Substituted benzo or pyridopyrimidine amine inhibitors and methods for their preparation and use

Abstract

The present invention relates to a substituted benzo or pyridopyrimidine amine inhibitor and its preparation method and use. Specifically, the compound of the present invention has the structure shown in formula (I). The present invention further discloses a preparation method of the compound and its use as an SOS1 inhibitor. The compound of the present invention has an excellent selective inhibitory effect on SOS1, and has better pharmacodynamic and pharmacokinetic properties, and lower toxicity and side effects. [Formula 1] JPEG2023546248000353.jpg3364

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field, specifically to substituted benzo or pyridopyrimidine amine inhibitors and their preparation and use. [Background technology]

[0002] Lung cancer is one of the leading causes of cancer-related deaths in humans. Based on cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for 85% of all lung cancer cases. Statistics show that the global NSCLC market was worth approximately $20.9 billion in 2016, with the United States accounting for half of the market, followed by Japan, Germany, and China. Based on current trends, the NSCLC market is expected to maintain sustained growth and reach $54 billion by 2023 (Nature, 2018; 553(7689): 446-454).

[0003] Currently, the main therapeutic agents for NSCLC are categorized into chemotherapy, molecular targeted drugs, and tumor immunotherapy. Among them, chemotherapy drugs mainly include gemcitabine, paclitaxel, platinum compounds, etc. However, these drugs generally have poor selectivity and high toxicity, which makes them prone to cause severe toxicity and side effects. In recent years, molecular targeted drugs have become a hot research topic due to their obvious advantages, such as high selectivity, relatively low toxicity and side effects, and the realization of high-precision treatment. Existing molecular targeted drugs for NSCLC include EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (e.g., Ceritinib, These include cerebrospinal fluid (Ceritinib), alectinib, brigatinib, lorlatinib, alkotinib, etc.), and VEGFR inhibitors (sorafenib, regorafenib, cabozantinib, sunitinib, donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).

[0004] KRAS mutations occur in 20% to 40% of lung adenocarcinomas, with a higher prevalence in Westerners (compared to Asians) (26% vs. 11%) and smokers (compared to non-smokers) (30% vs. 10%). The most common mutations occur in codons 12 and 13, and the most common mutations include G12C, G12V, and G12D. To date, there are no approved drugs on the market for KRAS mutations.

[0005] Within cells, the KRAS protein switches between an inactive and an active state. When KRAS binds guanosine diphosphate (GDP), it is inactive. When it binds guanosine triphosphate (GTP), it is active and can activate downstream signaling pathways. The switching of KRAS between the inactive and active states is regulated by two types of factors: guanine nucleotide exchange factors (GEFs), which catalyze the binding of KRAS to GTP and promote KRAS activation, including the SOS1 protein; and GTPase-activating proteins (GAPs), which inhibit KRAS activity by promoting the hydrolysis of KRAS-bound GTP to GDP.

[0006] To date, three classes of RAS-specific GEFs have been identified, and those found in tumors primarily involve SOS proteins. SOS proteins are widely expressed in the body and contain two isoforms, SOS1 and SOS2. Published data reveal that SOS1 plays a critical role in activating mutant KRAS and transmitting oncogenic signals. Reduced SOS1 levels result in reduced proliferation and viability of tumor cells harboring KRAS mutations, but not in KRAS wild-type cell lines. The effects of SOS1 deletion were not reversed by introducing SOS1 mutated in the catalytic site, indicating that SOS1 GEF activity plays a critical role in KRAS-mutant cancer cells (see WO2019122129A1).

[0007] Because both mutant and wild-type KRAS depend on SOS1 for GTP binding, selective inhibition of SOS1 prevents the interaction between SOS1 and KRAS, ultimately inhibiting KRAS activation, regardless of whether KRAS is mutated or not.

[0008] Because SOS1 target proteins are pathologically involved in many diseases, novel SOS1 inhibitors are currently needed for clinical treatment. Highly selective and active SOS1 inhibitors have the potential to more effectively treat diseases such as cancer caused by KRAS mutations and reduce off-target effects, making them an urgent clinical need. Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide novel compounds that have selective inhibitory effects on SOS1 and / or have better pharmacodynamic properties, and uses thereof. [Means for solving the problem]

[0010] In a first aspect, the present invention provides a substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I), a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, [ka] During the ceremony, X is CR 6 or N, among which R 6 is selected from hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, and 4- to 6-membered heterocyclyl group, Y is O, NH, NR 7 , S, SO, SO2, C≡C, substituted or unsubstituted 4- to 20-membered heterocyclyl group, substituted or unsubstituted C6 to C 14 aryl groups and 5- to 14-membered heteroaryl groups, among which R 7 is selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group, Z is a substituted or unsubstituted bond, a substituted or unsubstituted C1-C 18 alkylene groups, W is a substituted or unsubstituted bond, C3 to C20 Cycloalkylene group, 4- to 20-membered heterocyclylene group, OR 11 , N.R. 11 R 12 , SO2, NR 12 SO2, CO or NR 12 Selected from CO, R 11 is a substituted or unsubstituted C3-C 20 Cycloalkylene group, 4-20 membered heterocyclylene group, C3-C 20 Cycloalkylene C1-C 18 Alkylene group, 4-20 membered heterocyclylene C1-C 18 Alkylene group, C6-C 14 R is independently selected from an aryl group or a 5- to 14-membered heteroaryl group; 12 are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; R 1 , R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m R 8 , -(CH2) m (CH=CH)R 8 , -(CH2) m (C≡C)R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2 may be optionally substituted; 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 independently selected from an aryl group or a 5- to 14-membered heteroaryl group, or -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m S(O) q NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 In R 8 and R 9is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, R 3 is a substituted or unsubstituted C3-C 18 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 selected from an aryl group and a 5- to 14-membered heteroaryl group; R 4 , R 5 are each independently selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, an ester group, COOH, CONH2, a C2-C6 alkenyl group, and a C2-C6 alkynyl group; Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a 4- to 20-membered heterocyclyl-O-, a halogen, an oxo C1 to C6 alkyl group, a nitro group, a hydroxy group, a cyano group, a C2 to C6 ester group, a C1 to C6 amine group, a C1 to C6 acyl group, a C1 to C6 amido group, a C1 to C6 sulfonyl group, a C1 to C6 sulfonamido group, and a C1 to C6 urea group, among which the above C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 The aryl group, the 5- to 14-membered heteroaryl group, the 4- to 20-membered heterocyclyl group, and the 4- to 20-membered heterocyclyl-O- are each independently one or more R a may be further substituted by, among which R a is a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O-, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a C6-C 14 an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a 4- to 6-membered heterocyclyl-O-, a halogen, an oxo group (=O), a nitro group, a hydroxy group, a cyano group, a C2 to C6 ester group, a C1 to C6 amine group, a C1 to C6 amido group, a C1 to C6 sulfonamido group, or a C1 to C6 urea group, or two substituents located on the same carbon atom are -(CH2) n - or =O, m and n are each independently 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; q is 1 or 2; The limiting condition is that Y is O, NH, or NR 7 and Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is hydrogen, deuterium, halogen, cyano group, R 8 , O(CH2) p R 8 , C.O.R. 8 , ~C(O)OR 8 , N.R. 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9, -NR 8 C(O)NR 9 R 10 This is not the case.

[0011] In another preferred example, a substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, [ka] During the ceremony, X is CR 6 or N, among which R 6 is selected from hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, and 4- to 6-membered heterocyclyl group, Y is O, NH, NR 7 , S, SO, SO2, C≡C, among which R 7 is selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group, Z is a substituted or unsubstituted bond, a substituted or unsubstituted C1-C 18 Alkylene group (preferably deuterated C1-C 18 Alkylene group or halo C1-C 18 alkylene groups), W is a substituted or unsubstituted bond, C3 to C 20 Cycloalkylene group, 4- to 20-membered heterocyclylene group, OR 11 , N.R. 11 R 12 , SO2, NR 12 SO2, CO or NR 12 Selected from CO, R 11 is a substituted or unsubstituted C3-C 20 Cycloalkylene group, 4-20 membered heterocyclylene group, C3-C 20 Cycloalkylene C1-C 18 Alkylene group, 4-20 membered heterocyclylene C1-C 18 Alkylene group, C6-C 14R is independently selected from an aryl group or a 5- to 14-membered heteroaryl group; 12 are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; R 1 , R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m R 8 , -(CH2) m (CH=CH)R 8 , -(CH2) m (C≡C)R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2 may be optionally substituted; 8 , R 9 , R10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C1-C 18 Alkoxy group, C3-C 20 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 independently selected from an aryl group or a 5- to 14-membered heteroaryl group, or -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m S(O) q NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 In R 8 and R 9 but It is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, R 3 is a substituted or unsubstituted C3-C 18 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 selected from an aryl group and a 5- to 14-membered heteroaryl group; R 4 , R 5are each independently selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, an ester group, COOH, CONH2, a C2-C6 alkenyl group, and a C2-C6 alkynyl group; Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a 4- to 20-membered heterocyclyl-O-, a halogen, an oxo C1 to C6 alkyl group, a nitro group, a hydroxy group, a cyano group, a C2 to C6 ester group, a C1 to C6 amine group, a C2 to C6 amido group, a C2 to C6 sulfonamido group, and a C1 to C6 urea group, among which the above C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 The aryl group, the 5- to 14-membered heteroaryl group, the 4- to 20-membered heterocyclyl group, and the 4- to 20-membered heterocyclyl-O- are each independently one or more R a may be further substituted by, among which R ais a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O-, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a C6-C 14 an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a 4- to 6-membered heterocyclyl-O-, a halogen atom, an oxo C1 to C6 alkyl group, a nitro group, a hydroxy group, a cyano group, a C2 to C6 ester group, a C1 to C6 amine group, a C2 to C6 amido group, a C2 to C6 sulfonamido group, or a C1 to C6 urea group, or two substituents located on the same carbon atom are -(CH2) n - or =O, m and n are each independently 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; q is 1 or 2; The limiting condition is that Y is O, NH, or NR 7 and Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is hydrogen, deuterium, halogen, cyano group, R 8 , O(CH2) p R 8 , C.O.R. 8 , ~C(O)OR 8 , N.R. 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 This is not the case.

[0012] In another preferred example, a substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, [ka] During the ceremony, X is CR 6 or N, among which R 6 is selected from hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, and 4- to 6-membered heterocyclyl group, Y is O, NH, NR 7 , S, SO, SO2, C≡C, among which R 7 is selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group, Z is a substituted or unsubstituted bond, C1-C 18 Alkylene group, deuterated C1-C 18 Alkylene group or halo C1-C 18 alkylene groups, W is a substituted or unsubstituted bond, C3 to C 20 Cycloalkylene group, 4- to 20-membered heterocyclylene group, OR 11 , N.R. 11 R 12 , SO2, NR 12 SO2, CO or NR 12 Selected from CO, R 11 is a substituted or unsubstituted C3-C 20 Cycloalkylene group, 4-20 membered heterocyclylene group, C3-C 20 Cycloalkylene C1-C 18 Alkylene group or 4-20 membered heterocyclylene C1-C 18 alkylene groups; R 12 are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; R 1 , R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m R 8 , -(CH2) m (CH=CH)R 8 , (CH2) m (C≡C)R 8 , -(CH2) mO(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2 may be optionally substituted; 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, or -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m S(O) q NR 8 R 9 In R 8 and R9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, R 3 is a substituted or unsubstituted C3-C 18 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 selected from an aryl group and a 5- to 14-membered heteroaryl group; R 4 , R 5 are each independently selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a 4- to 6-membered heterocyclyl group; Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14"substituted by one or more (e.g., two, three, four) groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group"; m and n are each independently 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; q is 1 or 2; The limiting condition is that Y is O, NH, or NR 7 and Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is hydrogen, deuterium, halogen, cyano group, R 8 , O(CH2) p R 8 , C.O.R. 8 , ~C(O)OR 8 , N.R. 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 This is not the case.

[0013] In another preferred example, a substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, [ka] During the ceremony, X is CR 6 or N, among which R 6 is selected from hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, and 4- to 6-membered heterocyclyl group, Y is O, NH, or NR 7In particular, R 7 is selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group, Z is a substituted or unsubstituted C1-C 18 Alkylene group, deuterated C1-C 18 Alkylene group or halo C1-C 18 alkylene groups, W is a substituted or unsubstituted C3-C 20 Cycloalkylene group, 4- to 20-membered heterocyclylene group, OR 11 , N.R. 11 R 12 , SO2, NR 12 SO2, CO or NR 12 Selected from CO, R 11 is a substituted or unsubstituted C3-C 20 Cycloalkylene group, 4-20 membered heterocyclylene group, C3-C 20 Cycloalkylene C1-C 18 Alkylene group, or 4-20 membered heterocyclylene C1-C 18 alkylene groups; R 12 are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; R 1 , R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 5 R 8 , -(CH2) m C(O)NR 8 R 9 , -(CH2)m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2 is optionally substituted; 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group; R 3 is a substituted or unsubstituted C3-C 18 Cycloalkyl groups, 4-20 membered heterocyclyl groups, C6-C 14 selected from an aryl group and a 5- to 14-membered heteroaryl group; R 4 , R 5 are independently selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group; Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; m and n are each independently 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; q is 1 or 2. In another preferred embodiment, R 1 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m1 R 8 , -(CH2) m'1 (CH=CH)R 8 , -(CH2) m'1 (C≡C)R 8 , -(CH2) m1 O(CH2) p1 R 8 , -(CH2) m'1 SR 8 , -(CH2) m1 COR 8 , -(CH2) m1 C(O)OR 8 , -(CH2) m'1 S(O) q1 R 8 , -(CH2) m1 NR 8 R 9 , -(CH2) m1 C(O)NR 8 R 9 , -(CH2) m1 NR 8 C(O)R 9 , -(CH2) m1 NR 8 C(O)NR 9 R 10 , -(CH2) m'1 S(O) q1 NR 8 R 9 , -(CH2) m'1 NR 8 S(O) q1 R 9 , -(CH2) m'1 NR 8 S(O) q1 NR9 R 10 wherein H in CH2 may be optionally substituted; R 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, or -(CH2) m1 NR 8 R 9 , -(CH2) m1 C(O)NR 8 R 9 , -(CH2) m'1 S(O) q1 NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m1 NR 8 C(O)R 9 , -(CH2) m1 NR 8 C(O)NR 9 R 10 , -(CH2) m'1 NR 8 S(O) q1 R 9 , -(CH2) m'1 NR 8 S(O) q1 NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, m1 is 0, 1, 2, 3, 4 or 5; m'1 is 0, 1, 2, 3, 4 or 5; p1 is 0, 1, 2, 3, 4 or 5; q1 is 1 or 2, Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0014] In another preferred embodiment, Y is O, NH, or NR 7 and Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is not hydrogen, deuterium, halogen, or cyano group, and m1 is not 0.

[0015] In another preferred embodiment, each R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m2 R 8 , -(CH2) m'2 (CH=CH)R 8 , -(CH2) m'2 (C≡C)R 8 , -(CH2) m2 O(CH2) p2 R 8 , -(CH2) m'2 SR 8 , -(CH2) m2 COR 8 , -(CH2) m2 C(O)OR 8 , -(CH2) m'2 S(O) q2 R 8 , -(CH2) m2 NR 8 R9 , -(CH2) m2 C(O)NR 8 R 9 , -(CH2) m2 NR 8 C(O)R 9 , -(CH2) m2 NR 8 C(O)NR 9 R 10 , -(CH2) m'2 S(O) q2 NR 8 R 9 , -(CH2) m'2 NR 8 S(O) q2 R 9 , -(CH2) m'2 NR 8 S(O) q2 NR 9 R 10 wherein H in CH2 is optionally substituted; 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, or -(CH2) m2 NR 8 R 9 , -(CH2) m2 C(O)NR 8 R 9 , -(CH2) m'2 S(O) q2 NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m2 NR 8 C(O)R 9 , -(CH2) m2 NR 8 C(O)NR 9 R 10 , -(CH2) m'2 NR 8 S(O) q2 R9 , -(CH2) m'2 NR 8 S(O) q2 NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, m2 is 0, 1, 2, 3, 4 or 5; m'2 is 0, 1, 2, 3, 4 or 5; p2 is 0, 1, 2, 3, 4 or 5; q2 is 1 or 2, Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0016] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in general formula (II): [ka] In the formula, R 1 , R2 , R 3 , R 4 , X, Y, Z, W, and n are defined as above.

[0017] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in general formula (III): [ka] In the formula, R 1 , R 2 , R 3 , X, Y, Z, W, and n are defined as above.

[0018] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in general formula (IV): [ka] During the ceremony, R 1 , R 2 , R 3 , R 6 , X, Y, Z, W, and n are defined as above.

[0019] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in general formula (V): [ka] During the ceremony, R 1 , R 2 , R 3 , R 6 , Z, W, and n are defined as above.

[0020] In another preferred example, in formula IV, Z is selected from a substituted or unsubstituted bond, a C1-C6 alkylene group, a deuterated C1-C6 alkylene group, or a haloC1-C6 alkylene group, wherein the substitution is selected from deuterium, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a haloC1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a haloC1-C6 alkoxy group, a C6-C 10 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0021] In another preferred example, W is a bond, a substituted or unsubstituted C3-C 12 a cycloalkylene group, a substituted or unsubstituted 4- to 12-membered heterocyclylene group, OR 11 , N.R. 11 R 12 , SO2, NR 12 SO2, CO or NR 12 CO, Among them, R 11 is a substituted or unsubstituted C3-C 12 Cycloalkylene group, 4-12 membered heterocyclylene group, C3-C 12 Cycloalkylene C1-C6 alkylene group, 4-12 membered heterocyclylene C1-C6 alkylene group, C6-C 14 R is selected from an aryl group or a 5- to 14-membered heteroaryl group, preferably 11 is a substituted or unsubstituted C3-C6 cycloalkylene group, a 4- to 6-membered heterocyclylene group, a C3-C6 cycloalkylene C1-C3 alkylene group, a 4- to 6-membered heterocyclylene C1-C3 alkylene group, a C6-C 14 selected from an aryl group or a 5- to 14-membered heteroaryl group; R 12are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; Among these, the above substitutions include deuterium, C1-C6 alkyl group, deuterated C1-C6 alkyl group, halo C1-C6 alkyl group, halo C1-C6 alkylhydroxy group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, deuterated C1-C6 alkoxy group, halo C1-C6 alkoxy group, C6-C 10 "substituted by one or more (e.g., two, three, four) groups selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group"; The limiting condition is that Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is hydrogen, deuterium, halogen, cyano group, R 8 , O(CH2) p R 8 , C.O.R. 8 , ~C(O)OR 8 , N.R. 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 This is not the case.

[0022] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in formula (VI): [ka] During the ceremony, R 13 and R 14are each independently selected from H, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; Ring C is a substituted or unsubstituted C3 to C 12 a cycloalkylene group, and a 4- to 12-membered heterocyclylene group; R 2 are the same or different, and -(CH2) m O(CH2) p R 8 , -(CH2) m (CH=CH) p R 8 , (CH2) m (C≡C) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10wherein H in CH2 is optionally substituted, and m is selected from 1, 2, 3, 4, or 5; The above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; t is 1, 2, 3, 4, 5, or 6; R 1 , R 3 , R 6 , R 8 , R 9 , R 10 , p, q and n are defined as above.

[0023] In another preferred example, in formula (VI), [ka] Some of the [ka] Selected from Among them, Y1 and Y2 are NR b , O, each independently selected from R mis hydrogen, deuterium, C1-C6 alkyl group, deuterated C1-C6 alkyl group, halo C1-C6 alkyl group, halo C1-C6 alkylhydroxy group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, deuterated C1-C6 alkoxy group, halo C1-C6 alkoxy group, C6-C 10 are independently selected from an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen atom, a nitro group, a hydroxy group, an oxo group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; R b is H, C1-C6 alkyl group, deuterated C1-C6 alkyl group, halo C1-C6 alkyl group, C3-C6 cycloalkyl group, 4- to 6-membered heterocyclyl group, SO2R 30 , C.O.R. 30 , an ester group; R 30 are each independently selected from hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted 4- to 6-membered heterocyclyl group; n1 is 0, 1, 2, 3 or 4; n2 is 1, 2, 3 or 4; Among these, the above substitutions include hydrogen, deuterium, C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, halo C1-C6 alkyl groups, halo C1-C6 alkylhydroxy groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, deuterated C1-C6 alkoxy groups, halo C1-C6 alkoxy groups, C6-C 10 It refers to being substituted with one or more (e.g., two, three, or four) groups selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0024] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in formula (VII): [ka] During the ceremony, R 16 and R 17 are each independently selected from H, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; R 18 is OR 11 , N.R. 11 R 12 , N.R. 12 SO2R 2 , C.O.R. 2 or NR 12 COR 2 Selected from R 11 is substituted C3~C 12 Cycloalkyl groups, substituted or unsubstituted 4- to 12-membered heterocyclyl groups, substituted or unsubstituted C3-C 12 Cycloalkylene C1-C6 alkylene group, substituted or unsubstituted 4-12 membered heterocyclylene C1-C6 alkylene group, substituted or unsubstituted C6-C 14 R is independently selected from an aryl group, a substituted or unsubstituted 5- to 14-membered heteroaryl group, 12 are independently selected from substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups; or R 18 is -(CH2) m (CH=CH)R 8 , -(CH2) m (C≡C)R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2) m S(O) q NR 8 R 9 , -(CH2) m NR 8 S(O) q R 9 , -(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2 may be optionally substituted; R 8 , R 9 , R 10 is a substituted or unsubstituted C1-C 18 Alkyl groups, substituted or unsubstituted, C3-C 20 are each independently selected from a cycloalkyl group and a substituted or unsubstituted 4- to 20-membered heterocyclyl group; Among them, R 8 , R 9 and R 10 The above substitutions are C3 to C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; t is 1, 2, 3, 4, 5, or 6; Unless otherwise specified, the above substitutions include hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , R 10 , m, p and q are defined as above.

[0025] In another preferred embodiment, the above R 1 is H, cyano group, halogen, -(CH2) m R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m S(O) q R 8 , -(CH2) m (C≡C)R 8wherein H in CH2 may be optionally substituted; R 8 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C1-C 18 Alkoxy group, C3-C8 cycloalkyl group, 4-10 membered heterocyclyl group, C6-C 14 It is selected from an aryl group and a 5- to 14-membered heteroaryl group.

[0026] In another preferred example, R 1 is a halogen, a cyano group, -(CH2) m R 8 , -(CH2) m (C≡CH), -(CH2) m (C≡C)R 8 , -(CH2) m O(CH2) p R 8 Preferably, R 8 is substituted or unsubstituted C1-C 18 It is an alkyl group (preferably a C1 to C6 alkyl group).

[0027] In another preferred example, R 1 is selected from the group consisting of H, cyano group, halogen, hydroxy group, C1-C6 alkyl group, C1-C6 alkoxy group, haloC1-C6 alkyl group, haloC1-C6 alkylO-, deuterated C1-C6 alkylO-, substituted or unsubstituted C3-C6 cycloalkylO-, substituted or unsubstituted 4- to 6-membered heterocyclylO-, C1-C6 alkoxyC1-C6 alkylO-, substituted or unsubstituted phenyl group, substituted or unsubstituted 5- to 6-membered heteroaryl group, substituted or unsubstituted phenylO-, substituted or unsubstituted 5- to 6-membered heteroarylO-, and substituted or unsubstituted C2-C6 alkynyl group, wherein the "substituted" refers to substitution by one or more (e.g., two, three, or four) groups selected from the group consisting of halogen, C1-C6 alkyl group, C3-C6 cycloalkyl group, oxoC1-C6 alkyl group, and C2-C6 ester group.

[0028] In another preferred embodiment, in formula VII, R 18is OR 11 , N.R. 11 R 12 or NR 12 SO2R 2 Among them, R 11 is substituted C3~C 12 Cycloalkyl groups, substituted or unsubstituted 4- to 12-membered heterocyclyl groups, substituted or unsubstituted C3-C 12 Cycloalkylene C1-C6 alkylene group, substituted or unsubstituted 4-12 membered heterocyclylene C1-C6 alkylene group, substituted or unsubstituted C6-C 14 R is independently selected from an aryl group, a substituted or unsubstituted 5- to 14-membered heteroaryl group, 12 are independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups; or R 18 is -(CH2) m O(CH2) p R 8 wherein H in CH2 may be optionally substituted; R 8 is a substituted or unsubstituted C1-C 18 Alkyl groups, substituted or unsubstituted, C3-C 20 cycloalkyl groups, and substituted or unsubstituted 4- to 20-membered heterocyclyl groups, preferably R 8 is substituted or unsubstituted C1-C 18 an alkyl group (preferably a C1 to C6 alkyl group), The above substitutions include C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, halo C1-C6 alkyl groups, halo C1-C6 alkylhydroxy groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, deuterated C1-C6 alkoxy groups, halo C1-C6 alkoxy groups, C6-C 10 It refers to being substituted with one or more (e.g., two, three, or four) groups selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0029] In another preferred example, R 3 is substituted C6~C 14 an aryl group or a substituted 5- to 14-membered heteroaryl group, and the substitution is R 3a , hydrogen, deuterium, C1-C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means that the aryl group, the 5- to 14-membered heteroaryl group, the 4- to 20-membered heterocyclyl group, the 4- to 20-membered heterocyclyl-O-, halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group is substituted with one or more groups selected from the group consisting of the above C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkyl-O-, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 The aryl group, the 5- to 14-membered heteroaryl group, the 4- to 20-membered heterocyclyl group, and the 4- to 20-membered heterocyclyl-O- are each independently one or more R a may be further substituted by, among which R a is a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O-, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a C6-C14 an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a 4- to 6-membered heterocyclyl-O-, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group; 3a containing a substituent group, Among them, R 3a is a hydroxy-substituted C1-C 18 Alkyl, hydroxy-substituted C1-C 18 Haloalkyl groups, hydroxy-substituted C1-C 18 Deuterated alkyl groups, alkoxy-substituted C1-C 18 Alkyl, alkoxy substituted C1-C 18 Haloalkyl groups, alkoxy-substituted C1-C 18 Deuterated alkyl groups, cycloalkyloxy-substituted C1-C 18 Alkyl, cycloalkyloxy substituted C1-C 18 Haloalkyl, cycloalkyloxy substituted C1-C 18 Deuterated alkyl groups, heterocyclyloxy-substituted C1-C 18 Alkyl, heterocyclyloxy substituted C1-C 18 Haloalkyl group, heterocyclyloxy substituted C1-C 18 Deuterated alkyl groups, cycloalkyl-substituted C1-C 18 Haloalkyl group, heterocyclyl substituted C1-C 18 Haloalkyl groups, amine-substituted C1-C 18 Haloalkyl groups, cyano-substituted C1-C 18 Haloalkyl, amide substituted C1-C 18 Haloalkyl groups, substituted C3-C 12is selected from a cycloalkyl group, a substituted 4-12 membered heterocyclyl group, a substituted or unsubstituted haloalkyloxy group, a substituted or unsubstituted cycloalkyloxy group, a substituted or unsubstituted heterocyclyloxy group, a substituted or unsubstituted sulfonamide group, and a substituted or unsubstituted cycloalkylsulfone group, and the substitution is selected from a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a haloC1-C6 alkyl group, a haloC1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a haloC1-C6 alkoxy group, a C6-C 10 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0030] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in formula (VIII): [ka] In the formula, R 1 , R 2 , R 3 , R 6 and W is defined as above.

[0031] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in formula (IX-A) and (IX-B), [ka] In the formula, R 2 , R 3 , R 8 , R 9, X, Y, Z, W, n and q are defined as above.

[0032] In another preferred example, the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in formula (X): [ka] In the formula, R 8 is a substituted or unsubstituted C3-C 20 selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It means being substituted by one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen atom, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, and a urea group; R 2 , R 3 , X, Y, Z, W, n and q are defined as above.

[0033] In another preferred example, R 8is selected from substituted or unsubstituted C3-C6 cycloalkyl groups or 4- to 6-membered heterocyclyl groups, wherein the substitution includes hydrogen, deuterium, C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, halo C1-C6 alkyl groups, halo C1-C6 alkylhydroxy groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, deuterated C1-C6 alkoxy groups, halo C1-C6 alkoxy groups, C6-C 14 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0034] In another preferred example, Z and W are simultaneously a bond. In another preferred example, Y is O and Z and W are bonds.

[0035] In another preferred example, R 3 is selected from a substituted phenyl group, pyridinyl group, pyrimidinyl group, and pyridazinyl group, wherein the substitution refers to substitution with one or more (e.g., two, three, or four) groups selected from the group consisting of a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group, and preferably the substitution is one, two, or three selected from a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C1-C6 alkoxy group, a halogen, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group.

[0036] In another preferred example, R 1 is a methoxy group.

[0037] In another preferred example, [ka] teeth, [ka] where * represents the R or S configuration. Preferably, R 3 is chosen from: [ka]

[0038] In another preferred example, R 3 is chosen from: [ka]

[0039] In another preferred example, R 6 is selected from hydrogen, deuterium, halogen, cyano group, and C1 to C6 alkyl group.

[0040] In another preferred example, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, W, and n are the corresponding specific groups of each specific compound of the Examples.

[0041] In another preferred example, in the substituted benzo or pyridopyrimidine amine compound having the structure of the above general formula (I), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, said compound is selected from the following: [ka] [ka] [ka]

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[0042] In another preferred example, the compound is a compound prepared in the Examples.

[0043] In a second aspect of the present invention, there is provided a method for preparing a substituted benzo- or pyridopyrimidine amine compound having the structure of general formula (I), a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, comprising: [ka] (i) reacting a compound of formula V-1 with a compound of formula V-2 in the presence of a first base to obtain a compound of formula V-3; (ii) reacting a compound of formula V-3 with a sulfonyl chloride (formula V-4) in the presence of a second base and a catalyst (e.g., DMAP) to give a compound of formula V-5; (iii) reacting the compound of formula V-5 with an amine (formula V-6) in the presence of a third base to obtain the compound of formula (I); During the ceremony, R' is selected from halogens, OTs or OMs; R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W and n are defined above.

[0044] In another preferred example, the first base is potassium carbonate or cesium carbonate. In another preferred example, the second base is TEA or DIPEA. In another preferred example, the third base is TEA or DIPEA.

[0045] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising i) one or more compounds according to the first aspect, or a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; and ii) a pharmaceutically acceptable carrier.

[0046] In another preferred example, the pharmaceutical composition contains a PD-1 inhibitor (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM009, or biosimilars of the above drugs), a PD-L1 inhibitor (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20 , SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biosimilars of the above drugs), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan,tiuxetan, etc.), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, etc.), nib, lorlatinib, alkotinib), PI3K inhibitors (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib) (Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib,Osimertinib, etc.), VEGFR inhibitors (e.g., Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (e.g., Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, etc.), nostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (e.g., selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, The compound may further comprise one or more therapeutic agents selected from the group consisting of: U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.; mTOR inhibitors (e.g., Vistusertib), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.); or combinations thereof.

[0047] In a fourth aspect, the present invention provides use of a compound according to the first aspect, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, or a pharmaceutical composition according to the third aspect, for producing a pharmaceutical composition for preventing and / or treating a disease associated with SOS1 activity or expression level.

[0048] In another preferred example, the disease is cancer. In another preferred embodiment, the cancer is selected from lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

[0049] In a fifth aspect of the present invention, there is provided a method for non-diagnostic, non-therapeutic inhibition of SOS1, comprising administering to a patient in need thereof an effective amount of a compound of general formula (I) as defined in the first aspect, or a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition as defined in the third aspect.

[0050] It should be understood that within the scope of the present invention, any of the above technical features of the present invention and any of the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described individually in this specification due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0051] The present inventors have unexpectedly discovered, through long-term intensive research, novel compounds that have selective inhibitory effects on SOS1 and / or have better pharmacodynamic properties, and have completed the present invention based on this discovery.

[0052] term In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0053] The term "alkyl group" refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical "alkyl groups" include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, [ka] , pentyl group, isopentyl group, heptyl group, 4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, nonyl group, decyl group, undecyl group, dodecyl group, and the like.

[0054] Term “C1~C 18 The term "alkyl group" refers to a straight-chain, branched-chain, or cyclic alkyl group containing 1 to 18 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group ( [ka] ), n-butyl group, tert-butyl group, isobutyl group (e.g., [ka] ), n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, n-heptyl group, isoheptyl group. A "substituted alkyl group" refers to an alkyl group substituted at one or more positions, particularly 1 to 4 substituents, and can be substituted at any position. Typical substitutions include one or more of hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case, for example, trifluoromethyl group or alkyl group containing Cl), nitrile group, nitro group, oxygen (e.g., ═O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c, P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , N.R. b P(=O)2R e Including, but not limited to, R appearing herein a can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring; R b , R c , R d can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring, or an aromatic ring; in other words, R b and R c can form a heterocycle with the N atom, and R e can independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring. The above-mentioned typical substituents, for example, the alkyl group, the cycloalkyl group, the alkenyl group, the cycloalkenyl group, the alkynyl group, the heterocyclic ring, or the aromatic ring, may be optionally substituted.

[0055] The term "alkylene group" refers to a group formed by losing one more hydrogen atom from an "alkyl group," such as a methylene group, an ethylene group, a propylene group, an isopropylene group (e.g., [ka] ), butylene groups (e.g., [ka] ), pentylene groups (e.g., [ka] ), hexylene groups (e.g., [ka] ), heptylene groups (e.g., [ka] ) etc.

[0056] The term "cycloalkyl group" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings, each ring containing 3 to 8 carbon atoms. A "substituted cycloalkyl group" refers to a cycloalkyl group substituted at one or more positions, particularly 1 to 4 substituents, which may be substituted at any position. Typical substitutions include one or more of hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents, the latter being, for example, trifluoromethyl or alkyl groups containing Cl), nitrile, nitro, oxygen (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR, or the like. a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NRb R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , N.R. b P(=O)2R e Including, but not limited to, R appearing herein a can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring; R b , R c , R d can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring, or an aromatic ring; in other words, R b and R c can form a heterocycle with the N atom, and R ecan independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions further include spirocyclic, bridged ring, or fused ring substituents, particularly spirocycloalkyl groups, spirocycloalkenyl groups, spirocyclic heterocyclic rings (not including heteroaromatic rings), bridged cycloalkyl groups, bridged cycloalkenyl groups, bridged ring heterocyclic rings (not including heteroaromatic rings), fused cycloalkyl groups, fused cycloalkenyl groups, fused ring heterocyclyl groups, or fused ring aromatic ring groups, and the above-mentioned cycloalkyl groups, cycloalkenyl groups, heterocyclyl groups, and heterocycloaryl groups may be optionally substituted. Any two or more atoms of the ring may be further fused to other cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups.

[0057] The term "cycloalkylene group" refers to a group formed by the loss of two hydrogen atoms in a cycloalkyl group, e.g., [ka] And so on.

[0058] The term "alkylenecycloalkylene group" refers to a group formed by losing two hydrogen atoms from the above-mentioned cycloalkylalkyl group or alkylcycloalkyl group, and among them, "C1 to C 18 Alkylene C3~C 20 Cycloalkylene group and C3-C 20 Cycloalkylene C1-C 18 The "alkylene group" has the same meaning, and preferably is C1-C6 alkylene, C3-C 12 The cycloalkylene group is [ka] Including, but not limited to, the following:

[0059] The term "heterocyclyl group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3- to 7-membered monocyclic, 6- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) in which at least one heteroatom is present in a ring having at least one carbon atom. Each heteroatom-containing heterocycle may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocyclyl group may be attached to the residue of any heteroatom or carbon atom in the ring or ring system molecule. Exemplary monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxanyl, tetrahydro-1,1-dioxythiophene, and the like.Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, which are optionally connected to other groups by a single bond or further fused to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups by any two or more atoms of the ring; heterocyclyl groups may be substituted or unsubstituted; and when substituted, the substituents may be alkyl, deuterated alkyl, haloalkyl, alkoxy, or haloalkoxy groups. Preferably, the ring is one or more groups independently selected from the group consisting of alkenyl groups, alkynyl groups, alkylthio groups, alkylamino groups, halogen atoms, amino groups, nitro groups, hydroxy groups, mercapto groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylthio groups, oxo groups, carboxy groups, and carboxylic acid ester groups, and any two or more atoms of the ring may be further condensed and connected to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0060] The term "heterocyclylene group" refers to a group formed by losing two hydrogen atoms from a heterocyclyl group as defined above, [ka] Including, but not limited to, the following:

[0061] The term "heterocycloalkylene alkylene group" refers to a group formed by losing two hydrogen atoms in a cycloalkylalkyl group or an alkylcycloalkyl group, and includes "4- to 20-membered heterocycloalkylene C1-C 18 Alkylene group and C1-C 18 The "alkylene 4- to 20-membered heterocycloalkylene group" has the same meaning, and preferably is a 4- to 12-membered heterocycloalkylene C 1~6 The alkylene group is [ka] Including, but not limited to, the following:

[0062] The term "aryl group" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, particularly monocyclic and bicyclic groups, such as a phenyl group, a biphenyl group, or a naphthyl group. Two or more aromatic rings (e.g., bicyclic rings), as long as the aromatic rings containing the aryl group are connected by a single bond (e.g., biphenyl) or may be fused (e.g., naphthalene, anthracene, etc.). A "substituted aryl group" refers to an aryl group substituted at one or more positions, particularly one to three substituents, and can be substituted at any position. Typical substitutions include one or more hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case, e.g., trifluoromethyl or alkyl groups containing Cl), nitrile, nitro, oxygen (e.g., =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR, or the like. a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. dS(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , N.R. b P(=O)2R e Including, but not limited to, R appearing herein a can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring; R b , R c , R d can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring, or an aromatic ring; in other words, R b and R c can form a heterocycle with the N atom, and R e can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring. The above exemplary substituents may be optionally substituted. Typical substitutions further include fused ring substituents, particularly fused cycloalkyl groups, fused cycloalkenyl groups, fused ring heterocyclyl groups, or fused ring aromatic ring groups, and the above cycloalkyl groups, cycloalkenyl groups, heterocyclyl groups, and heterocycloaryl groups may be optionally substituted.

[0063] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen, and sulfur. Heteroaryl groups are preferably 5- to 10-membered rings, more preferably 5- or 6-membered rings, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl groups. The "heteroaryl group" may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkenyl group, an alkynyl group, an alkylthio group, an alkylamino group, a halogen atom, an amino group, a nitro group, a hydroxy group, a mercapto group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylthio group, an oxo group, a carboxy group, and a carboxylic acid ester group.

[0064] Term “C1~C 18 The term "alkoxy group" refers to a straight-chain, branched-chain, or cyclic alkoxy group having 1 to 18 carbon atoms, and includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, etc. A C1 to C8 alkoxy group is preferred, and a C1 to C6 alkoxy group is more preferred.

[0065] Term “C1~C 18 "Alkyleneoxy group" means "C1-C 18 This refers to a group obtained by losing one hydrogen atom from an "alkoxy group." The term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine. The term "halo" refers to substitution by halogen.

[0066] The term "deuterated" refers to substitution with deuterium. The term "hydroxy group" refers to a group with the structure OH. The term "nitro group" refers to a group having the structure NO2. The term "cyano group" refers to a group with the structure CN.

[0067] The term "acyl group" refers to a group having the structure -COR, where R represents hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, a cycloalkenyl group or a substituted cycloalkenyl group, an aryl group or a substituted aryl group, or a heterocyclic ring or a substituted heterocyclic ring. Preferably, the acyl group is a "C2-C6 acyl group" (e.g., a -COC1-C5 alkyl group). Examples of acyl groups include, but are not limited to, -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH2CH(CH3)2.

[0068] The term "ester group" refers to a group having the structure -COOR, where R represents hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, a cycloalkenyl group or a substituted cycloalkenyl group, an aryl group or a substituted aryl group, or a heterocyclic ring or a substituted heterocyclic ring. Preferably, the ester group is a "C2-C6 ester group" (e.g., -COOC1-C5 alkyl group). Examples of ester groups include, but are not limited to, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, and -COOCH2CH(CH3)2.

[0069] The term "amine group" refers to a group having the structure -NRR, where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in the dialkylamine moiety. Preferably, the amine group is a C1-C6 amine group (i.e., an alkylamine group containing 1 to 6 carbon atoms, e.g., C1-C6 alkylNH-). Examples of amine groups include, but are not limited to, NH2, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, isopropylamine, diisopropylamine, aniline, dianiline, and the like.

[0070] The term "amide group" refers to a group having the structure -CONRR, where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic, as defined above. Preferably, the amide group is a "C1-C6 amide group" (e.g., -CONHC1-C5 alkyl or -CONH2). R and R' can be the same or different in the dialkylamine moiety. Examples of amide groups include, but are not limited to, -CONH2, -CONHCH3, -CON(CH3)2, and the like.

[0071] The term "sulfonamide group" refers to a group having the structure -SONR-R' or -RSO-NR'-, where R and R' are, as defined above, independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic. R and R' may be the same or different in the dialkylamine moiety. Examples of sulfonamide groups include, but are not limited to, -SONH, -SONHCH, -SON(CH), CHSONH-, CHSONCH-, etc. In the present invention, a "C1-C6 sulfonamide group" refers to a C1-C6 alkylsulfonamide group, i.e., the total number of carbon atoms in R and R' is 1 to 6.

[0072] The term "urea group" refers to a group having the structure -NRCONR'R'', where R, R', and R'' are as defined above and can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic. R, R', and R'' can be the same or different in the dialkylamine moiety. Examples of urea groups include, but are not limited to, -NHCONH2, -NHCONHCH3, -NHCON(CH3)2, etc. In the present invention, the term "C1-C6 urea group" refers to a C1-C6 alkyl urea group, i.e., the total number of carbon atoms in R, R', and R'' is 1 to 6.

[0073] The term "alkylamine alkyl group" refers to a group having the structure -RNHR, where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different. Examples of alkylamine alkyl groups include, but are not limited to, -CHNHCH, -CHCHNHCH, and the like.

[0074] The term "dialkylamine alkyl group" refers to a group having the structure -RNR'R'', where R, R', and R'' can independently represent an alkyl group or substituted alkyl group, a cycloalkyl group or substituted cycloalkyl group, a cycloalkenyl group or substituted cycloalkenyl group, an aryl group or substituted aryl group, or a heterocycle or substituted heterocycle, as defined above. R, R', and R'' can be the same or different in the dialkylamine moiety. Examples of dialkylamine alkyl groups include, but are not limited to, -CHN(CH), -CHCHN(CH), and the like.

[0075] The term "sulfone group" refers to a group having the structure -S0R', where R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic, as defined above. Examples of sulfone groups include, but are not limited to, -S0CH3, -S0CHCH3, -S0-cyclopropyl, -S0-cyclobutyl, -S0-cyclopentyl, and -S0-cyclohexyl.

[0076] The term "heterocyclylalkyl group" refers to a group having the structure -RR', where R can independently represent an alkyl group or substituted alkyl group, a cycloalkyl group or substituted cycloalkyl group, a cycloalkenyl group or substituted cycloalkenyl group, or an aryl group or substituted aryl group, and R' represents a heterocycle or substituted heterocycle. Examples of heterocyclylalkyl groups include, but are not limited to, azetidinyl-CH2-, oxetanyl-CH2-, pyrrolidinyl-CH2-, oxacyclopentyl-CH2-, piperidinyl-CH2-, and oxacyclohexyl-CH2-.

[0077] In the present invention, the term "substituted" refers to one or more hydrogen atoms in a specific group being replaced with a specific substituent. The specific substituent is the substituent described above or appears in each example. Unless otherwise specified, a substituted group may have one substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents envisioned in the present invention are stable or chemically feasible combinations. Examples of the substituents include halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde ... 10 Acyl groups, C2-C 10 Ester group, amine group, C1-C6 alkoxy group, C1-C 10 Examples include, but are not limited to, a sulfonyl group, a C1-C6 urea group, and the like.

[0078] Unless otherwise specified, it is assumed that any undervalent heteroatoms have sufficient hydrogen atoms to complete the valences.

[0079] When a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkylene group for an alkyl group, a cycloalkylene group for a cycloalkyl group, a heterocyclylene group for a heterocyclyl group, an alkyleneoxy group for an alkoxy group, etc.

[0080] Active ingredient As used herein, "compounds of the invention" refers to compounds according to Formula I and further includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of Formula I.

[0081] The compound of formula I has the following structure: [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are defined as above.

[0082] Preferably, the compound of formula I has the structure shown in general formula (II): [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X, Y, Z, W, and n are defined as above.

[0083] Preferably, the compound of formula I has the structure shown in general formula (III): [ka] In the formula, R 1 , R 2 , R 3 , X, Y, Z, W, and n are defined as above.

[0084] Preferably, the compound of formula I has the structure shown in general formula (IV): [ka] During the ceremony, R 1 , R 2 , R 3 , R 6 , X, Y, Z, W, and n are defined as above.

[0085] Preferably, the compound of formula I has the structure shown in general formula (V): [ka] During the ceremony, R 1 , R 2 , R 3 , R6 , Y, Z, W, and n are defined as above.

[0086] Preferably, the compound of formula I has the structure shown in formula (VI): [ka] In the formula, R 1 , R 2 , R 3 , R 6 , R 13 , R 14 , the ring C, t and n are defined as above.

[0087] Preferably, the compound of formula I has the structure shown in formula (VII): [ka] During the ceremony, R 1 , R 3 , R 6 , R 16 , R 17 , R 18 and t are defined as above.

[0088] Preferably, the compound of formula I has the structure shown in formula (VIII): [ka] During the ceremony, R 1 , R 2 , R 3 , R 6 and W is defined as above.

[0089] Preferably, the compound of formula I has the structure shown in formula (IX-A) or formula (IX-B): [ka] In the formula, R 1 , R 2 , R 3 , R 8 , R 9, X, Y, Z, W, n and q are defined as above.

[0090] Preferably, the compound of formula I has the structure shown in formula (X): [ka] In the formula, R 1 , R 2 , R 3 , X, Y, Z, W, n and q are defined as above.

[0091] Preferably, in formulae I-VIII, R 1 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m1 R 8 , -(CH2) m'1 (CH=CH)R 8 , -(CH2) m'1 (C≡C)R 8 , -(CH2) m1 O(CH2) p1 R 8 , -(CH2) m'1 SR 8 , -(CH2) m1 COR 8 , -(CH2) m1 C(O)OR 8 , -(CH2) m'1 S(O) q1 R 8 , -(CH2) m1 NR 8 R 9 , -(CH2) m1 C(O)NR 8 R 9 , -(CH2) m1 NR 8 C(O)R 9 , -(CH2) m1 NR 8 C(O)NR 9 R 10 , -(CH2) m'1 S(O) q1 NR 8 R 9 , -(CH2) m'1 NR 8 S(O) q1 R9 , -(CH2) m'1 NR 8 S(O) q1 NR 9 R 10 wherein H in CH2 may be optionally substituted; R 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, or -(CH2) m1 NR 8 R 9 , -(CH2) m1 C(O)NR 8 R 9 , -(CH2) m'1 S(O) q1 NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m1 NR 8 C(O)R 9 , -(CH2) m1 NR 8 C(O)NR 9 R 10 , -(CH2) m'1 NR 8 S(O) q1 R 9 , -(CH2) m'1 NR 8 S(O) q1 NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, Each R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH2) m2 R8 , -(CH2) m'2 (CH=CH)R 8 , -(CH2) m'2 (C≡C)R 8 , -(CH2) m2 O(CH2) p2 R 8 , -(CH2) m'2 SR 8 , -(CH2) m2 COR 8 , -(CH2) m2 C(O)OR 8 , -(CH2) m'2 S(O) q2 R 8 , -(CH2) m2 NR 8 R 9 , -(CH2) m2 C(O)NR 8 R 9 , -(CH2) m2 NR 8 C(O)R 9 , -(CH2) m2 NR 8 C(O)NR 9 R 10 , -(CH2) m'2 S(O) q2 NR 8 R 9 , -(CH2) m'2 NR 8 S(O) q2 R 9 , -(CH2) m'2 NR 8 S(O) q2 NR 9 R 10 wherein H in CH2 is optionally substituted; 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C1-C 18 Alkyl groups, C3-C 20 independently selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group, or -(CH2) m2 NR 8 R 9 , -(CH2) m2 C(O)NR8 R 9 , -(CH2) m'2 S(O) q2 NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH2) m2 NR 8 C(O)R 9 , -(CH2) m2 NR 8 C(O)NR 9 R 10 , -(CH2) m'2 NR 8 S(O) q2 R 9 , -(CH2) m'2 NR 8 S(O) q2 NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, m1 is 0, 1, 2, 3, 4 or 5; m'1 is 0, 1, 2, 3, 4 or 5; p1 is 0, 1, 2, 3, 4 or 5; q1 is 1 or 2, m2 is 0, 1, 2, 3, 4 or 5; m'2 is 0, 1, 2, 3, 4 or 5; p2 is 0, 1, 2, 3, 4 or 5; q2 is 1 or 2, The limiting condition is that Y is O, NH, or NR 7 and Z is a bond and W is C3 to C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 is not hydrogen, deuterium, halogen, or cyano group, and m1 is not 0; Among them, the above substitutions are hydrogen, deuterium, C1 to C 18 Alkyl groups, deuterated C1-C 18 Alkyl group, halo C1-C 18 Alkyl group, halo C1-C 18 Alkylhydroxy group, C3-C 20 Cycloalkyl groups, C1-C 18 Alkoxy groups, deuterated C1-C 18 Alkoxy group, halo C1-C 18 Alkoxy group, C6-C 14 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 20-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an acyl group, an amide group, a sulfonyl group, a sulfonamide group, and a urea group.

[0092] Preferably, in formula IX, R 3 is a substituted or unsubstituted C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclyl groups, C6-C 10 aryl group, and 5- to 10-membered heteroaryl group, preferably R 3 is selected from substituted phenyl, pyridinyl, pyrimidinyl, and pyridazinyl groups, and more preferably, R 3 is chosen from: [ka] [ka] Among these, the above substitutions include hydrogen, deuterium, C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, halo C1-C6 alkyl groups, halo C1-C6 alkyl hydroxy groups, C3-C 12 Cycloalkyl groups, C1-C6 alkoxy groups, deuterated C1-C6 alkoxy groups, halo C1-C6 alkoxy groups, C6-C 14It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 12-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an acyl group, an amide group, a sulfonyl group, a sulfonamide group, and a urea group.

[0093] Preferably, in formula I, R 4 , R 5 are independently selected from a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclyl group; Among these, the above substitutions include hydrogen, deuterium, C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, halo C1-C6 alkyl groups, halo C1-C6 alkyl hydroxy groups, C3-C 12 Cycloalkyl groups, C1-C6 alkoxy groups, deuterated C1-C6 alkoxy groups, halo C1-C6 alkoxy groups, C6-C 14 It refers to being substituted with one or more groups selected from the group consisting of an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 12-membered heterocyclyl group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

[0094] Preferably, R 6 is selected from hydrogen, deuterium, halogen, cyano group, and C1 to C6 alkyl group.

[0095] Preferably, in the present invention, the substitution is hydrogen, deuterium, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O—, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a C6-C 14It means that the aryl group, the 5- to 14-membered heteroaryl group, the 4- to 6-membered heterocyclyl group, the 4- to 6-membered heterocyclyl-O-, halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group is substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a haloC1-C6 alkyl group, a haloC1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O-, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a haloC1-C6 alkoxy group, a C6-C 14 The aryl group, the 5- to 14-membered heteroaryl group, the 4- to 6-membered heterocyclyl group, and the 4- to 6-membered heterocyclyl-O- are each independently one or more R a may be further substituted by, among which R a is a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkylhydroxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-O-, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halo C1-C6 alkoxy group, a C6-C 14 It is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 4- to 6-membered heterocyclyl group, a 4- to 6-membered heterocyclyl-O-, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an acyl group, an amide group, a sulfonyl group, a sulfonamide group, or a urea group.

[0096] Salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are considered to include their salts. As used herein, the term "salt" refers to acidic or basic salts formed from inorganic or organic acids and bases. Furthermore, when the compounds of the present invention contain a basic moiety, including but not limited to pyridine or imidazole, and when they contain an acidic moiety, including but not limited to carboxylic acids, the zwitterions (internal salts) that may form are included within the scope of the term "salt." While pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts should be selected initially, other salts may also be used, for example, in separation or purification steps of the manufacturing process. The compounds of the present invention can form salts, for example, by reacting Compound I with a certain amount, e.g., the same equivalent amount, of acid or base, followed by salting out from the medium or by lyophilization in aqueous solution.

[0097] The compounds of the present invention contain a basic moiety (including, but not limited to, an amine or a pyridine or imidazole ring) that can form a salt with an organic or inorganic acid. Typical salts that can be formed from acids include acetate (e.g., acetate or trihaloacetate (e.g., trifluoroacetate)), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (e.g., methylisothiazolinone ... For example, 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., salts formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate (e.g., p-toluenesulfonate), dodecanoate, and the like.

[0098] Acidic moieties (including, but not limited to, carboxylic acids) that may be contained in some compounds of the present invention can form salts with a variety of organic or inorganic bases. Typical salts formed from bases include ammonium salts, alkali metal salts (e.g., sodium salts, lithium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts, magnesium salts), salts formed with organic bases (e.g., organic amines) (e.g., benzathine, dicyclohexylamine, hydrabamine (salts formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine), and salts formed with amino acids (e.g., arginine, lysine, etc.). Basic nitrogen-containing groups may form quaternary ammonium salts with halides (e.g., low molecular weight alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups)), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl groups), aralkyl halides (e.g., bromides of benzyl and phenyl groups), and the like.

[0099] Prodrugs and solvates of the compounds of the present invention are also included within the scope. As used herein, the term "prodrug" refers to a compound that undergoes chemical conversion by metabolic or chemical process to produce the compound, salt, or solvate of the present invention when treating the relevant disease. The compounds of the present invention include solvates (e.g., hydrates).

[0100] The compounds, salts or solvates of the present invention may exist in tautomeric forms (e.g., amides and iminoethers), and all of these tautomeric forms are included in the present invention.

[0101] All stereoisomers of the compounds (e.g., various substitutions of possible asymmetric carbon atoms), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may exist alone (e.g., as pure or substantially pure optical isomers having specific activity), or may be in admixture (e.g., racemates), or may be in admixture with all or some of the other stereoisomers. Chiral centers of the present invention have two configurations, S or R, according to the definition recommended by the International Union of Pure and Applied Chemistry (IUPAC) in 1974. Racemic forms can be obtained by physical methods, such as fractional crystallization, or by separation of diastereomers, or by chiral chromatography. Single optical isomers can be obtained from racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by recrystallization.

[0102] The compound of the present invention has a weight content of 90% or more, for example, 95% or more, or 99% or more (a "highly pure" compound) obtained by sequentially producing, separating, and purifying the compound as described herein. Such a "highly pure" compound of the present invention is also included in the present invention.

[0103] All configurational isomers of the compounds of the present invention are included within the scope, whether in mixtures or in pure or highly pure form. Included in the definition of the compounds of the present invention are the two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0104] Throughout the specification, groups and substituents may be chosen to provide stable moieties and compounds.

[0105] A detailed introduction of the definitions of specific functional groups and chemical terms is as follows: In the present invention, the definitions of chemical elements are based on the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th This text is consistent with the original text, "Organic Chemistry," Ed. Definitions of specific functional groups are also explained therein. Fundamental principles of organic chemistry and the reactivity of specific functional groups are also explained in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.

[0106] Some compounds of the present invention may exist in particular geometric or stereoisomeric forms. All compounds of the present invention include their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. In addition, asymmetric carbon atoms may represent substituents (e.g., alkyl groups). All isomers and mixtures thereof are included in the present invention.

[0107] According to the present invention, the isomer mixture may contain a variety of ratios of isomers. For example, a mixture containing only two isomers may be 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Those skilled in the art will recognize that similar ratios, as well as ratios of more complex isomer mixtures, are also within the scope of the present invention.

[0108] The present invention also includes isotopically labeled compounds, which are as disclosed herein. However, in practice, one or more atoms are often replaced by atoms with different atomic masses or mass numbers. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, each of which may be, for example, 2 H,3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compound of the present invention, or an enantiomer, diastereomer, isomer, or pharmaceutically acceptable salt or solvate thereof, which contains an isotope of the compound or other isotopic atoms, is within the scope of the present invention. Some isotopically labeled compounds of the present invention include, for example, 3 H and 14 It contains a radioactive C isotope, which can be used in tissue distribution studies of drugs and substrates. 3 H, and carbon-14, i.e. 14 C is easy to produce and detect, and should therefore be the isotope of choice. Also, heavier isotopes (e.g., deuterium, i.e. 2 Substitution with H) should be considered as a priority in some cases because its superior metabolic stability is advantageous for some therapies, for example, it can extend the half-life in the body or reduce the dosage. Isotopically labeled compounds can be produced in the exemplary disclosed technical solutions by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents in a conventional manner.

[0109] If a synthesis of a particular enantiomer of a compound of the present invention is designed, it may be prepared by asymmetric synthesis or derivatized with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and subsequent removal of the chiral auxiliary to yield the pure enantiomers. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, it may be formed into a diastereomeric salt with an appropriate optically active acid or base, which may then be separated by conventional means such as preparative crystallization or chromatography to yield the pure enantiomers.

[0110] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their scope. In general, whether the term "substituted" appears before or after the term "optionally," a generic formula containing a substituent in a formulation of the present invention refers to a substituent of a given structure replacing a hydrogen radical. When multiple positions in a particular structure are substituted with multiple specified substituents, the substituents at each position can be the same or different. As used herein, the term "substituted" includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, a heteroatom nitrogen may have its valency supplemented by a hydrogen substituent or any of the permissible organic compounds described above. Furthermore, the present invention is not intended to limit the permissible substitutions of organic compounds in any manner. In the present invention, combinations of substituents and variables that result in stable compounds are believed to be advantageous in the treatment of diseases, such as infectious diseases or proliferative disorders. The term "stable" as used herein refers to a stable compound sufficient to maintain the structural integrity of the compound for a long enough period of time, and preferably sufficient to be detected as effective for a long enough period of time, as used herein for the above purposes.

[0111] Metabolites of the compounds of the present application and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in the body to the structures of the compounds of the present application and pharmaceutically acceptable salts thereof, are also included in the scope of the claims of the present application.

[0112] Manufacturing method The methods for producing the compounds of formula (I) of the present invention will be described in more detail below, but these specific methods do not constitute any limitations on the present invention. The compounds of the present invention can be easily produced by optionally combining various synthetic methods described herein or known in the art, and such combinations are easily performed by those skilled in the art.

[0113] Typically, the process for preparing the compounds of the present invention is as follows: All raw materials and reagents used therein can be purchased from commercial sources unless otherwise specified. [ka] (i) reacting a compound of formula V-1 with a compound of formula V-2 (wherein R' is a leaving group such as a halogen, OTs, or OMs) in the presence of a first base (such as potassium carbonate or cesium carbonate) to form a compound of formula V-3; (ii) protecting the compound of formula V-3 with a sulfonyl chloride (formula V-4) in the presence of a second base (such as TEA or DIPEA) and a catalyst (such as DMAP) to form a compound of formula V-5; (iii) the reaction of a compound of formula V-5 with an amine (formula V-6) in the presence of a third base (such as TEA or DIPEA) to form a compound of formula (I); During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W and n are defined above.

[0114] Pharmaceutical compositions and methods of administration The pharmaceutical composition of the present invention is used for preventing and / or treating inflammation, cancer, cardiovascular disease, infectious disease, immune disease, and metabolic disease.

[0115] The compound of general formula (I) may be used in combination with other drugs for known treatments or for ameliorating similar conditions. In the case of combined administration, the compound of formula I may be administered simultaneously or sequentially, without changing the conventional drug administration method and dosage. When the compound of formula I and one or more other drugs are administered simultaneously, a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time is preferably used. The combination of drugs also includes administering the compound of formula I and one or more other known drugs at overlapping times. When the compound of formula I and one or more other drugs are administered in combination, the dose of the compound of formula I or the known drug may be lower than the dose when they are administered alone.

[0116] Drugs or active ingredients that can be used in combination with the above compounds of general formula (I) include PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM009, or biosimilars of the above drugs), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, H LX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biosimilars of the above drugs), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan,tiuxetan), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib) , Alkotinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Chitinib, etc.), Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Ico Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (e.g., Sorafenib, Pazopanib, Regorafenib), Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (e.g., Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (e.g., Palbociclib) , Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (e.g., Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (e.g., Vistusertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.

[0117] Dosage forms of the pharmaceutical compositions according to the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, film formulations, dripping pills, topical applications, controlled or sustained release formulations, or nanoformulations.

[0118] The pharmaceutical compositions of the present invention contain a compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount, together with a pharmacologically acceptable excipient or vector. The "safe and effective amount" refers to an amount of compound sufficient to clearly improve the condition without causing serious side effects. Generally, each pharmaceutical composition contains 1 to 2,000 mg of the compound of the present invention, and more preferably, 10 to 1,000 mg of the compound of the present invention. Preferably, the "single dosage" is a single capsule or tablet.

[0119] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel-like substances of sufficient purity and low toxicity to be suitable for human use. Here, "compatibility" means that the components of the composition can be mixed with the compounds of the present invention and with each other without appreciably reducing the effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0120] The route of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and typical routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) and topical administration.

[0121] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) adhesives, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; and (d) disintegrants, such as agar, carbonate, or the like. Calcium, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) retarders such as paraffin, (f) absorption accelerators such as quaternary amine compounds, (g) wetting agents such as cetanol and glycerol monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0122] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They may also contain opacifying agents, and the release of the active compound or compounds in such compositions may be delayed from a certain part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxy materials. If necessary, the active compound may be formed into a microcapsule form with one or more of the above-mentioned excipients.

[0123] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents (e.g., water or other solvents), solubilizing agents, and emulsifying agents commonly used in the art (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils), particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0124] Besides these inert diluents, compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0125] In addition to the active compound, suspensions may contain as suspending agents such as, for example, ethoxylated isooctadecanoI, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar, or mixtures of these substances.

[0126] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0127] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, propellants, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or enhancers, as may be required.

[0128] The therapeutic methods of the present invention may be practiced alone or in combination with other therapeutic procedures or drugs.

[0129] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, and the dosage at the time of administration is a dosage considered to be pharmaceutically effective, and for a human weighing 60 kg, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into consideration factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0130] The present invention further provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable carrier with the compound of the present invention represented by general formula (I) above or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, to form a pharmaceutical composition.

[0131] The present invention further provides a method of treatment comprising the step of administering to a subject in need of treatment a compound of the above general formula (I) of the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or administering the above pharmaceutical composition of the present invention, in order to selectively inhibit SOS1.

[0132] Compared with the prior art, the present invention has the following main advantages: (1) The compound has an excellent selective inhibitory effect on SOS1, (2) The compounds have better in vivo and in vitro pharmacodynamic and pharmacokinetic properties and lower toxicity and side effects.

[0133] The present invention will be further described below with reference to specific examples. It should be understood that these examples are merely for the purpose of illustrating the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not specified are generally performed under conventional conditions, for example, in accordance with the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are based on weight.

[0134] Unless otherwise defined, all technical terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are merely illustrative.

[0135] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography / mass spectrometry (LC-MS).

[0136] NMR was detected using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and the measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), etc. Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0137] Liquid chromatography / mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).

[0138] Qingdao GF254 silica gel plates are used for thin-layer chromatography, with 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin-layer chromatography. For column chromatography, Qingdao silica gel 200-300 mesh silica gel is generally used as the vector.

[0139] All starting materials for the embodiments of the present invention are commercially available and known, or may be synthesized according to literature sources disclosed in the art.

[0140] Unless otherwise specified, all reactions of the present invention are carried out under the protection of a dry inert gas (e.g., nitrogen or argon) with continuous magnetic stirring, and all reaction temperatures are in °C (degrees Celsius).

[0141] Example Intermediate-1 Preparation of (R)-1-(3-amino-5-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka]

[0142] Step 1: Preparation of tert-butyl (3-bromo-5-iodophenyl)carbamate 3-Bromo-5-iodobenzoic acid (4 g, 12.2 mmol) was added to tert-butanol (50 mL), and triethylamine (1.85 g, 18.3 mmol) and triphenylphosphoryl azide (3.7 g, 13.5 mmol) were added. The mixture was refluxed overnight, spun dry, and separated by silica gel column chromatography to obtain the desired product (3.4 g, yield: 71%). LC-MS: m / z 398 (M+H) + .

[0143] Step 2: Preparation of ethyl 2-(3-bromo-5-((tert-butoxycarbonyl)amino)phenyl)-2,2-difluoroacetate tert-Butyl (3-bromo-5-iodophenyl)carbamate (3.97 g, 10 mmol) was added to dimethyl sulfoxide (30 mL), and ethyl 2-bromo-2,2-difluoroacetate (5.1 g, 25 mmol) and copper powder (1.6 g, 25 mmol) were added. The temperature was then raised to 70 °C and the reaction was allowed to proceed overnight with stirring. The mixture was poured into water (100 mL) and extracted twice with ethyl acetate (300 mL). The combined organic phases were dried, spin-dried, and separated by silica gel column chromatography to obtain the desired product (3.4 g, yield: 79%). LC-MS: m / z 394 (M+H) + .

[0144] Step 3: Preparation of tert-butyl (3-bromo-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate Ethyl 2-(3-bromo-5-((tert-butoxycarbonyl)amino)phenyl)-2,2-difluoroacetate (3 g, 7.6 mmol) was added to tetrahydrofuran (30 mL), and methylmagnesium bromide (10.2 mL, 30.5 mmol) was added at 0°C. After reacting at room temperature for 1 h, the mixture was poured onto ice (50 g) and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, spin-dried, and separated by silica gel column chromatography to obtain the desired product (2.8 g). LC-MS: m / z 380 (M+H) + .

[0145] Step 4: Preparation of tert-butyl (3-acetyl-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate tert-Butyl (3-bromo-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate (3 g, 7.9 mmol) was added to tetrahydrofuran (30 mL), and n-butyllithium (2.5 M, 12.6 mL, 31.6 mmol) was added at -60 ° C. After the entire addition, the temperature was maintained and the mixture was stirred for 0.5 h. N-methoxy-N-methylacetamide (3.3 g, 31.6 mmol) was added, the mixture was slowly warmed to room temperature, and the mixture was allowed to react overnight with stirring. The mixture was poured onto ice (50 g) and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, spun dry, and separated by silica gel column chromatography to obtain the desired product (1.1 g). LC-MS: m / z 344 (M+H) + .

[0146] Step 5: Preparation of (R,Z)-tert-butyl(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate tert-Butyl (3-acetyl-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate (1 g, 2.9 mmol) was added to tetrahydrofuran (20 mL), and (R)-2-methylpropane-2-sulfinamide (0.53 g, 4.4 mmol) and tetraethyl titanate (2.6 g, 12 mmol) were added. The reaction mixture was then stirred at reflux overnight, cooled, concentrated, and purified by silica gel column chromatography to give the desired product (0.68 g, 52% yield). LC-MS: m / z 447 (M+H) + .

[0147] Step 6: Preparation of tert-butyl (3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-5-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)phenyl)carbamate (R,Z)-tert-Butyl(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate (0.68 g, 1.5 mmol) was added to tetrahydrofuran / water (8 mL / 0.16 mL), and sodium borohydride (116 mg, 3.0 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 0.5 h, and then saturated ammonium chloride solution (20 mL) was added. The mixture was extracted twice with ethyl acetate (60 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain the desired product (600 mg, yield: 88%). LC-MS: m / z 449 (M+H) + .

[0148] Step 7: Preparation of (R)-1-(3-amino-5-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride tert-Butyl (3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-5-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)phenyl)carbamate (600 mg, 1.34 mmol) was added to methanol (3 mL), and a 4N solution of hydrogen chloride in dioxane (6 mL) was added. The reaction mixture was then stirred at room temperature for 16 h. After concentration, the crude product was separated by preparative liquid chromatography to give the desired product (188 mg, yield: 50%). LC-MS: m / z 245 (M+H) + . 1 H NMR (400 MHz,DMSO) δ 8.37 (brs, 3H), 6.82-6.66 (m, 3H), 5.74-4.94 (m, 2H), 4.30-4.16 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.17 (s, 6H).

[0149] Intermediate-2 Preparation of (R)-1-(2-(1-aminoethyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka]

[0150] Step 1: Preparation of ethyl 2-(2-chloropyridin-4-yl)-2,2-difluoroacetate 2-Chloro-4-iodopyridine (4.0 g, 16.7 mmol), 2-bromo-2,2-difluoroethyl acetate (8.5 g, 41.8 mmol), and activated copper powder (2.7 g, 41.8 mmol) were added to dimethyl sulfoxide (30 mL) and stirred at 55 °C for 16 h under nitrogen protection. The mixture was cooled to room temperature, diluted with water / ethyl acetate (150 mL / 100 mL), stirred, and filtered to remove insoluble solids. The filtrate was layered and the aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate layers were washed three times with saturated brine (50 mL), dried, spun dry, and separated by silica gel column chromatography to obtain the desired product (3.5 g, yield: 86%). LC-MS: m / z 236 (M+H) + .

[0151] Step 2: Preparation of 1-(2-chloropyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol Ethyl 2-(2-chloropyridin-4-yl)-2,2-difluoroacetate (3.06 g, 13.0 mmol) was added to anhydrous toluene (30 mL), the mixture was purged with nitrogen three times, and methylmagnesium bromide (3 M, 10 mL, 30.0 mmol) was added dropwise in an ice bath. The reaction mixture was then stirred at room temperature for 1 h. Saturated ammonium chloride solution (100 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to give the desired product (1.8 g, purity: approximately 80%, yield: 58%). LC-MS: m / z 222 (M+H) + .

[0152] Step 3: Preparation of 1-(2-(1-ethoxyethenyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol 1-(2-chloropyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol (1.68 g, 7.6 mmol) was added to N,N-dimethylformamide (15 mL), and tributyl(1-ethoxyethenyl)stannane (3.29 g, 9.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (266 mg, 0.38 mmol) were added. The atmosphere was then purged with nitrogen. The reaction mixture was stirred at 120 °C overnight, then cooled to room temperature, poured into water / ethyl acetate (50 mL / 50 mL), placed over a layer of diatomaceous earth, and suction filtered to remove a fluffy black solid. The filtrate was layered, and the aqueous phase was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed three times with saturated brine (30 mL), dried, and concentrated to give the desired product. This product was used directly in the next step without further purification. LC-MS: m / z 258 (M+H) + .

[0153] Step 4: Preparation of 1-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethanone The crude 1-(2-(1-ethoxyethenyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol obtained in the previous step was dissolved in tetrahydrofuran (30 mL) and 2M aqueous hydrochloric acid (15 mL) was added. The reaction mixture was stirred at room temperature for 1 h, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography to give the desired product (1.29 g, 70% yield). LC-MS: m / z 230 (M+H) + .

[0154] Step 5: Preparation of (R,E)—N-(1-(4-(1,1-difluoro-2-hydroxy-2-methyl-2-methylpropyl)pyridin-2-yl)ethylene)-2-methylpropane-2-sulfinamide 1-(4-(1,1-Difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethanone (1.07 g, 4.69 mmol) was added to tetrahydrofuran (20 mL), and (R)-2-methylpropane-2-sulfinamide (850 mg, 7.03 mmol) and tetraethyl titanate (4.3 g, 18.76 mmol) were added. The reaction mixture was then stirred at reflux for 1.5 h, cooled, concentrated, and purified by silica gel column chromatography to give the desired product (455 mg, 29% yield). LC-MS: m / z 333 (M+H) + .

[0155] Step 6: Preparation of (R)—N—((R)-1-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (R,E)-N-(1-(4-(1,1-difluoro-2-hydroxy-2-methyl-2-methylpropyl)pyridin-2-yl)ethylene)-2-methylpropane-2-sulfinamide (455 mg, 1.37 mmol) was dissolved in tetrahydrofuran / water (7 mL / 0.14 mL). Sodium borohydride (78 mg, 2.06 mmol) was added in portions at -50 °C. The reaction mixture was then slowly warmed to room temperature. Semi-saturated brine (30 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (290 mg, yield: 56%). LC-MS: m / z 335 (M+H) + .

[0156] Step 7: Preparation of (R)-1-(2-(1-aminoethyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride (R)-N-((R)-1-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (290 mg, 0.87 mmol) was dissolved in methanol (2 mL), and hydrogen chloride / dioxane solution (4 M, 4 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, and the crude product was separated by preparative liquid chromatography to give the desired product (179 mg, yield: 77%). LC-MS: 231 m / z (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.73 (d, J = 4.8 Hz, 1H), 8.60 (brs, 3H), 7.65 (s, 1H), 7.49 (d, J = 5.2 Hz, 1H), 5.52 (s, 1H), 4.60 (q, J = 6.4 Hz, 1H), 1.52 (d, J = 7.2 Hz, 3H), 1.19 (s, 6H).

[0157] The following compounds are synthesized in the same manner as Intermediate-2, but with different starting materials: Intermediate-3 Preparation of (R)-1-(6-(1-aminoethyl)pyridin-2-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka] LC-MS: 231 m / z (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.61 (s, 3H), 8.04-8.00 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5.28 (s, 1H), 4.54 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.24 (s, 6H).

[0158] Intermediate-4 Preparation of (R)-1-(4-(1-aminoethyl)pyridin-2-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka] LC-MS: 231 m / z (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.86 (brs, 3H), 8.70 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 4.54-4.50 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.23 (s, 6H).

[0159] Intermediate-5 Preparation of (R)-1-(5-(1-aminoethyl)pyridin-3-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka] LC-MS: 231 m / z.

[0160] Intermediate-6 Preparation of (R)-1-(3-(1-aminoethyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka]

[0161] Step 1: Preparation of 2-bromo-1-fluoro-4-iodobenzene 3-Bromo-4-fluoroaniline (5 g, 26.5 mmol) was added to acetonitrile / water (50 mL / 8 mL), and concentrated hydrochloric acid (11 mL) and sodium nitrite (2 g, 29.1 mmol) were added at 0°C. The mixture was allowed to react for 0.5 h. A solution of potassium iodide (6.6 g, 39.8 mmol) in water (15 mL) was added, and the mixture was allowed to react with stirring at room temperature for 3 h. The mixture was then poured into water (100 mL) and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, spin-dried, and separated by silica gel column chromatography to obtain the desired product (15.8 g, yield: 100%).

[0162] Step 2: Preparation of ethyl 2-(3-bromo-4-fluorophenyl)-2,2-difluoroacetate 2-Bromo-1-fluoro-4-iodobenzene (15.8 g, 52.7 mmol) was added to dimethyl sulfoxide (110 mL), and 2-bromo-2,2-difluoroethyl acetate (26.8 g, 131.6 mmol) and copper powder (8.4 g, 131.6 mmol) were added. The temperature was then raised to 70 °C and the reaction was allowed to proceed overnight with stirring. The mixture was poured into water (300 mL) and extracted twice with ethyl acetate (800 mL). The combined organic phases were dried, spun dry, and separated by silica gel column chromatography to obtain the desired product (9.8 g, yield: 63%). 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 6.4 Hz, 2.0 Hz; 1H), 7.61-7.51 (m, 1H), 7.20 (t, J = 8.4 Hz; 1H), 4.32 (q, J = 7.2 Hz; 2H), 1.32 (t, J = 6.8Hz; 3H).

[0163] Step 3: Preparation of 1-(3-bromo-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol Ethyl 2-(3-bromo-4-fluorophenyl)-2,2-difluoroacetate (9.8 g, 33 mmol) was added to tetrahydrofuran (150 mL), and methylmagnesium bromide (33 mL, 99 mmol) was added at 0° C. After reacting at room temperature for 1 h, the mixture was poured onto ice (100 g) and extracted twice with ethyl acetate (400 mL). The organic phases were combined, dried, spin-dried, and separated by silica gel column chromatography to obtain the desired product (9 g, yield: 97%). 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 6.4 Hz, 2.0 Hz; 1H), 7.54-7.43 (m, 1H), 7.16 (t, J = 8.4 Hz; 1H), 1.32-1.29 (m, 6H).

[0164] Step 4: Preparation of 1-(3-(1-ethoxyethenyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol 1-(3-Bromo-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (9.3 g, 32.9 mmol) was added to N,N-dimethylformamide (100 mL), followed by the addition of tributyl(1-ethoxyethenyl)stannane (14.2 g, 39.4 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.65 mmol). After complete addition, the mixture was protected with nitrogen and the temperature was raised to 120 °C with stirring for 16 h. Upon completion, the reaction was cooled, poured into water (300 mL), and extracted twice with ethyl acetate (600 mL). The combined organic phases were dried and spun to give the desired product, which was used directly in the next step.

[0165] Step 5: Preparation of 1-(5-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone 1-(3-(1-ethoxyethenyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (crude product) was added to tetrahydrofuran (60 mL), and aqueous hydrochloric acid (20 mL, 4 mol / L) was added. After stirring at room temperature for 1 hour, the pH was adjusted to 7.0-8.0 with saturated aqueous sodium bicarbonate, and the mixture was extracted twice with ethyl acetate (600 mL). The organic phases were combined, dried, spin-dried, and separated by silica gel column chromatography to obtain the desired product (6.6 g, two-step yield: 81%). LC-MS: m / z 247 (M+H) + .

[0166] Step 6: Preparation of (R,Z)—N-(1-(5-(1,1-difluoro-2-hydroxy-2-methyl-2-methylpropyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide 1-(5-(1,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone (6.6 g, 26.8 mmol) was added to tetrahydrofuran (70 mL), and (R)-2-methylpropane-2-sulfinamide (4.9 g, 40.2 mmol) and tetraethyl titanate (23.9 g, 107 mmol) were added. The reaction mixture was then stirred at 60°C overnight, cooled, concentrated, and purified by silica gel column chromatography to give the desired product (6.4 g, 68% yield). LC-MS: m / z 350 (M+H) + .

[0167] Step 7: Preparation of (R)-N-((R)-1-(5-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (R,Z)-N-(1-(5-(1,1-difluoro-2-hydroxy-2-methyl-2-methylpropyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (6.3 g, 18.1 mmol) was added to tetrahydrofuran / water (80 mL / 1.6 mL), and sodium borohydride (1.4 g, 36.2 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 0.5 h, and then saturated ammonium chloride solution (100 mL) was added. The mixture was extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain the desired product (4.1 g, yield: 64%). LC-MS: m / z 352 (M+H) + .

[0168] Step 8: Preparation of (R)-1-(3-(1-aminoethyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride (R)-N-((R)-1-(5-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4 g, 11.4 mmol) was added to methanol (20 mL), and a 4N solution of hydrogen chloride in dioxane (20 mL) was added. The reaction mixture was then stirred at room temperature for 16 h. After concentration, the residue was separated by preparative liquid chromatography to give the desired product (2.32 g, 82% yield). LC-MS: m / z 248 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.70 (brs, 3H), 7.79 (dd, J = 7.2 Hz, 2.4 Hz; 1H), 7.56-7.49 (m, 1H), 7.37 (t, J = 9.6 Hz; 1H), 5.33 (s, 1H), 4.63 (q, J = 6.4 Hz; 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.18 (s, 6H).

[0169] The following compounds are synthesized in the same manner as Intermediate-6, but with different starting materials: Intermediate-7 Preparation of (R)-1-(3-(1-aminoethyl)-5-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka] LC-MS: m / z 248 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.72 (s, 3H), 7.62 (d, J = 9.7 Hz, 1H), 7.49 (s, 1H), 7.27 (d, J = 9.4 Hz, 1H), 4.52-4.47 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.18 (s, 6H).

[0170] Intermediate-8 Preparation of (R)-1-(5-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 248 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.57 (brs, 3H), 7.72 (s, 1H), 7.62-7.60 (m, 1H), 7.35 (dd, J = 10.8 Hz, 8.8 Hz, 1H), 5.38 (s, 1H), 4.50-4.44 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.21 (s, 6H).

[0171] Intermediate-9 Preparation of (R)-1-(3-(1-aminoethyl)-5-methoxyphenyl)-1,1-difluoro-2-methylpropanol-2-ol hydrochloride [ka] LC-MS: m / z 260 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.67 (s, 3H), 7.36 (s, 1H), 7.18 (s, 1H), 6.98 (s, 1H), 5.31 (brs, 1H), 4.44-4.40 (m, 1H), 3.81 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H), 1.18 (s, 6H).

[0172] Intermediate-10 Preparation of (R)-1-(3-(1-aminoethyl)-2-chlorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride [ka] LC-MS: m / z 264 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.74 (brs, 3H), 7.90 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 7.65-7.54 (m, 2H), 5.45 (s, 1H), 4.63 (q, J = 8.8 Hz, 1H), 1.54 (d, J = 8.8 Hz, 3H), 1.27 (s, 6H).

[0173] Intermediate-11 Preparation of (R)-1-(3-(1-aminoethyl)-2-methylphenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 244 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.49 (brs, 3H), 7.69 (d, J = 7.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.71-4.65 (m, 1H), 3.57 (s, 1H), 2.46 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.22 (s, 6H).

[0174] Intermediate-12 Preparation of (R)-3-(1-aminoethyl)-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)benzonitrile [ka] LC-MS: m / z 255 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 5.40 (s, 1H), 4.14 (q,J= 6.6 Hz, 1H), 1.28 (d,J= 6.6 Hz, 3H), 1.17 (s, 6H).

[0175] Intermediate-13 Preparation of 2-(1-aminoethyl)-6-(1-methylcyclopropyl)pyridin-4-amine [ka]

[0176] Step 1: Preparation of 2-bromo-6-(prop-1-en-2-yl)pyridin-4-amine Under nitrogen protection, a solution of 2,6-dibromopyridin-4-amine (19.0 g, 75.4 mmol, 1.00 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25.4 g, 151 mmol, 2.00 eq) in dioxane (150 mL) and HO (30 mL) was added with KCO (31.3 g, 226 mmol, 3.00 eq) and Pd(PPh)Cl (3.71 g, 5.28 mmol, 0.07 eq). The reaction mixture was heated at 80 °C for 16 h. The resulting mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (8.00 g, 37.6 mmol, yield 49.8%). LC-MS: m / z 213 (M+H) + .

[0177] Step 2: Preparation of tert-butyl (2-bromo-6-(prop-1-en-2-yl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate To a solution of 2-bromo-6-(prop-1-en-2-yl)pyridin-4-amine (8.00 g, 37.6 mmol, 1.00 eq) in DCM (80 mL) was added (Boc)O (32.8 g, 150 mmol, 34.5 mL, 4.00 eq) and DMAP (1.38 g, 11.3 mmol, 0.30 eq). The reaction mixture was reacted at 25 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (8.00 g, 19.4 mmol, 51.6% yield). LC-MS: m / z 413 (M+H) + .

[0178] Step 3: Preparation of tert-butyl (2-bromo-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate Under nitrogen protection, TFA (4.41 g, 38.7 mmol, 2.87 mL, 4.00 eq) was added to a solution of diethylzinc (1.00 M, 38.7 mL, 4.00 eq) in DCM (20 mL) at 0 °C. The reaction mixture was allowed to react at 0 °C for 15 min. Then, a solution of CHCl (10.4 g, 38.7 mmol, 3.12 mL, 4.00 eq) in DCM (20 mL) was added dropwise at 0 °C. The reaction mixture was allowed to react at 0 °C for 20 min. Then, a solution of tert-butyl (2-bromo-6-(prop-1-en-2-yl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (4.00 g, 9.68 mmol, 1.00 eq) in DCM (20 mL) was added at 0 °C. The reaction mixture was allowed to react at 20 °C for 5 h. The resulting reaction mixture was quenched with water (200 mL) and extracted with DCM (100 mL × 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (1.08 g, 2.64 mmol, yield 17.0%, purity 80.0%). LC-MS: m / z 327 (M+H) + .

[0179] Step 4: Preparation of tert-butyl (2-acetyl-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate Under nitrogen protection, tributyl(1-ethoxyethenyl)tin (1.43 g, 3.96 mmol, 1.34 mL, 1.24 eq), triethanolamine (649 mg, 6.42 mmol, 893 μL, 2.00 eq), and Pd(PPh3)2Cl2 (113 mg, 160 μmol, 0.05 eq) were added to a solution of tert-butyl (2-bromo-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (1.05 g, 3.21 mmol, 1.00 eq) in dioxane (5 mL). The reaction mixture was heated at 60 °C for 16 h. The resulting mixture was quenched with 1N HCl (50 mL) and extracted with EtOAc (200 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (560 mg, 1.93 mmol, yield 60.1%). LC-MS: m / z 291 (M+H) + .

[0180] Step 5: Preparation of tert-butyl (E)-(2-(1-((tert-butylsulfinyl)imine)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate To a solution of tert-butyl (2-acetyl-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (0.56 g, 1.93 mmol, 1.00 eq) and tert-butylsulfinamide (351 mg, 2.90 mmol, 1.50 eq) in THF (5 mL) was added Ti(OEt)4 (1.10 g, 4.82 mmol, 999 μL, 2.50 eq). The reaction mixture was incubated at 80 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (440 mg, 1.01 mmol, 52.1% yield, 90.0% purity). LC-MS: m / z 394 (M+H) + .

[0181] Step 6: Preparation of tert-butyl (2-(1-((tert-butylsulfinyl)amine)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate To a solution of tert-butyl (E)-(2-(1-((tert-butylsulfinyl)imine)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (440 mg, 1.12 mmol, 1.00 eq) in THF (5 mL) and HO (0.1 mL) was added NaBH (46.5 mg, 1.23 mmol, 1.10 eq) at 0 °C. The reaction mixture was reacted at 25 °C for 1 h. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (100 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (300 mg, 758 μmol, 67.8% yield). LC-MS: m / z 396 (M+H) + .

[0182] Step 7: Preparation of 2-(1-aminoethyl)-6-(1-methylcyclopropyl)pyridin-4-amine To a solution of tert-butyl (2-(1-((tert-butylsulfinyl)amine)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (300 mg, 758 μmol, 1.00 eq) in dioxane (1 mL) was added HCl / dioxane (1 mL) at 0°C. The reaction mixture was reacted at 25°C for 16 h and then filtered. The filter cake was dried under vacuum to give the desired product as a white solid (165 mg, 647 μmol, yield 85.4%, purity 89.3%). LC-MS: m / z 192 (M+H) + . 1H NMR (400MHz, CD3OD) δ 6.91 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.78 - 4.65 (m, 1H), 1.75 - 1.71 (m, 1H), 1.75 - 1.71 (m, 1H), 1.73 (d, J = 7.0 Hz, 4H), 1.54 - 1.50 (m, 1H), 1.51 (s, 3H), 1.15 - 1.10 (m, 2H), 1.01 - 0.95 (m, 2H).

[0183] Intermediate-14 Preparation of 2-(1-aminoethyl)-6-(1-fluorocyclopropyl)pyridin-4-amine [ka]

[0184] Step 1: Preparation of 2-chloro-6-(1-fluorocyclopropyl)-4-nitropyridine A mixture of 2-chloro-4-nitropyridine (16.0 g, 101 mmol, 1.00 eq), 1-fluorocyclopropane-1-formic acid (13.7 g, 131 mmol, 1.30 eq), and AgNO (3.43 g, 20.2 mmol, 0.200 eq) in ACN (50.0 mL) and HO (65.0 mL) was heated to 80 °C, followed by the addition of a solution of (NH)SO (46.0 g, 202 mmol, 43.9 mL, 2.00 eq) in HO (65.0 mL). The reaction was allowed to react at 80 °C for 48 h. The resulting reaction mixture was quenched with 2 M NaOH solution (500 mL) and extracted with EtOAc (500 mL). The combined organic phase was dried over anhydrous MgSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (2.50 g, 11.5 mmol, yield 11.4%). 1H NMR (400MHz, CDCl3) δ 8.55 - 8.62 (m, 1 H) 7.45 (d, J =5.25 Hz, 1 H) 1.48 - 1.55 (m, 2 H) 0.87 - 0.95 (m, 2 H).

[0185] Step 2: Preparation of 2-(1-ethoxyethenyl)-6-(1-fluorocyclopropyl)-4-nitropyridine Under nitrogen protection, a solution of 2-chloro-6-(1-fluorocyclopropyl)-4-nitropyridine (2.37 g, 11.0 mmol, 1.00 eq), tributyl(1-ethoxyethenyl)tin (7.00 g, 19.4 mmol, 6.54 mL, 1.75 eq), and Pd(PPh3)2Cl2 (778 mg, 1.11 mmol, 0.100 eq) in dioxane (25.0 mL) was reacted at 110 °C for 16 h. The reaction mixture was quenched with HO (60 mL) and extracted with EtOAc (60 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (1.66 g, 6.58 mmol, 59.4% yield). 1 H NMR (400MHz, CDCl3) δ 8.77 (dd, J=5.13, 1.25 Hz, 1 H) 7.49 (d, J=5.13 Hz, 1 H) 4.51 - 4.69 (m, 2 H) 3.94 (q, J=7.00 Hz, 2 H) 1.30 - 1.38 (m, 5 H) 0.77 - 0.85 (m, 2 H).

[0186] Step 3: Preparation of 1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethan-1-one To a solution of 2-(1-ethoxyethenyl)-6-(1-fluorocyclopropyl)-4-nitropyridine (1.63 g, 6.46 mmol, 1.00 eq) in THF (5.00 mL) was added aqueous HCl (2.00 M, 4.85 mL, 1.50 eq). The reaction mixture was allowed to react at 25 °C for 1 h. The resulting mixture was quenched with HO (30 mL) and extracted with EtOAc (50 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (1.44 g, 6.26 mmol, 96.8% yield, 97.4% purity). 1 H NMR (400MHz, CDCl3) δ (dd, J=5.14, 1.38 Hz, 1 H) 7.69 (d, J=5.27 Hz, 1 H) 2.74 (s, 3 H) 1.45 - 1.55 (m, 2 H) 0.77 - 0.86 (m, 2 H).

[0187] Step 4: Preparation of (E)-N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethene)-2-methylpropane-2-sulfonimide To a solution of 1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethan-1-one (1.24 g, 5.53 mmol, 1.00 eq) and tert-butylsulfinamide (1.01 g, 8.30 mmol, 1.50 eq) in THF (15.0 mL) was added Ti(OEt) (5.05 g, 22.1 mmol, 4.59 mL, 4.00 eq). The reaction mixture was heated at 80 °C for 16 h. The resulting mixture was quenched with HO (200 mL) and extracted with EtOAc (300 mL). The combined organic phases were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product (750 mg, 2.44 mmol, 44.1% yield). 1H NMR (400MHz, CDCl3) δ 8.89 (dd, J=5.02, 1.00 Hz, 1 H) 7.57 - 7.70 (m, 1 H) 2.65 - 2.87 (m, 3 H) 1.40 - 1.55 (m, 2 H) 1.31 (d, J=12.30 Hz, 9 H) 0.84 (dd, J=9.03, 2.51 Hz, 2H).

[0188] Step 5: Preparation of N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of (E)-N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethene)-2-methylpropane-2-sulfonimide (730 mg, 2.23 mmol, 1.00 eq) in THF (8.00 mL) and HO (0.100 mL) was added NaBH (126 mg, 3.34 mmol, 1.50 eq). The reaction mixture was stirred at 0 °C for 0.5 h. The resulting mixture was quenched with water (20 mL) at 0 °C and extracted with EtOAc (20 mL). The combined organic phase was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product as a yellow solid (0.300 g, 911 μmol, 40.8% yield). 1 H NMR (400MHz, CDCl3) δ 8.80 (br s, 1 H) 7.40 (br s, 1 H) 5.35 (br d, J=6.50 Hz, 1 H) 4.90 (br d, J=9.01 Hz, 1 H) 1.62 (br s, 5 H) 1.26 (br s, 9 H) 0.82 - 0.99 (m, 2H).

[0189] Step 6: Preparation of N-(1-(4-amino-6-(1-fluorocyclopropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide Under a nitrogen atmosphere, Pd / C (607 μmol, 2.00 mL, 10.0% purity, 1.00 eq) was added to a solution of N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 607 μmol, 1.00 eq) and BocO (159 mg, 729 μmol, 167 μL, 1.20 eq) in MeOH (2.00 mL). The reaction mixture was reacted under a hydrogen atmosphere at 25 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (140 mg, 468 μmol, 77.0% yield). LC-MS: m / z 300 (M+H) + .

[0190] Step 7: Preparation of 2-(1-aminoethyl)-6-(1-fluorocyclopropyl)pyridin-4-amine To a solution of N-(1-(4-amino-6-(1-fluorocyclopropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 401 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl / dioxane (1.80 mL). The reaction mixture was reacted at 25°C for 0.5 h and then concentrated under reduced pressure to give the desired product (52.0 mg, 259 μmol, 64.6% yield, 97.1% purity). LC-MS: m / z 196 (M+H) + . 1 H NMR (400MHz, DMSO) δ 9.02 - 9.39 (m, 3 H) 8.23 ​​(d, J=6.85 Hz, 1 H) 6.99 (d, J=6.85 Hz, 1 H) 5.20 (br d, J=5.50 Hz, 1 H) 1.68 (br d, J=6.85 Hz, 3 H) 1.56 - 1.66 (m, 2 H) 1.27 - 1.39 (m, 1 H) 0.95 (br s, 1 H).

[0191] Intermediate-15 Preparation of (R)-5-(7-bromo-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2-methylquinazolin-6-yl)-1-methylpyridin-2(1H)-one [ka]

[0192] Step 1: Preparation of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (2.00 g, 8.55 mmol, 1.00 eq) in DMF (20.0 mL) was added NIS (2.12 g, 9.40 mmol, 1.10 eq). The resulting mixture was reacted at 80 °C for 2 h, then quenched with water (100 mL) and filtered. The filter cake was collected and dried to give the desired product (2.20 g, yield: 67.2%). This product was used directly in the next step without further purification. LC-MS: m / z 360 (M+H) + .

[0193] Step 2: Preparation of 7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-ol A solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5.20 g, 14.5 mmol, 1.00 eq) in AcO (50 mL) was reacted at 138 °C for 12 h and then concentrated under reduced pressure. The residue was reacted in a mixture of EtOH (50 mL) and NH HO (50 mL) at 80 °C for 5 h and then filtered. The filter cake was collected and dried to give the desired product (4.00 g, yield: 69.6%). This product was used directly in the next step without further purification. LC-MS: m / z 383 (M+H) + .

[0194] Step 3: Preparation of (R)-1-(3-(1-((7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol To a solution of 7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-ol (1.60 g, 4.18 mmol, 1.00 eq) in DMF (16 mL) were added PyBOP (4.35 g, 8.36 mmol, 2.00 eq) and TEA (2.11 g, 20.9 mmol, 2.91 mL, 5.00 eq). The reaction mixture was reacted at room temperature for 0.5 h, followed by the addition of (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride (1.54 g, 5.43 mmol, 1.30 eq). The resulting mixture was reacted at 25 °C for 16 h, followed by the addition of EtOAc (50 mL) and HO (50 mL). The organic phase was separated, dried over anhydrous MgSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to give the desired product (1.10 g, yield: 43.2%). LC-MS: m / z 612 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.93 (s, 1 H) 8.78 (br d, J=7.21 Hz, 1 H) 7.59 (br t, J=6.54 Hz, 1 H) 7.29 - 7.36 (m, 1 H) 7.19 - 7.26 (m, 1 H) 5.76 (t, J=7.09 Hz, 1 H) 5.33 (s, 1 H) 2.36 (s, 3 H) 1.58 (d, J=7.09 Hz, 3 H) 1.22 (br d, J=10.27 Hz, 6 H).

[0195] Step 4: Preparation of (R)-5-(7-bromo-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2-methylquinazolin-6-yl)-1-methylpyridin-2(1H)-one Under nitrogen protection, a solution of (R)-1-(3-(1-((7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (1 g, 1.63 mmol, 1 eq), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (461 mg, 1.96 mmol, 1.2 eq), Pd(dppf)Cl2 (120 mg, 163 μmol, 0.1 eq), and K3PO4 (1.04 g, 4.90 mmol, 3 eq) in dioxane (5 mL), MeCN (5 mL), and HO (5 mL) was reacted at 90 °C for 6 h. Next, EtOAc (20 mL) and H2O (20 mL) were added. The organic phase was separated, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give the desired product (750 mg, yield: 77.4%). LC-MS: m / z 593 (M+H) + . 1 H NMR (400MHz, DMSO) δ 8.71 (br d, J=7.28 Hz, 1 H) 8.34 (s, 1 H) 8.00 (d, J=2.51 Hz, 1 H) 7.57 - 7.65 (m, 2 H) 7.29 - 7.36 (m, 1 H) 7.18 - 7.26 (m, 1 H) 6.53 (d, J=9.29 Hz, 1 H) 5.81 (br t, J=7.15 Hz, 1 H) 5.34 (s, 1 H) 3.54 (s, 3 H) 2.40 (s, 3 H) 1.58 (d, J=7.03 Hz, 3 H) 1.23 (br d, J=10.04 Hz, 6 H).

[0196] Example 1 Preparation of 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka]

[0197] Step 1: Preparation of (S)-2-(chloromethyl)-1-methylpyrroline N-Methyl-L-prolinol (500.0 mg, 4.34 mmol) was dissolved in toluene (5 mL) and thionyl chloride (2.0 mL) was added. The resulting reaction mixture was stirred at 100 °C for 2.0 h and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without purification.

[0198] Step 2: Preparation of (S)-7-methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4(3H)-one 6-Hydroxy-7-methoxy-2-methylquinazolin-4(3H)-one (120 mg, 0.58 mmol) was added to N,N-dimethylformamide (10 mL), followed by the (S)-2-(chloromethyl)-1-methylpyrroline (77.8 mg, 0.58 mmol) obtained in the previous step and potassium carbonate (402.2 mg, 2.91 mmol). The resulting reaction mixture was stirred at 100 °C for 3.0 h and then cooled to room temperature. The mixture was subjected to preparative liquid chromatography to give the desired product (39 mg, yield: 22%). LC-MS: m / z 304 (M+H) + .

[0199] Step 3: Preparation of (S)-7-methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (S)-7-Methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4(3H)-one (38.0 mg, 0.13 mmol) was added to dichloromethane (4 mL), and 2,4,6-triisopropylsulfonyl chloride (45.5 mg, 0.15 mmol), triethylamine (25.4 mg, 0.25 mmol), and 4-dimethylaminopyridine (1.5 mg, 0.013 mmol) were added. The resulting reaction mixture was stirred overnight at room temperature, poured into water, and extracted with dichloromethane (10 mL). The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the desired product (14.0 mg, yield: 20%). LC-MS: m / z 570 (M+H) + .

[0200] Step 4: Preparation of 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (S)-7-Methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (31.0 mg, 0.054 mmol) was added to dimethyl sulfoxide (2 mL), and (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (20.2 mg, 0.082 mmol) and triethylamine (0.4 mL) were added. The resulting reaction mixture was microwave-activated at 120°C for 2.0 h, then cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL). The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give the target compound (4 mg, yield: 13.9%). LC-MS: m / z 533 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.07 (m, 1H), 7.81 (m, 1H), 7.57 (d, J = 6.3 Hz, 1H), 7.30 (t, J = 7.1 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.02 (d, J = 3.0 Hz, 1H), 5.79 (m, 1H), 5.34 (m, 1H), 4.10 - 3.97 (m, 1H), 3.87 (m, 3H), 2.43 (m, 2H), 2.34 - 2.17 (m, 5H), 2.13 - 1.94 (m, 2H), 1.82 - 1.66 (m, 2H), 1.58 (m, 3H), 1.24 (m, 9H).

[0201] The following compounds were synthesized using the method of Example 1 with different starting materials: Example 2 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 490 (M+H) + .

[0202] Example 3 Preparation of N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 471 (M+H) + .

[0203] Example 4 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 460 (M+H) + .

[0204] Example 5 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy))quinazolin-4-amine [ka] LC-MS: m / z 474 (M+H) + .

[0205] Example 6 Preparation of (S)-5-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)methyl)-1-methylpyrrolin-2-one [ka] LC-MS: m / z 504 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 14.28 (brs, 1H), 9.71 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.17 (m, 3H), 6.88 (d, J = 4.3 Hz, 2H), 6.76 (s, 1H), 5.81 - 5.61 (m, 1H), 4.33 (m, 1H), 4.15 (m, 1H), 3.97 (m, 4H), 2.80 (s, 3H), 2.59 (s, 3H), 2.45 (m, 1H), 2.27 - 2.13 (m, 2H), 1.91 (m, 1H), 1.64 (d, J = 7.0 Hz, 3H).

[0206] Example 7 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-cyclopropoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H), 7.71 (s, 1H), 7.03(s, 1H), 6.86 (d, 1H), 6.69 (s, 1H), 5.57-5.53 (m, 3H), 4.22-4.18 (m, 2H), 3.91-3.84 (m, 5H), 3.44-3.39 (m, 1H), 2.35 (s, 3H), 1.55-1.53 ​​(d, 3H), 0.54-0.44 (m, 4H).

[0207] Example 8 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-(cyclopropyl(methyl)amino)ethoxy)-7-methoxy-2-methylquinolin-4-amine [ka] LC-MS: m / z 490 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.02 (s, 1H), 6.87 (d, J = 11.5 Hz, 2H), 6.70 (s, 1H), 5.64 - 5.44 (m, 3H), 4.23 - 4.07 (m, 2H), 3.86 (s, 3H), 2.96 (t, J = 5.9 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.87 - 1.74 (m, 1H), 1.52 (d, J = 8.0 Hz, 3H), 0.51 - 0.40 (m, 2H), 0.37 - 0.24 (m, 2H).

[0208] Example 9 Preparation of (R)-1-(3-(1-((6-(2-((cyclobutylmethyl)(methyl)amino)ethoxy)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 561 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J = 6.7 Hz, 1H), 7.30 (t, J = 6.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.02 (s, 1H), 5.80 (p, J = 7.0 Hz, 1H), 5.31 (s, 1H), 4.16 (m, 2H), 3.86 (s, 3H), 2.78 (t, J = 6.0 Hz, 2H), 2.27 (d, J = 10.1 Hz, 6H), 2.08 - 1.95 (m, 2H), 1.93 - 1.73 (m, 3H), 1.66 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (m, 8H).

[0209] Example 10 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-((cyclobutylmethyl)(methyl)amino)ethoxy)-7-methoxy-2-methylquinolin-4-amine [ka] LC-MS: m / z 518 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.93 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.02 (s, 1H), 6.87 (d, J = 11.0 Hz, 2H), 6.69 (s, 1H), 5.63 - 5.46 (m, 3H), 4.13 (m, 2H), 3.86 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.47 (m, 2H), 2.34 (s, 3H), 2.25 (s, 3H), 2.00 (m, 2H), 1.90 - 1.71 (m, 3H), 1.70 - 1.59 (m, 2H), 1.55 (d, J = 7.0 Hz, 3H).

[0210] Example 11 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 504 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 10.4 Hz, 2H), 6.69 (s, 1H), 5.62 - 5.46 (m, 3H), 3.96 (m, 2H), 3.88 (s, 3H), 2.39 - 2.10 (m, 11H), 1.54 (d, J = 7.1 Hz, 3H), 0.67 (s, 2H), 0.48 (s, 2H).

[0211] Example 12 (R)-1-(3-(1-((6-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.67 (s, 1H), 7.58 (t, J = 6.6 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.21 (m, 1H), 7.01 (s, 1H), 5.79 (m, 1H), 5.31 (s, 1H), 3.98 (m, 2H), 3.89 (s, 3H), 2.26 (m, 8H), 1.58 (d, J = 7.0 Hz, 3H), 1.32 - 1.12 (m, 9H), 0.68 (m, 2H), 0.48 (m, 2H).

[0212] Example 13 Preparation of (R)—N-(2-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)oxy)ethyl)-N-methylmethanesulfonamide [ka] LC-MS: m / z 528 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.05 (s, 1H), 6.86 (d, J = 10.6 Hz, 2H), 6.69 (s, 1H), 5.61 - 5.43 (m, 3H), 4.20 (t, J = 19.3 Hz, 2H), 3.87 (s, 3H), 3.59 (t, J = 5.5 Hz, 2H), 2.99 (s, 3H), 2.92 (s, 3H), 2.34 (s, 3H), 1.52 (t, J = 17.4 Hz, 3H).

[0213] Example 14 Preparation of 1-((S)-2-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)oxy)methyl)pyrrol-1-yl)ethan-1-one [ka] LC-MS: m / z 518 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 7.4 Hz, 1H), 7.79 (s, 1H), 7.02 (s, 1H), 6.87 (d, J = 14.3 Hz, 2H), 6.69 (s, 1H), 5.53 (m, 3H), 4.32 (m, 2H), 4.05 (m, 3H), 3.88 (s, 3H), 2.34 (m, 3H), 2.17 (m, 2H), 1.99 (m, 5H), 1.54 (d, J = 7.0 Hz, 3H).

[0214] Example 15 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((1-(morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 546 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.92 (d, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.01 (s, 1H), 6.87 (m, 2H), 6.70 (s, 1H), 5.66 - 5.44 (m, 3H), 4.28 - 3.93 (m, 2H), 3.87 (s, 3H), 3.60 - 3.48 (m, 4H), 2.66 - 2.56 (m, 1H), 2.50 (s, 3H), 2.35 (m, 4H), 2.07 - 1.95 (m, 1H), 1.56 (t, J = 8.6 Hz, 3H), 0.63 (m, 2H), 0.50 (m, 2H).

[0215] Example 16 tert-Butyl (S)-2-(((4-(((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)oxy)methyl)pyrroline-1-formate [ka] LC-MS: m / z 579 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.10 (m, 1H), 7.77 (m, 2H), 7.63 (t, J = 7.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.75 (m, 1H), 4.07 (m, 3H), 3.87 (s, 3H), 2.30 (s, 3H), 1.91 (m, 4H), 1.62 (d, J = 7.1 Hz, 3H), 1.40 (m, 11H).

[0216] Example 17 N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-pyrrolin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 479 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.14 (t, J = 8.6 Hz, 1H), 7.84 - 7.70 (m, 2H), 7.62 (t, J = 6.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.85 - 5.67 (m, 1H), 4.23 - 3.92 (m, 2H), 3.87 (s, 3H), 3.56 (m, 1H), 2.91 (m, 2H), 2.30 (s, 3H), 2.12 - 1.67 (m, 4H), 1.62 (d, J = 7.1 Hz, 3H).

[0217] Example 18 Preparation of N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 493 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 14.61 (brs, 1H), 10.00 (s, 1H), 8.21 (d, J = 19.4 Hz, 1H), 7.92 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.28 (s, 1H), 5.93 (m, 1H), 4.66 (d, J = 9.6 Hz, 1H), 4.54 - 4.37 (m, 1H), 4.23 (m, 1H), 3.98 (s, 3H), 3.71 (m, 2H), 3.03 (s, 3H), 2.54 (s, 3H), 2.37 (m, 1H), 2.25 - 1.90 (m, 3H), 1.73 (t, J = 10.3 Hz, 3H).

[0218] Example 19 Preparation of (R)-1-(3-(1-((6-(2-(((3,3-difluorocyclobutyl)methyl)(methyl)amino)ethoxy)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 597 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J = 6.7 Hz, 1H), 7.31 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.02 (s, 1H), 5.79 (m, 1H), 5.34 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 3.83 (s, 3H), 2.83 (t, J = 5.7 Hz, 2H), 2.75 (d, J = 10.4 Hz, 2H), 2.68 - 2.56 (m, 4H), 2.39 - 2.15 (m, 7H), 1.58 (d, J = 7.0 Hz, 3H), 1.20 (m, 6H).

[0219] Example 20 Preparation of N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 557 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.15 (d, J = 6.9 Hz, 1H), 7.79 (t, J = 7.1 Hz, 1H), 7.74 (s, 1H), 7.63 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.04 (s, 1H), 5.75 (p, J = 6.9 Hz, 1H), 4.15 (d, J = 10.8 Hz, 2H), 4.08 - 3.95 (m, 1H), 3.87 (s, 3H), 3.32 - 3.24 (m, 2H), 3.02 (s, 3H), 2.28 (s, 3H), 1.99 (m, 4H), 1.62 (d, J = 7.0 Hz, 3H).

[0220] Example 21 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-(((1-fluorocyclopropyl)methyl)(methyl)amino)ethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 522 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.21 - 7.98 (brs, 1H), 7.75 (s, 1H), 7.04 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.64 - 5.49 (m, 3H), 4.21 (m, 2H), 3.88 (s, 3H), 2.91 (m, 4H), 2.46 (s, 3H), 2.36 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 0.99 (m 2H), 0.70 (m, 2H).

[0221] Example 22 Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-(((3,3-difluorocyclobutyl)methyl)(methyl)amino)ethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 554 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.02 (s, 1H), 6.86 (m, 2H), 6.69 (s, 1H), 5.62 - 5.48 (m, 3H), 4.14 (m, 2H), 3.86 (s, 3H), 2.80 (m, 2H), 2.75 (m, 1H), 2.69 - 2.59 (m, 3H), 2.58 - 2.54 (m, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.20 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H).

[0222] Example 23 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((R)-morpholin-2-yl)methoxy)quinazolin-4-yl)amino)ethoxy)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + . 1H NMR (400 MHz, DMSO) δ 9.02 (brs, 1H), 7.96 (s, 1H), 7.63 (t, J = 6.9 Hz, 1H), 7.36 (t, J = 6.9 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 5.96 - 5.81 (m, 1H), 5.35 (s, 1H), 4.32 - 4.10 (m, 3H), 4.06 (m, 1H), 3.94 (s, 3H), 3.80 (m, 1H), 3.50 - 3.38 (m, 2H), 3.26 (m, 1H), 3.05 (m, 2H), 2.45 (s, 3H), 1.64 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 7.5 Hz, 6H).

[0223] Example 24 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-morpholin-2-yl)methoxy)quinazolin-4-yl)amino)ethoxy)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.73 (s, 1H), 7.65 - 7.51 (m, 1H), 7.30 (t, J = 6.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.02 (s, 1H), 5.80 (m, 1H), 5.33 (s, 1H), 4.14 - 3.94 (m, 2H), 3.87 (s, 3H), 3.78 (m, 2H), 3.51 (m, 1H), 2.97 (m, 1H), 2.68 (m, 2H), 2.60 - 2.52 (m, 2H), 2.28(s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.20 (t, J = 17.2 Hz, 6H).

[0224] Example 25 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-4-methylmorpholin-2-yl)methoxy)quinazolin-4-yl)amino)ethoxy)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 549 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J = 6.6 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (s, 1H), 5.80 (t, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.25 - 3.98 (m, 2H), 3.85 (m, 5H), 3.59 (m, 1H), 2.87 (m, 1H), 2.72 - 2.56 (m, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.04 (m, 1H), 1.94 (m, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.3 Hz, 6H).

[0225] Example 26 1-(3-((R)-1-((6-(((S)-1,4-dioxan-2-yl)methoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 536 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.3 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J = 6.9 Hz, 1H), 7.30 (t, J = 6.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (s, 1H), 5.88 - 5.70 (m, 1H), 5.32 (s, 1H), 4.17 - 4.02 (m, 2H), 4.01 - 3.84 (m, 5H), 3.80 (m, 1H), 3.74 - 3.62 (m, 2H), 3.60 - 3.41 (m, 2H), 2.28 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.20 (t, J = 17.3 Hz, 6H).

[0226] Example 27 1-(3-((R)-1-((6-(((R)-1,4-dioxan-2-yl)methoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 536 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 10.9 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.30 (t, J = 6.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (s, 1H), 5.88 - 5.72 (m, 1H), 5.33 (s, 1H), 4.09 (m, 2H), 4.01 - 3.84 (m, 5H), 3.80 (m, 1H), 3.76 - 3.63 (m, 2H), 3.50 (m, 2H), 2.29 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.0 Hz, 7H).

[0227] Example 28 6-(((S)-1,4-dioxan-2-yl)methoxy)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 493 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J = 7.1 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.87 (d, J = 10.7 Hz, 2H), 6.70 (s, 1H), 5.56 (brs, 2H), 4.15 - 4.01 (m, 2H), 4.01 - 3.84 (m, 5H), 3.79 (m, 1H), 3.74 - 3.60 (m, 2H), 3.58 - 3.44 (m, 3H), 2.36 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H).

[0228] Example 29 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-4-(methylsulfonyl)morpholin-2-yl)methoxy)quinazolin-4-yl)amino)ethoxy)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 613 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.79 (s, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.30 (t, J = 6.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04 (s, 1H), 5.81 (t, J = 7.1 Hz, 1H), 5.33 (s, 1H), 4.30 - 4.08 (m, 2H), 4.09 - 3.94 (m, 2H), 3.88 (s, 3H), 3.76 - 3.56 (m, 2H), 3.41 (m, 1H), 3.06 - 2.72 (m, 5H), 2.29 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.20 (t, J = 14.5 Hz, 6H).

[0229] Example 30 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 516 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.98 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.02 (s, 1H), 6.85 (t, J = 11.2 Hz, 2H), 6.69 (s, 1H), 5.64 - 5.45 (m, 3H), 4.14 - 3.98 (m, 2H), 3.86 (s, 3H), 2.91 (m, 1H), 2.61 (m, 1H), 2.53 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (dd, J = 12.6, 8.2 Hz, 1H), 1.67 - 1.44 (m, 4H), 0.63 - 0.39 (m, 4H).

[0230] Example 31 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 526 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.86 (d, J = 10.1 Hz, 2H), 6.69 (s, 1H), 5.66 - 5.46 (m, 3H), 4.11 (d, J = 5.2 Hz, 2H), 3.87 (s, 3H), 3.45 - 3.34 (m, 1H), 3.05 (t, J = 5.3 Hz, 1H), 2.80 - 2.56 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.30 - 2.12 (m, 1H), 1.56 (t, J = 7.2 Hz, 3H).

[0231] Example 32 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 554 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.99 (t, J = 13.1 Hz, 1H), 7.71 (s, 1H), 7.06 (d, J = 10.1 Hz, 1H), 6.87 (d, J = 9.9 Hz, 2H), 6.70 (s, 1H), 5.64 - 5.45 (m, 3H), 4.09 (t, J = 12.0 Hz, 2H), 3.99 (m, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 2.36 (s, 3H), 2.02 (m, 4H), 1.56 (d, J = 7.0 Hz, 3H).

[0232] Example 33 (R)—N-(2-((4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)ethyl)-N-methylmethanesulfonamide [ka] LC-MS: m / z 571 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.13 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 15.0 Hz, 1H), 7.60 (t, J = 6.7 Hz, 1H), 7.38 - 7.25 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 10.1 Hz, 1H), 5.81 (p, J = 6.8 Hz, 1H), 5.33 (s, 1H), 4.27 (t, J = 5.0 Hz, 2H), 3.87 (s, 3H), 3.61 (t, J = 5.4 Hz, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.29 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.1 Hz, 6H).

[0233] Example 34 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((1-(dimethylamino)cyclopropyl)methoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 490 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.93 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.5 Hz, 2H), 6.69 (s, 1H), 5.57 (d, J = 11.2 Hz, 3H), 4.19 - 4.02 (m, 2H), 3.87 (s, 3H), 2.42 (s, 6H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 0.70 (q, J = 6.8 Hz, 4H).

[0234] Example 35 (R)—N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-(2-cyclopropoxyethyloxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 495 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.04 (s, 1H), 6.89 - 6.79 (m, 1H), 6.70 (dd, J = 5.4, 2.7 Hz, 1H), 5.67 (p, J = 6.9 Hz, 1H), 5.33 (s, 2H), 4.35 - 4.11 (m, 2H), 3.87 (m, 5H), 3.43 (m, 1H), 2.31 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 0.62 - 0.35 (m, 4H).

[0235] Example 36 (R)-6-(2-cyclopropoxyethyloxy)-7-methoxy-2-methyl-N-(1-(4-(trifluoromethyl)pyridin-2-yl)ethyl)quinazolin-4-amine [ka] LC-MS: m / z 463 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.81 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 18.9 Hz, 2H), 7.63 (d, J = 4.3 Hz, 1H), 7.04 (s, 1H), 5.68 (m, 1H), 4.22 (d, J = 4.4 Hz, 2H), 3.87 (m, 5H), 3.46 - 3.40 (m, 1H), 2.30 (s, 3H), 1.65 (d, J = 6.9 Hz, 3H), 0.49 (m, 4H).

[0236] Example 37 (R)-6-(2-cyclopropoxyethyloxy)-7-methoxy-2-methyl-N-(1-(2-(trifluoromethyl)pyridin-2-yl)ethyl)quinazolin-4-amine [ka] LC-MS: m / z 463 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.70 (d, J = 4.6 Hz, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 7.73 (s, 2H), 7.05 (s, 1H), 5.69 - 5.51 (m, 1H), 4.23 (d, J = 3.8 Hz, 2H), 3.88 (s, 5H), 3.50 - 3.39 (m, 1H), 2.30 (s, 3H), 1.63 (d, J = 6.9 Hz, 3H), 0.64 - 0.30 (m, 4H).

[0237] Example 38 (R)—N-(1-(6-amino-4-(trifluoromethyl)pyridin-2-yl)ethyl)-6-(2-cyclopropoxyethyloxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 478 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 6.50 (s, 2H), 5.46 (m, 1H), 4.29 - 4.13 (m, 2H), 3.95 - 3.80 (m, 5H), 3.42 (m, 1H), 2.32 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H), 0.50 (m, 4H).

[0238] Example 39 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 477 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.1 Hz, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 4.31 - 4.16 (m, 1H), 4.04 (d, J = 5.3 Hz, 2H), 3.93 - 3.76 (m, 4H), 3.71 (m, 1H), 2.35 (s, 3H), 2.13 - 2.00 (m, 1H), 2.00 - 1.81 (m, 2H), 1.79 - 1.67 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H).

[0239] Example 40 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((R)-tetrahydrofuran-2-yl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.2 Hz, 2H), 6.69 (s, 1H), 5.65 - 5.44 (m, 3H), 4.33 - 4.18 (m, 1H), 4.04 (m, 2H), 3.94 - 3.78 (m, 4H), 3.71 (m, 1H), 2.35 (s, 3H), 2.13 - 2.04 (m, 1H), 2.02 - 1.81 (m, 2H), 1.81 - 1.67 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H).

[0240] Example 41 (R)—N-(1-(2-amino-6-(trifluoromethyl)pyridin-4-yl)ethyl)-6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 478 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 6.49 (s, 2H), 5.48 (m, 1H), 4.29 - 4.16 (m, 2H), 3.92 - 3.77 (m, 5H), 3.41 (m, 1H), 2.34 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H), 0.64 - 0.40 (m, 4H).

[0241] Example 42 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 451 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.87 (d, J = 10.9 Hz, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 4.30 - 4.14 (m, 2H), 3.89 (s, 3H), 3.73 (m, 2H), 3.32 (s, 3H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0242] Example 43 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((3-(methoxymethyl)oxetan-3-yl)methoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.06 (s, 1H), 6.88 (d, J = 8.1 Hz, 2H), 6.71 (s, 1H), 5.71 - 5.43 (m, 3H), 4.50 (m, 4H), 4.28 (m, 2H), 3.89 (s, 3H), 3.71 (s, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H).

[0243] Example 44 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 493 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.04 (s, 1H), 6.86 (d, J = 10.5 Hz, 2H), 6.69 (s, 1H), 5.65 - 5.43 (m, 3H), 4.75 - 4.60 (m, 3H), 4.44 (m, 2H), 4.28 - 4.14 (m, 2H), 3.88 (s, 3H), 3.80 (t, J = 4.5 Hz, 2H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0244] Example 45 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-cyclopropoxyethoxy)-2-methyl-7-(trifluoromethyl)quinazolin-4-amine [ka] LC-MS: m / z 515 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.61 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.80 (t, J = 7.0 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 5.76 (m, 1H), 4.34 (t, J = 14.1 Hz, 2H), 3.87 (m, 2H), 3.44 (m, 1H), 2.33 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H), 0.56 - 0.40 (m, 4H).

[0245] Example 46 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((1-methoxycyclopropyl)methoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 477 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.04 (s, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.70 (s, 1H), 5.66 - 5.43 (m, 3H), 4.20 (q, J = 11.1 Hz, 2H), 3.89 (s, 3H), 3.34 (s, 3H), 2.36 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 0.95 - 0.85 (m, 2H), 0.75 (t, J = 5.4Hz, 2H). H).

[0246] Example 47 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((S)-2-methoxypropyl)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 465 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.4 Hz, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 4.04 (m, 2H), 3.87 (s, 3H), 3.75 (m, 1H), 3.36 (s, 3H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H). H).

[0247] Example 48 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((R)-2-methoxypropyl)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 465 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.3 Hz, 2H), 6.69 (s, 1H), 5.69 - 5.42 (m, 3H), 4.09 (m, 1H), 3.99 (m, 1H), 3.87 (s, 3H), 3.75 (m, 1H), 3.36 (s, 3H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 6.3Hz, 3H). H).

[0248] Example 49 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-cyclobutoxyethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 491 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.88 (d, J = 10.2 Hz, 2H), 6.71 (s, 1H), 5.68 - 5.40 (m, 3H), 4.32 - 4.13 (m, 2H), 4.08 - 3.96 (m, 1H), 3.88 (s, 3H), 3.70 (t, J = 4.8 Hz, 2H), 2.36 (s, 3H), 2.24 - 2.10 (m, 2H), 1.95 - 1.78 (m, 2H), 1.69 - 1.35 (m, 5H).

[0249] Example 50 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(2-(2-methoxyethoxy)ethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 495 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.9 Hz, 2H), 6.69 (s, 1H), 5.64 - 5.38 (m, 3H), 4.28 - 4.14 (m, 2H), 3.94 - 3.77 (m, 5H), 3.69 - 3.57 (m, 2H), 3.48 (m, 2H), 3.25 (s, 3H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0250] Example 51 (R)—N-(1-(6-amino-4-(trifluoromethyl)pyridin-2-yl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 452 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.04 (s, 1H), 6.77 (s, 1H), 6.55 (m, 1H), 6.49 (s, 2H), 5.48 (m, 1H), 4.30 - 4.14 (m, 2H), 3.88 (s, 3H), 3.75 (t, J = 4.6 Hz, 2H), 3.35 (d, J = 3.1 Hz, 3H), 2.33 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

[0251] Example 52 (R)—N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 452 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.98 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.05 (s, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.70 (s, 1H), 6.49 (s, 2H), 5.49 (p, J = 7.0 Hz, 1H), 4.29 - 4.17 (m, 2H), 3.88 (s, 3H), 3.76 (t, J = 4.6 Hz, 2H), 3.35 (s, 3H), 2.34 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

[0252] Example 53 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3-cyclopropoxypropoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 491 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.99 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.87 (d, J = 11.3 Hz, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 4.23 - 4.05 (m, 2H), 3.87 (s, 3H), 3.70 - 3.58 (m, 2H), 3.29 (m, 1H), 2.35 (s, 3H), 2.02 (p, J = 6.1 Hz, 2H), 1.55 (d, J = 7.0 Hz, 3H), 0.55 - 0.36 (m, 4H).

[0253] Example 54 (R)—N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((1-((methylamine)methyl)cyclopropyl)methoxy)quinazolin-4-amine [ka] LC-MS: m / z 493 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.90 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 5.93 (t, J = 7.0 Hz, 1H), 4.09 (m, 2H), 3.98 (s, 3H), 3.08 (m, 2H), 2.63 (s, 3H), 2.54 (s, 3H), 1.70 (d, J = 7.0 Hz, 3H), 0.91 - 0.73 (m, 4H).

[0254] Example 55 (R)-(1-(((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amine)-7-methoxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methanol [ka] LC-MS: m / z 480 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.10 (d, J = 6.9 Hz, 1H), 7.83 - 7.73 (m, 1H), 7.70 (s, 1H), 7.62 (t, J = 6.9 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.83 - 5.68 (m, 1H), 4.68 (brs, 1H), 4.03 (m, 2H), 3.87 (s, 3H), 3.45 (m, 2H), 2.26 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H), 0.58 (s, 4H).

[0255] Example 56 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((1-(methoxymethyl)cyclopropyl)methoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 491 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 7.02 (s, 1H), 6.86 (d, J = 10.2 Hz, 2H), 6.69 (s, 1H), 5.64 - 5.46 (m, 3H), 3.97 (dd, J = 36.2, 9.9 Hz, 2H), 3.88 (s, 3H), 3.36 (dd, J = 19.9, 6.9 Hz, 2H), 3.26 (s, 3H), 2.35 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 0.63 (t, J = 12.3 Hz, 4H).

[0256] Example 57 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(2-(methoxy-d3)ethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 454 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.87 (d, J = 10.5 Hz, 2H), 6.70 (s, 1H), 5.67 - 5.40 (m, 3H), 4.27 - 4.09 (m, 2H), 3.87 (s, 3H), 3.79 - 3.68 (m, 2H), 2.36 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0257] Example 58 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-(cyclopropylmethoxy)ethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 491 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.75 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 6.84 (s, 1H), 6.68 (d, J = 10.3 Hz, 2H), 6.51 (s, 1H), 5.45 - 5.21 (m, 3H), 4.09 - 3.94 (m, 2H), 3.68 (s, 3H), 3.62 (t, J = 4.8 Hz, 2H), 3.16 (m, 2H), 2.17 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H), 0.37 - 0.20 (m, 2H), 0.01 (m, 2H).

[0258] Example 59 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((1,3-dimethoxypropan-2-yl)oxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 495 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.07 (s, 1H), 7.85 (s, 1H), 7.04 (s, 1H), 6.86 (d, J = 12.9 Hz, 2H), 6.70 (s, 1H), 5.67 - 5.46 (m, 3H), 4.98 - 4.77 (m, 1H), 3.87 (s, 3H), 3.67 - 3.49 (m, 4H), 3.32 (s, 6H), 2.37 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0259] Example 60 (R)—N-(1-(6-amino-4-(trifluoromethyl)pyridin-2-yl)ethyl)-7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 494 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 6.48 (s, 2H), 5.57 - 5.40 (m, 1H), 4.70 (d, J = 4.5 Hz, 3H), 4.46 (d, J = 5.4 Hz, 2H), 4.23 (d, J = 5.0 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J = 4.6 Hz, 2H), 2.33 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

[0260] Example 61 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-((3-methyloxetan-3-yl)oxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.87 (d, J = 10.6 Hz, 2H), 6.70 (s, 1H), 5.56 (m, 3H), 4.58 (d, J = 6.5 Hz, 2H), 4.32 (d, J = 6.6 Hz, 2H), 4.22 (dd, J = 10.0, 5.0 Hz, 2H), 3.87 (s, 3H), 3.79 (t, J = 5.0 Hz, 2H), 2.36 (s, 3H), 1.62 - 1.41 (m, 6H).

[0261] Example 62 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-(pyridin-3-oxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 514 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.21 (d, J = 3.5 Hz, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.50 (dd, J = 8.4, 1.8 Hz, 1H), 7.37 (dd, J = 8.3, 4.6 Hz, 1H), 7.06 (s, 1H), 6.87 (d, J = 10.1 Hz, 2H), 6.70 (s, 1H), 5.76 - 5.47 (m, 3H), 4.60 - 4.34 (m, 4H), 3.87 (s, 3H), 2.38 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H).

[0262] Example 63 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-(1-(1-(methoxymethyl)cyclopropyl)ethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 505 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.02 (s, 1H), 6.97 - 6.77 (m, 2H), 6.70 (s, 1H), 5.68 - 5.48 (m, 3H), 4.57 (dd, J = 19.7, 6.3 Hz, 1H), 3.86 (s, 3H), 3.52 (t, J = 9.7 Hz, 1H), 3.24 (m, 4H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.26 (m, 3H), 0.62 (m, 2H), 0.47 (m, 2H).

[0263] Example 64 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-(1-methylcyclobutoxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 505 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.9 Hz, 2H), 6.69 (s, 1H), 5.56 (d, J = 11.3 Hz, 3H), 4.18 (dd, J = 10.6, 5.2 Hz, 2H), 3.87 (s, 3H), 3.67 (t, J = 5.2 Hz, 2H), 2.35 (s, 3H), 2.17 - 2.03 (m, 2H), 1.82 (t, J = 8.9 Hz, 2H), 1.71 - 1.47 (m, 5H), 1.33 (s, 3H).

[0264] Example 65 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((1-(1-methoxyethyl)cyclopropyl)methoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 505 (M+H) + .

[0265] Examples 65A and 65B Chiral separation gave two isomers N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((1-((R)-1-methoxyethyl)cyclopropyl)methoxy)-2-methylquinazoline-4-formamine and N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-((1-((S)-1-methoxyethyl)cyclopropyl)methoxy)-2-methylquinazoline-4-formamine [ka]

[0266] Example 65A LC-MS: m / z 505 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.86 (d, J = 9.7 Hz, 2H), 6.69 (s, 1H), 5.66 - 5.40 (m, 3H), 4.11 (m, 1H), 3.88 (m, 4H), 3.29 (s, 3H), 3.13 (m, 2H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 0.76 - 0.42 (m, 4H).

[0267] Example 65B LC-MS: m / z 505 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.86 (d, J = 10.9 Hz, 2H), 6.69 (s, 1H), 5.65 - 5.44 (m, 3H), 4.17 (d, J = 10.2 Hz, 1H), 3.87 (s, 3H), 3.81 (d, J = 10.2 Hz, 1H), 3.28 (s, 3H), 3.11 (m, 2H), 2.33 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.73 - 0.46 (m, 4H).

[0268] Example 66 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-(((S)-tetrahydrofuran-3-yl)oxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 11.3 Hz, 2H), 6.69 (s, 1H), 5.56 (d, J = 10.7 Hz, 3H), 4.32 - 4.09 (m, 3H), 3.87 (s, 3H), 3.81 (d, J = 4.3 Hz, 2H), 3.77 - 3.61 (m, 4H), 2.35 (s, 3H), 1.95 (m, 2H), 1.54 (d, J = 7.0Hz, 3H).

[0269] Example 67 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(2-(((R)-tetrahydrofuran-3-yl)oxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J = 10.8 Hz, 2H), 6.69 (s, 1H), 5.55 (d, J = 13.1 Hz, 3H), 4.33 - 4.08 (m, 3H), 3.87 (s, 3H), 3.81 (d, J = 4.7 Hz, 2H), 3.70 (dt, J = 9.9, 6.4 Hz, 4H), 1.95 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H).

[0270] Example 68 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((R)-2-(oxetan-3-yloxy)propoxy)quinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.04 (s, 1H), 6.86 (d, J = 10.1 Hz, 2H), 6.70 (s, 1H), 5.68 - 5.44 (m, 3H), 4.79 (d, J = 5.9 Hz, 1H), 4.75 - 4.62 (m, 2H), 4.44 (dd, J = 9.5, 5.9 Hz, 2H), 4.02 (dd, J = 8.9, 2.6 Hz, 2H), 3.88 (s, 4H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H).

[0271] Example 69 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((S)-2-(oxetan-3-yloxy)propoxy)quinazolin-4-amine [ka] LC-MS: m / z 507 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.04 (s, 1H), 6.87 (d, J = 9.8 Hz, 2H), 6.70 (s, 1H), 5.56 (dd, J = 14.5, 6.7 Hz, 3H), 4.86 - 4.75 (m, 1H), 4.69 (dd, J = 14.7, 6.7 Hz, 2H), 4.44 (dd, J = 9.5, 5.9 Hz, 2H), 4.01 (dd, J = 9.5, 5.6 Hz, 2H), 3.89 (d, J = 7.1 Hz, 4H), 2.35 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H).

[0272] Example 70 (R)—N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 494 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.79 (s, 1H), 7.06 (s, 1H), 6.84 - 6.65 (m, 2H), 6.49 (s, 2H), 5.58 - 5.38 (m, 1H), 4.77 - 4.65 (m, 3H), 4.45 (d, J = 5.5 Hz, 2H), 4.22 (d, J = 2.6 Hz, 2H), 3.90 (s, 3H), 3.80 (t, J = 4.5 Hz, 2H), 2.36 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H).

[0273] Example 71 (S)-1,1-Difluoro-1-(2-fluoro-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol formate [ka] LC-MS: m / z 494 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.58 (t, J = 6.6 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.22 (m, 1H), 7.03 (s, 1H), 5.80 (p, J = 6.9 Hz, 1H), 5.34 (s, 1H), 4.24 (m, 2H), 3.87 (s, 3H), 3.77 (t, J = 4.6 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.3 Hz, 6H).

[0274] Example 72 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 494 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.10 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.64 (t, J = 6.5 Hz, 1H), 7.36 (t, J = 6.8 Hz, 1H), 7.28 (m, 1H), 7.09 (s, 1H), 6.00 - 5.77 (m, 1H), 5.39 (s, 1H), 4.30 (d, J = 3.4 Hz, 2H), 3.93 (s, 3H), 3.82 (t, J = 4.2 Hz, 2H), 3.41 (s, 3H), 2.34 (s, 3H), 1.64 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 11.1 Hz, 6H).

[0275] Example 73 (R)—N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-methoxy-2-methyl-6-(2-(1-methylcyclobutoxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 506 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 7.5 Hz, 1H), 7.79 (s, 1H), 7.06 (s, 1H), 6.73 (d, J = 22.6 Hz, 2H), 6.49 (s, 2H), 5.57 - 5.37 (m, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.32 (d, J = 6.3 Hz, 2H), 4.23 (s, 2H), 3.88 (s, 3H), 3.80 (s, 2H), 2.34 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H), 1.51 (s, 3H).

[0276] Example 74 (R)-1-(3-amino-5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 491 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.77 (s, 1H), 7.04 (s, 1H), 6.70 (d, J = 10.8 Hz, 2H), 6.56 (s, 1H), 5.67 - 5.46 (m, 1H), 5.19 (s, 2H), 5.08 (s, 1H), 4.30 - 4.14 (m, 2H), 3.88 (s, 3H), 3.81 - 3.69 (m, 2H), 3.35 (s, 3H), 2.38 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0277] Example 75 (R)-1,1-Difluoro-1-(2-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.63 (d, J = 5.0 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J = 7.2 Hz, 1H), 5.38 (s, 1H), 4.21 (d, J = 2.7 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J = 4.6 Hz, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.64 (d, J = 7.1 Hz, 3H), 1.10 (d, J = 6.5 Hz, 6H).

[0278] Example 76 (R)-1,1-Difluoro-1-(6-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.04 (s, 1H), 5.62 (t, J = 7.2 Hz, 1H), 5.28 (s, 1H), 4.29 - 4.19 (m, 2H), 3.88 (s, 3H), 3.82 - 3.69 (m, 2H), 3.36 (s, 3H), 2.29 (s, 3H), 1.62 (d, J = 7.1 Hz, 3H), 1.18 (d, J = 7.7 Hz, 6H).

[0279] Example 77 (R)-1,1-Difluoro-1-(5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.03 (s, 1H), 5.69 - 5.51 (m, 1H), 5.40 (s, 1H), 4.28 - 4.10 (m, 2H), 3.87 (s, 3H), 3.80 - 3.68 (m, 2H), 3.35 (s, 3H), 2.33 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H), 1.14 (d, J = 9.2 Hz, 6H).

[0280] Example 78 (R)-1,1-Difluoro-1-(4-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 477 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.56 (d, J = 5.0 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.52 (d, J = 4.3 Hz, 1H), 7.04 (s, 1H), 5.58 (t, J = 7.2 Hz, 1H), 5.26 (s, 1H), 4.22 (d, J = 2.8 Hz, 2H), 3.88 (s, 3H), 3.76 (t, J = 4.7 Hz, 2H), 3.36 (s, 3H), 2.30 (s, 3H), 1.61 (d, J = 7.1 Hz, 3H), 1.18 (d, J = 5.4 Hz, 6H).

[0281] Example 79 (R)-1,1-difluoro-1-(4-fluoro-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 494 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.3 Hz, 1H), 7.75 (s, 1H), 7.65 - 7.52 (m, 1H), 7.37 - 7.31 (m, 1H), 7.23 (t, J = 9.4 Hz, 1H), 7.02 (s, 1H), 5.75 (t, J = 7.1 Hz, 1H), 5.20 (s, 1H), 4.29 - 4.15 (m, 2H), 3.87 (s, 3H), 3.80 - 3.71 (m, 2H), 3.36 (s, 3H), 2.29 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H), 1.08 (s, 3H), 0.99 (s, 3H).

[0282] Example 80 (R)-1,1-difluoro-1-(3-fluoro-5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 494 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.98 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.44 - 7.32 (m, 2H), 7.10 (d, J = 9.3 Hz, 1H), 7.03 (s, 1H), 5.60 (t, J = 7.2 Hz, 1H), 5.30 (s, 1H), 4.22 (dd, J = 5.3, 3.5 Hz, 2H), 3.87 (s, 3H), 3.82 - 3.73 (m, 2H), 3.35 (s, 3H), 2.32 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 5.5 Hz, 6H).

[0283] Example 81 (R)-1,1-difluoro-1-(2-fluoro-5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 494 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 7.7 Hz, 1H), 7.68 (s, 1H), 7.55 (m, 2H), 7.21 (dd, J = 11.1, 8.6 Hz, 1H), 7.02 (s, 1H), 5.59 (t, J = 7.2 Hz, 1H), 5.27 (s, 1H), 4.24 - 4.16 (m, 2H), 3.87 (s, 3H), 3.81 - 3.72 (m, 2H), 3.35 (s, 3H), 2.34 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.15 (s, 6H).

[0284] Example 82 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-(2,2-difluorocyclopropyloxy)ethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 513 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.94 (t, J = 18.5 Hz, 1H), 7.75 (s, 1H), 7.04 (s, 1H), 6.85 (t, J = 16.3 Hz, 2H), 6.70 (s, 1H), 5.56 (dd, J = 16.5, 9.2 Hz, 3H), 4.35 - 4.19 (m, 2H), 4.08 - 3.92 (m, 3H), 3.88 (s, 3H), 2.36 (s, 3H), 1.82 - 1.47 (m, 5H).

[0285] Example 83 (R)—N-(1-(3-amino-5-(trifluoromethoxy)phenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 467 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.60 (s, 1H), 6.47 (d, J = 16.9 Hz, 1H), 6.32 (d, J = 11.2 Hz, 1H), 5.59 - 5.40 (m, 3H), 4.28 - 4.14 (m, 2H), 3.87 (s, 3H), 3.75 (t, J = 4.7 Hz, 2H), 3.34 (d, J = 12.2 Hz, 3H), 2.35 (s, 3H), 1.51 (t, J = 11.5 Hz, 3H).

[0286] Example 84 (R)-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)benzenesulfonamide [ka] LC-MS: m / z 447 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.05 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H), 7.79 - 7.61 (m, 3H), 7.52 (t, J = 7.7 Hz, 1H), 7.32 (s, 2H), 7.03 (s, 1H), 5.67 (m, 1H), 4.22 (dd, J = 7.1, 4.2 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J = 4.7 Hz, 2H), 3.35 (s, 3H), 2.35 (s, 3H), 1.61 (d, J = 7.1Hz, 3H).

[0287] Example 85 (R)-2,2-Difluoro-2-(3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 448 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.01 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.66 - 7.52 (m, 2H), 7.51 - 7.33 (m, 2H), 7.03 (s, 1H), 5.63 (m, 2H), 4.22 (d, J = 2.5 Hz, 2H), 3.94 - 3.71 (m, 7H), 3.35 (s, 3H), 2.35 (s, 3H), 1.60 (d, J = 7.1 Hz, 3H).

[0288] Example 86 (R)-1-(3-(1-((6,7-bis(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 538 (M+H) +. 1 H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.85 (s, 1H), 7.62 (t, J = 6.8 Hz, 1H), 7.27 (dt, J = 15.5, 7.3 Hz, 2H), 7.06 (s, 1H), 5.91 - 5.77 (m, 1H), 5.32 (s, 1H), 4.31 - 4.17 (m, 4H), 3.83 - 3.66 (m, 4H), 3.38 (m, 6H), 2.32 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 10.7Hz, 6H).

[0289] Example 87 (R)-1,1-Difluoro-1-(3-methoxy-5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 506 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.15 (d, J = 13.3 Hz, 2H), 7.04 (s, 1H), 6.87 (s, 1H), 5.68 - 5.53 (m, 1H), 5.22 (s, 1H), 4.29 - 4.12 (m, 2H), 3.88 (s, 3H), 3.75 (d, J = 7.3 Hz, 5H), 3.36 (s, 3H), 2.35 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H), 1.14 (s, 6H).

[0290] Example 88 (R)-1-(2-chloro-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 510 (M+H) + . H NMR (400 MHz, DMSO) δ 8.13 (d, J = 7.1 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 6.6 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.02 (s, 1H), 5.95 (t, J = 7.0 Hz, 1H), 5.30 (s, 1H), 4.26 (dd, J = 9.7, 4.7 Hz, 2H), 3.87 (s, 3H), 3.77 (t, J = 4.6 Hz, 2H), 3.37 (s, 3H), 2.25 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 13.6 Hz, 6H).

[0291] Example 89 (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazoline-7-carbonitrile [ka] LC-MS: m / z 489 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.52 (d, J = 7.1 Hz, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.32 (t, J = 6.7 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 5.79 (p, J = 6.8 Hz, 1H), 5.30 (s, 1H), 4.40 (dd, J = 5.0, 2.9 Hz, 2H), 3.89 - 3.75 (m, 2H), 3.39 (s, 3H), 2.33 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.4 Hz, 6H).

[0292] Example 90 (R)-1,1-Difluoro-1-(3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-methylphenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 490 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.07 (d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.30 - 7.14 (m, 2H), 7.01 (s, 1H), 5.79 (t, J = 7.1 Hz, 1H), 5.24 (s, 1H), 4.32 - 4.18 (m, 2H), 3.86 (s, 3H), 3.76 (t, J = 4.6 Hz, 2H), 3.36 (s, 3H), 2.63 (s, 3H), 2.30 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 10.1 Hz, 6H).

[0293] Example 91 (R)-3-(1,1-difluoro-2-hydroxy-2-methylpropane)-5-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)benzonitrile [ka] LC-MS: m / z 501 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.03 (d, J = 10.3 Hz, 2H), 7.87 (s, 1H), 7.70 (d, J = 11.1 Hz, 2H), 7.03 (s, 1H), 5.58 (dd, J = 14.1, 7.0 Hz, 1H), 5.41 (s, 1H), 4.22 (dd, J = 5.5, 3.6 Hz, 2H), 3.87 (s, 3H), 3.82 - 3.71 (m, 2H), 3.36 (s, 3H), 2.31 (s, 3H), 1.62 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 10.2 Hz, 6H).

[0294] Example 92 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 536 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.29 (d, J = 6.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.04 (s, 1H), 5.80 (s, 1H), 5.33 (s, 1H), 4.76 - 4.62 (m, 3H), 4.46 (dd, J = 5.7, 3.6 Hz, 2H), 4.24 (dd, J = 8.0, 4.2 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J = 4.6 Hz, 2H), 2.29 (s, 3H), 1.58 (d, J = 7.0 z, 3H), 1.22 (d, J = 11.2 Hz, 6H).

[0295] Example 93 (R)-1-(3-(1-((6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 520 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.29 (d, J = 6.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.03 (s, 1H), 5.81 (d, J = 7.2 Hz, 1H), 5.32 (s, 1H), 4.23 (dd, J = 7.5, 4.4 Hz, 2H), 3.86 (d, J = 6.5 Hz, 5H), 3.43 (td, J = 5.9, 3.0 Hz, 1H), 2.28 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.0 Hz, 6H).

[0296] Example 94 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 464 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.21 (d, J = 7.3 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.38 (dd, J = 9.1, 2.5 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 5.80 (t, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.25 (d, J = 3.1 Hz, 2H), 3.75 (t, J = 4.5 Hz, 2H), 3.36 (s, 3H), 2.30 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.3 Hz, 6H).

[0297] Example 95 (R)-1-(3-(1-((7-bromo-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 542 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.39 (d, J = 7.0 Hz, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.31 (t, J = 6.6 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 5.80 (t, J = 7.1 Hz, 1H), 5.31 (s, 1H), 4.34 (dd, J = 7.2, 4.1 Hz, 2H), 3.81 (t, J = 4.6 Hz, 2H), 3.40 (s, 3H), 2.31 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.6 Hz, 6H).

[0298] Example 96 (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-ol [ka] LC-MS: m / z 480 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.71 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 11.6 Hz, 2H), 7.28 (t, J = 6.7 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.67 (s, 1H), 5.91 - 5.60 (m, 1H), 4.20 (d, J = 4.0 Hz, 2H), 3.75 (t, J = 4.5 Hz, 2H), 3.35 - 3.19 (m, 3H), 2.19 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 11.8 Hz, 6H).

[0299] Example 97 (R)-1,1-Difluoro-1-(2-fluoro-3-(1-((7-deuterated methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 497 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.03 (d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.29 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 5.84 - 5.76 (m, 1H), 5.42 - 5.20 (m, 1H), 4.24 (dd, J = 7.6, 4.3 Hz, 2H), 3.76 (t, J = 4.6 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 11.0 Hz, 6H).

[0300] Example 98 (R)-1-(3-(1-((7-ethoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 508 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.58 (t, J = 6.5 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.00 (s, 1H), 5.79 (t, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.28 - 4.21 (m, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.77 (t, J = 4.7 Hz, 2H), 3.38 (s, 3H), 2.28 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 1.22 (d, J = 11.2 Hz, 6H).

[0301] Example 99 (R)-1,1-Difluoro-1-(2-fluoro-3-(1-((7-isopropoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 522 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.58 (t, J = 6.5 Hz, 1H), 7.30 (t, J = 6.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.01 (s, 1H), 5.79 (t, J = 7.2 Hz, 1H), 5.31 (s, 1H), 4.79 - 4.67 (m, 1H), 4.24 (dd, J = 6.0, 3.4 Hz, 2H), 3.76 (t, J = 4.7 Hz, 2H), 3.38 (s, 3H), 2.28 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.32 (dd, J = 5.6, 4.9 Hz, 6H), 1.22 (d, J = 11.3 Hz, 6H).

[0302] Example 100 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((7-cyclopropoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 520 (M+H) + .

[0303] Example 101 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-(pyridin-3-yl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropyl-2-ol [ka] LC-MS: m / z 541 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J = 2.3 Hz, 1H), 8.61 - 8.56 (m, 1H), 8.32 (d, J = 7.4 Hz, 1H), 8.08 - 8.01 (m, 1H), 7.95 (s, 1H), 7.65 - 7.58 (m, 2H), 7.49 (dd, J = 7.9, 4.8 Hz, 1H), 7.32 (t, J = 6.9 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 5.87 - 5.79 (m, 1H), 5.32 (s, 1H), 4.38 - 4.27 (m, 2H), 3.72 (t, J = 4.7 Hz, 2H), 3.30 (s, 3H), 2.33 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H), 1.24 (s, 3H), 1.22 (s, 3H).

[0304] Example 102 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropyl-2-ol [ka] LC-MS: m / z 544 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 2H), 7.64 - 7.57 (m, 1H), 7.35 - 7.27 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 5.88 - 5.76 (m, 1H), 5.32 (s, 1H), 4.42 - 4.29 (m, 2H), 3.92 - 3.85 (m, 5H), 3.43 (s, 3H), 2.31 (s, 3H), 1.61 (d, J = 7.1 Hz, 3H), 1.24 (s, 3H), 1.22 (s, 3H).

[0305] Example 103 (R)-1,1-difluoro-1-(2-fluoro-3-(1-(6-(2-methoxyethoxy)-2-methyl-7-(oxyethyl-3-amino)quinazolin-4-yl)aminoethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 536 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.28 (d, J = 6.5 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.63 (s, 1H), 5.78 (d, J = 7.0 Hz, 1H), 5.42 - 5.30 (m, 1H), 4.99 (t, J = 6.4 Hz, 2H), 4.58 (dd, J = 12.2, 5.1 Hz, 2H), 4.27 (d, J = 2.5 Hz, 2H), 3.79 (t, J = 4.7 Hz, 2H), 3.39 (s, 4H), 2.26 (s, 3H), 1.57 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 11.0 Hz, 6H).

[0306] Example 104 tert-Butyl (R)-3-(4-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)azetidine-1-carboxylate [ka] LC-MS: m / z 635 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.09 (d, J = 7.4 Hz, 1H), 7.84 (s, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.77 (s, 1H), 5.88 - 5.72 (m, 1H), 5.10 (s, 1H), 4.63 (d, J = 6.1 Hz, 1H), 4.44 - 4.21 (m, 4H), 3.81 (dd, J = 13.2, 8.4 Hz, 4H), 3.40 (s, 3H), 2.30 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H), 1.40 (d, J = 5.9 Hz, 9H), 1.23 (d, J = 11.2 Hz, 6H).

[0307] Example 105 (R)-1-(3-(1-((7-(azetidin-3-yloxy)-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + .

[0308] Example 106 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-((1-methylazetidin-3-yl)oxy)quinazoline-4-quinazoline)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 549 (M+H) + .

[0309] Example 107 (R)-1-(3-((4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)oxy)azetidin-1-yl)ethan-1-one [ka] LC-MS: m / z 577 (M+H) + .

[0310] Example 108 (R)-1,1-difluoro-1-(2-fluoro-3-(1-(6-(2-methoxyethoxy)-2-methyl-7-(pyridin-3-oxy)quinazolin-4-yl)aminoethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 557 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.52 - 8.37 (m, 1H), 8.24 (d, J = 16.4 Hz, 1H), 8.02 (s, 1H), 7.60 (s,1H), 7.45 (s, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 5.79 (s, 1H), 5.32 (s, 1H), 4.26 (s, 2H), 3.62 (s,2H), 3.22 (s, 3H), 2.28 (s, 3H), 1.59 (s, 3H), 1.21 - 1.14 (m, 6H).

[0311] Example 109 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((7-fluoro-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 482 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.28 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.80 (m, 1H), 5.33 (s, 1H), 4.36-4.33 (m, 2H), 3.79 (t, J = 4.0 Hz, 2H), 3.34 (s, 3H), 2.31 (s, 3H), 1.60 (d, J = 8.0 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).

[0312] Example 110 (R)-1-(3-(1-((7-chloro-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 498 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.41 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.24-7.20 (m, 1H), 5.80 (m, 1H), 5.34 (s, 1H), 4.36-4.33 (m, 2H), 3.81 (t, J = 4.0 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).

[0313] Example 111 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-(trifluoromethyl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 532 (M+H) + .

[0314] Example 112 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((fluoro-6-(2-methoxyethoxy)-2-methyl-7-(trifluoromethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 548 (M+H) + .

[0315] Example 113 (R)-1-(3-amino-5-(1-((6,7-bis(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.03 (s, 1H), 6.70 (d, J = 12.1 Hz, 2H), 6.56 (d, J = 4.9 Hz, 1H), 5.61 - 5.47 (m, 1H), 5.15 (s, 3H), 4.27 - 4.14 (m, 4H), 3.83 - 3.62 (m, 4H), 3.36 (s, 3H), 3.34 (s, 3H), 2.34 (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0316] Example 114 (R)—N-(1-(6-amino-4-(trifluoromethyl)pyridin-2-yl)ethyl)-6,7-bis(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 496 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 6.46 (s, 2H), 5.54 - 5.36 (m, 1H), 4.23 (dt, J = 10.2, 5.2 Hz, 4H), 3.74 (dt, J = 11.1, 4.5 Hz, 4H), 3.36 (s, 3H), 3.34 (s,3H), 2.32 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

[0317] Example 115 (R)-1-(3-amino-5-(1-(7-methoxy-2-methyl-6-(2-(pyridin-3-oxy)ethoxy)quinazolin-4-yl)amino)ethyl)benzene-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 554 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.37 (d, J = 2.9 Hz, 1H), 8.20 (dd, J = 4.6, 1.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.50 (dd, J = 8.4, 1.7 Hz, 1H), 7.36 (dd, J = 8.4, 4.6 Hz, 1H), 7.04 (s, 1H), 6.70 (d, J = 10.3 Hz, 2H), 6.55 (s, 1H), 5.60 - 5.48 (m, 1H), 5.18 (s, 2H), 4.47 (dd, J = 20.2, 3.9 Hz, 4H), 3.86 (s, 3H), 2.35 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0318] Example 116 (R)-1-(3-amino-5-(1-((6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropyl-2-ol [ka] LC-MS: m / z 517 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.02 (s, 1H), 6.74 - 6.66 (m, 2H), 6.56 (t, J = 1.9 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.16 (s, 2H), 5.08 (s, 1H), 4.19 (dd, J = 5.9, 4.0 Hz, 2H), 3.87 (s, 3H), 3.92 - 3.81 (m, 2H), 3.46 - 3.38 (m, 1H), 2.35 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H), 0.56 - 0.41 (m, 4H).

[0319] Example 117 (R)-1-(3-amino-5-(1-((7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropyl-2-ol [ka] LC-MS: m / z 533 (M+H) +. 1H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.74 - 6.66 (m, 2H), 6.56 (t, J = 1.9 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.17 (s, 2H), 5.09 (s, 1H), 4.76 - 4.62 (m, 3H), 4.50 - 4.40 (m, 2H), 4.20 (dd, J = 5.8, 3.8 Hz, 2H), 3.88 (s, 3H), 3.79 (dd, J = 5.8, 3.7 Hz, 2H), 2.35 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0320] Example 118 1-(3-amino-5-(1R)-1-(6-(2-(2,2-difluorocyclopropoxy)ethoxy)-7-methoxy-2-methylquinazolin-4-yl)aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 553 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.69 (d, J = 11.5 Hz, 2H), 6.55 (s, 1H), 5.62 - 5.46 (m, 1H), 5.16 (s, 2H), 5.07 (s, 1H), 4.23 (d, J = 4.5 Hz, 2H), 4.11 - 3.95 (m, 3H), 3.87 (s, 3H), 2.34 (s, 3H), 1.81 - 1.44 (m, 5H), 1.19 - 1.07 (m, 6H).

[0321] Example 119 (R)-1-(3-amino-5-(1-(7-methoxy-6-(2-(2-methoxyethoxy)ethoxy)-2-methylquinazolin-4-yl)amino)ethylphenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.02 (s, 1H), 6.70 (d, J = 11.6 Hz, 2H), 6.55 (s, 1H), 5.59 - 5.42 (m, 1H), 5.16 (s, 2H), 4.20 (t, J = 4.8 Hz, 2H), 3.92 - 3.77 (m, 5H), 3.63 (dd, J = 5.6, 3.9 Hz, 2H), 3.48 (dd, J = 5.6, 3.8 Hz, 2H), 3.26 (s, 3H), 2.34 (s, 4H), 1.53 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 10.9 Hz, 6H).

[0322] Example 120 (R)—N-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-5-(1-(7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-ylamino)ethyl)phenylacetamide [ka] LC-MS: m / z 533 (M+H) + . 1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 8.03 (s, 1H), 7.75 (d, J = 12.1 Hz, 2H), 7.61 (s, 1H), 7.26 (s, 1H), 7.04 (s, 1H), 5.65 - 5.51 (m, 1H), 5.19 (s, 1H), 4.27 - 4.15 (m, 2H), 3.88 (s, 3H), 3.81 - 3.70 (m, 2H), 3.37 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H), 1.60 (d, J = 7.1 Hz, 3H), 1.14 (s, 6H).

[0323] Example 121 (R)-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-5-(1-(7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-ylamino)ethyl)phenylcarbamate methyl [ka] LC-MS: m / z 549 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 5.65 - 5.51 (m, 1H), 5.17 (s, 1H), 4.30 - 4.15 (m, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.64 (s, 3H), 2.34 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0324] Example 122 (R)-1-(3-amino-5-(1-(7-methoxy-6-(2-(2-methoxyethoxy)ethoxy)-2-methylquinazolin-4-yl)amino)ethylphenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.03 (s, 1H), 6.72 (d, J = 12.9 Hz, 2H), 6.58 (s, 1H), 5.56 (d, J = 7.3 Hz, 1H), 5.16 (s, 2H), 5.06 (s, 1H), 4.96 - 4.83 (m, 1H), 3.88 (s, 3H), 3.69 - 3.52 (m, 4H), 3.30 (s, 6H), 2.36 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 2.7 Hz, 6H).

[0325] Example 123 (R)-1-(3-amino-5-(1-((6-(2-methoxyethoxy)-2-methyl-7-(1H-pyrazolyl-3-yl)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 527 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 13.05 (s, 1H), 8.14 (s, 2H), 7.82 (d, J = 23.4 Hz, 2H), 6.98 (s, 1H), 6.73 (d, J = 10.4 Hz, 2H), 6.57 (s, 1H), 5.64 - 5.50 (m, 1H), 5.16 (s, 2H), 5.08 (s, 1H), 4.34 (s, 2H), 3.85 (s, 2H), 3.39 (s, 3H), 2.39 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H), 1.13 (s, 6H).

[0326] Example 124 (R)-4-((1-(3-amino-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazoline-7-cyano [ka] LC-MS: m / z 486 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.41 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 6.74 - 6.66 (m, 2H), 6.57 (t, J = 1.9 Hz, 1H), 5.60 - 5.50 (m, 1H), 5.19 (s, 2H), 5.10 (s, 1H), 4.41 - 4.33 (m, 2H), 3.83 - 3.76 (m, 2H), 3.38 (s, 3H), 2.39 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.12 (s, 6H).

[0327] Example 125 (R)-1-(5-amino-2-fluoro-3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 509 (M+H) + .

[0328] Example 126 (R)-1-(5-amino-3-(1-((6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + .

[0329] Example 127 (R)-1-(5-amino-2-fluoro-3-(1-((7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 551 (M+H) + .

[0330] Example 128 (R)-1-(5-amino-2-chloro-3-(1-((7-methoxy-2-methyl-6-(2-methoxyethoxy)2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 525 (M+H) + .

[0331] Example 129 (R)-1-(5-amino-2-chloro-3-(1-((6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 535 (M+H) + .

[0332] Example 130 (R)-1-(5-amino-2-chloro-3-(1-((7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 567 (M+H) + .

[0333] Example 131 (R)-1,1-difluoro-1-(3-(1-((7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 476 (M+H) + .

[0334] Example 132 (R)-1-(3-(1-((6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 502 (M+H) + .

[0335] Example 133 (R)-1,1-difluoro-1-(3-(1-((7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 518 (M+H) + .

[0336] Example 134 N-(1-(4-amino-6-(1-methylcyclopropyl)pyridin-2-yl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 438 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.86 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.38 - 5.34 (m, 1H), 4.23 - 4.21 (m, 2H), 3.88 (s, 3H), 3.76 - 3.74 (m, 2H), 3.35 (s, 3H), 2.35 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.38 (s, 3H), 1.24-1.12 (m, 2H), 0.65 (m, 2H).

[0337] Example 135 N-(1-(4-amino-6-(1-methylcyclopropyl)pyridin-2-yl)ethyl)-6-(2-cyclopropoxyethoxy)-7-methoxy-2-methylquinazolin-4-amine [ka] LC-MS: m / z 464 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.86 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 1H), 6.37 (d, J = 1.6 Hz, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.46 - 5.17 (m, 1H), 4.28 - 4.13 (m, 2H), 3.95 - 3.78 (m, 5H), 3.46 - 3.35 (m, 1H), 2.35 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.38 (s, 3H), 1.15 (m 2H), 0.65 (m, 2H), 0.56 - 0.36 (m, 4H).

[0338] Example 136 N-(1-(4-amino-6-(1-methylcyclopropyl)pyridin-2-yl)ethyl)-7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 480 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 7.88 (m, 1H), 7.64 (s, 1H), 7.05 (s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.37 (m, 1H), 4.72 - 4.69 (m, 3H), 4.46 - 4.42 (m, 2H), 4.22 (m, 2H), 3.89 (s, 3H), 3.81 - 3.79 (m, 2H), 2.35 (s, 3H), 1.49 (d, J = 8.0 Hz, 3H), 1.38 (s, 3H), 1.19 (m, 2H), 0.66 (m, 2H).

[0339] Example 137 N-(1-(4-amino-6-(1-fluorocyclopropyl)pyridin-2-yl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 442 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.96-7.94 (m, 2H), 7.74 (s, 1H), 6.97 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 6.14 (s, 2H), 4.19 (m, 2H), 3.85 (s, 3H), 3.74 - 3.72 (m, 2H), 3.35 (s, 3H), 2.28 (s, 3H), 1.88 (m, 1H), 1.62-1.57 (m, 2H), 1.48 (d, J = 8.0 Hz, 3H), 0.93 (m, 1H).

[0340] Example 138 (R)—N-(1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 480 (M+H) + .

[0341] Example 139 (R)—N-(1-(3-(2-cyclopropyloxy-1,1-difluoroethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 506 (M+H) + .

[0342] Example 140 (R)—N-(1-(3-(1,1-difluoro-2-(oxetan-3-yloxy)ethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 522 (M+H)+ .

[0343] Example 141 N-((1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine (Isomer A and Isomer B) [ka]

[0344] Isomer A LC-MS: m / z 506 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.04-8.01 (m, 1H), 7.75 (s, 1H), 7.64-7.60 (m, 1H), 7.40-7.37 (m, 1H), 7.25-7.22 (m, 1H), 7.03 (s, 1H), 5.81-5.75 (m, 1H), 4.54-4.48 (m, 1H), 4.26-4.23 (m, 2H), 3.87 (s, 3H), 3.78-3.74 (m, 4H), 3.36 (s, 3H), 2.29 (s, 3H), 2.03-1.94 (m, 2H), 1.85-1.82 (m, 2H), 1.59 (d, J = 4 Hz, 2H).

[0345] Isomer B LC-MS: m / z 506 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.03-8.01 (m, 1H), 7.75 (s, 1H), 7.64-7.60 (m, 1H), 7.40-7.37 (m, 1H), 7.25-7.22 (m, 1H), 7.03 (s, 1H), 5.81-5.75 (m, 1H), 4.54-4.48 (m, 1H), 4.26-4.23 (m, 2H), 3.87 (s, 3H), 3.76-3.74 (m, 4H), 3.36 (s, 3H), 2.29 (s, 3H), 2.03-1.94 (m, 2H), 1.86-1.82 (m, 2H), 1.59 (d, J = 4 Hz, 2H).

[0346] Example 142 N-((1R)-1-(3-(difluoro(4-methylmorpholin-2-yl)methyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 536 (M+H) + .

[0347] Example 143 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((8-fluoro-7-methoxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 512 (M+H) + .

[0348] Example 144 (R)-1-(3-(1-((6-(2-cyclopropoxyethoxy)-8-fluoro-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 538 (M+H) + .

[0349] Example 145 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((8-fluoro-7-methoxy-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 554 (M+H) + .

[0350] Preparation of Examples 146 to 148 [ka]

[0351] Step 1: Methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (1.2 g), ethyl cyanoformate (0.932 g), and 2M HCl in dioxane (20 mL) were heated in a sealed tube for 20 h and then concentrated under reduced pressure. DMF and DBU were added to the residue to dissolve the solid, which was then separated by preparative liquid chromatography to give the desired product (230 mg, yield: 15%). LC-MS: m / z 323 (M+H). + .

[0352] Step 2: Ethyl 4-hydroxy-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-formate (230 mg) was dissolved in DMF (5 mL), DBU (540 mg) was added, and BOP (628 mg) was slowly added in an ice-water bath. After stirring at room temperature for 1 h, (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (201 mg) was added. The mixture was stirred at 100 °C for 16 h. The desired product was then separated by preparative liquid chromatography (LC) to obtain the desired product (150 mg, yield: 39%). LC-MS: m / z 540 (M+H).+ .

[0353] Step 3: Ethyl 4-hydroxy-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-formate (20 mg, 0.04 mmol) was added to ethanol (5 mL) and water (2 mL), followed by the addition of ammonium chloride (42 mg, 0.80 mmol) and iron powder (23 mg, 0.40 mmol). The mixture was heated to 80 °C and reacted with stirring for 3 h. The desired product was then separated by preparative liquid chromatography.

[0354] Example 146 (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-formate ethyl ester [ka] LC-MS: m / z 495 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.29 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.27 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.56 (m, 3H), 4.28 (d, J = 6.6 Hz, 4H), 3.93 (s, 3H), 3.77 (m, 2H), 3.36 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 6.9 Hz, 3H).

[0355] Example 147 (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-formic acid [ka] LC-MS: m / z 467 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.80 - 5.67 (m, 1H), 5.54 (s, 2H), 4.27 (d, J = 4.5 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J = 4.4 Hz, 2H), 3.51 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H).

[0356] Example 148 (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-carboxamide [ka] LC-MS: m / z 466 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.22 (d, J = 8.0 Hz, 1H), 7.82 (s, 2H), 7.46 (s, 1H), 7.23 (s, 1H), 6.91 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.73 - 5.58 (m, 1H), 5.51 (s, 2H), 4.27 (d, J = 4.1 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J = 4.5 Hz, 2H), 3.36 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H).

[0357] Example 149 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-cyclopropyl-6,7-dimethoxyquinazolin-4-amine [ka]

[0358] Step 1: Preparation of methyl 2-amino-5-hydroxy-4-methylbenzoate Methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (10 g) was dispersed in MeOH (100 mL), palladium on carbon (10% wt, 1.5 g) was added, and the mixture was purged with hydrogen three times and stirred at room temperature overnight. THF was added to the reaction mixture to dissolve the solids, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the desired product (8.0 g, yield: 92%). The product was used directly in the next step without further purification. LC-MS: m / z 198 (M+H) + .

[0359] Step 2: Preparation of 2-cyclopropyl-7-methoxyquinazoline-4,6-diol A mixture of methyl 2-amino-5-hydroxy-4-methylbenzoate (6 g), cyclopropionitrile (6.1 g), and 4M HCl in dioxane (100 mL) was heated to 110 °C and stirred overnight. The resulting reaction mixture was cooled, filtered, and the filter cake was collected and dried in air to give the desired product (6.0 g, 85% yield). This product was used directly in the next step without further purification. LC-MS: m / z 233 (M+H). + .

[0360] Step 3: Preparation of 2-cyclopropyl-6,7-dimethoxyquinazolin-4-ol A mixture of 2-cyclopropyl-7-methoxyquinazoline-4,6-diol (400 mg), ethyl p-toluenesulfonate (500 mg), potassium carbonate (476 mg), and DMF (5 mL) was heated to 100°C and stirred overnight. The resulting mixture was separated by chromatography under medium pressure to give the desired product (50 mg, yield: 12%). LC-MS: m / z 247 (M+H). + .

[0361] Step 4: Preparation of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-cyclopropyl-6,7-dimethoxyquinazolin-4-amine 2-Cyclopropyl-6,7-dimethoxyquinazolin-4-ol (50 mg) was dissolved in DMF (5 mL), DBU (152 mg) was added, and then BOP (177 mg) was slowly added while cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 1 h, followed by the addition of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (49 mg). The reaction mixture was stirred at 100 °C for 16 h, then cooled and separated by preparative chromatography to give the desired product (21 mg, yield: 26%). LC-MS: m / z 433 (M+H). + . 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 6.9 Hz, 1H), 7.68 (s, 1H), 6.98 (s, 1H), 6.83 (s, 1H), 6.79 - 6.76 (m, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 5.39 - 5.22 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.86 (dd, J = 8.2, 3.6 Hz, 1H), 1.54 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 4.6 Hz, 1H), 0.85 - 0.55 (m, 3H).

[0362] The following compounds are synthesized in the same manner as in Example 149, but with different starting materials: Example 150 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-cyclopropyl-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine [ka] LC-MS: m / z 477 (M+H) + . 1H NMR (400 MHz, DMSO) δ 7.93 (d, J = 7.1 Hz, 1H), 7.70 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 5.30 (t, J = 7.0 Hz, 1H), 4.21 (dd, J = 8.5, 4.3 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J = 4.6 Hz, 2H), 1.86 (m, 1H), 1.53 (d, J = 7.0 Hz, 3H), 0.98 (m, 1H), 0.84 - 0.57 (m, 3H).

[0363] Example 151 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-(3,3-difluorocyclobutyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine [ka] LC-MS: m / z 527 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.90 (s, 1H), 7.09 (s, 1H), 6.87 (d, J = 14.5 Hz, 2H), 6.69 (s, 1H), 5.59 - 5.35 (m, 3H), 4.27 (dd, J = 9.9, 4.8 Hz, 2H), 3.89 (s, 3H), 3.76 (t, J = 4.6 Hz, 2H), 3.35 (s, 4H), 2.91 - 2.72 (m, 4H), 1.60 (d, J = 7.0 Hz, 3H).

[0364] Example 152 (R)-1-(3-amino-5-(1-((2-(3,3-difluorocyclobutyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 567 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.06 (d, J = 7.3 Hz, 1H), 7.75 (s, 1H), 7.07 (s, 1H), 6.69 (s, 2H), 6.56 (s, 1H), 5.58 - 5.38 (m, 1H), 5.13 (s, 2H), 5.05 (s, 1H), 4.22 (d, J = 5.3 Hz, 2H), 3.89 (s, 3H), 3.81 - 3.70 (m, 2H), 3.37 (s, 3H), 3.26 - 3.20 (m, 1H), 2.94 - 2.72 (m, 4H), 1.56 (d, J = 7.0 Hz, 3H), 1.09 (s, 6H).

[0365] Example 153 Preparation of (R)-1-(3-(1-(7-ethynyl-6-(2-methoxyethoxy)-2-methylquinazoline-4-amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka]

[0366] Step 1: Preparation of (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-((trimethylsilyl)ethynyl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol Under argon protection, (R)-1-(3-(1-(7-bromo-6-(2-methoxyethoxy)-2-methylquinazolin-4-amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (100 mg, 0.18 mmol) was added to dioxane (5 mL), and triethylamine (56 mg, 0.55 mmol), cuprous iodide (20 mg), Pd(PPh)Cl, (20 mg), and ethynyltrimethylsilane (54 mg, 0.55 mmol) were added at room temperature. The reaction mixture was heated to 80 °C in a microwave oven for 2 h and then concentrated under reduced pressure to give the desired product (120 mg). This product was used directly in the next step without further purification.

[0367] Step 2: Preparation of (R)-1-(3-(1-(7-ethynyl-6-(2-methoxyethoxy)-2-methylquinazolin-4-amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (R)-1,1-Difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-((trimethylsilyl)ethynyl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (120 mg, 0.21 mmol) obtained in the previous step was added to methanol (5 mL) at room temperature, followed by potassium fluoride (38 mg, 0.64 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give the desired product (65 mg, yield: 64%). LC-MS: m / z 488 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.32 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.72 - 7.52 (m, 3H), 7.31 (t, J = 6.6 Hz, 1H), 7.23 (dd, J = 24.6, 16.9 Hz, 1H), 5.79 (t, J = 7.1 Hz, 1H), 5.31 (s, 1H), 4.48 (s, 1H), 4.38 - 4.22 (m, 2H), 3.79 (t, J = 4.7 Hz, 2H), 3.39 (s, 3H), 2.30 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.9 Hz, 6H).

[0368] The following compounds are synthesized in the same manner as in Example 153 with different starting materials: Example 154 (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-(prop-1-yn-1-yl)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol [ka] LC-MS: m / z 502 (M+H) + .

[0369] Example 155 (R)-1-(3-(1-((7-(cyclopropylethynyl)-6-(2-methoxyethoxy)-2-methylquinazoline-4-amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 528 (M+H) + .

[0370] Example 156 (R)-1-(3-(1-((6-(2-cyclopropoxyethoxy)-7-ethynyl-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 514 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.32 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.31 (t, J = 6.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 5.78 (dd, J = 14.1, 7.0 Hz, 1H), 5.30 (s, 1H), 4.48 (s, 1H), 4.28 (t, J = 6.7 Hz, 2H), 3.89 (t, J = 4.6 Hz, 2H), 3.49 (m, 1H), 2.30 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.8 Hz, 6H), 0.65 - 0.39 (m, 4H).

[0371] Example 157 (R)-1-(3-(1-((7-ethynyl-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 530 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.34 (d, J = 8 Hz, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.59 (m, 1H), 7.31 (m, 1H), 7.23-7.21 (m, 1H), 5.79 (m, 1H), 5.37 (brs, 1H), 4.74-4.72 (m, 3H), 4.53 (s, 1H), 4.48 - 4.46 (m, 2H), 4.31 - 4.30 (m, 2H), 3.84 (t, J = 4.0 Hz, 2H), 2.30 (s, 3H), 1.60 (d, J = 8.0 Hz, 3H), 1.22 (d, J = 8.0 Hz, 6H).

[0372] Example 158 1-(3-((R)-1-((7-ethynyl-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 500 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.32 (d, J = 6.5 Hz, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.58 (t, J = 6.6 Hz, 1H), 7.31 (t, J = 6.6 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 5.80 (t, J = 7.1 Hz, 1H), 5.30 (d, J = 8.2 Hz, 1H), 5.28 (m, 1H), 4.49 (s, 1H), 4.04 (dd, J = 10.2, 4.6 Hz, 1H), 3.97 - 3.77 (m, 3H), 2.43 - 2.24 (m, 4H), 2.11 - 1.97 (m, 1H), 1.61 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.5 Hz, 6H).

[0373] Example 159 (R)-1-(3-(1-((7-ethynyl-2-methyl-6-(2-(pyridin-3-yloxy)ethoxy)quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 551 (M+H) + .

[0374] Example 160 (R)—N-(2-((4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-7-ethynyl-2-methylquinazolin-6-yl)oxy)ethyl)-N-methylmethanesulfonamide [ka] LC-MS: m / z 565 (M+H) + .

[0375] Example 161 (R)-5-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-7-ethynyl-2-methylquinazolin-6-yl)-1-methylpyridin-2(1H)-one [ka] LC-MS: m / z 521 (M+H) + .

[0376] Example 162 (R)-1-(4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-7-ethynyl-2-methylquinazolin-6-yl)-4-methoxypiperidin-1-yl)ethan-1-one [ka] LC-MS: m / z 569 (M+H)+ .

[0377] Example 163 (R)-1-(3-amino-5-(1-((7-ethynyl-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 485 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 8.18 (d, J = 8 Hz, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 6.71-6.68 (m, 2H), 6.56 (s, 1H), 5.56-5.52 (m, 1H), 5.17 (s, 2H), 5.06 (s, 1H), 4.45 (s, 1H), 4.28 - 4.26 (m, 2H), 3.78 - 3.76 (m, 2H), 3.38 (s, 3H), 2.36(s, 3H), 1.56 (d, J = 4.0 Hz, 3H), 1.12 (s, 6H).

[0378] Example 164 1-(3-amino-5-((R)-1-((7-ethynyl-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 497 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.22 (m, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 6.56 (s, 1H), 5.57 (m, 1H), 5.23-5.20 (m, 3H), 5.08 (s, 1H), 4.00 (m, 1H), 3.92-3.82 (m, 3H), 2.37 (s, 3H), 2.32-2.30 (m, 1H), 1.56 (d, J = 8.0 Hz, 3H), 1.11 (s, 6H).

[0379] Example 165 (R)-1-(3-(1-((7-ethynyl-8-fluoro-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] LC-MS: m / z 506 (M+H) + .

[0380] Example 166 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethynyl-6-(2-methoxyethoxy)-2-methylquinazolin-4-amine [ka] LC-MS: m / z 445 (M+H) + .

[0381] Example 167 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethynyl-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine [ka] LC-MS: m / z 457 (M+H) + .

[0382] Example 168 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(2-cyclopropoxyethoxy)-7-ethynyl-2-methylquinazolin-4-amine [ka] LC-MS: m / z 471 (M+H) + .

[0383] Example 169 (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethynyl-2-methyl-6-(2-(oxetan-3-yloxy)ethoxy)quinazolin-4-amine [ka] LC-MS: m / z 487 (M+H) + .

[0384] Example 170 (R)-5-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-7-ethynyl-8-fluoro-2-methylquinazolin-6-yl)-1-methylpyridin-2(1H)-one [ka] LC-MS: m / z 539 (M+H) + . 1H NMR (400 MHz, DMSO) δ 8.67 (d, J = 7.3 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 9.4, 2.6 Hz, 1H), 7.60 (t, J = 6.7 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.52 (d, J = 9.4 Hz, 1H), 5.81 (t, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.81 (s, 1H), 3.54 (s, 3H), 2.39 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 10.0 Hz, 6H).

[0385] Example 171 Biological testing and evaluation The following biological test examples further illustrate and explain the present invention, but are not intended to limit the scope of the invention.

[0386] Compound KRAS G12C and SOS1 binding inhibition experiments. Experimental steps (1) Gradient dilution of test compounds: 10 mM stock solutions (dissolved in 100% DMSO) were added to a 384-well test plate, and the final content of DMSO was 0.25%. (2) 5 μL of Tag1-SOS1 solution was added to the test plate, and 5 μL of dilution buffer was added to the control plate. (3) Add 5 μL of Tag2-KRAS to the test plate. G12C The solution was added. (4) 10 μL of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 detection solution was added to the test plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 2 hours. (5) The plate was read. (6) Finally, the IC of the compound was calculated using the software GraphPad Prism. 50 Values ​​were calculated and curve fitting was performed.

[0387] KRAS G12C See Table 1 for the inhibitory activity of the compounds of the examples of the present invention against the binding of enzymes to SOS1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] As can be seen from Table 1, The compounds of the examples of the present invention inhibit KRAS G12C It exhibits excellent inhibitory activity against the binding of SOS1 to ATP.

[0388] Example 172: Inhibition of H358 cell proliferation by compounds Experimental steps 1. Cell culture (a) Cells were resuscitated in a T75 cell culture flask: [Table 2] (b) When the cells reached 80% to 90% confluence, they were passaged.

[0389] 2. Detection of cell proliferation Experimental steps The diluted test compound was added to a 384-well cell culture plate using a nanoliter dispensing system, and the wells were set up in multiple wells. An equal volume of medium was added to the positive control group, and an equal volume of DMSO was added to the negative control group. The plates were then centrifuged at 1000 rpm for 1 minute at room temperature. Cells were seeded into a 384-well culture plate. An equal volume of cells was added to the negative control group, and an equal volume of medium alone was added to the positive control group. The plates were centrifuged at 1000 rpm for 1 minute at room temperature, and the final compound DMSO concentration was 0.5%. The plates were then incubated at 37°C in a 5% CO2 incubator for 7 days. CellTiter-GloR 3D was added to a 384-well cell culture plate (b) at 20 μL / well, shaken at 320 rpm in the dark for 20 min, and then incubated at room temperature in the dark for 2 h. Luminescence values ​​were read using an Envision multipurpose microplate reader.

[0390] 3. Data analysis Formula: IR(%)=(1-(RLU) 化合物 -RLU ブランク対照 ) / (RLU 溶媒対照 -RLU ブランク対照 The inhibition rate (IR) of the test compound was calculated by multiplying the inhibition rate by 100%. The inhibition rates of the compounds at different concentrations were calculated using Excel, and then the inhibition curves were plotted using the software GraphPad Prism. The relevant parameters were the minimum inhibition rate, maximum inhibition rate, and IC 50 The experimental results are shown in Table 3.

[0391] [Table 3]

[0392] Evaluation by pharmacokinetic studies Male SD rats weighing approximately 220 g were fasted overnight and then intragastrically administered 10 mg / kg of a solution of the compound of the present invention (vector: CMC / TW80). Blood samples were collected 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, and 48 hours after administration of the compound of the present invention, and the plasma concentrations of the compound of the present invention were measured by LC / MS / MS. The detection results show that the compounds of the present invention have good pharmacokinetic properties.

[0393] Pharmacodynamic antitumor evaluation 5x10 6 Nude mice were inoculated subcutaneously into the right hind flank with 100 μL of a suspension containing MIA PaCa-2 tumor cells. Mice were monitored daily for health status, and measurements were initiated when tumors were palpable. Tumor volume was calculated using the formula: 0.5 × L × W. 2 where L and W represent the length and width of the tumor, respectively. 3 Once the mice reached the age of 18, they were randomly assigned to groups. The mice were intragastrically administered with a CMC-Na suspension of the corresponding compound (50 mg / kg) twice daily, while their general condition was monitored. Tumors were measured three times a week, and body weights were measured twice a week. The test results are shown in Table 4.

[0394] The structure of the reference compound BI3406 is as follows: [ka] [Table 4] The detection results showed that the compounds of the present invention have better antitumor effects than the reference compound BI3406.

[0395] All documents mentioned in this application are incorporated herein by reference, as if each document were incorporated by reference individually. It should be understood that after reading the above disclosure of the present invention, a person skilled in the art may make various changes or modifications to the present invention, and that equivalents thereof are also within the scope defined by the claims appended hereto.

Claims

1. A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I), its stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate, 【Chemistry 1】 During the ceremony, X is CR 6 Among them, R 6 is selected from hydrogen, deuterium, and halogen; Y is O, Z is unsubstituted or C 1 ~C 6 Alkyl group or C 3 ~C 6 C substituted by cycloalkyl group 1 ~C 18 is an alkylene group, W is a substituted or unsubstituted bond, C 3 ~C 20 a cycloalkylene group, a 4- to 20-membered heterocyclylene group containing one or two heteroatoms selected from O and N, OR 11 , N.R. 11 R 12 , SO 2 , N.R. 12 SO 2 , CO, and NR 12 Selected from CO, R 11 is C 1 ~C 6 C, substituted or unsubstituted by alkoxy groups 3 ~C 20 Cycloalkylene group, 4- to 20-membered heterocyclylene group containing one heteroatom O, C 1 ~C 18 alkylene groups, and 5- to 14-membered heteroaryl groups containing one N heteroatom; R 12 is a substituted or unsubstituted hydrogen, deuterium, C 1 ~C 6 Alkyl groups, and C 3 ~C 6 cycloalkyl groups, R 1 , R 2 represents hydrogen, deuterium, halogen, cyano group, -(CH 2 ) m R 8 , -(CH 2 ) m (CH=CH)R 8 , -(CH 2 ) m (C≡C)R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , -(CH 2 ) m SR 8 , -(CH 2 ) m COR 8 , -(CH 2 ) m C(O)OR 8 , -(CH 2 ) m S (O) q R 8 , -(CH 2 ) m NR 8 R 9 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C(O)NR 9 R 10 , -(CH 2 ) m S (O) q NR 8 R 9 , -(CH 2 ) m NR 8 S (O) q R 9 , -(CH 2 ) m NR 8 S (O) q NR 9 R 10 wherein CH 2 The H in R may be optionally substituted. 8 , R 9 , R 10 is a substituted or unsubstituted hydrogen, C 1 ~C 18 Alkyl group, C 1 ~C 18 Alkoxy group, C 3 ~C 20 cycloalkyl groups, 4- to 20-membered heterocyclyl groups containing one heteroatom selected from O and N, C 6 ~C 14 independently selected from an aryl group or a 5- to 14-membered heteroaryl group, or -(CH 2 ) m NR 8 R 9 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m S (O) q NR 8 R 9 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C(O)NR 9 R 10 , -(CH 2 ) m NR 8 S (O) q R 9 , -(CH 2 ) m NR 8 S (O) q NR 9 R 10 In R 8 and R 9 is cyclized with the adjacent N atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group, or R 9 and R 10 is cyclized with the adjacent atom to form a substituted or unsubstituted 4- to 8-membered heterocyclyl group; R 3 is a substituted or unsubstituted C 6 ~C 14 selected from aryl groups and 5- to 14-membered heteroaryl groups containing one N heteroatom; Among them, the substitutions include hydrogen, deuterium, C 1 ~C 18 Alkyl groups, deuterated C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkylhydroxy group, C 3 ~C 20 Cycloalkyl groups, C 3 ~C 20 Cycloalkyl-O-, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group, haloC 1 ~C 18 Alkoxy group, 4- to 20-membered heterocyclyl group, 4- to 20-membered heterocyclyl-O-, halogen, cyano group, C 2 ~C 6 Ester group, C 1 ~C 6 Amine group, C 2 ~C 6 Acyl group, C 1 ~C 6 Amide group, C 1 ~C 6 sulfonyl group, and C 1 ~C 6 It means that the alkyl group is substituted with one or more groups selected from the group consisting of sulfonamide groups, 1 ~C 18 Alkyl groups, deuterated C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkylhydroxy group, C 3 ~C 20 Cycloalkyl groups, C 3 ~C 20 Cycloalkyl-O-, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group or haloC 1 ~C 18 The alkoxy group may be one or more R a may be further substituted by, among which R a is C 1 ~C 6 Alkyl groups, deuterated C 1 ~C 6 Alkyl group, halo C 1 ~C 6 Alkyl group, halo C 1 ~C 6 Alkylhydroxy group, C 3 ~C 6 Cycloalkyl groups, C 3 ~C 6 Cycloalkyl-O-, C 1 ~C 6 Alkoxy group, deuterated C 1 ~C 6 Alkoxy group, haloC 1 ~C 6 Alkoxy group, C 6 ~C 14 Aryl group, 5- to 14-membered heteroaryl group, 4- to 6-membered heterocyclyl group, 4- to 6-membered heterocyclyl-O-, halogen, oxoC 1 ~C 6 Alkyl group, nitro group, hydroxy group, cyano group, C 2 ~C 6 Ester group, C 1 ~C 6 Amine group, C 2 ~C 6 Amide group, and C 1 ~C 6 sulfonamide group, or two substituents located on the same carbon atom are -(CH 2 ) n - or =O, R 4 is halogenated or unsubstituted C 1 ~C 6 is an alkyl group, R 5 is halogenated or unsubstituted, C 1 ~C 6 Alkyl group, C 3 ~C 6 Cycloalkyl groups, ester groups, COOH, and CONH 2 are independently selected from m and n are each independently 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; q is 1 or 2; The limiting condition is that Y is O, Z is a bond, and W is C. 3 ~C 20 When R is a cycloalkylene group or a 4- to 20-membered heterocyclylene group, 1 represents hydrogen, deuterium, halogen, cyano group, O(CH 2 ) p R 8 , C.O.R. 8 , C(O)OR 8 , N.R. 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 It is not that, A substituted benzo or pyridopyrimidine amine compound having the structure of the general formula (I), its stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate.

2. It has a structure represented by general formula (III), 【Chemistry 2】 In the formula, R 1 , R 2 , R 3 , X, Y, Z, W, n are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

3. It has a structure represented by general formula (IV), 【Transformation 3】 In the formula, R 1 , R 2 , R 3 , R 6 , X, Y, Z, W, n are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

4. having a structure shown in formula (VI): 【Chemistry 4】 During the ceremony, R 13 and R 14 is H, C 1 ~C 6 Alkyl groups, deuterated C 1 ~C 6 Alkyl groups, and halo groups 1 ~C 6 alkyl groups, Ring C is a substituted or unsubstituted C 3 ~C 12 a cycloalkylene group, a 4- to 12-membered heterocyclylene group, Each R 2 are homologous or different, and -(CH 2 ) m O(CH 2 ) p R 8 , -(CH 2 ) m (CH=CH) p R 8 , (CH 2 ) m (C≡C) p R 8 , -(CH 2 ) m SR 8 , -(CH 2 ) m COR 8 , -(CH 2 ) m C(O)OR 8 , -(CH 2 ) m S (O) q R 8 , -(CH 2 ) m NR 8 R 9 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C(O)NR 9 R 10 , -(CH 2 ) m S (O) q NR 8 R 9 , -(CH 2 ) m NR 8 S (O) q R 9 , -(CH 2 ) m NR 8 S (O) q NR 9 R 10 Independently selected from the group consisting of 2 wherein H is optionally substituted; m is 1, 2, 3, 4 or 5; t is 1, 2, 3, 4, 5, or 6; Among them, the substitutions include hydrogen, deuterium, C 1 ~C 18 Alkyl groups, deuterated C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkylhydroxy group, C 3 ~C 20 Cycloalkyl groups, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group, haloC 1 ~C 18 It means being substituted with one or more groups selected from the group consisting of an alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group; R 1 , R 3 , R 6 , R 8 , R 9 , R 10 , p, q and n are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

5. having a structure shown in formula (VII): 【Transformation 5】 During the ceremony, R 16 and R 17 H, and C 1 ~C 6 alkyl groups, R 18 is OR 11 , N.R. 11 R 12 , N.R. 12 SO 2 R 2 , C.O.R. 2 or NR 12 COR 2 Selected from R 11 is a substitution C 3 ~C 12 Cycloalkyl groups, substituted or unsubstituted 4- to 12-membered heterocyclyl groups, substituted or unsubstituted C 6 ~C 14 R is independently selected from an aryl group, a substituted or unsubstituted 5- to 14-membered heteroaryl group, 12 is a substituted or unsubstituted hydrogen, C 1 ~C 6 Alkyl groups, and C 3 ~C 6 cycloalkyl groups, or R 18 is -(CH 2 ) m (CH=CH)R 8 , -(CH 2 ) m (C≡C)R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , -(CH 2 ) m SR 8 , -(CH 2 ) m COR 8 , -(CH 2 ) m C(O)OR 8 , -(CH 2 ) m S (O) q R 8 , -(CH 2 ) m NR 8 R 9 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C(O)NR 9 R 10 , -(CH 2 ) m S (O) q NR 8 R 9 , -(CH 2 ) m NR 8 S (O) q R 9 , -(CH 2 ) m NR 8 S (O) q NR 9 R 10 Among them, CH 2 The H in R may be optionally substituted. 8 , R 9 , R 10 is a substituted or unsubstituted C 1 ~C 18 Alkyl groups, substituted or unsubstituted C 3 ~C 20 are each independently selected from a cycloalkyl group, a substituted or unsubstituted 4- to 20-membered heterocyclyl group, Among them, R 8 , R 9 and R 10 The substitution in C 3 ~C 20 Cycloalkyl groups, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group, haloC 1 ~C 18 It means being substituted with one or more groups selected from the group consisting of an alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group; t is 1, 2, 3, 4, 5, or 6; Unless otherwise specified, the substitutions include hydrogen, deuterium, C 1 ~C 18 Alkyl groups, deuterated C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkylhydroxy group, C 3 ~C 20 Cycloalkyl groups, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group, haloC 1 ~C 18 It means being substituted with one or more groups selected from the group consisting of an alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group; R 1 , R 2 , R 3 , R 6 , m, p and q are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

6. R 18 is OR 11 , N.R. 11 R 12 or NR 12 SO 2 R 2 Among them, R 11 is a substitution C 3 ~C 12 Cycloalkyl groups, substituted or unsubstituted 4- to 12-membered heterocyclyl groups, substituted or unsubstituted C 6 ~C 14 independently selected from an aryl group and a substituted or unsubstituted 5- to 14-membered heteroaryl group; R 12 is hydrogen, substituted or unsubstituted C 1 ~C 6 Alkyl groups, and substituted or unsubstituted C 3 ~C 6 independently selected from the group consisting of cycloalkyl groups; or R 18 is -(CH 2 ) m O(CH 2 ) p R 8 Among them, CH 2 The H in R may be optionally substituted. 8 is a substituted or unsubstituted C 1 ~C 18 Alkyl groups, substituted or unsubstituted C 3 ~C 20 a cycloalkyl group, a substituted or unsubstituted 4- to 20-membered heterocyclyl group, The substitution is C 1 ~C 6 Alkyl groups, deuterated C 1 ~C 6 Alkyl group, halo C 1 ~C 6 Alkyl group, halo C 1 ~C 6 Alkylhydroxy group, C 3 ~C 6 Cycloalkyl groups, C 1 ~C 6 Alkoxy group, deuterated C 1 ~C 6 Alkoxy group, haloC 1 ~C 6 Substitution with one or more groups selected from the group consisting of an alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group, 6. The compound of claim 5, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

7. having a structure represented by formula (IX-A) or formula (IX-B), 【Transformation 6】 In the formula, R 2 , R 3 , R 8 , R 9 , X, Y, Z, W, n and q are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

8. having a structure shown in formula (X), 【Transformation 7】 In the formula, R 8 is a substituted or unsubstituted C 3 ~C 20 selected from a cycloalkyl group or a 4- to 20-membered heterocyclyl group; Among them, the substitutions include hydrogen, deuterium, C 1 ~C 18 Alkyl groups, deuterated C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkyl group, halo C 1 ~C 18 Alkylhydroxy group, C 3 ~C 20 Cycloalkyl groups, C 1 ~C 18 Alkoxy group, deuterated C 1 ~C 18 Alkoxy group, haloC 1 ~C 18 It means being substituted with one or more groups selected from the group consisting of an alkoxy group, a halogen, an oxo group, a nitro group, a hydroxy group, a cyano group, an ester group, an amine group, an amide group, and a sulfonamide group; R 2 , R 3 , X, Y, Z, W, n and q are defined as in claim 1, A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates.

9. R 3 A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, characterized in that it is selected from the following: a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. 【Transformation 8】 【Chemistry 9】

10. A substituted benzo or pyridopyrimidine amine compound having the structure of general formula (I) according to claim 1, characterized in that it is a compound selected from the following: a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】

11. A method for preparing the compound of any one of claims 1 to 10, its stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate, comprising: 【Chemistry 59】 (i) reacting a compound of formula V-1 with a compound of formula V-2 in the presence of a first base to obtain a compound of formula V-3; (ii) reacting a compound of formula V-3 with a sulfonyl chloride V-4 in the presence of a second base and a catalyst to form a compound of formula V-5; (iii) reacting a compound of formula V-5 with an amine V-6 in the presence of a third base to obtain a compound of formula (I); During the ceremony, R' is selected from halogens, OTs or OMs; R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W and n are defined as in claim 1, The manufacturing method.

12. A pharmaceutical composition comprising: i) one or more compounds according to any one of claims 1 to 10, or stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, or solvates thereof; and ii) a pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the prevention and / or treatment of a disease associated with SOS1 activity or expression level.

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