. LCMS: m/z = 324.13 [M+1]⁺. Step 3. Synthesis of 5-((tert-butoxycarbonyl)amino)-4-fluoropyrazolo[1,5-a]pyridine-3- carboxylic acid Ethyl 5-((tert-butoxycarbonyl) amino)-4-fluoropyrazolo[1,5-a] pyridine-3-carboxylate (1.3 g, 4 mmol, 1 eq) and LiOH (290 mg,12 mmol, 3 eq) were dissolved in THF/H₂O/MeOH (1:1:1= 8mL:8mL:8mL). The mixture was stirred at 60 °C for 3 h. The reaction mixture was acidified with 2N aqueous HCl to pH 5~6, extracted with EtOAc (50 mL x 3), dried over Na₂SO₄, concentrated under reduced pressure to afford 5-((tert-butoxycarbonyl)amino)-4- fluoropyrazolo[1,5-a] pyridine-3-carboxylic acid (800 mg, 67% yield) as a white solid. LCMS: m/z = 296.10 [M+1]⁺. Step 4. Synthesis of 4-fluoropyrazolo[1,5-a] pyridin-5-amine A solution of 5-((tert-butoxycarbonyl)amino)-4-fluoropyrazolo[1,5-a]pyridine-3- carboxylic acid (800 mg, 2.71 mmol, 1 eq) in 40% aqueous H₂SO₄ (10 mL) was stirred at 100 °C for 18 h. The solution was cooled to 0 °C and ice water (10 mL) was added. The reaction mixture was neutralized to pH 7 by 6M NaOH solution and extracted with DCM (100 mL x 2). The combined organic extracts were washed with brine (10 mL) and dried over Na₂SO₄. The solvent was evaporated under reduced pressure to afford 4-fluoropyrazolo[1,5-a] pyridin-5- amine (370 mg, 90 % yield) as a brown solid. LCMS: m/z = 152.06 [M+1]⁺. Synthesis of 1-(pyrimidin-4-yl)ethanol (1A-6-1)

Step 1. Synthesis of 1-(pyrimidin-4-yl)ethanol To a solution of 1-(pyrimidin-4-yl)ethanone (300 mg, 2.45 mmol, 1 eq) in MeOH (10 mL) was added NaBH4 (139 mg, 3.68 mmol, 1.5 eq) at 0 °C. The mixture was stirred at room temperature for 1 h under nitrogen, then diluted with H₂O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 2:1) to afford the title compound (180 mg, 59% yield) as colorless oil. Synthesis of cyclopropyl(pyrimidin-2-yl)methanol (1A-6-2)

To a solution of 2-iodopyrimidine (500 mg, 2.43 mmol, 1.1 eq) in dry THF (3 mL) was added i-PrMgBr·LiCl (2.2 mL, 2.87 mmol, 1.3 eq, 1.3 M) dropwise at 0 °C, and stirred for 0.5 h under nitrogen. The solution of cyclopropanecarbaldehyde (155 mg, 2.2 mmol, 1 eq) in dry THF (2 mL) was added and then stirred at 0 °C for 1 h. The mixture was cooled to room temperature and quenched with saturated aqueous NH₄Cl (10 mL) solution, extracted with DCM (20 mL x 2) and washed with brine (10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM : MeOH = 96 : 4) to afford the title compound (150 mg, 45% yield) as yellow oil. LCMS: m/z = 151.30 [M+1]⁺. Synthesis of (E)-N,N'-bis(3-chloro-2-fluorophenyl)formimidamide (1B-19)

A solution of 3-chloro-2-fluoroaniline (2 g, 14 mmol, 1 eq), trimethoxymethane (642 mg, 6 mmol, 0.44 eq) and AcOH (36 mg, 0.6 mmol, 0.044 eq) in hexane (40 mL) was stirred at 48 °C for 16 h under nitrogen. The mixture was cooled to 20 °C and stirred at 20 °C for 3 h. The mixture was filtered. The filter cake was washed with hexane (3 x 10 mL) and concentrated under reduced pressure to afford the title compound (660 mg, 16% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.09 (s, 1H), 7.24 – 7.00 (m, 6H). Synthesis of 2-(pyrimidin-2-yl)propan-2-ol (1A-6-3)

To a solution of methyl pyrimidine-2-carboxylate (2 g, 14.5 mmol, 1 eq) in THF (20 mL) was added methyl magnesium bromide (19.3 mL, 57.9 mmol, 4 eq) at 0 °C and stirred at room temperature for 2 h. The mixture was quenched with saturated NH₄Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and purified by column chromatography (PE:EA=3:2) to afford the title compound (700 mg, 34% yield) as yellow oil. LCMS: m/z = 139.30 [M+1]⁺. Synthesis of (S)-1-(pyrimidin-4-yl)ethan-1-ol (1A-6-4)

To a solution of HCO₂H (396 mg, 8.6 mmol, 3.5 eq) was added TEA (745 mg, 7.4 mmol, 1 eq) dropwise at 0 °C, followed by the addition of a solution of 1-(pyrimidin-4- yl)ethan-1-one (300 mg, 2.46 mmol, 1 eq) in DCM (8 ml) and RuCl(p-cymene)[(S,S)-Ts- DPEN] (47 mg, 0.074 mmol, 0.03 eq). The reaction mixture was stirred at rt for 2 h under nitrogen. The mixture was concentrated at 25 °C under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM:MeOH= 99:1 ) to afford the title compound (283 mg, 93% yield, 66% ee) as black oil. LCMS: m/z = 125.25 [M+1]⁺. Synthesis of 1-(5-(difluoromethyl)pyrimidin-2-yl)ethan-1-ol (1A-6-5)

Step 1. Synthesis of 2-chloro-5-(difluoromethyl)pyrimidine To a solution of 2-chloropyrimidine-5-carbaldehyde (3 g, 21 mmol, 1 eq) in CHCl₃ (60 mL) was added DAST (3.39 g, 21 mmol, 1 eq). The mixture was stirred at 70 °C for 1 h. After cooling to rt, the resulting mixture was diluted with NaHCO₃ (50 mL) and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (15:1) to afford the title compound (2.4 g, 69.4% yield) as a white solid. LCMS: m/z = 165.00 [M+1]⁺. Step 2. Synthesis of 1-(5-(difluoromethyl)pyrimidin-2-yl)ethan-1-one To a solution of 2-chloro-5-(difluoromethyl)pyrimidine (1.2 g, 7.29 mmol, 1 eq) and tributyl(1-ethoxyethenyl)stannane (3.42 g, 9.48 mmol, 1.3 equiv.) in 1,4-dioxane (20 mL) was added Pd(PPh₃)₂Cl₂ (255.9 mg, 0.36 mmol, 0.05 equiv.). The reaction mixture was degassed, purged with nitrogen 3 times and the mixture was stirred at 100 °C for 16 h under nitrogen. The reaction solution was cooled to room temperature. KF aqueous solution (40 mL) was added and stirred for 1 h. The mixture was extracted with EA (40 mL x 3). To the combined organic layers was added 4N HCl aqueous solution (20 mL) and stirred for 6 h at rt. The resulting mixture was diluted with saturated NaHCO₃ (20 mL) and extracted with EtOAc (20 mL x 3), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (3:1) to afford the title compound (820 mg, 65.3% yield) as a white solid. LCMS: m/z = 173.10 [M+1]⁺. Step 3. Synthesis of 1-(5-(difluoromethyl)pyrimidin-2-yl)ethan-1-ol To a solution of 1-(5-(difluoromethyl)pyrimidin-2-yl)ethan-1-one (620 mg, 3.6 mmol, 1 eq) in MeOH (10 mL) was added NaBH₄ (164 mg, 4.325 mmol, 1.2 eq) in one portion. The mixture was stirred at 0 °C for 0.1 h under nitrogen. The resulting mixture is quenched with H₂O (10 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (1:1) to afford the title compound (420 mg, 67 % yield) as white oil. LCMS: m/z = 175.00 [M+1]⁺. Synthesis of 1-(4-(difluoromethyl)phenyl)ethan-1-ol (1A-6-6)

Step 1. Synthesis of 1-(4-(difluoromethyl)phenyl)ethan-1-one To a solution of 1-bromo-4-(difluoromethyl)benzene (1 g, 4.8 mmol, 10 equiv.) and tributyl(1-ethoxyethenyl)stannane (2.27 g, 6.28 mmol, 1.3 equiv.) in 1,4-dioxane (20 mL) was added Pd(PPh₃)₂Cl₂ (169 mg, 0.24 mmol, 0.05 equiv.). The reaction mixture was degassed and purged with nitrogen 3 times and stirred at 100 °C for 16 h under nitrogen. The reaction solution was cooled to room temperature. A KF aqueous solution (20 mL) was added and stirred for 1 h. The solution was extracted with EA (30 mL x 3). To the combined organic layers was added 1N HCl aqueous solution (40 mL). The mixture was stirred for 1 h, diluted with saturated NaHCO₃ (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (10:1) to afford the title compound (710 mg, 86.3% yield) as colorless oil. 1H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 6.68 (t, J = 56.0 Hz, 1H), 2.62 (s, 3H) ppm. Step 2. Synthesis of 1-(4-(difluoromethyl)phenyl)ethan-1-ol To a solution of 1-(4-(difluoromethyl)phenyl)ethan-1-one (930 mg, 5.47 mmol, 1 eq) in MeOH (15 mL) was added NaBH4 (414 mg, 10.94 mmol, 2 eq) in one portion. The mixture was stirred at 0 °C for 1 h under nitrogen. The resulting mixture was quenched with H₂O (10 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (3:1) to afford the title compound (850 mg, 90.4% yield) as colorless oil. 1H NMR (400 MHz, CDCl₃) δ 7.59-7.38 (m, 4H), 6.62 (t, J = 56.4 Hz, 1H), 4.94 (q, J = 6.4 Hz, 1H), 1.49 (d, J = 6.4 Hz, 3H). Synthesis of 1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethan-1-ol (1A-6-7)

Step 1. Synthesis of methyl 1-(difluoromethyl)-1H-pyrazole-3-carboxylate To a solution of methyl 1H-pyrazole-3-carboxylate (9 g, 0.07 mol, 1 eq) in DMA (100 mL) was added sodium 2-chloro-2,2-difluoroacetate (13.5 g, 0.09 mmol, 1.3 eq) and Cs₂CO₃ (49 g, 0.14 mol, 2 eq) at 25 °C. After stirring for 16 h at 100 °C the reaction mixture was allowed to cool to room temperature. The resulting mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE : EtOAc = 2 : 1) to afford the title compound (3.8 g, 30% yield) as a white solid. LCMS: m/z = 177.25 [M+1]⁺ Step 2. Synthesis of (1-(difluoromethyl)-1H-pyrazol-3-yl)methanol To a solution of methyl 1-(difluoromethyl)-1H-pyrazole-3-carboxylate (3.8 g, 0.02 mol, 1 eq) in anhydrous THF (50 mL) was added dropwise DIBAL-H (50.3 mL, 50.3 mol, 2.5 eq, 1M) at 0 °C and stirred for 2 h under nitrogen. The mixture was cooled to 0 °C, THF (100 mL) was added to the reaction mixture, followed by H₂O (2.01 mL). After stirring for 15 minutes, 15% NaOH (aq) (2 mL) was added, followed by H₂O (5.21 mL). It was again stirred at rt for 15 min. The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (2.9 g, 97% yield) as yellow oil. LCMS: m/z = 149.15 [M+1]⁺ _. Step 3. Synthesis of 1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde A mixture of (1-(difluoromethyl)-1H-pyrazol-3-yl)methanol (1.3 g, 8.7 mmol, 1 eq) and MnO₂ (7.6 g, 0.32 mol, 1.3 eq) in DCM (13 mL) was stirred at 25 °C for 16 h under nitrogen. The resulting mixture was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 94% yield) as yellow oil. LCMS: m/z = 147.30 [M+1]⁺. Step 4. Synthesis of 1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethan-1-ol To a mixture of 1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde (1.2 g, 0.0087 mol, 1 eq) in dry THF (30 mL) was added dropwise MeMgBr (6.3 mL, 0.019 mol, 2.2 eq, 3 M) at -78 °C and stirred for 4 h under nitrogen. The resulting mixture was diluted with NH₄Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE : EtOAc = 10 : 1) to afford the title compound (454 mg, 32% yield) as a white solid. LCMS: m/z = 163.20 [M+1]⁺. Synthesis of 1-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethan-1-ol (1A-6-8)

Step 1. Synthesis of 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde To a solution of 1H-pyrazole-4-carbaldehyde (2.1 g, 0.022 mol, 1 eq) in MeCN (30 mL) was added diethyl (bromodifluoromethyl)phosphonate (10 g, 0.037 mol, 1.7 eq) and KF (3.4 g, 0.06 mol, 3 eq) at 25 °C and the reaction mixture was stirred for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 100:1) to afford the title compound (1.4 g, 43% yield) as colorless oil. LCMS: m/z = 147.30 [M+1]⁺. Step 2. Synthesis of 1-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethan-1-ol To a solution of 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde (633 mg, 4.3 mmol, 1 eq) in THF (10 mL) was added dropwise MeMgBr (2.8 mL, 8.6 mmol, 2 eq, 3 M) at -78 °C and stirred for 4 h at rt under nitrogen. The resulting mixture was diluted with NH₄Cl (10 mL) and extracted with EtOAc (3 x 510 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with PE/EtOAc (10/1) to afford the title compound (670 mg, 96% yield) as yellow oil. LCMS: m/z = 163.20 [M+1]⁺ . Synthesis of 2-(3-methylpyridin-4-yl)propan-2-ol (IA-6-9)

Step 1. Synthesis of methyl 3-methylisonicotinate Thionyl chloride (2.33 mL, 32 mmol) was added dropwise over 5 minutes to a stirred solution of 3-methyl-isonicotinic acid (4 g, 29 mmol) in MeOH (60 mL) at 0 °C under Argon atmosphere. The resulting solution was stirred and heated at reflux for 2 h. The mixture was allowed to cool to rt. The solvent was evaporated under reduced pressure. The mixture was dissolved in CH₂Cl₂ (100 mL) and washed with saturated NaHCO₃ (aq.) (30 mL). The organic layer was dried (MgSO₄) and evaporated under reduced pressure to give methyl 3-methyl- isonicotinate (4 g, 91%) as colorless oil. LC-MS: m/z = 152.1 [M+1]⁺. Step 2. Synthesis of 2-(3-methylpyridin-4-yl)propan-2-ol MeMgBr (66.15 mL in THF, 66 mmol) was added dropwise over 10 min to a stirred solution of methyl 3-methylisonicotinate (4.0 g, 26.46 mmol) in THF (60 mL) at -78 °C under argon atmosphere. The resulting solution was stirred at 0 °C for 2 h. The mixture was quenched with saturated NH₄Cl (aq.) (50 mL) at 0 °C and extracted with EA (50 mL x 3). The combined organic layers were dried (MgSO₄), concentrated and purified by flash chromatography with PE/EA=3/1-1/1 to give the title product, 2-(3-methylpyridin-4-yl)propan-2-ol (2.1 g, 52.5%) as a white solid. LC-MS: m/z = 152.1 [M+1]⁺. EXAMPLE 1: (R)-N-(5-fluoroquinolin-6-yl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1-(pyrimidin- 2-yl)ethoxy)quinazolin-4-amine (Compound 1).

Step 1. Synthesis of (E)-N'-(5-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide. A mixture of 2-amino-4-bromo-6-fluorobenzonitrile (2 g, 9.3 mmol, 1 eq) in DMF- DMA (20 mL) was stirred at 120 °C for 2 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ethyl ether (20 mL), filtered and dried to afford the title compound (2.2 g, 88% yield) as a white solid. LC-MS: m/z =270.15/272.15 [M+1]⁺. Step 2. Synthesis of 7-bromo-5-fluoro-N-(5-fluoroquinolin-6-yl)quinazolin-4-amine. A mixture of (E)-N'-(5-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide (1 g, 3.7 mmol, 1 eq) and 5-fluoroquinolin-6-amine (660 mg, 4.1 mmol, 1.1 eq) in AcOH (12 mL) was stirred at 100 °C for 16 h under nitrogen. The mixture was poured into water (30 mL). The precipitated solid was filtered, washed with water, dried under reduced pressure to afford the title compound (965 mg, 67% yield) as a brown solid. LC-MS: m/z = 387.20/389.20 [M+1]⁺. Following steps 1 and 2 above, intermediates 1A-12-2, 1A-12-3, 1A-12-4, 1A-12-5, and 1A-12-6 were synthesized.

Step 3. Synthesis of (R)-7-bromo-N-(5-fluoroquinolin-6-yl)-5-(1-(pyrimidin-2-yl)ethoxy)- quinazolin-4-amine To a solution of (R)-1-(pyrimidin-2-yl)ethanol (48 mg, 0.39 mmol, 3 eq) in anhydrous THF (2 mL) was added NaH (31 mg, 0.77 mmol, 6 eq, 60%) at 0 °C and stirred for 0.5 h under nitrogen. A solution of 5-fluoro-N-(5-fluoroquinolin-6-yl)quinazolin-4-amine (50 mg, 0.13 mmol, 1 eq) in THF (1 mL) was added and then stirred at 80 °C for 4 h. The mixture was cooled to room temperature and poured into water (10 mL). The precipitated solid was filtered, washed with water, and dried under reduced pressure to afford the title compound (61 mg, 96% yield) as a brown solid. LC-MS: m/z = 491.35/493.35 [M+1]⁺. Following steps 1-3 described above, intermediates 1A-13-2, 1A-13-3, 1A-13-4, 1A- 13-5, 1A-13-6, 1A-13-7, 1A-13-8 and 1A-13-9 below were synthesized.

Step 4. Synthesis of (R)-N-(5-fluoroquinolin-6-yl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 1). A mixture of (R)-7-bromo-N-(5-fluoroquinolin-6-yl)-5-(1-(pyrimidin-2-yl)ethoxy)- quinazolin-4-amine (61 mg, 0.12 mmol, 1 eq), (1-methyl-1H-pyrazol-4-yl)boronic acid (20 mg, 0.16 mmol, 1.3 eq), K₂CO₃ (51 mg, 0.372 mmol, 3 eq), and Pd(dppf)Cl₂ (9.9 mg, 0.012 mmol, 0.1 eq) in dioxane (3 mL) and H₂O (0.4 mL) was degassed and purged with nitrogen 3 times. The mixture was stirred at 80 °C for 16 h under nitrogen, diluted with H₂O (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford the title compound (18 mg, 30% yield) as a white solid. LC-MS: m/z = 493.25 [M+1]+. 1H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.92 (dd, J = 4.1, 1.4 Hz, 1H), 8.75 (d, J = 4.9 Hz, 2H), 8.54 (t, J = 8.8 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.61 (dd, J = 8.5, 4.2 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.42 (t, J = 4.9 Hz, 1H), 6.23 (q, J = 6.0 Hz, 1H), 3.87 (s, 3H), 1.82 (d, J = 6.3 Hz, 3H). EXAMPLES 2-11 Following the procedure described in Example 1, Compounds 2-11 were synthesized. Compound 2: (R)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 49%. LC-MS: m/z = 476.10 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.70– 8.68 (m, 3H), 8.36 (s, 1H), 8.10 (s, 1H), 7.86 – 7.79 (m, 1H), 7.68 (d, J = 0.9 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.35 (td, J = 8.2, 1.5 Hz, 1H), 6.23 (q, J = 6.4 Hz, 1H), 3.98 (s, 3H), 1.91 (d, J = 6.4 Hz, 3H). Compound 3: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 23%. LC-MS: m/z = 494.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.74 – 8.66 (m, 3H), 8.39 (s, 1H), 8.12 (s, 1H), 7.82- 7.78 (m, 1H), 7.70 (s, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.42 (t, J = 5.0 Hz, 1H), 7.34 (td, J = 9.0, 2.0 Hz, 1H), 6.23 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 1.91 (d, J = 6.4 Hz, 3H). Compound 4: (R)-N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5- [1-(pyrimidin-2-yl)ethoxy]quinazolin-4-amine. Yield 34%. LC-MS: m/z = 494.12 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.73 – 8.66 (m, 3H), 8.39 (s, 1H), 8.12 (s, 1H), 7.84- 7.78 (m, 1H), 7.70 (s, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.34 (td, J = 9.0, 1.9 Hz, 1H), 6.23 (q, J = 6.3 Hz, 1H), 3.98 (s, 3H), 1.91 (d, J = 6.4 Hz, 3H). Compound 5: N-(3-chloro-2,4-difluorophenyl)-5-(cyclopropyl(pyrimidin-2-yl)meth- oxy)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine. Yield 39%. LC-MS: m/z = 520.20 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.76 (d, J = 4.8 Hz, 2H), 8.45 (s, 1H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 8.00 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.44-7.38 (m, 3H), 5.61 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 1.65-1.53 (m, 1H), 0.68-0.65 (m, 2H), 0.62-0.51 (m, 2H). Compound 6: (S)-N-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 28.5%. LC-MS: m/z = 476.20 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.87 (d, J = 4.9 Hz, 2H), 8.48 (d, J = 9.2 Hz, 2H), 8.32 – 8.26 (m, 1H), 8.14 (s, 1H), 7.86 – 7.79 (m, 1H), 7.57 – 7.46 (m, 4H), 6.26 (q, J = 5.6 Hz, 1H), 3.87 (s, 3H), 1.75 (d, J = 6.2 Hz, 3H). Compound 7: (S)-N-(3-bromo-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 30%. LC-MS: m/z = 538.20/540.20 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.74 (d, J = 4.8 Hz, 2H), 8.42 (d, J = 6.4 Hz, 2H), 8.16-8.09 (m, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.49-7.43 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.20 (q, J = 6.8 Hz, 1H), 3.87 (s, 3H), 1.78 (d, J = 6.4 Hz, 3H). Compound 8: (S)-N-(3-bromo-4-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 28%. LC-MS: m/z = 520.20/522.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 4.9 Hz, 2H), 8.42 (s, 1H), 8.29 (dd, J = 6.3, 2.5 Hz, 1H), 8.18 (d, J = 0.6 Hz, 1H), 7.99 (s, 1H), 7.91 – 7.85 (m, 1H), 7.47 – 7.43 (m, 2H), 7.36 (s, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.08 (q, J = 6.9 Hz, 1H), 3.95 (s, 3H), 1.85 (d, J = 6.3 Hz, 3H). Compound 9: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 23.6%. LC-MS: m/z = 480.35 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J = 4.8 Hz, 2H), 8.41 (s, 1H), 8.26 (s, 2H), 8.08 (dd, J = 14.0, 8.8 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.44 (t, J = 4.8 Hz, 1H), 7.38 (t, J = 8.8 Hz, 1H), 6.19 (q, J = 6.4 Hz, 1H), 1.77 (d, J = 6.4 Hz, 3H). Compound 10: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)- 5-(1-(pyrimidin-4-yl)ethoxy)quinazolin-4-amine. Yield 41 %. LC-MS: m/z = 494.20 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.99 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.2 Hz, 1H), 8.84 (s, 1H), 8.49 (s, 1H), 8.08 (s, 1H), 7.87 (td, J = 8.7, 5.8 Hz, 1H), 7.73 (dd, J = 5.2, 1.1 Hz, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.51 (td, J = 9.0, 1.7 Hz, 1H), 6.40 (q, J = 6.4 Hz, 1H), 3.90 (s, 3H), 1.77 (d, J = 6.4 Hz, 3H). Compound 11: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)- 5-(1-(pyridin-2-yl)ethoxy)quinazolin-4-amine. Yield 23 %. LC-MS: m/z = 493.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.27 (t, J = 7.8 Hz, 1H), 8.06 (s, 1H), 8.05 – 7.96 (m, 2H), 7.72 – 7.66 (m, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.31 (t, J = 8.2 Hz, 1H), 6.41 (q, J = 6.1 Hz, 1H), 3.97 (s, 3H), 1.97 (d, J = 6.4 Hz, 3H). EXAMPLE 12: (R)-N-(4-fluoropyrazolo[1,5-a] pyridin-5-yl)-7-(1-methyl-1H-pyrazol-4-yl)- 5-(1-(pyrimidin-2-yl) ethoxy) quinazolin-4-amine (Compound 12).

Step 1. Synthesis of 7-bromo-5-fluoroquinazolin-4(3H)-one A solution of 2-amino-4-bromo-6-fluorobenzonitrile (2 g, 9.3 mmol, 1 eq) in HCOOH (30 mL) and H₂SO₄ (0.3 mL) was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, the crude was diluted with cold water (30 mL) and stirred for 20 min at room temperature. The residue was triturated with water (5 mL) at room temperature and filtered to afford 7-bromo-5-fluoroquinazolin-4(3H)-one (370 mg, 90 % yield) as a white solid. LC-MS: m/z = 243.10/245.10 [M+1]⁺. Step 2. Synthesis of 7-bromo-4-chloro-5-fluoroquinazoline To a solution of 7-bromo-5-fluoroquinazolin-4(3H)-one (500 mg, 2 mmol, 1 eq) in CHCl₃ (30 mL) was added (COCl)₂ (1 mL) and DMF (5 drop). The resulting mixture was stirred at 70 °C for 2 h under nitrogen. After completion, the reaction mixture was added to ice cold saturated NaHCO₃ solution (10 mL), extracted with DCM/MeOH (10/1) (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE/EA (5/1)) to afford 7-bromo-4-chloro-5-fluoroquinazoline (470 mg, 87.5% yield) as a white solid. LC-MS: m/z = 260.95/262.95 [M+1]⁺. Step 3. Synthesis of 7-bromo-5-fluoro-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)quinazolin-4- amine A mixture of 4-fluoropyrazolo[1,5-a]pyridin-5-amine (75.1 mg, 0.497 mmol, 1 eq.) and 7-bromo-4-chloro-5-fluoroquinazoline (130 mg, 0.497 mmol, 1 eq.) in isopropyl alcohol (5 ml) was stirred at 90°C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by FCC (10% methanol in DCM) to afford 7-bromo-5-fluoro-N-{4- fluoro-pyrazolo[1,5-a]pyridin-5-yl}quinazolin-4-amine (110 mg, 0.292 mmol, 58.8%) as a yellow solid. LC-MS: m/z = 375.95/377.95 [M+1]⁺. Following the procedure described above, the intermediates 1A-5-2 and 1A-5-3 were prepared.

Step 4. Synthesis of (R)-7-bromo-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-5-(1-(pyrimidin-2- yl)ethoxy)quinazolin-4-amine To a solution of (1R)-1-(pyrimidin-2-yl)ethan-1-ol (145 mg, 1.17 mmol, 4 eq.) in THF (10 ml) at 0 °C was added sodium hydride (28 mg, 1.17 mmol, 4 eq.) and stirred at 0 °C for 20 minutes, followed by addition of 7-bromo-5-fluoro-N-(4-fluoropyrazolo[1,5-a]pyridin-5- yl)quinazolin-4-amine (110 mg, 0.292 mmol, 4 eq.). After stirring for 16 h at 80 °C, the reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by FCC (8% methanol/DCM) to afford 7-bromo-N-{4-fluoropyrazolo[1,5- a]pyridin-5-yl}-5-[(1R)-1-(pyrimidin-2-yl)ethoxy]quinazolin-4-amine (100 mg, 0.2 mmol, 71%) as a yellow solid. LC-MS: m/z = 480.10/482.10 [M+1]⁺. Following the procedure described above, intermediates 1A-7-2 and 1A-7-3 were synthesized.

Step 5. Synthesis of (R)-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-7-(1-methyl-1H-pyrazol-4- yl)-5-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 12) A mixture of (1-methyl-1H-pyrazol-4-yl)boronic acid (34 mg, 0.271 mmol, 1.3 equiv.), 7-bromo-N-{4-fluoropyrazolo[1,5-a]pyridin-5-yl}-5-[(1R)-1-(pyrimidin-2-yl)ethoxy]quina- zolin-4-amine (100 mg, 0.2 mmol, 1 eq.) and potassium carbonate (86 mg, 0.62 mmol, 3 eq.) in 1,4-dioxane (5 ml) and H₂O (0.5 ml) was degassed with N₂ three times. [1,1'-Bis(diphenyl- phosphino)ferrocene]palladium(II) chloride (15.3 mg, 0.021 mmol, 0.1 equiv.) was added. The resulting mixture was stirred at 100 °C for 5 h, warmed to rt, filtered, and concentrated under vacuum to yield crude product. The crude was purified by Prep-HPLC to afford N-{4-fluoro- pyrazolo[1,5-a]pyridin-5-yl}-7-(1-methyl-1H-pyrazol-4-yl)-5-[(1R)-1-(pyrimidin-2-yl)- ethoxy]quinazolin-4-amine HCl salt (44.9 mg, 0.093 mmol, 44.8%) as a yellow solid. LC-MS: m/z = 482.35 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.75 (s, 2H), 8.60 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.43 (t, J = 4.8 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.29 (q, J = 6.4 Hz, 1H), 4.02 (s, 3H), 1.95 (d, J = 6.4 Hz, 3H). EXAMPLES 13 and 14 Following the procedure described in Example 12 above, Compounds 13 and 14 were synthesized. Compound 13: N-(5-Fluoroquinolin-6-yl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1- (pyrimidin-4-yl)ethoxy)quinazolin-4-amine. Yield 25%. LC-MS: m/z = 493.10 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.11 (s, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.85-8.80 (m, 2H), 8.52 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.73 (d, J = 4.7 Hz, 1H), 7.60 (dd, J = 8.4, 4.2 Hz, 1H), 7.55 (s, 1H), 7.31 (s, 1H), 6.21 (q, J = 6.9 Hz, 1H), 3.86 (s, 3H), 1.84 (d, J = 6.3 Hz, 3H). Compound 14: (R)-7-Fluoro-N-(7-(1-methyl-1H-pyrazol-4-yl)-5-(1-(pyrimidin-2-yl)- ethoxy)quinazolin-4-yl)benzo[d]isothiazol-6-amine. Yield 22.7%. LC-MS: m/z = 499.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 9.10 (d, J = 4.2 Hz, 1H), 8.70-8.68 (m, 3H), 8.40 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 8.00-7.96 (m, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.39 (t, J = 4.9 Hz, 1H), 6.29-6.24 (m, 1H), 3.99 (s, 3H), 1.93 (d, J = 6.4 Hz, 3H). EXAMPLE 15: Synthesis of N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)- 5-((2-(pyrimidin-2-yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 15).

Step 1. Synthesis of 7-bromo-N-(3-chloro-2,4-difluorophenyl)-5-((2-(pyrimidin-2-yl)- propan-2-yl)oxy)quinazolin-4-amine To a solution of 2-(pyrimidin-2-yl)propan-2-ol (204.5 mg, 1.48 mmol, 3 eq) in dry THF (8 mL) was added NaH (118.4 mg, 2.96 mmol, 6.0 eq, 60% wt) at 0 °C and stirred for 0.5 h under nitrogen atmosphere. A solution of 7-bromo-N-(3-chloro-2,4-difluorophenyl)-5-fluoro- quinazolin-4-amine (190 mg, 0.494 mmol, 1.0 eq) in dry THF (2 mL) was added and stirred at 80 °C for 24 h. The mixture was cooled to room temperature and diluted with water (5 mL), extracted with EA (50 mL x 3) and washed with brine (5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (EA: PE = 30:70) to afford the title compound (100 mg, 40.5% yield) as a yellow solid. LC-MS: m/z = 506.15/508.15 [M+1]⁺. Following the above method, intermediate 1A-13-11 was synthesized.

Step 2. Synthesis of N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-((2- (pyrimidin-2-yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 15) A mixture of 7-bromo-N-(3-chloro-2,4-difluorophenyl)-5-((2-(pyrimidin-2-yl)propan- 2-yl)oxy)quinazolin-4-amine (80 mg, 0.158 mmol, 1 eq), (1-methyl-1H-pyrazol-4-yl)boronic acid (60 mg, 0.475 mmol, 3 eq) and K₂CO₃ (65.6 mg, 0.475 mmol, 3 eq) in mixture of dioxane (6.4 mL) and H₂O (0.8 mL) was degassed and purged with nitrogen 3 times. Pd(dppf)Cl₂ (26 mg, 0.032 mmol, 0.2 eq) was added and purged with nitrogen 3 times, then the mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with H₂O (10 mL), cooled to rt, extracted with EtOAc (3 x 20 mL) and washed with brine (10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC (0.04% NH₄HCO₃ in H₂O/CH₃CN) to afford the title compound (30.61 mg, 38% yield) as a white solid. LC-MS: m/z = 508.30 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.77 (d, J = 4.8 Hz, 2H), 8.42 (s, 1H), 8.21 (s, 1H), 8.12-8.06 (m, 1H), 7.80 (s, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.41- 7.36 (m, 1H), 6.88 (d, J = 1.6 Hz, 1H), 3.84 (s, 3H), 2.01 (s, 6H). EXAMPLE 16 Following the procedure described in Example 15, Compound 16 was prepared. Compound 16: N-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-((2-(pyrimidin- 2-yl)propan-2-yl)oxy)quinazolin-4-amine. Yield 66.8%. LC-MS: m/z = 490.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 4.8 Hz, 2H), 8.62 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.90 (dd, J = 6.8, 2.4 Hz, 1H), 7.60-7.56 (m, 1H), 7.45-7.42 (m, 3H), 7.41-7.39 (m, 1H), 3.97 (s, 3H), 2.17 (s, 6H). EXAMPLE 17 Compound 17: Synthesis of (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1H-pyrazol-1-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. A mixture of (S)-7-bromo-N-(3-chloro-2,4-difluorophenyl)-5-(1-(pyrimidin-2-yl)eth- oxy)quinazolin-4-amine (1A-13-7, 150 mg, 0.31 mmol, 1 eq), 1H-pyrazole (83 mg, 1.22 mmol, 4 eq), Cs₂CO₃ (299.5 mg, 0.92 mmol, 3 eq) and Ephos-Pd-G4 (30 mg, 0.1 mmol, 0.1 eq) in dioxane (5 mL) was degassed under vacuum and purged with nitrogen 3 times and then the mixture was stirred at 100 °C for 24 h under nitrogen. The resulting mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH = 25:1) to afford the title compound (21 mg, 14.4% yield) as a white solid. LC-MS: m/z = 480.20 [M+1]⁺. 1H NMR (400 MHz, CDCl₃) δ11.00 (s, 1H), 8.67 (d, J = 4.8 Hz, 2H), 8.59 (s, 1H), 8.20- 8.14 (m, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.26-7.24 (m, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.52 (s, 1H), 6.04-5.95 (m, 1H), 1.96 (d, J = 6.4 Hz, 3H). EXAMPLES 18-22 Following the procedure described in Example 17, Compounds 18-22 were synthesized. Compound 18: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(4-methyl-1H-pyrazol-1-yl)-5- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 9.0 %. LC-MS: m/z = 494.25 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.74 (d, J = 4.8 Hz, 2H), 8.55 (s, 1H), 8.46 (s, 1H), 8.11-8.03 (m, 1H), 7.68 (s, 2H), 7.64 (s, 1H), 7.44 (t, J = 4.8 Hz, 1H), 7.40 (t, J = 8.8 Hz, 1H), 6.15 (q, J = 6.4 Hz, 1H), 2.08 (s, 3H), 1.79 (d, J = 6.4 Hz, 3H). Compound 19: (S)-N-(3-chloro-4-fluorophenyl)-7-(1H-pyrazol-1-yl)-5-(1-(pyrimidin- 2-yl)ethoxy)quinazolin-4-amine. Yield 19%. LC-MS: m/z = 462.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.77 (d, J = 5.0 Hz, 2H), 8.72 (s, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.06 (dd, J = 6.6, 2.6 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.48 – 7.42 (m, 2H), 6.68 (dd, J = 2.7, 1.7 Hz, 1H), 6.26 (q, J = 6.4 Hz, 1H), 1.92 (d, J = 6.5 Hz, 3H). Compound 20: N-(3-chloro-4-fluorophenyl)-7-(1H-pyrazol-1-yl)-5-((2-(pyrimidin-2- yl)propan-2-yl)oxy)quinazolin-4-amine. Yield 60.9%. LC-MS: m/z = 476.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.67-8.66 (m, 3H), 8.47 (d, J = 2.4 Hz, 1H), 7.91-7.89 (m, 2H), 7.86 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.41 (t, J = 4.8 Hz, 1H), 6.66 (s, 1H), 2.19 (s, 6H). Compound 21: N-(3-chloro-2,4-difluorophenyl)-7-(1H-pyrazol-1-yl)-5-((2- (pyrimidin-2-yl)propan-2-yl)oxy)quinazolin-4-amine. Yield 18.5%. LC-MS: m/z = 494.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.67 (d, J = 4.8 Hz, 2H), 8.64 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 7.95-7.76 (m, 3H), 7.70 (d, J = 2.0 Hz, 1H), 7.40 (t, J = 5.0 Hz, 1H), 7.37-7.29 (m, 1H), 6.65 (s, 1H), 2.18 (s, 6H). Compound 22: (S)-N-(3-chloro-4-fluorophenyl)-7-(4-fluoro-1H-pyrazol-1-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 12%. LC-MS: m/z = 480.10 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.16 (d, J = 4.4 Hz, 1H), 8.84 (s, 1H), 8.81 (d, J = 4.9 Hz, 2H), 8.12 (dd, J = 6.8, 2.5 Hz, 1H), 8.07 (d, J = 4.0 Hz, 1H), 7.88 (s, 2H), 7.78-7.73 (m, 1H), 7.60 (t, J = 8.9 Hz, 1H), 7.56 (t, J = 4.9 Hz, 1H), 6.33 (q, J = 6.4 Hz, 1H), 1.80 (d, J = 6.4 Hz, 3H). EXAMPLE 23: Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-5-(1-(pyrimidin-2-yl)ethoxy)- quinazolin-4-amine (Compound 23). To a mixture of 7-bromo-N-(3-chloro-4-fluorophenyl)-5-[(1S)-1-(pyrimidin-2-yl)- ethoxy]quinazolin-4-amine (200 mg, 0.42 mmol, 1 eq), triethylsilane (147 mg, 1.26 mmol, 3 eq) and CsF (128 mg, 0.84 mmol, 2 eq) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl₂ (16 mg, 0.02 mmol, 0.05 eq.). After degassed and purged with nitrogen 3 times, the mixture was stirred at 50 °C for 16 h under nitrogen, then diluted with H₂O (10 mL), cooled to rt, and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH = 15:1) to afford the title compound (91.7 mg, 54.6% yield) as a white solid. LC-MS: m/z = 396.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.75 (d, J = 5.2 Hz, 2H), 8.71 (s, 1H), 8.07 (dd, J = 6.8, 2.4 Hz, 1H), 8.01 (t, J = 8.4 Hz, 1H), 7.80 – 7.75 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.42 – 7.38 (m, 1H), 6.11 (q, J = 6.8 Hz, 1H), 1.88 (d, J = 6.4 Hz, 3H). EXAMPLE 24 Following the procedure described in Example 23, Compound 24 was synthesized. Compound 24: N-(3-chloro-4-fluorophenyl)-5-((2-(pyrimidin-2-yl)propan-2-yl)oxy)- quinazolin-4-amine. Yield 67%. LC-MS: m/z = 410.15 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.66-8.63 (m, 3H), 7.93 (t, J = 8.4 Hz, 1H), 7.90 (dd, J = 6.4, 2.4 Hz, 1H), 7.61-7.56 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.8 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 2.12 (s, 6H). EXAMPLE 25: N-(3-chloro-2-fluorophenyl)-6-(1-(1-(difluoromethyl)-1H-pyrazol-3- yl)ethoxy)-7-methoxyquinazolin-4-amine (Compound 25).

To a mixture of 4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (105 mg, 0.32 mmol, 1 eq) in toluene (2 mL) was added 1-(1-(difluoromethyl)-1H-pyrazol-3- yl)ethan-1-ol (160 mg, 0.96 mmol, 3 eq) and PPh₃ (368 mg, 1.4 mmol, 4.4 eq). A solution of DIAD (239 mg, 1.2 mmol, 3.7 eq) in THF was added at 0 °C under N2. The resulting mixture was stirred at 100 °C for 16 h. After cooling to rt, it was diluted with H₂O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford the title compound (28.7 mg, 18% yield) as a white solid. LC-MS: m/z = 464.10 [M+1]⁺. 1H NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.54-7.42 (m, 2H), 7.30-7.26 (m, 2H), 6.59 (d, J = 2.6 Hz, 1H), 5.83 (q, J = 6.2 Hz, 1H), 4.08 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H). EXAMPLE 26 Following the procedure described in Example 25, Compound 26 was prepared. Compound 26: N-(3-chloro-2-fluorophenyl)-6-(1-(1-(difluoromethyl)-1H-pyrazol-4- yl)ethoxy)-7-methoxyquinazolin-4-amine. Yield 7%. LC-MS: m/z = 464.15 [M+1]⁺. 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.59 – 7.42 (m, 3H), 7.31 – 7.27 (m, 1H), 7.26 (s, 1H), 5.82 (q, J = 6.3 Hz, 1H), 4.08 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H). EXAMPLE 27: (S)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 27).

Step 1. Synthesis of (S)-methyl 4-bromo-2-nitro-5-(1-(pyrimidin-2-yl)ethoxy)benzoate To a solution of (S)-1-(pyrimidin-2-yl)ethanol (1 g, 8 mmol, 1.5 eq) in DMF (20 mL) was added NaH (322 mg, 8 mmol, 1.5 eq, 60%) at 0 °C and stirred for 0.5 h under nitrogen. A solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (1.49 g, 5.37 mmol, 1 eq) in DMF (15 mL) was added and stirred at room temperature for 1 h. The mixture was quenched with sat NH₄Cl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE : EA = 5 : 1) to afford the title compound (1.19 g, 58% yield) as a yellow solid. LC-MS: m/z = 382.25 and 384.25 [M+1]⁺. Following the above procedure, intermediates 1B-2-2, 1B-2-3 and 1B-2-4 were prepared.

Step 2. Synthesis of (S)-methyl 2-amino-4-bromo-5-(1-(pyrimidin-2-yl)ethoxy)benzoate A mixture of (S)-methyl 4-bromo-2-nitro-5-(1-(pyrimidin-2-yl)ethoxy)benzoate (185 mg, 0.48 mmol, 1 eq), Fe (135 mg, 2.42 mmol, 5 eq) and NH₄Cl (259 mg, 4.84 mmol, 10 eq) in EtOH (5 mL) and H₂O (0.5 mL) was degassed and purged with nitrogen 3 times. It was stirred at 80 °C for 2 h under nitrogen, filtered and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-TLC (PE:EA = 5:1) to afford the title compound (120 mg, 71% yield) as a white solid. LC-MS: m/z = 352.10/354.10 [M+1]⁺. Following the above procedure, intermediates 1B-3-2, 1B-3-3, and 1B-3-4 were prepared.

Step 3. Synthesis of (S)-7-bromo-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4(3H)-one A mixture (S)-methyl 2-amino-4-bromo-5-(1-(pyrimidin-2-yl)ethoxy)benzoate (120 mg, 0.34 mmol, 1 eq), formimidamide acetate (106 mg, 1.02 mmol, 3 eq) and p-TSA (6.4 mg, 0.034 mmol, 0.1 eq) in EtOH (5 mL) was stirred at 100 °C for 12 h, concentrated, and purified by FCC (DCM : MeOH = 40 : 1) to afford the title compound (105 mg, 89 % yield) as a white solid. LC-MS: m/z = 347.20/349.20 [M+1] ⁺. Following the above procedure, intermediates 1B-4-2, 1B-4-3, and 1B-4-4 were prepared.

Step 4. Synthesis of (S)-7-bromo-4-chloro-6-(1-(pyrimidin-2-yl)ethoxy)quinazoline. To a solution of (S)-7-bromo-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4(3H)-one (105 mg, 0.3 mmol, 1 eq) in CHCl₃ (50 mL) was added (COCl)₂ (0.2 mL) and DMF (2 drops). The mixture was stirred at 70 °C for 2 h under nitrogen and then concentrated to afford a crude title compound (110 mg, 100% yield) as a yellow solid. LCMS: m/z 365.40/367.40 [M+1]⁺. Following the above procedure, intermediates 1B-5-2 1B-5-3, and 1B-5-4 were prepared.

Step 5. Synthesis of (S)-7-bromo-N-(3-chloro-2-fluorophenyl)-6-(1-(pyrimidin-2-yl)ethoxy) quinazolin-4-amine A mixture of (S)-7-bromo-4-chloro-6-(1-(pyrimidin-2-yl)ethoxy)quinazoline (110 mg, 0.3 mmol, 1 equiv.) and 3-chloro-2-fluoroaniline (132 mg, 0.9 mmol, 3 equiv.) in ACN (5 ml) was stirred at 70 °C for 1 h, subsequently quenched with saturated NaHCO₃, and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (DCM:MeOH = 30:1) to afford the title compound (110 mg, 0.29 mmol, 76%) as a white solid. LC-MS: m/z = 474.55/476.55 [M+1]⁺. Following the above procedure, intermediates 1B-6-2, 1B-6-3, 1B-6-4, 1B-6-5 and 1B- 6-6 were prepared.

Step 6. Synthesis of (S)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 27) A mixture of (S)-7-bromo-N-(3-chloro-2-fluorophenyl)-6-(1-(pyrimidin-2-yl)ethoxy)- quinazolin-4-amine (110 mg, 0.23 mmol, 1 eq), (1-methyl-1H-pyrazol-4-yl)boronic acid (44 mg, 0.348 mmol, 1.5 eq), K₂CO₃ (96 mg, 0.696 mmol, 3 eq) and Pd(dppf)Cl₂ (18 mg, 0.023 mmol, 0.1 eq) in dioxane (5 mL) and H₂O (0.6 mL) was degassed and purged with nitrogen 3 times, then stirred at 80 °C for 4 h under nitrogen, diluted with H₂O (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford the title compound (61.2 mg, 56% yield) as a white solid. LC-MS: m/z = 476.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 4.9 Hz, 2H), 8.53 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 5.94 (q, J = 6.6 Hz, 1H), 3.97 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H). EXAMPLES 28-35 Following the procedure described in Example 27, Compounds 28-35 of this invention were prepared. Compound 28: (R)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 59%. LC-MS: m/z = 476.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD): δ 8.82 (d, J = 4.9 Hz, 2H), 8.53 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 5.94 (q, J = 6.4 Hz, 1H), 3.97 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H). Compound 29: (R)-N-(3-chloro-2-fluorophenyl)-7-(1-(difluoromethyl)-1H-pyrazol-4- yl)-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 57%. LC-MS: m/z = 512.00 [M+1]⁺. 1H NMR (400 MHz, dmso-d₆): δ 9.79 (s, 1H), 9.35 (s, 1H), 8.86 (d, J = 4.9 Hz, 2H), 8.66 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.91 (t, J = 59.1 Hz, 1H), 7.55 – 7.44 (m, 3H), 7.26 (t, J = 8.2 Hz, 1H), 6.06 (q, J = 6.5 Hz, 1H), 1.76 (d, J = 6.3 Hz, 3H). Compound 30: N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-7-(1-methyl-1H-pyrazol-4- yl)-6-(1-(pyrimidin-4-yl)ethoxy)quinazolin-4-amine. Yield 29%. LC-MS: m/z = 482.25 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 9.36 (s, 1H), 8.90 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 5.4 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.81 (s, 1H), 6.11 (q, J = 6.4 Hz, 1H), 4.04 (s, 3H), 1.94 (d, J = 6.4 Hz, 3H). Compound 31: (S)-N-(3,4-dichloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 36%. LC-MS: m/z = 510.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 4.9 Hz, 2H), 8.52 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.54-7.51 (m, 1H), 7.61 (t, J = 5.0 Hz, 1H), 7.41-7.37 (m, 2H), 3.97 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H). Compound 32: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 52.8%. LC-MS: m/z = 494.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.83 (d, J = 4.8 Hz, 2H), 8.54 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.55 (dd, J = 14.0, 8.4 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 5.95 (q, J = 6.4 Hz, 1H), 3.98 (s, 3H), 1.87 (d, J = 6.4 Hz, 3H). Compound 33: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-cyclopropyl-1H-pyrazol-4- yl)-5-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 51.5%. LC-MS: m/z = 520.25 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.84 (d, J = 4.9 Hz, 2H), 8.70 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.56 (dd, J = 14.1, 8.6 Hz, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 5.96 (q, J = 6.2 Hz, 1H), 3.76-3.70 (m, 1H), 1.85 (d, J = 6.4 Hz, 3H), 1.20 – 1.08 (m, 4H). Compound 34: (R)-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-7-(1-methyl-1H-pyrazol- 4-yl)-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine. Yield 33%. LC-MS: m/z = 482.15 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.85 (d, J = 4.8 Hz, 2H), 8.58 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 8.03-7.96 (m, 2H), 7.84 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.04-5.94 (m, 1H), 4.00 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H). Compound 35: (S)-6-(1-(4-fluorophenyl)ethoxy)-N-(4-fluoropyrazolo[1,5-a]pyridin- 5-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine . Yield 29%. LC-MS: m/z = 498.30 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 4.4 Hz, 2H), 7.49 (dd, J = 8.8, 5.2 Hz, 2H), 7.12-7.04 (m, 3H), 6.84 (d, J = 1.6 Hz, 1H), 5.94 (q, J = 6.8 Hz, 1H), 4.02 (s, 3H), 1.85 (d, J = 6.4 Hz, 3H). EXAMPLE 36: Synthesis of (S)-N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 36).

Step 1. Synthesis of 4-bromo-2-fluorophenyl ethyl carbonate To a solution of 4-bromo-2-fluorophenol (35 g, 183 mmol, 1 eq) and TEA (22.2 g, 220 mmol, 1.2 eq) in dry DCM (350 mL) at 0 °C was added dropwise a solution of ethyl carbonochloridate (23.9 g, 220 mmol, 1.2 eq). The reaction mixture was stirred at 0 °C for 1 h under N₂, then allowed to warm to room temperature, quenched with H₂O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (48.5 g, 100% yield) as yellow oil. 1HNMR (400 MHz, CDCl₃) δ 7.33 (dd, J = 9.5, 2.3 Hz, 1H), 7.26 (ddd, J = 8.6, 2.3, 1.4 Hz, 1H), 7.12 – 7.06 (m, 1H), 4.37 – 4.29 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of 4-bromo-2-fluoro-5-nitrophenyl ethyl carbonate To a solution of 4-bromo-2-fluorophenyl ethyl carbonate (48.5 g, 184 mmol, 1 eq) in H₂SO₄ (90 mL) was added dropwise HNO₃ (13.1 mL, 276 mmol, 1.5 eq) at 0 °C. After 1 h, the reaction mixture was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water, NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (53.2 g, 93% yield) as a yellow oil. 1H NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 4.40 – 4.32 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H). Step 3. Synthesis of 4-bromo-2-fluoro-5-nitrophenol To a solution of 4-bromo-2-fluoro-5-nitrophenyl ethyl carbonate (53.2 g, 173 mmol, 1 eq) in MeOH (550 mL) was added NaHCO₃ (29.1 g, 345 mmol, 2 eq). The reaction mixture was stirred at 0 °C for 3 h. MeOH was evaporated under reduced pressure. Water (200 mL) was added to the residue and the aqueous layer was acidified to pH = 5 by the addition of 4N HCl. The aqueous layer was filtered. The filter cake was washed with water (x 3) and concentrated under reduced pressure to afford the title compound (29.4 g, 72% yield) as a yellow solid. LC-MS: m/z = 234.10/236.10 [M+1]⁺. Step 4. Synthesis of 1-bromo-5-fluoro-2-nitro-4-(vinyloxy)benzene A mixture of 4-bromo-2-fluoro-5-nitrophenol (18.3 g, 77.5 mmol, 1 eq), vinyl acetate (33.4 g, 387 mmol, 5 eq), [Ir(COD)Cl]₂ (1.57 g, 2.33 mmol, 0.03 eq) and Na₂CO₃ (4.93 g, 46.5 mmol, 0.6 eq) in toluene (190 mL) was stirred at 120 °C for 16 h under nitrogen in a sealed tube. The mixture was cooled, concentrated, and purified by prep-FCC (PE: EA=100:1) to afford the title compound (12.76 g, 62% yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 6.59 (ddd, J = 13.5, 5.9, 0.7 Hz, 1H), 4.91 (dd, J = 13.5, 2.5 Hz, 1H), 4.69 (dd, J = 6.0, 2.5 Hz, 1H). Step 5. Synthesis of 1-bromo-4-cyclopropoxy-5-fluoro-2-nitrobenzene Diethylzinc (195 mL, 1M in hexane, 4 eq) was dissolved in dry DCM (200 mL) at 0 °C, then TFA (22.2 g, 195 mmol, 4 eq) in dry DCM was added dropwise at 0 °C, 10 min later diiodomethane (52.2 g, 195 mmol, 4 eq) in dry DCM was added dropwise at 0 °C. After stirring the mixture at 0 °C for 15 min, 1-bromo-5-fluoro-2-nitro-4-(vinyloxy)benzene (12.76 g, 48.7 mmol, 1 eq) in dry DCM was added dropwise. The reaction mixture was stirred at 0 to 30 °C for 16 h under nitrogen atmosphere. The mixture was quenched with 1N HCl, extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with (PE:EA=100:1) to afford the title compound (4.27 g, 31% yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 9.9 Hz, 1H), 3.85 (dt, J = 5.7, 2.7 Hz, 1H), 0.90 – 0.86 (m, 4H). Step 6. Synthesis of 4-cyclopropoxy-5-fluoro-2-nitrobenzonitrile To a solution of 1-bromo-4-cyclopropoxy-5-fluoro-2-nitrobenzene (4.27 g, 15.5 mmol, 1 eq) in NMP (50 mL) was added CuCN (1.8 g, 20 mmol, 1.3 eq) at room temperature and stirred at 130 °C for 2 h under nitrogen. The mixture was filtered through diatomite and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (5 x ^{20 mL), dried over anhydrous Na}2^SO4 ^{and filtered. The filtrate was concentrated under reduced} pressure and purified by silica gel column chromatography, eluting with (PE:EA=80:1) to afford the title compound (2.35 g, 68% yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ 8.24 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 9.6 Hz, 1H), 4.02 – 3.94 (m, 1H), 1.03 – 0.89 (m, 4H). Step 7. Synthesis of (S)-4-cyclopropoxy-2-nitro-5-(1-(pyrimidin-2-yl)ethoxy)benzonitrile To a solution of (S)-1-(pyrimidin-2-yl)ethan-1-ol (251 mg, 2 mmol, 1.5 eq) in THF (5 mL) was added NaH (81 mg, 2 mmol, 1.5 eq) at 0 °C and stirred for 0.5 h under nitrogen. A solution of 4-cyclopropoxy-5-fluoro-2-nitrobenzonitrile (300 mg, 1.35 mmol, 1 eq) was added and then stirred at 0 °C to room temperature for 0.5 h. The mixture was quenched with an aqueous saturated NH₄Cl (5 mL) solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE: EA = 1:1) to afford the title compound (440 mg, 98% yield) as a yellow solid. LCMS: m/z 327.15 [M+1]⁺. Following the above procedure, intermediates 1B-17-2 and 1B-17-3 were prepared.

Step 8. Synthesis of (S)-2-amino-4-cyclopropoxy-5-(1-(pyrimidin-2-yl)ethoxy)benzonitrile To a solution of (S)-4-cyclopropoxy-2-nitro-5-(1-(pyrimidin-2-yl)ethoxy)benzonitrile (200 mg, 0.61 mmol, 1 eq) in THF (3 mL) and H₂O (3 mL) was added Na₂S₂O₄ (320 mg, 1.84 mmol, 3 eq) at 0 °C and stirred at 0 °C for 2 minutes under nitrogen atmosphere. The ^{mixture was quenched with aqueous NaHCO}3^{, extracted with EtOAc (3 x 10 mL). The} combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (79 mg, 43% yield) as a yellow solid. LC-MS: m/z = 297.35 [M+1]⁺. Following the above procedure, intermediates 1B-18-2 and 1B-18-3 were prepared.

Step 9. Synthesis of (S)-N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-(1-(pyrimidin-2- yl)ethoxy)quinazolin-4-amine (Compound 36) To a solution of (S)-2-amino-4-cyclopropoxy-5-(1-(pyrimidin-2-yl)ethoxy)- benzonitrile (79 mg, 0.27 mmol, 1 eq) in 2-MeTHF (4 mL) was added (E)-N,N'-bis(3-chloro- 2-fluorophenyl)formimidamide (100 mg, 0.33 mmol, 1.25 eq) at room temperature. The reaction mixture was heated to 80 °C and AcOH (0.4 mL) was added. After stirring the reaction mixture at 90 °C for 16 h, the mixture was cooled to rt and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with aqueous NaHCO₃ (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and purified by prep-HPLC to afford the desired product (28 mg, 23% yield) as a white solid. LC-MS: m/z = 452.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.78 (d, J = 4.9 Hz, 2H), 8.31 (s, 1H), 7.61 (s, 1H), 7.56 –7.50 (m, 2H), 7.39 (t, J = 4.9 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H), 5.68 (q, J = 6.5 Hz, 1H), 4.01 – 3.92 (m, 1H), 1.78 (d, J = 6.5 Hz, 3H), 0.95 – 0.88 (m, 2H), 0.86 – 0.79 (m, 2H). EXAMPLES 37 and 38 Following the procedure described in Example 36, Compounds 37 and 38 were prepared. Compound 37: N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-(1-(5-(difluorometh- yl)pyrimidin-2-yl)-ethoxy)quinazolin-4-amine. Yield 33.4%. LC-MS: m/z = 502.25 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.96 (s, 2H), 8.32 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 55.0 Hz, 1H), 5.76 (q, J = 6.8 Hz, 1H), 3.98-3.94 (m, 1H), 1.80 (d, J = 6.8 Hz, 3H), 0.94-0.89 (m, 2H), 0.82-0.78 (m, 2H). Compound 38: N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-(1-(4-(difluorometh- yl)phenyl)-ethoxy)quinazolin-4-amine. Yield 29.8%. LC-MS: m/z = 500.25 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.67 (s, 1H), 7.56-7.54 (m, 4H), 7.52-7.49 (m, 2H) 7.37 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.70 (t, J = 56.0 Hz, 1H), 5.69 (q, J = 6.0 Hz, 1H), 4.02-3.99 (m, 1H), 1.68 (d, J = 6.4 Hz, 3H), 0.97-0.93 (m, 2H), 0.87-0.82 (m, 2H). EXAMPLE 39: Synthesis of N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-{[2-(pyrimidin- 2-yl)propan-2-yl]oxy}quinazolin-4-amine (Compound 39).

Step 1. Synthesis of 4-cyclopropoxy-2-nitro-5-{[2-(pyrimidin-2-yl)propan-2-yl]oxy}- benzonitrile To a solution of 2-(pyrimidin-2-yl)propan-2-ol (251 mg, 1.82 mmol, 1.5 eq) in dry THF (5 mL) was added NaH (44 mg, 1.82 mmol, 1.5 eq) at 0 °C and stirred for 0.5 h under nitrogen. The solution of 4-cyclopropoxy-5-fluoro-2-nitrobenzonitrile (270 mg, 1.21 mmol, 1 eq) in dry THF (5 mL) was added and then stirred at room temperature for 0.5 h. The mixture was quenched with saturated NH₄Cl (5 mL) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE: EA=3:1) to afford the title compound (370 mg, 89% yield) as a yellow solid. LC-MS: m/z = 341.10 [M+1]⁺. Step 2. Synthesis of 2-amino-4-cyclopropoxy-5-{[2-(pyrimidin-2-yl)propan-2-yl]oxy}- benzonitrile To a solution of 4-cyclopropoxy-2-nitro-5-{[2-(pyrimidin-2-yl)propan-2-yl]oxy}- benzonitrile (288 mg, 0.85 mmol, 1 eq) in THF (3 mL) and H₂O (3 mL) was added Na₂S₂O₄ (442 mg, 2.54 mmol, 3 eq) at 0 °C and stirred at 0 °C for 10 min under nitrogen. The mixture was quenched with NaHCO₃ (aq), extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with (DCM: MeOH=50:1) to afford the title compound (83 mg, 31% yield) as a yellow solid. LC-MS: m/z = 311.10 [M+1]⁺. Step 3. Synthesis of N-(3-chloro-2-fluorophenyl)-7-cyclopropoxy-6-{[2-(pyrimidin-2-yl)- propan-2-yl]oxy}quinazolin-4-amine (Compound 39) To a solution of 2-amino-4-cyclopropoxy-5-{[2-(pyrimidin-2-yl)propan-2-yl]oxy}- benzonitrile (83 mg, 0.27 mmol, 1 eq) in 2-MeTHF (5 mL) was added (E)-N,N'-bis(3-chloro- 2-fluoro-phenyl)formimidamide (100 mg, 0.33 mmol, 1.25 eq) at room temperature. The reaction mixture was heated to 80 °C and AcOH (0.5 mL) was added. The reaction mixture was stirred at 90 °C for 16 h, then cooled to rt and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaHCO₃(aq) (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and purified by prep-HPLC to afford the desired product (62.1 mg, 49% yield) as a white solid. LC-MS: m/z = 466.05 [M+1]^{+ 1}H NMR (400 MHz, CD₃OD) δ 8.79 (d, J = 4.9 Hz, 2H), 8.33 (s, 1H), 7.56 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.40 (t, J = 4.9 Hz, 1H), 7.37 – 7.33 (m, 1H), 7.20 – 7.15 (m, 1H), 3.77 – 3.74 (m, 1H), 1.80 (s, 6H), 0.81 – 0.78 (m, 2H), 0.58 – 0.54 (m, 2H). EXAMPLE 40: Synthesis of (S)-N-(3-chloro-2-fluorophenyl)-N-methyl-7-(1-methyl-1H- pyrazol-4-yl)-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 40). To a mixture of (S)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 27, 80 mg, 0.19 mmol, 1 eq.) and Cs₂CO₃ (109 mg, 0.34 mmol, 2 eq.) in DMF (2 mL), iodomethane (71.6 mg, 0.5 mmol, 3 eq.) was added dropwise and the reaction was stirred at rt for 1 h. The mixture was diluted with EA (20 mL), washed with brine (10 mL x3), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (0.04% NH₄HCO₃ in H₂O/CH₃CN) to afford the title compound (20 mg, 0.041 mmol, 24.3%) as a yellow solid. LC-MS: m/z = 490.05 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.81 (d, J = 4.8 Hz, 2H), 8.52 (s, 1H), 8.23 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.39 (t, J = 4.8 Hz, 1H), 7.05 (td, J = 8.4, 6.8 Hz, 2H), 6.92 (td, J = 7.2, 2.0 Hz, 1H), 5.80 (q, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.69 (s, 3H), 1.83 (d, J = 6.4 Hz, 3H). EXAMPLE 41: Synthesis of (S)-N-(3-chloro-2-fluorophenyl)-N-(difluoromethyl)-7-(1- methyl-1H-pyrazol-4-yl)-6-(1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 41). A mixture of (S)-N-(3-chloro-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-6-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 27, 80 mg, 0.17 mmol, 1 eq.), sodium 2-chloro-2,2-difluoroacetate (76.9 mg, 0.5 mmol, 3 eq.) and dipotassium carbonate (69.7 mg, 0.5 mmol, 3 eq.) in CH₃CN (5 mL) was stirred at 60 °C for 16 h. The mixture was diluted with EA (50 mL), washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC (0.04% NH₄HCO₃ in H₂O/CH₃CN) to afford the title compound (21.52 mg, 0.041 mmol, 24.3%) as a yellow solid. LC-MS: m/z = 526.25 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 4.8 Hz, 2H), 8.46 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.84-7.79 (m, 2H), 7.57 (t, J = 57.6 Hz, 1H), 7.41 (t, J = 4.8 Hz, 1H), 7.15-7.01 (m, 2H), 6.91 (td, J = 7.6, 2.0 Hz, 1H), 5.81 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 1.85 (d, J = 6.4 Hz, 3H). EXAMPLE 42: Synthesis of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-((2-(3-methyl- pyridin-4-yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 42).

Step 1. Synthesis of 4-(2-(5-bromo-2-methoxy-4-nitrophenoxy)propan-2-yl)-3-methylpyridine To a mixture of NaH (0.48 g, 12 mmol) in DMF (25 mL) was added 2-(3- methylpyridin-4-yl)propan-2-ol (0.91 g, 6 mmol) under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene (1.5 g, 6 mmol) was added. The resulting mixture was stirred at rt for 1 h, then poured into water (25 ml), extracted with EA (25 mL x 3), washed with brine solution (25 mL x 3), concentrated, and purified by flash chromatography with PE/EA=5/1-2/1 to give 4-[2-(5-bromo-2-methoxy-4- nitrophenoxy)propan-2-yl]-3-methylpyridine (1.2 g, 2.833 mmol, 47%) as a green solid. LC-MS: m/z = 381.35/383.35 [M+1]⁺. Step 2. Synthesis of methyl 4-methoxy-5-((2-(3-methylpyridin-4-yl)propan-2-yl)oxy)-2- nitrobenzoate To a solution of 4-{2-[(5-bromo-2-methoxy-4-nitrophenyl)oxy]prop-2-yl}-3-methyl- pyridine (1 g, 2.623 mmol) in CH₃OH (25 mL) was added Pd(dppf)Cl₂ (0.38 g, 0.525 mmol) under CO. The reaction mixture was stirred at 70 °C for 18 h, then poured into water (25 ml), cooled to rt and extracted with EA (25.0 ml x 3), washed with NaCl solution (25 ml x 3), concentrated, and purified by flash chromatography with PE/EA=5/1-2/1 to give methyl 4- methoxy-5-{[2-(3-methylpyridin-4-yl)prop-2-yl]oxy}-2-nitrobenzoate (700 mg, 1.9 mmol, 73%) as a green solid. LC-MS: m/z = 361.4 [M+1]⁺. Step 3. Synthesis of methyl 2-amino-4-methoxy-5-((2-(3-methylpyridin-4-yl)propan-2-yl)oxy) benzoate To a solution of methyl 4-methoxy-5-{[2-(3-methylpyridin-4-yl)prop-2-yl]oxy}-2- nitrobenzoate (700 mg, 1.9 mmol) in CH₃OH (25 mL) was added Pd/C under H₂. The reaction mixture was stirred at rt for 1 h, then poured into water (25 ml), extracted with EA (25 ml x 3), washed with brine (25 ml x 3), concentrated under reduced pressure, and purified by flash chromatography with PE/EA=5/1-2/1 to give methyl 2-amino-4-methoxy-5-{[2-(3-methyl- pyridin-4-yl)prop-2-yl]oxy}benzoate (500 mg, 1.4 mmol, 70%) as an colorless solid. LC-MS: m/z = 331.4 [M+1]⁺. Step 4. Synthesis of 7-methoxy-6-((2-(3-methylpyridin-4-yl)propan-2-yl)oxy)quinazolin-4-ol To a solution of methyl 2-amino-4-methoxy-5-{[2-(3-methylpyridin-4-yl)prop-2-yl]- oxy}benzoate (500 mg, 1.5 mmol) in ethanol (25 mL) was added formamidine acetate (315 mg, 3 mmol) under N₂ atmosphere. The reaction mixture was stirred at 85°C for 18 h, then poured into water (25 mL), cooled to rt, and extracted with EA (25 mL x 3). The combined organic layers were washed with brine (25 ml x 3), concentrated under reduced pressure, and purified by flash chromatography with PE/EA=5/1-2/1 to give 7-methoxy-6-{[2-(3-methylpyridin-4- yl)prop-2-yl]oxy}quinazolin-4-ol (300 mg, 0.83 mmol, 55%) as a colorless solid. LC-MS: m/z = 326.4 [M+1]⁺. Step 5. Synthesis of 4-chloro-7-methoxy-6-((2-(3-methylpyridin-4-yl)propan-2-yl)oxy) quinazoline To a solution of 7-methoxy-6-{[2-(3-methylpyridin-4-yl)prop-2-yl]oxy}quinazolin-4- ol (300 mg, 0.92 mmol) in CHCl₃ (25 mL) was added (COCl)₂ (234 mg, 1.8 mmol) and DMF (3.37 mg, 0.046 mmol) under N₂. The reaction mixture was stirred at 85 °C for 2 h, then poured into water (25 mL), cooled to rt, and extracted with EA (25 mL x 3). The combined organic extract was washed with brine (25 mL x 3), concentrated under reduced pressure, and purified by flash chromatography with PE/EA=3/1-1/1 to give 4-chloro-7-methoxy-6-{[2-(3- methylpyridin-4-yl)prop-2-yl]oxy}quinazoline (200 mg, 0.52 mmol, 57%) as a colorless solid. LC-MS: m/z = 343.8 [M+1]⁺. Step 6. Synthesis of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-((2-(3-methylpyridin-4- yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 42) To a solution of 4-chloro-7-methoxy-6-{[2-(3-methylpyridin-4-yl)prop-2-yl]oxy}qui- nazoline (250 mg, 0.727 mmol) in IPA (25 mL) was added 3-chloro-2-fluoroaniline (423 mg, 2.9 mmol) under N₂. The reaction mixture was stirred at 100 °C for 18 h, then poured into water (25 ml), cooled to rt, and extracted with EA (25 mL x3). The combined organic extract was washed with a saturated NaCl solution (25 mL x 3), concentrated under reduced pressure, and purified by flash chromatography with PE/EA=3/1-1/1 to give the title product N-(3-chloro-2- fluorophenyl)-7-methoxy-6-((2-(3-methylpyridin-4-yl)propan-2-yl)oxy)quinazolin-4-amine (180 mg, 0.39 mmol, 54%) as a white solid. LC-MS: m/z = 453.0 [M+1]⁺. 1H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.55 – 7.43 (m, 3H), 7.39 (s, 1H), 7.30 – 7.23 (m, 2H), 3.89 (s, 3H), 2.44 (s, 3H), 1.81 (s, 6H). EXAMPLES 43-49 Compounds 43-49 of this invention were prepared following the procedure described in Example 1. N-(3-chloro-2,4-difluorophenyl)-7-(1H-pyrazol-4-yl)-5-((2-(pyrimidin-2-yl)propan-2- yl)oxy)quinazolin-4-amine (Compound 43) was prepared from (1H-pyrazol-4-yl)boronic acid (CAS:763120-58-7) and intermediate 1A-13-10. LC-MS: m/z = 494.10, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 8.32 (s, 2H), 7.83- 7.71 (m, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.41 (t, J = 4.8 Hz, 1H), 7.36 (td, J = 9.0, 2.0 Hz, 1H). N-(3-chloro-4-fluorophenyl)-7-(1H-pyrazol-4-yl)-5-((2-(pyrimidin-2-yl)propan-2- yl)oxy)quinazolin-4-amine (Compound 44) was prepared from (1H-pyrazol-4-yl)boronic acid (CAS:763120-58-7) and intermediate 1A-13-11. LC-MS: m/z = 476.15, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 4.9 Hz, 2H), 8.63 (s, 1H), 8.19 (s, 2H), 7.91 (dd, J = 6.5, 2.4 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.48 (s, 2H), 7.46 – 7.39 (m, 2H), 2.17 (s, 6H). (S)-N-(3-chloro-4-fluorophenyl)-7-(1H-pyrazol-4-yl)-5-(1-(pyrimidin-2-yl)ethoxy)- quinazolin-4-amine (Compound 45) was prepared from (1H-pyrazol-4-yl)boronic acid (CAS: 763120-58-7) and intermediate 1A-13-4. LC-MS: m/z = 462.10, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.77 (d, J = 4.9 Hz, 2H), 8.69 (s, 1H), 8.35 (s, 2H), 8.07 (dd, J = 6.7, 2.7 Hz, 1H), 7.81-7.75 (m, 2H), 7.50 (s, 1H), 7.48 – 7.42 (m, 2H), 6.27 (q, J = 6.6 Hz, 1H), 1.90 (d, J = 6.4 Hz, 3H). N-(3-chloro-2,4-difluorophenyl)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-5-((2-(pyrimidin- 2-yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 46) was prepared from (1-(methyl-d3)- 1H-pyrazol-4-yl)boronic acid (CAS: 2256709-52-9) and intermediate 1A-13-10. LC-MS: m/z = 511.30, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.72–8.55 (m, 3H), 8.33 (s, 1H), 8.03 (s, 1H), 7.82- 7.69 (m, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.41 (t, J = 4.8 Hz, 1H), 7.36 (t, J = 8.8 Hz, 1H), 2.19 (s, 6H). N-(3-chloro-4-fluorophenyl)-7-(1-(methyl-d₃)-1H-pyrazol-4-yl)-5-((2-(pyrimidin-2- yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 47) was prepared from (1-(methyl-d₃)- 1H-pyrazol-4-yl)boronic acid (CAS: 2256709-52-9) and intermediate 1A-13-11. LC-MS: m/z = 493.20, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 4.9 Hz, 2H), 8.62 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.92-7.87 (m, 1H), 7.61-7.56 (m, 1H), 7.47-7.42 (m, 3H), 7.41 (t, J = 4.8 Hz, 1H), 2.17 (s, 6H). (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-(methyl-d₃)-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 48) was prepared from (1-(methyl- d3)-1H-pyrazol-4-yl)boronic acid (CAS: 2256709-52-9) and intermediate 1A-13-7. LC-MS: m/z = 497.10, [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.69 (d, J = 2.7 Hz, 2H), 8.45 (s, 1H), 8.20 (s, 1H), 7.85-7.78 (m, 1H), 7.71 (s, 1H), 7.52 (s, 1H), 7.43 (t, J = 4.9 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 6.24 (q, J = 6.4 Hz, 1H), 1.91 (d, J = 6.4 Hz, 3H). (S)-N-(3-chloro-4-fluorophenyl)-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 49) was prepared from (1-(difluoro- methyl)-1H-pyrazol-4-yl)boronic acid (CAS:1312693-57-4) and intermediate 1A-13-4. LC-MS: m/z = 512.10, [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 8.77 (d, J = 4.9 Hz, 2H), 8.71 (s, 1H), 8.37 (s, 1H), 8.07 (dd, J = 6.6, 2.6 Hz, 1H), 7.82 (s, 1H), 7.80 – 7.75 (m, 1H), 7.60 – 7.58 (m, 2H), 7.49 – 7.43 (m, 2H), 6.28 (q, J = 6.4 Hz, 1H), 1.90 (d, J = 6.4 Hz, 3H). EXAMPLE 50: Synthesis of N-(3-chloro-2,4-difluorophenyl)-7-(pyrimidin-2-yl)-5-((2- (pyrimidin-2-yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 50).

A mixture of 7-bromo-N-(3-chloro-2,4-difluorophenyl)-5-((2-(pyrimidin-2-yl)propan- 2-yl)oxy)quinazolin-4-amine (IA-13-10, 86 mg, 0.17 mmol, 1 eq.), 2-(tributylstannyl)- pyrimidine (75 mg, 0.203 mmol, 1.2 eq.), CuI (3.23 mg, 0.017 mmol, 0.1 eq.) and Pd(dppf)Cl₂ (12.4 mg, 0.017 mmol, 0.1 eq.) in DMF (3 mL) was degassed and purged with nitrogen three times and then the mixture was stirred at 100 °C for 24 h under nitrogen atmosphere. The resulting mixture was diluted with H₂O (10 mL), cooled to rt, and extracted with DCM/MeOH (10/1) (3 x 30 mL). The combined organic layers were washed with 10% aqueous KF (10 mL x 2), brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC (TFA (0.1%) in H₂O/CH₃CN) to afford the title compound (13.4 mg, 15.6% yield) as a gray solid. LC-MS: m/z = 506.20 [M+1]⁺. 1H NMR (400 MHz, CD₃OD) δ 8.95 (d, J = 4.8 Hz, 2H), 8.68 (d, J = 4.8 Hz, 2H), 8.67 (s, 1H), 8.49 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 1.2 Hz, 1H), 7.92 (td, J = 8.8, 5.6 Hz, 1H), 7.49 (t, J = 4.8 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 7.37-7.29 (m, 1H), 2.19 (s, 6H). EXAMPLES 51-58 Compounds 51-58 of this invention can be readily prepared following the procedure described in Example 1. N-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1-(4-methyl-4H-1,2,4- triazol-3-yl)ethoxy)quinazolin-4-amine (Compound 51) can be prepared from 1-(4-methyl- 4H-1,2,4-triazol-3-yl)ethan-1-ol (CAS:149762-18-5) and intermediate 1A-12-4.

N-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-5-(1-(pyrimidin-2-yl) cyclopropoxy)quinazolin-4-amine (Compound 52) can be prepared from 1-(pyrimidin-2- yl)cyclopropan-1-ol (CAS:2229094-28-2) and intermediate 1A-12-4.

N-(3-chloro-4-fluorophenyl)-5-(1-(1-methyl-1H-imidazol-2-yl)ethoxy)-7-(1-methyl- 1H-pyrazol-4-yl)quinazolin-4-amine (Compound 53) can be prepared from 1-(1-methyl-1H- imidazol-2-yl)ethan-1-ol (CAS:41507-36-2) and intermediate 1A-12-4.

(S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(1- (pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 54) can be prepared from (1-(di- fluoromethyl)-1H-pyrazol-4-yl)boronic acid (CAS:1312693-57-4) and intermediate 1A-13-7. N-(3-chloro-2,4-difluorophenyl)-7-(isothiazol-5-yl)-5-((2-(pyrimidin-2-yl)propan-2- yl)oxy)quinazolin-4-amine (Compound 55) can be prepared from isothiazole-5-boronic acid (CAS:1162262-43-1) and intermediate 1A-13-7. N-(3-chloro-2,4-difluorophenyl)-5-(1-(1-(methyl)-1H-indol-2-yl)ethoxy)-7-(1- (methyl-d3)-1H-pyrazol-4-yl)quinazolin-4-amine (Compound 56) can be prepared from 1-(1- methylindol-2-yl)ethanol (CAS: 29124-10-5), (1-(methyl-d₃)-1H-pyrazol-4-yl)boronic acid (CAS: 2256709-52-9), and intermediate 1A-12-3.

N-(3-chloro-4-fluorophenyl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((2-(pyrimidin-2- yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 57) can be prepared from (1-cyclopropyl- 1H-pyrazol-4-yl)boronic acid (1678534-30-9) and intermediate 1A-13-11. N-(3-chloro-2,4-difluorophenyl)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-5-((2-(thiazol-2- yl)propan-2-yl)oxy)quinazolin-4-amine (Compound 58) can be prepared from 2-thiazol-2-yl- propan-2-ol (CAS:16077-78-4), (1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (CAS: 2256709- 52-9) and intermediate 1A-12-3.

EXAMPLE 59: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(1-(methyl-d₃)-1H-pyrazol-4-yl)-6- (1-(pyrimidin-2-yl)ethoxy)quinazolin-4-amine (Compound 59) Compound 59 can beprepared from (1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (CAS: 2256709-52-9) and intermediate 1B-6-4 following the procedure of Example 27. EXAMPLE 60: N-(3-chloro-2,4-difluorophenyl)-5-((2-(pyrimidin-2-yl)propan-2-yl)oxy)-7- (thiazol-2-yl)quinazolin-4-amine (Compound 60) Compound 60 can be prepared from 1,3-thiazole-2-boronic acid (CAS: 389630-95-9) and intermediate 1A-13-10 following the procedure of Example 1. EXAMPLE 61: (S)-N-(3-chloro-2,4-difluorophenyl)-7-(pyrimidin-2-yl)-5-(1-(pyrimidin-2- yl) ethoxy)quinazolin-4-amine (Compound 61) Compound 61 can be prepared following the procedure of Example 50, using intermediate 1A-13-7 and 2-(tributylstannyl)pyrimidine (CAS# 153435-63-3). EXAMPLE 62: N-(3-chloro-2,4-difluorophenyl)-7-methoxy-5-((2-(pyrimidin-2-yl)propan-2- yl)oxy)quinazolin-4-amine (Compound 62) Compound 62 can be prepared following general scheme II, Step 4, using intermediate 1A-13-10 and methanol. EXAMPLE 63: (S)-N-(3-chloro-2,4-difluorophenyl)-7-methoxy-5-(1-(pyrimidin-2-yl)eth- oxy)quinazolin-4-amine (Compound 63) Compound 63 can be prepared following general scheme II, Step 4, using intermediate 1A-13-9 and methanol. EXAMPLE 64: N-(3-chloro-4-fluorophenyl)-7-methoxy-5-((2-(pyrimidin-2-yl)propan-2-yl)- oxy)quinazolin-4-amine (Compound 64) Compound 64 can be prepared following general scheme II, Step 4, using intermediate 1A-13-11 and methanol. EXAMPLE 65: (S)-N-(3-chloro-4-fluorophenyl)-7-methoxy-5-(1-(pyrimidin-2-yl)ethoxy) quinazolin-4-amine (Compound 65) Compound 65 can be prepared following general scheme II, Step 4, using intermediate 1A-13-4 and methanol. Biological assays pERK Potency assay: EGFR mediates downstream signaling cascades, i.e., ERK phosphorylation in cells with EGFR aberrations. EGFR aberrations become constitutively active and thus induces cascades of cellular signaling events that result in increased phosphorylation of ERK at Threonine 202 and Tyrosine 204 (pERK). The so-called In Cell ELISA procedure as described below measures the level of cellular pERK in response to EGFR specific inhibitors in EGFR aberrations of three EGFR cell lines: PC-9 (EGFR/del19), A431 (EGFR amplification), and 11-18 (EGFR/L858R). PC-9 cells were obtained from the American Type Culture Collection (ATCC, Manassas, Virginia) and 11-18 and A431 cells were commercially available from RIKEN Cell Bank (Japan). PC-9 and 11-18 cells were grown and maintained using RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum. A431 cells were grown and maintained using DMEM (low glucose) supplemented with 10% heat-inactivated fetal bovine serum. On the day before a compound was added, cells were plated in poly-D-lysine coated 96-well cell culture plates (Corning® Biocoat® Cat#356640) at 50000 cells/well/100 μL for PC-9 and 11-18 cells and 20000 cells/well/100 μL for A431 cells. They were grown overnight in an incubator at 37°C with 5% CO₂. Test compounds were prepared with 3-fold serial dilutions in DMSO, with a top concentration of 10 mM. On the day of the assay, 50 μL of a test compound diluted in media was added to each well of cell culture plate with the final concentration of the compound spanning from 0.00005 μM to 10 μM. After adding the test compound, the cells were incubated for 3 hours at 37°C with 5% CO₂. After the culture medium was removed, the cells were fixed with 200 μL of 4% formaldehyde in phosphate- buffered saline (PBS) and incubated at RT for 20 min. The plate was then washed three times with PBST (PBS with 0.05% Tween® 20), followed by incubation with 100 μL of pre-cooled methanol at -20°C for 20 min. After incubation, methanol was removed. The plate was washed with PBST. The cells were then permeabilized with 100 μL/well of 0.1% Triton^TM X-100 in PBS at RT for 20 min and then quenched with a buffer (PBST containing 1% H₂O₂ and 0.1% sodium azide) for 20 min at RT with gentle shaking. After washing twice with PBST, a blocking buffer (250 ul/well, Pierce™ Protein-Free-PBS Blocking Buffer, Cat# 37572) was added to the cells for 1-h incubation at RT, followed by anti-pERK antibody (cell signaling, 1:1000 dilution in 5% BSA in PBST) incubation overnight at 4°C and secondary antibody- HRP (Jackson immunoresearch,1:3000 dilution in 1% BSA in PBST) incubation at RT for 1h. PBST wash was carried out after each step three times. Before adding a substrate (ELISABright^TM, commercially available from Advansta, San Jose, California), the plate was washed with PBS twice to remove detergent residues. The cellular pERK level was determined using a microplate reader (Biotek® Synergy^TM H1, Agilent Technologies Inc., Santa Clara, California) to detect the chemiluminescence signal. IC₅₀ values were determined by fitting a 4-parameter sigmoidal concentration-response model. The pERK assay results showed that each of Compounds 1-34 ,36, 37, and 39-41 has an IC₅₀ of no more than 10 nM and each of Compounds 35, 38, and 42 has an IC₅₀ between 10.1 nm and 50 nM. The results demonstrated that the compounds of this invention are highly effective in inhibiting EGFR. 2D Cell Proliferation Assay: A cell proliferation assay was used to examine the potency with which compounds inhibit in vitro cell proliferation of cancer cell lines carrying EGFR aberrations or EGFR wild type. The assay demonstrated the molecular mode of action of compounds. Low IC₅₀ values are indicative of high potency of EGFR inhibitors. It was observed that EGFR inhibitors demonstrated potent inhibitory effects on the proliferation of human cancer cell lines or Baf/3 mouse cell lines carrying EGFR aberrations. The cell proliferation assay was performed in two-dimensional (2D) anchorage-dependent conditions in 96 well plates (Black/Clear Flat Bottom commercially available from Corning Inc., Corning, New York) with the following cell lines: Ba/F3 EGFR-Del19/C797S (human EGFR): a mouse Ba/F3 cell line stably expressed exogenous human EGFR with del19 and C797S mutation, Ba/F3 EGFR-L858/C797S (human EGFR): a mouse Ba/F3 cell line stably expressed exogenous human EGFR with L858R and C797S mutation, Ba/F3 EGFR-C797S (human EGFR): a mouse Ba/F3 cell line stably expressed exogenous human EGFR with C797S mutation, PC-9: a human lung cancer cell line with EGFR del19 mutation, 11-18: a human lung cancer cell line with EGFR L858R mutation, A431: a human epidermoid cancer cell line with over expression of wild type EGFR, and H1568: a human lung cancer cell line with over expression of wild type EGFR. Cell lines were purchased from the American Type Culture Collection (ATCC, Manassas, Virginia) or RIKEN Cell Bank (Japan). All Baf/3 EGFR mutant cell lines were commercially available from Kyinn Inc (China). All cell lines were maintained in RPMI-1640 or DMEM supplemented with 10% heat-inactivated fetal bovine serum. 2D cell proliferation Assay conditions: Cells growing in the log phase were collected for Baf/3 cells and detached with Gibco™ TrypLE™ Express Enzyme for A431, PC-9, 11-18 and H1568 and plated in 96 well plate at 1500 to 3000 cells/well in 100 μL of media. After overnight incubation at 37°C, 5% CO₂ incubator, the cells were treated with a test compound (50 μL/well) at a final concentration spanning from 0.000025 μM to 5 μM. They were incubated at 37°C, 5% CO₂, and 95% humidity for 96 hours. At the end of incubation, a 2D CTG reagent from Promega was added to each well according to the vendor’s recommendation and mixed for 10 min in dark. Luminescence signals were determined with a Biotek® Synergy^TM H1 plate reader (Agilent Technologies Inc., Santa Clara, California). The data were fitted using a sigmoidal curve analysis program (GraphPad Prism^TM, Dotmatics Inc., San Diego, California) with variable hill slope and IC₅₀ was determined. The results showed that, unexpectedly, (i) Compounds 1, 3, 4, 6-12, 15-19, 20, 21, 27- 29, 32, and 34 each have an IC₅₀ of no more than 10 nM for inhibiting BaF3/LR/CS cells, (ii) Compounds 1, 3, 4, 6-12, 15-19, 20, 21, 27-29, and 32 each have an IC₅₀ of no more than 10 nM for inhibiting BaF3/del19/CS cells, (iii) Compounds 3, 4, 6, 7, 9, 10, and 15-17 each have an IC₅₀ of no more than 10 nM for inhibiting BaF3 CS cells, and Compounds 8, 11, 18, 20 and 21 each have an IC₅₀ of 10 nM to 50 nM for inhibiting BaF3 CS cells, (iv) Compounds 3, 4, 6, 7, 15-17, 21, 27-29, and 32 each have an IC₅₀ of no more than 10 nM for inhibiting PC-9 cells, and Compounds 1, 10, 12, 19, 20, and 34 each have an IC₅₀ of 10 nM to 50 nM for inhibiting PC-9 cells, and (v) Compound 32 has an IC₅₀ of 10 nM to 50 nM for inhibiting A431 cells. Brain penetration assay conditions: Brain to plasma ratio was determined with 5 in 1 cassette dosing or 4 in 1 cassette dosing or 3 in 1 cassette dosing or 2 in 1 cassette dosing or discrete dosing using non-tumor bearing Sprague Dawley (SD) rats. For each 5 in 1 cassette dosing or 4 in 1 cassette dosing or 3 in 1 cassette dosing or 2 in 1 cassette dosing or discrete dosing studies a total of 3 male SD rats were selected from the animal pool of SD rats. The compounds were dissolved in a mixture of 5% EtOH/85%PE 400/10% H₂O solution and the animals were dosed orally at 2 mg/kg dose with a concentration of 0.2 mg/mL. The plasma and brain samples were collected 2h after dosing. For plasma samples, 0.3 mL blood was collected from each animal into K₂EDTA tubes kept on ice. The samples were centrifuged within 30 minutes of collection under refrigeration at 5 °C for 5 minutes at 6000 rpm to obtain plasma samples. A plasma sample (20 μL) was added to 2 μL MeOH and 200 μL of 5 ng/mL Terfenadine in methanol/acetonitrile (1:1, v/v). It was agitated for 1 minute and centrifuged at 4000 rpm for 15 minutes. A supernatant was separated and diluted with 5 volumes of MeOH/H₂O (1;1, v/v, 0.1% FA) for analysis below. For brain samples, after a rat was euthanized, its brain was removed and weighed. Water (4x) was added to homogenize the brain tissue in a high-speed homogenizer. To a 50 μL of brain homogenate was added 5 µL MeOH and 200 μL of 5 ng/mL Terfenadine in Methanol/ Acetonitrile (1:1, v/v). After vortex for 1 minute and centrifugation at 4000 rpm for 15 min, a supernatant was separated and diluted with 3 volumes of MeOH/H₂O (1:1, v/v, 0.1% FA) for analysis below. All samples were analysed via LC/MS/MS on AB Sciex 5500 using Kintex 1.7μ C18 100A column (50 x 2.1mm). Brain to plasma ratios (Concentration_brain/Concentration_plasma) of each test compound was calculated. The results showed that, surprisingly, Compounds 1-8, 10, 12, 15, 17-19, 25, 26, 31-33, and 39 each have a brain to plasma ratio of 0.5 or greater. The results demonstrated that compounds of this invention effectively penetrate the blood-brain barrier. Pharmacokinetic Studies in Balb/c mice: The pharmacokinetic (PK) properties of compounds of the invention were obtained following a single intravenous (IV) bolus (e.g., 1 mg/kg) and a single oral gavage (PO) (e.g., 10 mg/kg) administration to female Balb/c mice (fed, ages within 5-7 weeks). For the IV studies (5 ml/kg), the vehicle was 5% DMA/5% EtOH/40% PEG 400/50% H₂O (solution) and the blood samples were collected at 0 (pre-dose), 0.083, 0.25, 1, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose. For the PO (10 ml/kg) studies, the vehicle was 1% HEC/0.25% Tween-80/0.05% Antifoam/H₂O (suspension) and the blood samples were collected at 0 (pre-dose), 0.25, 1, 4, 8, 12, 24, 48, 72, 96, and 120 hours post- dose for PO. The plasma samples were prepared by centrifugation at 4ºC and 3200xg for 10 minutes, and then quickly frozen over dry ice and kept at -60ºC or lower until analysis. The concentrations of the test article and its potential metabolites (if detectable) in the plasma samples were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters (e.g., t_1/2, C₀, C_max, T_max, CL, AUC, etc.) were estimated by a non-compartmental analysis (NCA) using WinNonlin® (Certara, Radnor, Pennsylvania). The results showed that the compounds as tested unexpectedly exhibited great oral bioavailability (>50%) and prolonged t_1/2, e.g., greater than 10 or 20 hours. KC-2253-Ba/F3 EGFR Del19-C797S-luc2 situ brain Model: The cell line used was Ba/F3 EGFR Del19-C797S-luc2 (Kyinno, Cat. Number: cKC-2253) engineered by introducing human EGFR containing Del19 and C797 mutations and luciferase reporter gene into Ba/F3 cells. Ba/F3 EGFR Del19-C797S-luc2 cells were maintained and expanded in RPMI-1640 containing 10% fetal bovine serum at 37ºC, 5% CO₂ incubator. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. BALB/c nude mice (female, 6-8 weeks, weighing approximately 18-22g) from Biocytogen (Beijing, China) were used. After one week of acclimation, animals were anesthetized by ip injection of Pentobarbital sodium (30 mg/kg). The anesthetized mice were prepared with an injection point in the skull located on the right parietal bone, 3-3.5 mm lateral to the sagittal suture, and 0.5 mm posterior to the coronal suture. Each mouse was inoculated intracranially with the Ba/F3 EGFR Del19-C797S-luc2 (5 × 10⁴ cells in 2 μL PBS) via a microinjector. The needle was inserted to a depth of 4 mm, then retracted by 0.7 mm. After the injection, the mouse was kept warm until they recovered from the anesthesia. Animals were observed post-anesthesia until all animals recovered. For pain relief, the animals were dosed with meloxicam (5 mg/kg, once daily for 3 days) after the mouse recovered from the anesthesia. On day 7 post-tumor inoculation, the inoculated mice were weighed and were pre-anesthetized with 1.25% tribromoethanol solution (20 µl/g). When the animals were in a complete anesthetic state, intraperitoneally injected D-Luciferin solution at a concentration of 15 mg/mL and a volume of 0.2 mL. All mice were measured for bioluminescence at 9 minutes after the luciferin administration and intensity of bioluminescence for each mouse was recorded. Mice bearing established brain tumors based on bioluminescence were selected and randomized into 7 groups according to bioluminescence intensity and body weight. Mice were dosed once daily for 31 consecutive days with indicated test articles in suspension formulation with vehicle (1% HEC (w/v)/0.25% Twen-80 (v/v)/0.05% Antifoam (v/v)/H₂O) or vehicle control by oral gavage. During dosing, mouse body weight was measured three times a week and tumor growth based on bioluminescence intensity was measured on day 3, 7, 10, 14, 17 and 31. After dosing stopped at day 32, mice were kept alive to observe extended survival until day 51 which study was terminated. The results showed that a compound of the invention exhibited excellent brain penetration with improved antitumor activity and survival. All the animals in the treatment groups, dosed in the range of 0.6 to 6 mg/kg/day, survived for more than 44 days, while all the animals in the controlled group died before D15 post-treatment. Intracranial PC-9_Luc human lung cancer xenograft model: PC-9_Luc (EGFR/del19 mutation) human lung cancer cells derived from RCB4455 (RIKEN BioResource Center, Tsukuba, Japan) was used for the study. The cells were maintained in vitro as a monolayer culture in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Antibiotic- Antimycotic at 37 °C in an atmosphere of 5% CO₂ in air. The cells were subcultured twice a week by trypsin-EDTA treatment. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. BALB/c nude mice (female, 6-8 weeks, weighing approximately 18-22g) were purchased from Zhejiang Vital River Laboratory Animal Co., LTD. and used for the study. After one week of acclimation, animals were anesthetized by ip injection of 1.25% avertin solution with dosing volume of 20 μL/g. The anesthetized mice were properly positioned. The head skin of the mouse was sterilized with 70% alcohol and was draped in a sterile fashion. A ~1cm length incision was made just at the right of the midline and anterior to the interaural line. Each mouse was inoculated intracranially with the PC-9_Luc cells (3 ×10⁵ cells in 3 μL PBS+20% Matrigel) at a depth of 3.5 mm via the microinjector. It was kept warm and observed post-anesthesia until recovered. For pain relief from surgery and tumor inoculation, the mouse was dosed orally with 10 mg/kg of meloxicam (10 μL/g ). All mice were treated again with 5 mg/kg meloxicam (10 μL/g) in the morning of the next day post-surgery. To monitor tumor growth and mouse status, the body weight was obtained. Bioluminescence measurements were performed by intraperitoneal injection of luciferin at 150 mg/kg. After 10 minutes of the luciferin administration, the mice were anesthetized before bioluminescence determination with IVIS (Lumina II). The bioluminescence of the whole animal body, including metastatic tumors, was determined and recorded. On day 7 post-tumor inoculation, mice were randomized into 7 groups based on the intensity of bioluminescence measured and body weight and dosed daily for 28 consecutive days with indicated test articles in suspension formulation with vehicle (1% HEC (w/v)/0.25% Twen-80 (v/v)/0.05% Antifoam (v/v)/H₂O) or vehicle control by oral gavage. During dosing, mouse body weight was measured twice a week and tumor growth based on bioluminescence intensity was measured once a week. After dosing stopped on day 28, mice were observed for extended survival. The results showed that a compound of the invention showed very potent anti-tumor activity with improved survival. All the animals in the treatment groups, dosed in the range of 0.6 to 6 mg/kg/day, survived for more than 60 days, while all the animals in the controlled group died before D24 post-treatment. OTHER EMBODIMENTS All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, compounds structurally analogous to the compounds of this invention also can be made, screened for their efficacy in treating an inflammatory condition. Thus, other embodiments are also within the claims.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I:

I, or a pharmaceutically acceptable salt or stereoisomers or racemates thereof, wherein: one of X and Y is H, deuterium, or halo; the other of X and Y is

, in which each of R₁ is F, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 4-6 membered heterocyclyl, R₂ is H, deuterium, F, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 4-6 membered heterocyclyl, or R₁ and R₂, together with the carbon atom they bond to, are C₃-C₆ cycloalkyl or 4-6 membered heterocyclyl; R₃ is 5-10 membered heteroaryl or C₆-C₁₀ aryl; and n is 1, 2, or 3; R₄ is H, halo, cyano, C₃-C₆ cycloalkyl, OR_a, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, in which Ra is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl; R₅ is H or deuterium; R₆ is H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; R₇ is 6-10 membered aryl or 5-10 membered heteroaryl; R₈ is H, deuterium, halo, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; alkyl is optionally substituted with one or more groups selected from the group consisting of deuterium, halo, cyano, C₁-C₄ alkoxy, NR_1aR_1b, C₃-C₆ cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-6 membered heterocyclyl, in which R₁a and R₁b, independently, is H, deuterium, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl, or R_1a and R_1b, together with the nitrogen atom they bond to, are C4-C₆ heterocyclyl; and each of cycloalkyl, heteroccyclyl, aryl, and heteroaryl, independently, is optionally substituted with one or more groups selected from the group consisting of deuterium, halo, cyano, acetylenyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, 4-6 membered heterocyclyl, and NR_1aR_1b.

2. The compound of claim 1, wherein (i) n is 1, and (ii) R₁ is F, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃; or R₁ and R₂, together with the carbon atom they bond to, are C₃-C₆ cycloalkyl. 3. The compound of claim 1 or 2, wherein R₂ is H, F, C₁-C₃ alkyl or C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃; or R₁ and R₂, together with the carbon atom they bond to, are C₃-C₆ cycloalkyl. 4. The compound of any one of the preceding claims, wherein R₃ is imidazolyl, pyrazolyl, triazolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, or pyrimidinyl. 5. The compound of any one of claims 1 to 3, wherein R₃ is

. 7. The compound of any one of the preceding claims, wherein R₄ is 5- or 6-membered heteroaryl, preferably imidazolyl, pyrazolyl, thiazolyl, or pyrimidinyl, optionally substituted with CD₃, fluoro, methyl, trifluoromethyl or difluoromethyl.

8. The compound of any one of the preceding claims, wherein R₄ is

. 9. The compound of any one of the preceding claims, wherein R₇ is phenyl optionally substituted with one or more groups selected from the group consisting of F, Cl, Br and acetylenyl； preferably, R₇ is

. 10. The compound of any one of claims 1 to 8, wherein R₇ is 9- or 10- membered bicyclic heteroaryl optionally substituted with halo, preferably quinolinyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, benzo[c]isothiazolyl, or benzo[d]isothiazolyl, more preferably, R₇ is

11. The compound of any one of the preceding claims, wherein R₆ is H, CH₃, CD₃, or CHF₂. 12. The compound of any one of the preceding claims, wherein R₈ is H or deuterium. 13. The compound of any one of the preceding claims, wherein n is 1. 14. The compound of any one of the preceding claims, wherein the compound is of Formula IA:

IA. 15. The compound of claim 14, wherein R₄ is

. 16. The compound of any one of claims 1 to 13, wherein the compound is of Formula IB:

IB. 17. The compound of claim 16, wherein R₄ is

. 18. The compound of claim 14, wherein n is 1; R₅ is H or deuterium; R₁ is F, C₁-C₃ alkyl or C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃, and R₂ is H, F, C₁-C₃ alkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃; or R₁ and R₂, together with the carbon atom they are bonded to, is cyclopropyl; R₃ is

,

19. The compound of claim 16, wherein n is 1; R₅ is H or deuterium; R₁ is F, C₁-C₃ alkyl or C₃-C₆ cycloalkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃, and R₂ is H, F, C₁-C₃ alkyl, preferably methyl, CF₃, CHF₂, cyclopropyl, or CD₃; or R₁ and R₂, together with the carbon atom they are bonded to, is cyclopropyl; R₃ is

R₄ is

. 20. A compound that is one of Compounds 1-65. 21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier. 22. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutical composition of claim 21. 23. The method of claim 22, wherein the cancer is a lung cancer or a brain cancer. 24. A method of inhibiting EGFR comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutical composition of claim 21.