Quinazoline derivative as KRAS mutation inhibitor for treatment of cancer

Abstract

The present invention relates to an inhibitor having a quinazoline-containing structure for the treatment of cancer. Specifically, the present invention relates to a derivative as represented by formula (I) having a quinazoline-containing structure, and a pharmaceutically acceptable salt thereof. The compound or the salt thereof can simultaneously inhibit a plurality of mutation types of the KRAS proteins, including KRAS G12C, G12D and G12V mutant proteins, and can be used as a KRAS small-molecule inhibitor for treating various diseases caused by KRAS mutations. The present invention relates to the structure of an inhibitor derivative having a quinazoline-containing structure and a preparation method therefor. The present invention further relates to a pharmaceutical composition containing the compound or the salt thereof, and a method for treating diseases related to KRAS mutations by means of using the compound and the salt thereof.

Description

Quinazoline derivatives as KRAS mutation inhibitors for treating cancer TECHNICAL FIELD

[0001] The present application provides a class of inhibitors with quinazoline structure for KRAS mutation. The present application relates to the structure and chemical synthesis method of quinazoline derivatives, which are mainly used as KRAS mutation small molecule inhibitors for treating various diseases caused by mutations, such as pancreatic cancer. BACKGROUND

[0002] Kirsten rat sarcoma viral oncogene homolog (KRAS) is a membrane-bound protein located inside the cell membrane, which acts as a molecular switch of GTPase, and is inactivated or activated by binding guanosine diphosphate (GDP) or guanosine triphosphate (GTP), respectively, to regulate the signal pathway inside the cell and participate in normal life activities of the cell; when KRAS mutation leads to abnormal coding protein, the mutant protein will activate downstream RAF-MEK-ERK, PI3K-AKT-mTOR and RAL-NF-Kb signal pathways, and cause excessive activation of cell proliferation, differentiation, survival, etc., thereby leading to tumor occurrence and spread.

[0003] As a member of the Ras oncogene family, compared with NRAS and HRAS, KRAS accounts for 85% of the entire Ras oncogenic mutation, and about 22% of cancer patients have KRAS mutation, for example, 90% of pancreatic cancer patients have KRAS mutation (Nat. Med. 2017, 23, 703); KRAS gene mutation often occurs at codons 12, 13 and 61, and in the past four decades of research, KRAS as a GTPase, its ability to hydrolyze GTP to GDP is relatively weak, and it needs the assistance of GTPase-activating protein (GAP) to promote the rapid hydrolysis of GTP to GDP, so as to make KRAS enter the inactivated state; missense mutation affects the binding of KRAS protein structure to GAP by changing the key amino acid, thereby hindering the normal conversion between GTP and GDP, attenuating the GTPase activity, and ultimately leading to KRAS being in an activated and overexcited state after binding with GTP, which causes the downstream signal pathway to be overactivated, thereby leading to cancer.

[0004] KRAS mutations are prevalent in human cancers, with G12C, G12D and G12V mutations caused by Glycine (Gly) mutation at position 12 of KRAS occurring at a high rate, especially in pancreatic cancer, with a high proportion of patients having at least two, or even all three of these mutations (Nat. Rev. Cancer 2018, 18, 767). If an inhibitor that can simultaneously inhibit at least two of KRAS G12C, G12D and G12V mutations (e.g. G12C and G12D), more preferably all three mutations, is obtained, the success rate of treatment for patients with cancer (especially pancreatic cancer) having the corresponding mutations will undoubtedly be greatly improved.

[0005] However, due to the structural characteristics of KRAS protein itself, there is no suitable pocket on the surface for drug action target, and for a long time, the research of drugs specifically targeting KRAS mutations has been slow, and only in recent years, for KRAS G12C mutation, due to the 12th cysteine as a covalent binding anchor, strong specific binding with covalent inhibitors, certain progress has been made, and currently MRTX849, AMG510, etc. have entered phase II or phase III clinical trials. However, for KRAS G12D, G12V and other mutations, there has been no breakthrough in the development of small molecule inhibitors for a long time, and the known KRAS G12D inhibitors such as MRTX1133 have low activity and cannot meet the needs of clinical use; the inhibitors specifically targeting G12V are even less reported. Moreover, there is no small molecule inhibitor in the prior art that can simultaneously inhibit multiple mutations, especially at least two of G12C, G12D and G12V, or even all three of them.

[0006] The structures of the foregoing prior art compounds are as follows:

[0007] Therefore, there is an urgent need for an inhibitor that can simultaneously inhibit multiple mutations, especially at least two of G12C, G12D and G12V (e.g. G12C and G12D), or even all three of them. In order to be suitable for being made into a drug (e.g. an oral drug or an injection), the inhibitor also needs to have excellent solubility. SUMMARY

[0008] In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and stereoisomers:

[0009] wherein

[0010] each R1is independently selected from the group consisting of deuterium, halogen (e.g., F, CI, Br, etc.), cyano, amino, hydroxyl, deuterated hydroxyl, nitro, carboxyl, -N(R4)2, -C(=O)N(R4)2, -NHC(=O)R4, -S-R4, -S(=O)2R7, -NHS(=O)2R7, -S(=O)2NHR4, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g., -CF3), C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl (e.g., cyclopropyl), mono C 1-6 alkylamino, di C 1-6 alkylamino, aminoacyl, mono C 1-6 alkylaminoacyl, di C 1-6 alkylaminoacyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or alkoxy is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, nitro, carboxyl, -CF3, C 1-4 alkyl or C 1-4 alkoxy; when n > 1, R1may be the same or different;

[0011] n is 0, 1, 2, 3, 4, or 5;

[0012] R2is selected from the group consisting of independently selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, deuterated hydroxyl, nitro, C 1- 4alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 2-4 alkynyl, C 2-4 alkenyl, C 1-4 alkylcyano, C 3-6 cycloalkyl, C 1-4 haloalkyl (e.g., -CF3), C 1-4 haloalkoxy (e.g., -OCF3, -OCHF2, etc.), aminoacyl, mono C 1-6 alkylaminoacyl, di C 1-6 alkylaminoacyl; when m > 1, R2may be the same or different;

[0013] m is 0, 1, or 2;

[0014] R3is selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, deuterated hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g., -CF3), C 2-4 alkynyl, C 2-4 alkenyl, C 3-6cycloalkyl (e.g., cyclopropyl), -N(R5)2, -C(=O)N(R5)2, -C(=O)NHR5, -NHC(=O)R5, -S-R5, -S(=O)2R7, -NR5S(=O)2R7, -S(=O)2N(R5)2, -S(=O)2NHR5, -NR5C(=O)-C 1-6 alkyl, -NR5C(=O)-3- to 8-membered heterocyclyl, -(CH2) k NHC(=O)-C 1-6 alkyl, -(CH2) k NHC(=O)-3- to 8-membered heterocyclyl, -NR5C(=O)-C 6-10 aryl, -NR5C(=O)-C 6-10 heteroaryl, -N(R5)(R6), -(CH2) k N(R5)(R6), -(CH2) k NH(R5), -(CH2) k OC(=O)N(R5)(R6), -C(=O)N(R5)(R6), -NHC(=NH)NH2, =CH2; said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl or =CH2is optionally substituted with 1 to 4 substituents independently selected from deuterium, halogen, cyano, amino, hydroxy, nitro, carboxy, -CF3, C 1-4 alkyl or C 1-4 alkoxy; when p is greater than 1, R3may be the same or different; or when p is greater than or equal to 2, 2 R3groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (preferably cyclopropyl);

[0015] R4is selected from hydrogen, deuterium, or deuterated or non-deuterated C 1-6 alkyl, C 1-6 haloalkyl;

[0016] R5and R6are each independently selected from hydrogen, deuterium, deuterated or non-deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1- 6haloalkyl;

[0017] R7is selected from deuterated or non-deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or amino;

[0018] p is 0, 1, 2, 3, 4 or 5;

[0019] k is 0, 1, 2, 3, 4 or 5.

[0020] In a preferred embodiment, n is 0, 1, 2 or 3.

[0021] In a preferred embodiment, R1is selected from the group consisting of hydroxy, deuterated hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl.

[0022] In a preferred embodiment, when n is not 0, one of R1is selected from the group consisting of hydroxy and deuterated hydroxy, preferably located at the 6-position of the oxazepane (i.e. the position which is separated by one carbon atom from each of the ring nitrogen and oxygen atoms); when n is greater than or equal to 2, the groups R1other than the above are selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl.

[0023] In a preferred embodiment,

[0024] is selected from the group consisting of:

[0025] In a preferred embodiment, is selected from the group consisting of:

[0026] In a more preferred embodiment,

[0027] is selected from the group consisting of:

[0028] In a further more preferred embodiment,

[0029] is selected from the group consisting of:

[0030] In a preferred embodiment, when m is not 0, R2is preferably selected from the group consisting of halogen and -CN, more preferably F.

[0031] In a preferred embodiment,

[0032] is selected from the group consisting of:

[0033] In a more preferred embodiment,

[0034] is selected from the group consisting of:

[0035] In a more preferred embodiment,

[0036] selected from the group consisting of:

[0037] more preferably selected from the group consisting of:

[0038] In a preferred embodiment, p is 0, 1 or 2. When p is other than 0, R3is preferably selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, deuterated hydroxyl, -S-R5(R5is preferably deuterated or non-deuterated C 1-6 alkyl), and C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, =CH2(optionally substituted with halogen), -S(=O)2R7, wherein said C 1-6 alkyl is optionally substituted with cyano or C 1-6 alkoxy; further, R3is preferably selected from the group consisting of halogen, cyano, amino, hydroxyl, deuterated hydroxyl, and C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, =CH2(optionally substituted with halogen), -S(=O)2R7; or when p is greater than or equal to 2, 2 R3groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (preferably cyclopropyl).

[0039] In a preferred embodiment,

[0040] selected from the group consisting of:

[0041] More preferably,

[0042] selected from the group consisting of:

[0043] In a particular embodiment, the present application relates to compounds or pharmaceutically acceptable salts thereof and stereoisomers, said compounds being selected from the group consisting of the compounds in the following table:

[0044] The compounds of the present application are capable of simultaneously inhibiting a plurality of mutations, particularly at least two of G12C, G12D and G12V (e.g. G12C and G12D), more preferably all three. In addition, the compounds of the present application also have excellent solubility, and are thus suitable for use in pharmaceuticals (e.g. oral preparations or injections, etc.).

[0045] The inventors of the present application have found that the compounds of the present application are capable of achieving the above-mentioned effects in close relation to the fixed structures shown in the compounds of formula (I), particularly the specific combination of the following fixed structural elements: substituted benzothiophene, trifluoromethyl and fluoro-substituted quinazoline, oxazepane (which more preferably has a hydroxyl or deuterated hydroxyl substituent), and piperidinylmethylcyclopropyl structure. As shown by the activity and solubility data of the compounds of the examples and comparative examples of the present application, one or more aspects of the aforementioned technical effects of the present application will be significantly deteriorated when one of the above-mentioned fixed structural elements is absent. In addition, the experimental data of the present application also show that the compounds of the present application are significantly superior to the compounds known in the prior art in the above-mentioned aspects. Specific embodiments

[0046] In a preferred aspect of the compounds of formula (I) of the present application, there are provided compounds of formula (I-A) or (I-B), or pharmaceutically acceptable salts and stereoisomers thereof:

[0047] wherein R3, p have the definitions given above, and when the substituent R1 on the oxazepane is a hydroxyl group, the hydroxyl group can be -OH or -OD. In addition, the definitions given above for the groups of the compounds of formula (I) also apply to the compounds of formula (I-A) and (I-B)

[0048] As understood by the person skilled in the art, the symbols used in the present specification represent the position of the bond when the group is bonded to other groups; or, when represents that the bond can be in any position in the plane of the double bond when the group is bonded to a double bond.

[0049] The present application provides a pharmaceutical composition comprising the above-mentioned compound, pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, and pharmaceutically acceptable carriers thereof.

[0050] As used herein, the term "pharmaceutically acceptable salts" refers to the compounds prepared in situ during the final isolation and purification of the compounds, or purified separately as the free acid or free base, and the compounds prepared by reaction with the appropriate acids or bases.

[0051] As used herein, the term "aryl" alone or in combination with another radical means a carbocyclic aromatic monocyclic ring group containing 6-10 carbon atoms, which can be further fused to one or more 5- or 6-membered carbocyclic groups which can be aromatic, saturated, or unsaturated.

[0052] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or tricyclic ring system which can contain 1-4 heteroatoms selected from N, O, and S. In the case of bicyclic or tricyclic ring systems, the "heteroaryl" group can be fused, bridged or spirocyclic. The "heteroaryl" group can be optionally substituted with one or more substituents.

[0053] The term "heterocyclyl" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic ring system in which at least one ring is a non-aromatic ring which can contain 1-4 heteroatoms selected from N, O, and S. In the case of bicyclic or tricyclic ring systems, the "heterocyclyl" group can be fused, bridged or spirocyclic. The "heterocyclyl" group can be optionally substituted with one or more substituents.

[0054] The term "halo" or "halogen" includes fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0055] In the case where a compound of Formula (I) contains an asymmetric atom (e.g., a carbon atom), it can exist in the form of an enantiomer, a diastereomer, or a combination of enantiomers or diastereomers in any ratio (e.g., a racemate).

[0056] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described above and a pharmaceutically acceptable diluent or carrier.

[0057] In another embodiment, there is also provided a method of treating a disease comprising, but not limited to, a condition involving KRAS G12D mutation (e.g., cancer) with a compound or a pharmaceutical composition of the present application.

[0058] General synthetic methods

[0059] The compounds of the present application can be prepared by the synthetic methods and reactions illustrated in the following schemes using commercially available reagents, or by other reagents and conventional methods well known to the skilled artisan.

[0060] The compounds of the present application can be prepared by a number of methods, including standard chemical methods. Illustrative general synthetic methods are set out below, and compounds of formula (I) can be prepared by methods known in the art of organic synthesis. In referring to the methods described in the examples below, it will be appreciated that group substitutions can be made to the substituents of the moieties as are well known in the art to give analogous derivatives without departing from the spirit of the application. If necessary, protecting groups are used for sensitive or reactive groups, in accordance with general principles or chemistry. Protecting groups are manipulated in accordance with standard practice in organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage by methods clear to those skilled in the art. The choice of method and the reaction conditions and their sequence will depend on the compounds of formula (I) being prepared.

[0061] The skilled person will be able to identify whether a stereocentre is present in a compound of formula (I). The present application therefore includes possible stereoisomers and includes both racemic compounds and individual enantiomers. Where the desired compound is an individual enantiomer, it can be obtained by stereospecific synthesis or by resolution of the final product, or of any convenient intermediate, using methods known in the art. Resolution of the final product, an intermediate, or a starting material can be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen and L. N. Mander (Wiley-Interscience, 1994).

[0062] The following examples can further describe the present application, however, these examples should not be construed as limiting the scope of the present application. Compounds encompassed by formula (I) can be prepared according to the synthetic routes of Examples 1, 2 or 3.

[0063] Example 1: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1- (piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene- 3-carbonitrile:

[0064] The synthesis of Example 1 (Compound 1) is mainly divided into the synthesis of fragment 1d, and the synthesis of Example 1 itself, which is shown in the specific routes as follows:

[0065] The synthesis route of fragment 1d is as follows:

[0066] The full synthetic route of Example 1 is as follows:

[0067] Step one: Synthesis of 1-(chloroacyl)cyclopropane-1-carboxylic acid methyl ester

[0068] Dissolve 1-(methylcarboxylate)cyclopropane-1-carboxylic acid (2.90 g, 20.1 mmol) and N,N-dimethylformamide (73.5 mg, 1.01 mmol) in dichloromethane (22 mL), slowly drop oxalyl chloride (3.83 g, 30.1 mmol) into it at 0 °C, stir for 2 hours at 20 °C. TLC monitor the end of the reaction, concentrated to get yellow liquid compound 1-(chloroacyl)cyclopropane-1-carboxylic acid methyl ester (6.50 g, 39.9 mmol, 99.3% yield).

[0069] Step two: Synthesis of 1-(piperidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester

[0070] Dissolve piperidine (2.04 g, 23.9 mmol) and triethylamine (4.85 g, 47.9 mmol) in dichloromethane (20 mL), slowly add 1-(chloroacyl)cyclopropane-1-carboxylic acid methyl ester (3.90 g, 23.9 mmol) into it at 0 °C, stir for 12 hours at 20 °C. LCMS monitor the end of the reaction, extract with dichloromethane, the organic phase is washed with saturated brine, dried over sodium sulfate, filtered and concentrated, column chromatography purification to get yellow liquid compound 1-(piperidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester (4.10 g, 19.4 mmol, 80.9% yield).

[0071] 1 H NMR (400 MHz, CDCl3) δ = 3.75-3.70 (m, 2H), 3.76-3.69 (m, 1H), 3.60-3.54 (m, 2H), 3.47-3.41 (m, 2H), 1.68-1.60 (m, 2H), 1.55 (br d, J = 4.8 Hz, 4H), 1.49-1.44 (m, 2H), 1.35-1.29 (m, 2H) ppm.

[0072] Step three: Synthesis of (1-(piperidin-1-ylmethyl)cyclopropyl)methanol

[0073] To a solution of methyl 1-(piperidin-1-ylcarbonyl)cyclopropane-1-carboxylate (4.00 g, 18.9 mmol) in tetrahydrofuran (40 mL) was added lithium aluminum hydride (13.6 mL, 2.5 M) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction was monitored by TLC. The reaction was quenched by the addition of sodium sulfate decahydrate. The mixture was filtered and concentrated to give compound (1-(piperidin-1-ylmethyl)cyclopropyl)methanol (2.60 g, 15.3 mmol, 81.1 % yield) as a colorless liquid.

[0074] 1 H NMR (400 MHz, CDC13) δ = 6.12 (br s, 1H), 3.54 (s, 2H), 2.59-2.41 (m, 5H), 1.59 (td, J = 5.6, 11.2 Hz, 4H), 1.44 (br s, 2H), 0.51-0.48 (m, 2H), 0.38-0.32 (m, 2H) ppm.

[0075] Step Four: Synthesis of methyl 2-amino-4-bromo-3-fluorobenzoate

[0076] To a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (16.0 g, 64.5 mmol) in N,N-dimethylformamide (150 mL) was added N-iodosuccinimide (15.1 g, 67.1 mmol) and p-toluenesulfonic acid (5.55 g, 32.2 mmol) at 80 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure and triturated with petroleum ether and ethyl acetate to give methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (19.0 g, 50.8 mmol, 78.8 % yield) as a yellow solid.

[0077] Step Five: Synthesis of methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate

[0078] To a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (16.0 g, 64.5 mmol) in N,N-dimethylformamide (150 mL) was added N-iodosuccinimide (15.1 g, 67.1 mmol) and p-toluenesulfonic acid (5.55 g, 32.2 mmol) at 80 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure and triturated with petroleum ether and ethyl acetate to give methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (19.0 g, 50.8 mmol, 78.8 % yield) as a yellow solid.

[0079] LCMS: m / z 373.7 [M+H] + .

[0080] Step six: synthesis of methyl 2-acetylamino-4-bromo-3-fluoro-5-iodobenzoate

[0081] Methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (20.0 g, 53.5 mmol) was dissolved in acetic acid (60 mL) and acetic anhydride (38.2 g, 374 mmol) was added. The reaction was stirred at 90 °C for 12 h. The reaction was monitored by LCMS. The reaction was concentrated under reduced pressure and the residue was slurried with petroleum ether and ethyl acetate to give methyl 2-acetylamino-4-bromo-3-fluoro-5-iodobenzoate (22.0 g, crude) as a yellow solid.

[0082] LCMS: m / z 415.7 [M+H] + .

[0083] Step seven: synthesis of methyl 2-acetylamino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate

[0084] Methyl 2-acetylamino-4-bromo-3-fluoro-5-iodobenzoate (22.0 g, 52.9 mmol) was dissolved in N-methylpyrrolidine (200 mL) and cuprous iodide (3.02 g, 15.9 mmol) and methyl fluorosulfonyldifluoroacetate (20.3 g, 105 mmol) were added. The reaction was stirred at 90 °C for 24 h. The reaction was monitored by LCMS. The reaction was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried with petroleum ether and ethyl acetate to give methyl 2-acetylamino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (10.0 g, 27.9 mmol, 52.8% yield) as a yellow solid.

[0085] LCMS: m / z 357.9 [M+H] + .

[0086] 1 H NMR (400 MHz, CDC13) δ = 9.24 (br s, 1H), 8.13-8.08 (m, 1H), 3.97 (s, 3H), 2.28 (s, 3H) ppm.

[0087] Step eight: synthesis of methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate

[0088] Methyl 2-acetylamino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (10.0 g, 27.9 mmol) was dissolved in methanol (20 mL) and hydrochloric acid in methanol (2 M, 100 mL) was added and the reaction was stirred at 80 °C for 3 h. The reaction was monitored by LCMS. The reaction was concentrated, basified with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with petroleum ether and ethyl acetate to obtain methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (8.50 g, 26.9 mmol, 96.3% yield) as a yellow solid.

[0089] LCMS: m / z 317.9 [M+H] + .

[0090] Step IX: Synthesis of methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)-5- (trifluoromethyl)benzoate

[0091] Methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (8.50 g, 26.9 mmol) was dissolved in tetrahydrofuran (60 mL) and trichloroacetyl isocyanate (6.08 g, 32.3 mmol) was added and the reaction was stirred at 20 °C for 1 h. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure to obtain methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)-5-(trifluoromethyl)benzoate (13.5 g, crude) as a yellow solid.

[0092] Step X: Synthesis of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol

[0093] Methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)-5-(trifluoromethyl)benzoate (22.0 g, 52.9 mmol) was dissolved in methanol (100 mL) and ammonia in methanol (7 M, 38.4 mL) was added and the reaction was stirred at 20 °C for 2 h. The reaction was monitored by LCMS. The reaction was filtered and the filter cake was triturated with dichloromethane to obtain 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (10.0 g, 27.9 mmol, 52.8% yield) as a white solid.

[0094] 1 H NMR (400 MHz, (CD3)2SO) δ = 7.89 (s, 1H) ppm.

[0095] Step XI: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline

[0096] To a solution of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (6.50 g, 19.9 mmol) in phosphorus oxychloride (19.8 g, 129 mmol, 30 mL) was added N,N-diisopropylethylamine (7.71 g, 59.6 mmol) dropwise slowly at 110 °C for 2 h. The reaction was monitored by LCMS. The reaction was concentrated and quenched with warm water. The mixture was extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 7-bromo-2,4-dichloro-8-fluoro-6- (trifluoromethyl)quinazoline (6.00 g, 16.5 mmol, 82.9% yield) as a yellow solid.

[0097] LCMS: m / z 364.8 [M+H] + .

[0098] 1 H NMR (400 MHz, CD3Cl) δ = 8.44 (d, J = 0.8 Hz, 1H) ppm.

[0099] Step Twelve: Synthesis of 4-(7-bromo-2-chloro-8-fluoro-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0100] To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (500 mg, 1.37 mmol) and N,N-diisopropylethylamine (532 mg, 4.12 mmol) in dichloromethane (35 mL) was added a solution of 6-methyl-1,4-oxazepan-6-ol (189 mg, 1.44 mmol) in dichloromethane (3 mL) dropwise at -60 °C. The reaction was stirred at -60 °C for 2 h. The reaction was monitored by LCMS. The reaction was extracted with water and dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (560 mg, 1.22 mmol, 88.8% yield) as a yellow solid.

[0101] LCMS: m / z 459.9 [M+H] + .

[0102] Step Thirteen: Synthesis of 4-(7-bromo-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0103] Dissolve 4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (800 mg, 1.74 mmol), (1-(piperidin-1-ylmethyl)cyclopropyl)methanol (1.20 g, 7.09 mmol) and potassium fluoride (1.01 g, 17.4 mmol) in dimethylformamide (20 mL), replace with nitrogen after nitrogen protection and stir at 100 °C for 12 hours. Monitor the reaction end by LCMS. The reaction solution is quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. Purify by prep-HPLC to obtain compound 4-(7-bromo-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (350 mg, 23.8% yield) as a yellow solid.

[0104] LCMS: m / z 593.0 [M+H] + .

[0105] Step Fourteen: Synthesis of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl- 1,4-oxazepan-4-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzo[d]thiophen-2-yl)carbamate

[0106] Dissolve 4-(7-bromo-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (300 mg, 507 µmol), tert-butyl N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- benzo[d]thiophen-2-yl)carbamate (318 mg, 761 µmol), cesium carbonate (363 mg, 1.12 mmol), bis(diphenylphosphino phenyl ether) palladium dichloride (72.6 mg, 101 µmol) in dioxane (6 mL), replace with nitrogen after nitrogen protection and stir at 85 °C for 2 hours. Monitor the reaction end by LCMS. Filter the reaction solution and concentrate. Purify by prep-HPLC to obtain compound tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiophen-2-yl)carbamate (180 mg, 44.2% yield) as a yellow solid.

[0107] LCMS: m / z 803.4 [M+H] + .

[0108] Step fifteen: synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0109] To a solution of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzothiophen-2-yl)carbamate (180 mg, 224 pmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (921 mg, 8.08 mmol) and the reaction was stirred at 20 °C for 12 h. The reaction was monitored to completion by LCMS and the reaction was basified and extracted, dried, filtered and concentrated. Purification by prep-TLC gave the compound 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile as a white solid (60.0 mg, 37.3% yield).

[0110] LCMS: m / z 703.3 [M+H] + .

[0111] 1 H NMR (400 MHz, (CD3)2SO) d = 8.88 (s, 1H), 8.05 (s, 2H), 7.24 (dd, J = 5.3, 8.3 Hz, 1H), 7.17 - 7.09 (m, 1H), 5.30 (s, 1H), 4.31 - 4.20 (m, 3H), 4.14 - 4.03 (m, 2H), 3.98 - 3.89 (m, 2H), 3.75 - 3.66 (m, 1H), 3.62 - 3.52 (m, 2H), 2.43 - 2.21 (m, 6H), 1.52 - 1.42 (m, 4H), 1.34 (br d, J = 4.5 Hz, 2H), 1.13 (s, 3H), 0.71 - 0.59 (m, 2H), 0.44 - 0.33 (m, 2H).

[0112] Example 2: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)- 2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0113] The synthetic route of Example 2 (compound 2) is as follows, starting from intermediate 1J of Example 1:

[0114] Step one: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-methoxypiperidin-1- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol

[0115] 4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol (700 mg, 1.53 mmol) and potassium fluoride (443 mg, 7.63 mmol), (1- ((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methanol (760 mg, 3.82 mmol) were dissolved in dimethyl sulfoxide (15 mL) and stirred at 90 °C for 2 hours. The reaction was monitored to completion by LCMS, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the product 4-(7-bromo-8-fluoro-2-((1-((4- methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)- 6-methyl-1,4-oxazepan-6-ol (240 mg, 25.3% yield) as a yellow solid.

[0116] LCMS: m / z 622.8 [M+H] + .

[0117] Step two: Synthesis of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzothiophene-2-yl)carbamate

[0118] Under nitrogen protection, 4-(7-bromo-8-fluoro-2-((1-(((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol (210 mg, 338 μmol), N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-benzothiophene-2-yl)carbamate tert-butyl ester (283 mg, 676 μmol), cesium carbonate (330 mg, 1.01 mmol), and bis(diphenylphosphine phenyl ether)palladium(II) dichloride (72.6 mg, 101 μmol) were dissolved in dioxane (6 mL), and then the mixture was purged with nitrogen three times. The reaction was carried out at 90 °C under a nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS until it ended. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by mechanical fractionation to give a yellow solid (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxacyclopenten-4-yl)-2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzothiophene-2-yl)tert-butyl carbamate (130 mg, 75.8% purity, 35.0% yield).

[0119] LCMS: m / z 833.4 [M+H] + .

[0120] Step 3: Synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-yl)-2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-onitrile

[0121] tert-Butyl (3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[d]thiophen-2- yl)carbamate (110 mg, 132 pmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) at 0 °C, then stirred at 20 °C for 2 hours. The reaction was monitored by LCMS, and the reaction was quenched with sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3- carbonitrile (27.4 mg, 28.2% yield) as a white solid.

[0122] LCMS: m / z 733.4 [M+H] + .

[0123] 1 H NMR (400 MHz, (CD3)2SO) d = 8.88 (s, 1H), 8.06 (s, 2H), 7.27-7.22 (m, 1H), 7.16-7.10 (m, 1H), 5.30 (s, 1H), 4.31-4.21 (m, 3H), 4.13-4.02 (m, 2H), 3.98-3.89 (m, 2H), 3.74-3.66 (m, 1H), 3.61-3.53 (m, 2H), 3.19 (s, 3H), 3.15-3.07 (m, 1H), 2.83-2.63 (m, 2H), 2.38-2.18 (m, 2H), 2.13-1.93 (m, 2H), 1.84-1.72 (m, 2H), 1.46-1.27 (m, 2H), 1.13 (s, 3H), 0.64 (br s, 2H), 0.40 (br s, 2H) ppm.

[0124] Example 3: 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0125] The synthetic route of Example 3 (Compound 3) is as follows, starting from Intermediate 1J of Example 1:

[0126] Step 1: Synthesis of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl- 1,4-oxaazacycloheptan-6-ol

[0127] To a solution of 4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl- 1,4-oxaazacycloheptan-6-ol (1.00 g, 2.18 mmol) and potassium fluoride (1.27 g, 21.8 mmol) in dimethyl sulfoxide (15 mL) was stirred at 90 °C for 5 h under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 10- 40% ethyl acetate in petroleum ether) to give 4-(7-bromo-2,8-difluoro-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl- 1,4-oxaazacycloheptan-6-ol (600 mg, 62.2% yield) as a yellow solid.

[0128] LCMS: m / z 441.7 [M+H] + .

[0129] Step 2: Synthesis of 4-(7-bromo-8-fluoro-2-((l-((4-fluoropiperidin-l- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl- 1,4-oxaazacycloheptan-6-ol

[0130] To a solution of (l-((4-fluoropiperidin-l-yl)methyl)cyclopropyl)methanol (762 mg, 4.07 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (150 mg, 3.75 mmol) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 1 h. Then the above solution was added slowly to a solution of 4-(7-bromo-2,8-difluoro-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl- 1,4-oxaazacycloheptan-6-ol (600 mg, 1.36 mmol) in tetrahydrofuran (5 mL) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 10- 40% ethyl acetate in petroleum ether) to give 4-(7-bromo-8-fluoro-2-((l-((4- fluoropiperidin- 1 -yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl- 1,4-oxaazacycloheptan-6-ol (600 mg, 63.3% yield) as a white solid.

[0131] LCMS: m / z 611.0 [M+H] + .

[0132] Step three: synthesis of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophen-2-yl)carbamate

[0133] Dissolve 4-(7-bromo-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)- 6-(trifluoromethyl)quinolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (260 mg, 427 pmol), tert- butyl N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen- 2-yl)carbamate (357 mg, 853 pmol), cesium carbonate (417 mg, 1.28 mmol), bis(diphenyl- phosphino)phenyl ether palladium(II) chloride (91.6 mg, 128 pmol) in dioxane (15 mL), and stir at 90 °C under nitrogen atmosphere for 12 hours after nitrogen replacement. Monitor the reaction by LCMS until completion. Filter the reaction mixture and concentrate. Purify by column chromatography to give tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophen-2-yl)carbamate (350 mg, 19.5% yield) as a white solid.

[0134] LCMS: m / z 821.2 [M+H] + .

[0135] Step four: synthesis of 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0136] To a solution of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophen-2-yl)carbamate (320 mg, 152 pmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (2.30 g, 20.2 mmol) and the reaction was stirred at 20 °C for 3 h. The reaction was monitored to completion by LCMS and the reaction was basified and extracted, dried, filtered and concentrated. Purification by prep-HPLC gave 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile (8.00 mg, 7.30% yield) as a white solid.

[0137] LCMS: m / z 721.1 [M+H] + .

[0138] 1 H NMR (400 MHz, (CD3)2SO) d = 8.88 (s, 1H), 8.05 (s, 2H), 7.24 (dd, J1= 5.4 Hz, J2= 8.4 Hz, 1H), 7.17-7.07 (m, 1H), 5.30 (s, 1H), 4.74-4.53 (m, 1H), 4.35-4.20 (m, 3H), 4.14-4.02 (m, 2H), 3.99-3.87 (m, 2H), 3.76-3.67 (m, 1H), 3.59-3.53 (m, 2H), 2.60-2.56 (m, 2H), 2.32 (br dd, J1= 2.6 Hz, J2= 7.0 Hz, 4H), 1.80 (br d, J = 3.8 Hz, 2H), 1.71-1.54 (m, 2H), 1.13 (s, 3H), 0.64 (s, 2H), 0.40 (s, 2H) ppm.

[0139] Example 4: 1-((1-((((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-2-yl)oxy)methyl) cyclopropyl)methyl)piperidine-4-carbonitrile:

[0140] The synthesis of Example 4 (Compound 4) is mainly divided into the synthesis of fragment 4e, and the synthesis of Example 4 itself, which is shown in the specific route as follows:

[0141] The synthetic route of fragment 1e is as follows:

[0142] Step one: synthesis of (1-((methoxymethoxy)methyl)cyclopropyl)methanol

[0143] (2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methanol (5.00 g, 48.9 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (1.96 g, 48.9 mmol, 60% purity) was added. Reaction was carried out at 0 °C for 30 min. Bromomethyl methyl ether (6.12 g, 48.9 mmol) was added and reaction was carried out at 0 °C for 3 h. TLC was monitored till completion of reaction. Ammonium chloride solution was used for quenching, ethyl acetate was used for extraction, brine was used for washing. Organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, which was purified by column chromatography to get (1-((methoxymethoxy)methyl)cyclopropyl)methanol (2.10 g, yield 29.3%).

[0144] 1 H NMR (400 MHz, CDCl3) d = 4.66 (s, 2H), 3.57 (s, 2H), 3.53 (s, 2H), 3.39 (s, 3H), 2.24 (br s, 1H), 0.56 (d, J = 3.6 Hz, 2H), 0.53 (d, J = 3.6 Hz, 2H) ppm.

[0145] Step two: synthesis of 1-((methoxymethoxy)methyl)cyclopropane-1-carbaldehyde

[0146] (1-((methoxymethoxy)methyl)cyclopropyl)methanol (2.50 g, 17.1 mmol) was dissolved in dichloromethane (50 mL), Dess-Martin oxidizing agent (8.70 g, 20.5 mmol) was added at 0 °C. Reaction was carried out at 20 °C for 1 h. TLC was monitored till completion of reaction. The reaction mixture was poured into sodium bicarbonate at 0 °C for quenching, ethyl acetate was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated at low temperature, which was purified by column chromatography to get 1-((methoxymethoxy)methyl)cyclopropane-1-carbaldehyde (1.5 g, yield 60.8%).

[0147] 1 H NMR (400 MHz, CDCl3) d = 9.04-8.95 (m, 1H), 4.67-4.62 (m, 2H), 3.75 (s, 2H), 3.40-3.35 (m, 3H), 1.26 (br s, 2H), 1.13 (br s, 2H) ppm.

[0148] Step three: synthesis of 1-((1-((methoxymethoxy)methyl)cyclopropyl)methyl)piperidine-4- carbonitrile

[0149] Dissolve 1-((methoxymethoxy)methyl)cyclopropane-1-carbaldehyde (1.50 g, 10.4 mmol) and piperidine-4-carbonitrile (1.72 g, 15.6 mmol) in methanol (30 mL), then add acetic acid (625 mg, 10.4 mmol) and sodium borohydride (20.6 g, 97.4 mmol). React at 20 °C for 1 h. Monitor the reaction to completion by LCMS. Quench with sodium bicarbonate, extract with ethyl acetate, wash with saturated brine, dry over sodium sulfate, concentrate under reduced pressure, then pass through column chromatography to obtain 1-((1-((methoxymethoxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile (700 mg, 28.2% yield).

[0150] 1 H NMR (400 MHz, CDCl3) δ = 4.63 (s, 2H), 3.42 (s, 2H), 3.36 (s, 3H), 2.74-2.58 (m, 3H), 2.34-2.26 (m, 4H), 1.94-1.83 (m, 4H), 0.53-0.48 (m, 2H), 0.36-0.32 (m, 2H) ppm.

[0151] Step four: synthesis of 1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidine-4-carbonitrile

[0152] Dissolve 1-((1-((methoxymethoxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile (700 mg, 19.4 mmol) in methanol (5 mL), add hydrochloric acid in methanol (2 M, 10 mL) at 0 °C. React at 20 °C for 2 h. Monitor the reaction to completion by LCMS. Concentrate the reaction, quench with ammonium hydroxide, and pass through column chromatography to obtain 1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidine-4-carbonitrile (270 mg, 47.3% yield).

[0153] The synthesis route of Example 4 (Compound 4) is as follows, starting from the intermediate 1J of Example 1:

[0154] Step five: synthesis of 1-((1-(((7-bromo-8-fluoro-4-(-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile

[0155] Sodium hydride (137 mg, 60% purity) was dissolved in tetrahydrofuran (8 ml) followed by dropwise addition of l-((l-(hydroxymethyl)cyclopropyl)methyl)piperidine-4- carbonitrile (700 mg, 3.60 mmol) and then reaction at 0 °C for 30 minutes. Subsequently, dropwise addition to a solution of 4-(7-bromo-2-chloro-8-fluoro-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-l,4-oxazepan-6-ol (800 mg, 1.81 mmol) in tetrahydrofuran (8 ml) and reaction at 20 °C for 3 hours. The reaction was monitored to completion by LCMS, quenched with ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to give l-((l-(((7-bromo-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile (440 mg, 37.9% yield) as a yellow solid.

[0156] LCMS: m / z 618.2 [M+H] + .

[0157] Step six: Synthesis of tert-butyl ((3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl- 1,4-oxazepan-4-yl)-2-(((((4-methoxypiperidin-l-yl)methyl)cyclopropyl)methyl)oxy)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophen-2-yl)amino)carbamate

[0158] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4- methoxypiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-6-(trifluoromethyl)quinolin-7-yl)-1- benzo[b]thiophene-2-yl)carbamate (130 mg, 47.2% yield) was obtained as a yellow solid. LCMS: m / z 828.5 [M+H]

[0159] LCMS: m / z 828.5 [M+H] + .

[0160] Step seven: synthesis of 1-((1-((((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro- 4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-2-yl)oxy)methyl) cyclopropyl)methyl)piperidine-4-carbonitrile

[0161] ((3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4- methoxypiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-6-(trifluoromethyl)quinolin-7- yl)benzo[b]thiophen-2-yl)carbamic acid tert-butyl ester (260 mg, 314 pmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) at 0 °C and stirred at 20 °C for 1 h. The reaction was monitored to completion by LCMS, neutralized with sodium bicarbonate, extracted with dichloromethane, washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The yellow solid 1-((1-((((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile (77.7 mg, 34.1% yield) was obtained by HPLC purification.

[0162] LCMS: m / z 728.3 [M+H] + .

[0163] 1 H NMR (400 MHz, (CD3)2SO) d = 8.89 (s, 1H), 8.06 (br s, 2H), 7.28-7.21 (m, 1H), 7.13 (t, J = 8.8 Hz, 1H), 5.31 (s, 1H), 4.33-4.20 (m, 3H), 4.15-4.02 (m, 2H), 3.98-3.88 (m, 2H), 3.74-3.66 (m, 1H), 3.63-3.52 (m, 2H), 2.85-2.75 (m, 1H), 2.63-2.52 (m, 2H), 2.36-2.20 (m, 4H), 1.86-1.74 (m, 2H), 1.71-1.55 (m, 2H), 1.13 (s, 3H), 0.63 (s, 2H), 0.40 (s, 2H) ppm.

[0164] Using similar methods to those described previously, the following compounds of the Examples can be synthesized by selecting appropriate starting materials:

[0165] Example 5: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinolin-7- yl)benzo[b]thiophene-3-carbonitrile:

[0166] LCMS: m / z 771.2 [M+H] + .

[0167] Example 6: 2-amino-4-(2-((1-((4-ethylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-8- fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7- fluorobenzo[b]thiophene-3-carboxylic acid:

[0168] LCMS: m / z 731.2 [M+H] + .

[0169] Example 7: 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carboxylic acid:

[0170] The synthetic route of Example 7 (Compound 7) is as follows, starting from Intermediate 1J of Example 1:

[0171] Step one: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-4-yl)-6-methyl-1,4-oxazepan- 6-ol

[0172] Sodium hydride (126 mg, 60% purity) was dissolved in tetrahydrofuran (5 ml), followed by dropwise addition of (1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methanol (700 mg, 3.60 mmol), then reacted at 0 °C for 30 minutes. Then dropwise addition to a solution of 4-(7-bromo-2-chloro-8-fluoro-6- (trifluoromethyl)quinolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (500 mg, 1.13 mmol) in tetrahydrofuran (5 ml), reacted at 20 °C for 3 hours. The reaction was monitored to completion by LCMS, quenched with ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated. The yellow solid 4-(7-bromo-8-fluoro-2-((1-((4- (fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (180 mg, 25.6% yield) was obtained by machine.

[0173] LCMS: m / z 622.9 [M+H] + .

[0174] Step two: Synthesis of tert-butyl ((3-cyano-7-fluoro-4-(8-fluoro-2-(((((4- (fluoromethyl)hexahydropyridin-l-yl)methyl)cyclopropyl)methyl)oxy)-4-(6-hydroxy- 6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophen-2- yl)carbamate

[0175] Step two: Synthesis of tert-butyl ((3-cyano-7-fluoro-4-(8-fluoro-2-(((((4- (fluoromethyl)hexahydropyridin-l-yl)methyl)cyclopropyl)methyl)oxy)-4-(6-hydroxy- 6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophen-2- yl)carbamate

[0176] LCMS: m / z 622.9 [M+H] + .

[0177] Step three: Synthesis of 2-amino-7-fluoro-4-(8-fluoro-2-((l-((4- (fluoromethyl)piperidin-l-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl- 1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0178] ((3-cyano-7-fluoro-4-(8-fluoro-2-(((((4-(fluoromethyl)hexahydropyridin-l- yl)methyl)cyclopropyl)methyl)oxy)-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-2-yl)carbamic acid tert-butyl ester (90.0 mg, 108 μmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) at 0 °C, then stirred at 20 °C for 1 h. The reaction was monitored by LCMS, and the reaction was quenched with sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC to give 2-amino-7-fluoro-4-(8-fluoro-2-((l-((4- (fluoromethyl)piperidin-l-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl- 1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile (25.7 mg, 32.4% yield) as a white solid.

[0179] LCMS: m / z 733.3 [M+H] + .

[0180] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.94 (s, 1H), 8.12 (s, 2H), 7.33-7.26 (m, 1H), 7.24-7.15 (m, 1H), 6.83-6.56 (m, 1H), 5.37 (s, 1H), 4.41-4.27 (m, 3H), 4.21-4.08 (m, 2H), 4.04-3.94 (m, 2H), 3.81-3.73 (m, 1H), 3.68-3.59 (m, 2H), 2.49-2.43 (m, 4H), 2.41-2.34 (m, 2H), 2.28-2.22 (m, 2H), 2.08-2.00 (m, 2H), 1.19 (s, 3H), 0.75-0.67 (m, 2H), 0.51-0.42 (m, 2H) ppm.

[0181] Using the appropriate starting materials and following the procedures described above, the following compounds of the Examples can be synthesized:

[0182] Example 8: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)- 2-((l-((4-(methylsulfonyl)piperidin-l-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0183] LCMS: m / z 781.3 [M+H] + .

[0184] Example 9: 1-((1-((((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-sulfonamide:

[0185] LCMS: m / z 782.3 [M+H] + .

[0186] Example 10: 2-amino-4-(2-((1-((4-cyclopropylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-8- fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7- fluorobenzo[b]thiophene-3-carbonitrile:

[0187] LCMS: m / z 743.3 [M+H] + .

[0188] Example 11 : 4-(2-((1-((6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-2-amino-7- fluorobenzo[b]thiophene-3-carbonitrile:

[0189] LCMS: m / z 729.3 [M+H] + .

[0190] Example 12: 6-((1-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-2-yl)oxy)methyl)cyclopropyl)methyl)-6-azaspiro[2.5]octane-1-carbonitrile:

[0191] LCMS: m / z 754.3 [M+H] + .

[0192] Example 13: 2-amino-4-(2-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0193] LCMS: m / z 765.2 [M+H] + .

[0194] Example 14: 2-amino-4-(2-((1-((4,4-dimethylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0195] LCMS: m / z 731.3 [M+H] + .

[0196] Example 15: 2-amino-4-(2-((1-((4,4-difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0197] LCMS: m / z 739.2 [M+H] + .

[0198] Example 16: 2-amino-4-(2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0199] LCMS: m / z 751.3 [M+H] + .

[0200] Example 17: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carboxylic acid:

[0201] The synthetic route for Example 17 (Compound 17) is as follows, starting from Intermediate 1J of Example 1:

[0202] Step one: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0203] Sodium hydride (113 mg, 60% purity) was dissolved in tetrahydrofuran (5 ml) under nitrogen atmosphere, followed by dropwise addition of a solution of (1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methanol (686 mg, 3.39 mmol) at 0 °C for 30 minutes. Then added to a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (500 mg, 1.13 mmol) in tetrahydrofuran (5 ml) at 20 °C for 3 hours. The reaction was monitored to completion by LCMS, quenched with ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product, 4-(7-bromo-8-fluoro-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (220 mg, 31.1% yield), was obtained after purification by machine.

[0204] LCMS: m / z 626.1 [M+H] + .

[0205] Step two: Synthesis of tert-butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzothiophen-2-yl)carbamate

[0206] Under nitrogen protection, 4-(7-bromo-8-fluoro-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazapyridine-heptane-6-ol (100 mg, 338 μmol), N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborenyl-2-yl)-1-benzothiophene-2-yl)carbamate tert-butyl ester (134 mg, 320 μmol), cesium carbonate (156 mg, 480 mmol), and bis(diphenylphosphine ether)palladium(II) dichloride (34.4 mg, 48.0 μmol) were dissolved in dioxane (5 mL), then purged three times with nitrogen, and the reaction was carried out at 110 °C under a nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by mechanical fractionation to obtain a yellow solid N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazapyridine-heptane-4-yl)-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzothiophene-2-yl)carbamate (133 mg, 92.0% purity, 47.2% yield).

[0207] LCMS: m / z 836.4 [M+H] + .

[0208] Step 3: Synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-yl)-2-((1-((4-(methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-onitrile

[0209] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- (methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7- yl)-1-benzothiophen-2-yl)carbamate (120 mg, 143 pmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) at 0 °C, then stirred at 20 °C for 1 h. The reaction was monitored by LCMS, and the reaction was quenched with sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to give 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- (methoxy-d3)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile (40.1 mg, 37.9% yield) as a white solid.

[0210] LCMS: m / z 736.4 [M+H] + .

[0211] 1 H NMR (400 MHz, (CD3)2SO) d = 8.83 (s, 1H), 8.01 (s, 2H), 7.23-7.16 (m, 1H), 7.12-7.05 (m, 1H), 5.26 (s, 1H), 4.28-4.15 (m, 3H), 4.09-3.98 (m, 2H), 3.93-3.83 (m, 2H), 3.68-3.60 (m, 1H), 3.57-3.50 (m, 2H), 3.07 (br s, 1H), 2.74-2.61 (m, 2H), 2.31-2.18 (m, 2H), 2.08-1.91 (m, 2H), 1.78-1.68 (m, 2H), 1.37-1.23 (m, 2H), 1.08 (s, 3H), 0.59 (br s, 2H), 0.35 (br s, 2H) ppm.

[0212] Using the appropriate starting materials and following the procedures described above, the following compounds of the Examples can be synthesized:

[0213] Example 18: 2-amino-7-fluoro-4-(8-fluoro-4-(6-(hydroxy-d)-6-methyl-1,4-oxazepan-4-yl)-2-((1- (piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene- 3-carbonitrile:

[0214] LCMS: m / z 704.2 [M+H] + .

[0215] Example 19: 2-amino-7-fluoro-4-(8-fluoro-4-(6-(hydroxy-d)-6-methyl-1,4-oxazepan-4-yl)- 2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin- 7-yl)benzo[b]thiophene-3-carboxylic acid:

[0216] LCMS: m / z 734.3 [M+H] + .

[0217] Example 20: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-3,6-dimethyl-1,4-oxazepan-4-yl)-2- ((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b] thiophene-3-carboxylic acid:

[0218] LCMS: m / z 717.3 [M+H] + .

[0219] Example 21: 2-amino-4-(2-((1-((4-aminopiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro- 4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b] thiophene-3-carboxylic acid:

[0220] LCMS: m / z 718.3 [M+H] + .

[0221] Example 22: 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-hydroxy-4-methylpiperidin-1-yl)methyl) cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin- 7-yl)benzo[b]thiophene-3-carboxylic acid:

[0222] LCMS: m / z 733.2 [M+H] + .

[0223] Example 23: 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-hydroxy-4- (trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6- methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3- carbonitrile:

[0224] LCMS: m / z 787.3 [M+H] + .

[0225] Example 24: 2-amino-4-(2-((1-(((3R,5R)-3,5-dimethylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0226] LCMS: m / z 731.3 [M+H] + .

[0227] Example 25: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)- 2-((1-(((R)-3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0228] LCMS: m / z 717.2 [M+H] + .

[0229] Example 26: 2-amino-7-fluoro-4-(8-fluoro-2-(1-(((R)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0230] LCMS: m / z 721.2 [M+H] + .

[0231] Example 27: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)- 2-((1-(((R)-3-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0232] LCMS: m / z 733.3 [M+H] + .

[0233] Example 28: 2-amino-4-(2-((2,2-difluoro-l-(piperidin-l-ylmethyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0234] LCMS: m / z 739.1 [M+H] + .

[0235] Example 29: 2-amino-4-(2-((2,2-difluoro-l-((4-methoxypiperidin-l-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0236] LCMS: m / z 769.2 [M+H] + .

[0237] Example 30: 2-amino-4-(2-((2,2-difluoro-l-((4-fluoropiperidin-l-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0238] LCMS: m / z 757.2 [M+H] + .

[0239] Example 31: 2-amino-4-(2-((l-((4-ethylpiperidin-l-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carboxylic acid:

[0240] LCMS: m / z 767.3 [M+H] + .

[0241] Example 32: 2-amino-4-(2-((2,2-difluoro-l-((4-(fluoromethyl)piperidin-l- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0242] LCMS: m / z 769.3 [M+H] + .

[0243] Example 33: 4-(2-((l-((6-azaspiro[2.5]octan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)- 8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-2- amino-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0244] LCMS: m / z 765.3 [M+H] + .

[0245] Example 34: 2-amino-4-(2-((2,2-difluoro-l-((4-hydroxy-4-methylpiperidin-l- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0246] LCMS: m / z 769.3 [M+H] + .

[0247] Example 35: 2-amino-4-(2-((2,2-difluoro-l-((4-hydroxy-4-(trifluoromethyl)piperidin-l- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0248] LCMS: m / z 823.2 [M+H] + .

[0249] Example 36: 2-amino-4-(2-(2-cyano-l-(piperidin-l-ylmethyl)cyclopropyl)methoxy)-8- fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7- fluorobenzo[b]thiophene-3-carbonitrile:

[0250] LCMS: m / z 728.3 [M+H] + .

[0251] Example 37: 2-amino-4-(2-((2,2-difluoro-1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-8- fluoro-4-(1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3- carbonitrile:

[0252] LCMS: m / z 709.3 [M+H] + .

[0253] Example 38: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-3-methoxy-6-methyl-1,4-oxazepan-4- yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene- 3-carbonitrile:

[0254] LCMS: m / z 733.3 [M+H] + .

[0255] Example 39: 2-amino-4-(4-(6-ethynyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-((1-(piperidin-1- ylmethyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)-7-fluorobenzo[b]thiophene-3- carbonitrile:

[0256] LCMS: m / z 713.3 [M+H] + .

[0257] Example 40: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl)1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6- H4)piperidin-1-yl)yl)methyl)cyclopropyl)methoxy)-6(trifluoromethyl)quinolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile 2

[0258] The synthesis of Example 40 (Compound 40) is mainly divided into the synthesis of fragment 40g, and the synthesis of Example 40 itself, which is shown in the specific route as follows:

[0259] The synthesis route of fragment 40g is as follows: ​

[0260] Step one: synthesis of 1-benzylpiperidine-2,6-dione

[0261] Piperidine-2,6-dione (3.00 g, 26.5 mmol) and benzyl bromide (5.44 g, 31.8 mmol) were dissolved in acetone (60 mL), to which potassium carbonate (7.33 g, 53.0 mmol) and tetrabutylammonium iodide (1.96 g, 5.30 mmol) solution was added, the reaction was reacted at 20 °C for 5 hours. The reaction was monitored to completion by LCMS. The reaction solution was filtered and concentrated. Column chromatography purification gave compound 1-benzylpiperidine-2,6-dione (5.00 g, 90.4% yield) as yellow oil.

[0262] LCMS: m / z 203.9 [M+H] + .

[0263] 1 H NMR (400 MHz, CDC13) δ = 7.36 - 7.16 (m, 5H), 4.92 (s, 2H), 2.63 (t, J = 6.6 Hz, 4H), 1.90 (quin, J = 6.6 Hz, 2H) ppm.

[0264] Step two: synthesis of 1-benzyl(2,2,6,6-2H4)piperidine

[0265] 1-benzylpiperidine-2,6-dione (5.00 g, 24.6 mmol) was dissolved in tetrahydrofuran (100 mL), deuterated tetrahydroaluminum lithium (3.73 g, 98.4 mmol) was added portionwise under nitrogen atmosphere at 0 °C, the reaction was reacted at 50 °C for 1.5 hours. The reaction was monitored to completion by LCMS. The reaction solution was quenched with sodium sulfate decahydrate under ice bath, filtered and concentrated. Column chromatography purification gave compound 1-benzyl(2,2,6,6-2H4)piperidine (3.00 g, 68.0% yield) as yellow oil.

[0266] LCMS: m / z 180.0 [M+H] + .

[0267] 1 H NMR (400 MHz, CDC13) δ = 7.26 - 7.13 (m, 5H), 3.40 (s, 2H), 1.52 - 1.45 (m, 4H), 1.39 - 1.30 (m, 2H) ppm.

[0268] Step three: synthesis of (2,2,6,6-2H4)piperidine hydrochloride

[0269] Dissolve 1 -benzyl(2,2,6,6-2H4)piperidine (3.00 g, 16.7 mmol) in methanol (50 mL) and add wet palladium on carbon (1.00 g, 10% purity) under nitrogen atmosphere. After purging with hydrogen, the reaction was stirred at 45 °C under hydrogen atmosphere (45 psi) for 12 h. The reaction was monitored by TLC. The reaction mixture was filtered and to the filtrate was added hydrochloric acid in methanol and concentrated to get white solid compound (2,2,6,6-2H4)piperidine hydrochloride (2.10 g, 99.9% yield).

[0270] 1 H NMR (400 MHz, CDC13) δ = 9.25 (br s, 2H), 1.93 - 1.75 (m, 4H), 1.68 - 1.56 (m, 2H) ppm.

[0271] Step Four: Synthesis of methyl 1-((2,2,6,6-2H4)piperidine-l-carbonyl)cyclopropane-l- carboxylate

[0272] Dissolve (2,2,6,6-2H4)piperidine hydrochloride (2.10 g, 16.7 mmol) and triethylamine (10.3 g, 101 mmol) in dichloromethane (50 mL) and cool to 0 °C under nitrogen atmosphere. To this was added dropwise a solution of methyl l-(chloroacyl)cyclopropane-l-carboxylate (3.30 g, 20.3 mmol) in dichloromethane (50 mL) and the reaction was stirred at 20 °C for 3 h. The reaction was monitored by LCMS. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave compound methyl l-((2,2,6,6-2H4)piperidine-l-carbonyl)cyclopropane-l-carboxylate (600 mg, 52.7% yield) as yellow oil.

[0273] LCMS: m / z 216.0 [M+H] + .

[0274] 1 H NMR (400 MHz, CDC13) δ = 3.72 (s, 3H), 1.63 (dt, J = 3.4, 7.4 Hz, 2H), 1.56 - 1.51 (m, 4H), 1.50 - 1.43 (m, 2H), 1.36 - 1.28 (m, 2H) ppm.

[0275] Step Five: Synthesis of (l-(((2,2,6,6-2H4)piperidin-l-yl)methyl)cyclopropyl)methanol

[0276] Methyl 1-((2,2,6,6-2H4)piperidine-1-carbonyl)cyclopropane-1-carboxylate (3.00 g, 13.9 mmol) was dissolved in tetrahydrofuran (60 mL) and lithium aluminum hydride solution (2.5 M, 10.0 mL) was added dropwise at 0 °C under nitrogen atmosphere and then allowed to react for 3 h at 0 °C. The reaction was monitored by TLC. To the reaction mixture was added sodium sulfate decahydrate at 0 °C to quench the reaction, filtered and the filtrate was concentrated. Compound (1-(((2,2,6,6-2H4)piperidin-1-yl)methyl)cyclopropyl)methanol (2.10 g, 86.9% yield) was obtained as a colorless oil.

[0277] LCMS: m / z 174.2 [M+H] + .

[0278] 1 H NMR (400 MHz, CDC13) δ = 6.57 - 5.76 (m, 1H), 3.53 (s, 2H), 2.42 (s, 2H), 1.61 - 1.52 (m, 4H), 1.43 (br s, 2H), 0.51 - 0.42 (m, 2H), 0.39 - 0.29 (m, 2H) ppm.

[0279] The synthesis route of Example 40 (Compound 40) is as follows, starting from Intermediate 1J of Example 1:

[0280] Step Six: Synthesis of 4-(7-bromo-8-fluoro-2-((1-(((2,2,6,6-2H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0281] Sodium hydride (110 mg, 2.75 mmol) was added to tetrahydrofuran (5 mL) at 0 °C under nitrogen atmosphere, then (1-(((2,2,6,6-2H4) piperidin-1-yl)methyl)cyclopropyl)methanol (500 mg, 2.89 mmol) was also added to it, stirred for 1 h at 0 °C under nitrogen atmosphere. The above mixture was added to a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (500 mg, 1.13 mmol) in tetrahydrofuran (5 mL) at 0 °C, stirred for 2 h at 0 °C. The reaction was monitored by LC-MS. The reaction was quenched with water and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, purified by prep-HPLC to get compound 4-(7-bromo-8-fluoro-2-((1-(((2,2,6,6-2H4) piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (220 mg, 29.2% yield) as a yellow solid.

[0282] LCMS: m / z 597.0 [M+H] + .

[0283] Step seven: Synthesis of tert-butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6-2H4) piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzo[b]thiophen-2-yl)carbamate

[0284] Dissolve 4-(7-bromo-8-fluoro-2-((1-(((2,2,6,6-2H4) piperidin-1-yl) methyl) cyclopropyl) methoxy)-6-(trifluoromethyl) quinolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (100 mg, 168 μmol), N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-2-yl) carbamic acid tert-butyl ester (175 mg, 420 μmol), cesium carbonate (164 mg, 504 μmol), bis(diphenylphosphino phenyl ether) palladium dichloride (60.1 mg, 83.9 μmol) in dioxane (10 mL), after nitrogen substitution, stir at 110 °C under nitrogen atmosphere for 12 hours. Monitor the reaction by LCMS. Filter the reaction solution. Purify by prep-HPLC to give compound N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6-2H4) piperidin-1-yl) methyl) cyclopropyl) methoxy)-6-(trifluoromethyl) quinolin-7-yl)-1- benzo[b]thiophen-2-yl) carbamic acid tert-butyl ester (130 mg, 40.0% yield) as yellow solid.

[0285] LCMS: m / z 807.4 [M+H] + .

[0286] Step eight: synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl) 1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6- 2 H4) piperidin-1-yl) methyl) cyclopropyl) methoxy)-6-(trifluoromethyl) quinolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile

[0287] To a solution of tert-butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6-2H4) piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)-1- benzo[b]thiophene-2-yl)carbamate (130 mg, 161 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2.03 g, 17.7 mmol) and the reaction was stirred at 20 °C for 2 h. The reaction was monitored to completion by LCMS and the reaction was basified and extracted, dried, filtered and concentrated. Purification by prep-HPLC gave compound 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-(((2,2,6,6- 2 H4) piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile (55.0 mg, 68.7% yield) as a white solid.

[0288] LCMS: m / z 707.2 [M+H] + .

[0289] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.89 (s, 1H), 8.07 (s, 2H), 7.24 (dd, J1= 5.4, J2= 8.4 Hz, 1H), 7.18-7.10 (m, 1H), 5.31 (s, 1H), 4.45-4.20 (m, 3H), 4.16-4.02 (m, 2H), 3.99-3.87 (m, 2H), 3.73-3.67 (m, 1H), 3.61-3.53 (m, 2H), 1.63-1.45 (m, 4H), 1.44-1.35 (m, 2H), 1.22-1.16 (m, 2H), 1.13 (s, 3H), 0.69 (br s, 2H), 0.49 (br s, 2H) ppm.

[0290] Example 41: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4- (methylsulfanyl)piperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-6-(trifluoromethyl)quinolin-7- yl)benzo[b]thiophene-3-carbonitrile

[0291] The synthesis of Example 41 (Compound 41) is mainly divided into the synthesis of fragment 41c, and the synthesis of Example 41 itself, which is shown in the specific route as follows:

[0292] The synthetic route of fragment 41c is as follows:

[0293] Step one: synthesis of methyl 2-(l-((4-(methylmercapto)piperidin-l- yl)methyl)cyclopropyl)carboxylate

[0294] Methyl 2-(l-((4-(methylmercapto)piperidin-l-yl)methyl)cyclopropyl)carboxylate (2.30 g, 8.94 mmol) was dissolved in tetrahydrofuran (30 mL), then lithium aluminum hydride (2.5 M, 7.15 mL, 17.9 mmol) was added slowly dropwise at 0 °C, finally reacted at 0 °C for 2 hours under nitrogen protection, TLC monitored the end of the reaction, quenched with sodium sulfate decahydrate, filtered, concentrated. The crude product was column chromatography to give colorless oil (l-((4-(methylmercapto)piperidin-l-yl)methyl)cyclopropyl)methanol (1.90 g, 89.7% yield).

[0295] LCMS: m / z 258.2 [M+H] + .

[0296] Step two: synthesis of (l-((4-(methylmercapto)piperidin-l-yl)methyl)cyclopropyl)methanol

[0297] Methyl 2-(l-((4-(methylmercapto)piperidin-l-yl)methyl)cyclopropyl)carboxylate (2.30 g, 8.94 mmol) was dissolved in tetrahydrofuran (30 mL), then lithium aluminum hydride (2.5 M, 7.15 mL, 17.9 mmol) was added slowly dropwise at 0 °C, finally reacted at 0 °C for 2 hours under nitrogen protection, TLC monitored the end of the reaction, quenched with sodium sulfate decahydrate, filtered, concentrated. The crude product was column chromatography to give colorless oil (l-((4-(methylmercapto)piperidin-l-yl)methyl)cyclopropyl)methanol (1.90 g, 89.7% yield).

[0298] The synthetic route of Example 41 (Compound 41) starting from intermediate 1J of Example 1 is as follows:

[0299] Step three: synthesis of 4-(7-bromo-8-fluoro-2-((l-((4-(methylmercapto)piperidin-l- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl- 1,4-oxazepan-6-ol

[0300] To a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (600 mg, 1.36 mmol), (1-((4-(methylthio)piperidin-1-yl)methyl)cyclopropyl)methanol (1.02 g, 4.75 mmol), N,N-diisopropylamine (705 mg, 5.43 mmol) in dry dioxane (12 ml) was heated at 100 °C for 12 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated and purified by prep-HPLC to give 4-(7-bromo-8-fluoro-2-((1-((4-(methylthio)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (260 mg, 30.1% yield) as white solid.

[0301] LCMS: m / z 639.1 [M+H] + .

[0302] Step four: Synthesis of N-(3-cyano-7-fluoro-4-(8-fluoro-4-(-6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-((1-((4-(methylthio)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-1-benzo[b]thiophene-2-yl)aminotert-butyl

[0303] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2- ((1-((4-(methylsulfanyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-7-yl)-1-benzo[b]thiophene-2-yl)carbamate (200 mg, 57.8% yield) was obtained as a yellow solid after prep-HPLC purification.

[0304] LCMS: m / z 849.5 [M+H] + .

[0305] Step five: synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-((((4-(methylsulfanyl)piperidin-1-yl)methyl)cyclopropyl)methyl) oxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0306] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2- ((1-((4-(methylsulfanyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinolin-7-yl)-1-benzo[b]thiophene-2-yl)carbamate (200 mg, 236 pmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) at 0 °C, then stirred at 25 °C for 2 h. LCMS monitored the reaction was completed, sodium bicarbonate was added to adjust the pH, dichloromethane was extracted, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and prep-HPLC purified to give a white solid (26.8 mg, 15.2% yield).

[0307] LCMS: m / z 749.2 [M+H] + .

[0308] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.90 (br s, 1H), 8.07 (s, 2H), 7.26 (dd, J1= 5.3, J2= 8.3 Hz, 1H), 7.16-7.12 (m, 1H), 5.31 (s, 1H), 4.31-4.22 (m, 3H), 4.14-4.04 (m, 2H), 3.98-3.91 (m, 2H), 3.74-3.67 (m, 1H), 3.62-3.54 (m, 2H), 2.97-2.79 (m, 2H), 2.36-2.22 (m, 2H), 2.01 (br s, 3H), 1.99-1.90 (m, 2H), 1.89-1.76 (m, 2H), 1.50-1.31 (m, 2H), 1.14 (s, 3H), 0.71-0.56 (m, 2H), 0.40 (br s, 2H) ppm.

[0309] Example 42: 2-Amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl)-1,4-oxazepan-4-yl)-2-((1-((4-methoxy(2,2,6,6- 2 H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile

[0310] The synthesis of Example 42 (Compound 42) is mainly divided into the synthesis of fragment 42h, and the synthesis of Example 42 itself, which is shown in the specific route as follows:

[0311] The synthesis route of fragment 42h is as follows:

[0312] Step one: synthesis of 1-benzyl-4-((tert-butyldimethylsilyl)oxy)piperidine-2,6-dione

[0313] To a solution of 4-((tert-butyldimethylsilyl)oxy)oxane-2,6-dione (10.0 g, 40.9 mmol) in tetrahydrofuran (100 mL) was added benzylamine (4.60 g, 43.0 mmol) at 20 °C and the reaction was allowed to proceed for 30 min. The reaction was then concentrated, quenched with aqueous hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was dissolved in acetic anhydride (12.5 g, 123 mmol), triethylamine (6.21 g, 61.4 mmol) was added and the reaction was allowed to proceed at 80 °C for 1 h. The reaction was then concentrated, quenched with aqueous hydrochloric acid, extracted with ethyl acetate, washed with sodium bicarbonate solution, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography to give 1-benzyl-4-((tert-butyldimethylsilyl)oxy)piperidine-2,6-dione (7.80 g, 57.1 % yield).

[0314] LCMS: m / z 334.2 [M+H] + .

[0315] Step two: Synthesis of 1-benzyl-4-hydroxypiperidine-2,6-dione

[0316] To a solution of 1-benzyl-4-((tert-butyldimethylsilyl)oxy)piperidine-2,6-dione (7.10 g, 21.3 mmol) in tetrahydrofuran (60 mL) was added triethylamine trihydrofluoride (34.3 g, 213 mmol) slowly dropwise at 0 °C and finally the reaction was allowed to proceed at 25 °C for 12 h under nitrogen atmosphere. The reaction was monitored by LCMS and quenched with sodium sulfate decahydrate, filtered and concentrated. The crude was purified by column chromatography to give 1-benzyl-4-hydroxypiperidine-2,6-dione (4.40 g, 94.3 % yield).

[0317] LCMS: m / z 219.9 [M+H] + .

[0318] 1 H NMR (400 MHz, CDC13) δ = 7.38 - 7.20 (m, 5H), 4.99 (s, 2H), 4.34 (quin, J = 4.0 Hz, 1H), 2.88 - 2.75 (m, 4H) ppm.

[0319] Step three: Synthesis of 1-benzyl-4-methoxypiperidine-2,6-dione

[0320] To a solution of 1 -benzyl-4-hydroxypiperidine-2,6-dione (4.30 g, 19.6 mmol) and 1,8-diazabicycloundec-7-ene (DBU) (3.20 g, 25.6 mmol) in dichloromethane (100 mL) was added 1,8-diazabicycloundec-7-ene (DBU) (3.20 g, 25.6 mmol) at 20 °C, then stirred for 2 h at 20 °C, LCMS monitored the reaction was completed, filtered, the filtrate was quenched with hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, concentrated. The crude product was purified by column chromatography to give 1 -benzyl-4-methoxypiperidine-2,6-dione (3.30 g, 72.1 % yield).

[0321] LCMS: m / z 233.9 [M+H] + .

[0322] 1 H NMR (400 MHz, CDC13) d = 7.30-7.15 (m, 5H), 4.92 (s, 2H), 3.80-3.75 (m, 1H), 3.31 (s, 3H), 2.96-2.86 (m, 2H), 2.78-2.69 (m, 2H) ppm.

[0323] Step four: synthesis of 1 -benzyl-4-methoxy(2,2,6,6- 2 H4)piperidine

[0324] To a solution of 1 -benzyl-4-methoxypiperidine-2,6-dione (3.30 g, 14.1 mmol) in tetrahydrofuran (40 mL) was added deuterated lithium aluminum hydride (2.60 g, 56.6 mmol) slowly dropwise at 0 °C, then stirred for 10 h at 50 °C under nitrogen protection, LCMS monitored the reaction was completed, quenched with sodium sulfate decahydrate, filtered, concentrated. The crude product was purified by column chromatography to give yellow oil 1 -benzyl-4-methoxy(2,2,6,6- 2 H4)piperidine (1.40 g, 39.2% yield).

[0325] LCMS: m / z 210.2 [M+H] + .

[0326] Step five: synthesis of 1 -benzyl-4-methoxy(2,2,6,6- 2 H4)piperidine

[0327] To a solution of 1 -benzyl-4-methoxy(2,2,6,6- 2H4)piperidine (1.40 g, 1.69 mmol) was sent to a fluid chemistry laboratory. The reaction was monitored by LCMS until completion. A sample was taken, and hydrochloric acid and ethyl acetate were added to form a salt. The solution was then concentrated. 4-Methoxy(2,2,6,6-) was obtained. 2 H4) Piperidine (1.00g, crude product, hydrochloride).

[0328] LCMS: m / z 120.2 [M+H] + .

[0329] Step Six: Methyl 1-(4-methoxy(2,2,6,6-) 2 Synthesis of H4)piperidine-1-carbonyl)cyclopropane-1-carboxylate

[0330] 4-methoxy(2,2,6,6- 2 H4) piperidine (1.00 g, 6.42 mmol, hydrochloride) and N,N-diisopropylethylamine (3.32 g, 25.7 mmol) were dissolved in dichloromethane (10 mL), and then a solution of 1-(chlorocarbonyl)cyclopropane-1-methyl ester (1.15 g, 7.07 mmol) was slowly added dropwise at 0 °C. The reaction was then carried out at 20 °C for 2 hours. The reaction was monitored by LCMS until completion. The mixture was extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was then subjected to column chromatography to obtain a yellow oil containing methyl 1-(4-methoxy(2,2,6,6-) 2 H4)piperidine-1-carbonyl)cyclopropane-1-carboxylate (500 mg, 31.7% yield).

[0331] LCMS: m / z 246.0 [M+H] + .

[0332] 1 H NMR (400MHz, CDCl3) δ=3.73(s,3H),3.49-3.42(m,1H),3.37(s,3H),1.88-1.80(m,2H),1.60-1.53(m,2H),1.52-1.47(m,2H),1.35-1.30(m,2H)ppm.

[0333] Step 7: (1-((4-methoxy(2,2,6,6-) 2 Synthesis of H4)piperidin-1-yl)methyl)cyclopropyl)methanol

[0334] Methyl 1-(4-methoxy(2,2,6,6-) 2H4) piperidin-1 -yl)methyl)cyclopropyl)methanol (370 mg, crude) was dissolved in tetrahydrofuran (5 mL), then lithium aluminum hydride (2.5 M, 1.22 mL) was added slowly dropwise at 0 °C, finally reacted at 0 °C for 1 hour under nitrogen protection, the reaction was monitored to end by LCMS, quenched with sodium sulfate decahydrate, filtered, concentrated. Yellow oil was obtained (1-((4-methoxy(2,2,6,6- 2 H4) piperidin-1 -yl)methyl)cyclopropyl)methanol (370 mg, crude) was dissolved in tetrahydrofuran (5 mL), then lithium aluminum hydride (2.5 M, 1.22 mL) was added slowly dropwise at 0 °C, finally reacted at 0 °C for 1 hour under nitrogen protection, the reaction was monitored to end by LCMS, quenched with sodium sulfate decahydrate, filtered, concentrated. Yellow oil was obtained (1-((4-methoxy(2,2,6,6-

[0335] LCMS: m / z 200.1 [M+H] + .

[0336] 1 H NMR (400 MHz, CDC13) d = 3.54 (s, 2H), 3.33 (s, 3H), 3.31-3.22 (m, 1H), 2.47 (s, 2H), 1.92-1.85 (m, 2H), 1.60-1.54 (m, 2H), 0.53-0.49 (m, 2H), 0.38-0.32 (m, 2H) ppm.

[0337] The synthetic route of Example 42 (Compound 42) is as follows, starting from Intermediate 1J of Example 1:

[0338] Step Eight: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-methoxy(2,2,6,6- 2 Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-methoxy(2,2,6,6-

[0339] Step Eight: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-methoxy(2,2,6,6- 2 H4) piperidin-1 -yl)methyl)cyclopropyl)methanol (370 mg, crude) was dissolved in tetrahydrofuran (5 mL), then lithium aluminum hydride (2.5 M, 1.22 mL) was added slowly dropwise at 0 °C, finally reacted at 0 °C for 1 hour under nitrogen protection, the reaction was monitored to end by LCMS, quenched with sodium sulfate decahydrate, filtered, concentrated. Yellow oil was obtained (1-((4-methoxy(2,2,6,6- 2H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazapyridine-heptane-6-ol (240 mg, 37.7% yield).

[0340] LCMS:m / z 627.1[M+H] + .

[0341] Step Nine: N-(3-cyano-7-fluoro-4-(8-fluoro-4-((6-hydroxy-6-methyl-1,4-oxazapyridine-heptane-4-yl)-2-((1-((4-methoxy(2,2,6,6-)) 2 Synthesis of H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzothiophene-2-yl)tert-butyl carbamate

[0342] Under nitrogen protection, 4-(7-bromo-8-fluoro-2-((1-((4-methoxy(2,2,6,6-) 2 H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazapyridine-heptane-6-ol (230 mg, 367 μmol), N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-benzothiophene-2-yl)carbamate tert-butyl ester (307 mg, 735 μmol), cesium carbonate (359 mg, 1.10 mmol), and bis(diphenylphosphine ether)palladium(II) dichloride (79.0 mg, 110 μmol) were dissolved in dioxane (6 mL) and toluene (6 mL), then purged three times with nitrogen, and the reaction was carried out at 110 °C under a nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by mechanical fractionation to give a yellow solid N-(3-cyano-7-fluoro-4-(8-fluoro-4-((6-hydroxy-6-methyl-1,4-oxazapyridine-heptane-4-yl)-2-((1-((4-methoxy(2,2,6,6-) 2 H4)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzothiophene-2-yl)tert-butyl carbamate (100 mg, 32.5% yield).

[0343] LCMS: m / z 837.4 [M+H] + .

[0344] Step ten: Synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl)1,4-oxazepan-4-yl)-2-((1-((4-methoxy(2,2,6,6- 2 H4)Piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile

[0345] tert-Butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-((6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4-methoxy(2,2,6,6- 2 tert-Butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-((6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4-methoxy(2,2,6,6- 2 H4)Piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile (30.2 mg, 34.3% yield).

[0346] LCMS: m / z 737.4 [M+H] + .

[0347] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.88 (s, 1H), 8.06 (s, 2H), 7.27-7.22 (m, 1H), 7.16-7.10 (m, 1H), 5.30 (s, 1H), 4.30-4.20 (m, 3H), 4.13-4.03 (m, 2H), 3.98-3.89 (m, 2H), 3.74-3.66 (m, 1H), 3.61-3.53 (m, 2H), 3.19 (s, 3H), 3.15-3.07 (m, 1H), 2.33-2.23 (m, 2H), 1.79-1.71 (m, 2H), 1.38-1.28 (m, 2H), 1.13 (s, 3H), 0.62 (s, 2H), 0.39 (s, 2H) ppm.

[0348] Example 43: 2-amino-4-(2-((1-((4-(cyanomethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazoline-7-yl-7-fluoro-1-benzo[b]thiophene-3-carbonitrile

[0349] The synthesis of Example 43 (Compound 43) is mainly divided into the synthesis of fragment 43e, and the synthesis of Example 43 itself, which is shown in the specific route as follows:

[0350] The synthesis route of fragment 43e is as follows:

[0351] Step one: synthesis of (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol

[0352] (1-(hydroxymethyl)cyclopropyl)methanol (5.00 g, 48.9 mmol), tert-butyldiphenylchlorosilane (14.1 g, 51.4 mmol), 4-dimethylaminopyridine (1.20 g, 9.79 mmol), triethylamine (5.20 g, 51.4 mmol) were dissolved in dichloromethane (50 mL) and reacted at 20 °C for 12 hours. The reaction was monitored by TLC plate. The reaction solution was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain compound (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (10.0 g, 59.1% yield) as colorless oil.

[0353] LCMS: m / z 363.0 [M+Na] + .

[0354] 1 H NMR (400 MHz, CDCl3) δ = 7.69 (br d, J = 6.8 Hz, 4H), 7.50-7.37 (m, 6H), 3.63 (d, J = 2.8 Hz, 4H), 1.08 (s, 9H), 0.55-0.47 (m, 2H), 0.41-0.34 (m, 2H) ppm.

[0355] Step two: synthesis of tert-butyl(((1-(iodomethyl)cyclopropyl)methoxy))diphenylsilane

[0356] Dichlorodicyanoquinone (3.50 g, 15.4 mmol) was dissolved in dichloromethane (60 mL), triphenylphosphine (4.04 g, 15.4 mmol), cooled to 0 °C, and tetrabutylammonium iodide (5.69 g, 15.4 mmol) was added to the reaction. Finally, (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (5.69 g, 15.4 mmol) was dissolved in dichloromethane (50 mL) and the reaction was allowed to react at 20 °C for 2 h. The reaction was monitored by LCMS. After the reaction was quenched with water, the reaction was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl(((1-(iodomethyl)cyclopropyl)methoxy))diphenylsilane (4.70 g, 67.5% yield) as a colorless oil.

[0357] 1 H NMR (400 MHz, CDC13) δ = 7.69 (dd, J1= 1.6, J2= 7.8 Hz, 4H), 7.49 - 7.34 (m, 6H), 3.58 (s, 2H), 3.43 (s, 2H), 1.08 (s, 9H), 0.81 - 0.74 (m, 2H), 0.63 - 0.56 (m, 2H) ppm.

[0358] Step Three: Synthesis of 2-(l-((l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile

[0359] Tert-butyl(((l-(iodomethyl)cyclopropyl)methoxy))diphenylsilane (1.80 g, 4.00 mmol) and potassium carbonate (1.66 g, 11.9 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 50 °C for 12 h. The reaction was monitored by TLC. After the reaction was quenched with water, the reaction was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give 2-(l-((l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile (2.30 g, crude) as a yellow oil.

[0360] Step Four: Synthesis of 2-(l-((l-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile

[0361] To a solution of 2-(1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile (2.00 g, 461 μmol), ammonium fluoride (663 mg, 17.9 mmol), cesium fluoride (136 g, 895 mmol) in tetrahydrofuran (10 mL) and methanol (20 mL) was stirred at 65 °C for 18 h. The reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give compound 2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile (830 mg, 89.0% yield) as yellow oil.

[0362] 1 H NMR (400 MHz, CDC13) δ = 3.54 (s, 2H), 3.25 (br d, J = 10.6 Hz, 2H), 2.48 (s, 2H), 2.29 (d, J = 7.0 Hz, 2H), 2.02 - 1.83 (m, 4H), 1.71 (ddd, Ji = 4.2, J2= 7.4, J3= 11.2 Hz, 1H), 1.46 - 1.31 (m, 2H), 0.57 - 0.49 (m, 2H), 0.40 - 0.31 (m, 2H) ppm.

[0363] The synthesis route for Example 43 (Compound 43) is as follows, starting from Intermediate 1J of Example 1:

[0364] Step Five: Synthesis of 2-(1-((1-(((7-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile

[0365] To a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (450 mg, 1.02 mmol), 2-(1-((1-(hydroxymethyl)cyclopropyl) methyl)piperidin-4-yl)acetonitrile (635 mg, 3.05 mmol), N,N-diisopropylamine (328 mg, 2.54 mmol) in dioxane (10 mL) was stirred at 100 °C for 12 h. The reaction was monitored by LC-MS. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give compound 2-(1-((1-(((7-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)acetonitrile as a white solid (369 mg, 57.1% yield).

[0366] LCMS: m / z 632.3 [M+H] + .

[0367] Step six: Synthesis of tert-butyl N-(3-cyano-4-(2-((1-((4- cyanomethylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl- 1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluoro-1- benzo[b]thiophen-2-yl)carbamate

[0368] tert-Butyl N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- benzothiophen-2-yl)carbamate (238 mg, 571 μmol), 2-(l-((l-(((7-bromo-8-fluoro-4-(6- hydroxy-6-methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl) cyclopropyl)methyl)piperidin-4-yl)acetonitrile (180 mg, 285 μmol), bis(diphenylphosphino phenyl ether)palladium(II) dichloride (61.3 mg, 85.6 μmol), cesium carbonate (279 mg, 856 μmol) were dissolved in dioxane (7 mL) and stirred at 120 °C for 4 h. The reaction was monitored by LC-MS. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and purified by prep-HPLC to give compound tert-butyl N-(3-cyano-4-(2-((l-((4-(cyanomethyl)piperidin-l- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-7-yl)-7-fluoro-l-benzo[b]thiophen-2-yl)carbamate (290 mg, 60.3% yield) as a yellow solid.

[0369] LCMS: m / z 842.6 [M+H] + .

[0370] Step Seven: Synthesis of 2-amino-4-(2-((l-((4-(cyanomethyl)piperidin-l- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-7-yl)-7-fluoro-l-benzo[b]thiophene-3-carbonitrile

[0371] To a solution of tert-butyl N-(3-cyano-4-(2-((1-((4-(cyanomethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinolin-7-yl)-7-fluoro-1-benzo[b]thiophene-2-yl)carbamate (270 mg, 320 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), the reaction was stirred at 20 °C for 2 hours. The reaction was monitored by LC-MS, the reaction was quenched by adding water, extracted with dichloromethane, dried, filtered and concentrated. The residue was purified by HPLC to give tert-butyl N-(3-cyano-4-(2-((1-((4-(cyanomethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-7-fluoro-1-benzo[b]thiophene-2-yl)carbamate (130.0 mg, 68.3% yield) as a white solid.

[0372] LCMS: m / z 742.2 [M+H] + .

[0373] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.88 (s, 1H), 8.05 (s, 2H), 7.24 (dd, J1= 5.4, J2= 8.4 Hz, 1H), 7.17-7.04 (m, 1H), 5.30 (s, 1H), 4.30-4.20 (m, 3H), 4.14-4.02 (m, 2H), 3.98-3.88 (m, 2H), 3.75-3.65 (m, 1H), 3.62-3.51 (m, 2H), 2.94 (br d, J = 10.4 Hz, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.33-2.27 (m, 2H), 1.84 (br t, J = 10.8 Hz, 2H), 1.63 (br d, J = 11.6 Hz, 2H), 1.58-1.47 (m, 1H), 1.28-1.18 (m, 2H), 1.13 (s, 3H), 0.68-0.57 (m, 2H), 0.39 (s, 2H) ppm.

[0374] Example 44: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl)1,4-oxazepan-4-yl)-2- ((1-((4-(methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl) quinolin-7-yl)-1-benzo[b]thiophene-3-carbonitrile

[0375] The synthesis of Example 44 (Compound 44) is mainly divided into the synthesis of fragment 44c, and the synthesis of Example 44 itself, the specific route is as follows:

[0376] The synthesis route of fragment 44c is as follows:

[0377] Step one: synthesis of methyl 1-(4-(methoxymethyl)piperidine-1-carbonyl)cyclopropane-1-carboxylate

[0378] 4-(Methoxymethyl)piperidine (1.00 g, 7.74 mmol), N,N-diisopropylethylamine (4.00 g, 31.0 mmol) were dissolved in dichloromethane (10 mL), then 1-(chloroacyl)cyclopropane-1-carboxylate methyl ester (1.32 g, 8.13 mmol) was slowly added dropwise at 0°C, and finally reacted at 20°C for 2 hours. The reaction was monitored by LCMS, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated. Column chromatography of the crude product gave methyl 1-(4-(methoxymethyl)piperidine-1-carbonyl)cyclopropane-1-carboxylate (1.60 g, 80.9% yield).

[0379] LCMS: m / z 256.2 [M+H] + .

[0380] Step two: synthesis of (1-((4-(methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methanol

[0381] Methyl 1-(4-(methoxymethyl)piperidine-1-carbonyl)cyclopropane-1-carboxylate (1.60 g, 6.27 mmol) was dissolved in tetrahydrofuran (20 mL), then lithium aluminum hydride (2.5 M, 3.76 mL) was slowly added dropwise at 0°C, and finally reacted at 0°C for 1 hour under nitrogen protection. The reaction was monitored by LCMS, quenched with sodium sulfate decahydrate, filtered, and concentrated. Column chromatography of the crude product gave yellow oil (1-((4-(methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methanol (800 mg, 59.8% yield).

[0382] LCMS: m / z 214.3 [M+H] + .

[0383] The synthesis route of Example 44 (Compound 44) is as follows, starting from the intermediate 1J of Example 1:

[0384] Step three: synthesis of 4-(7-bromo-8-fluoro-2-((1-((4- (methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0385] Dissolve 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (400 mg, 904 pmol) in dioxane (12 ml), then add N,N- diisopropylethylamine (584 mg, 452 mmol) and (1-((4-(methoxymethyl)piperidin-1- yl)methyl)cyclopropyl)methanol (579 mg, 2.71 mmol), react at 100 °C for 12 hours. Monitor the reaction end by LCMS, quench with ammonium chloride solution, extract with ethyl acetate, wash with brine, dry over sodium sulfate, filter, concentrate. Subject the yellow solid to machine to give 4-(7-bromo-8-fluoro-2-((1-((4- (methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (400 mg, 69.6% yield) as a yellow solid.

[0386] LCMS: m / z 637.1 [M+H] + .

[0387] Step four: synthesis of tert-butyl N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6- methyl-1,4-oxazepan-4-yl)-2-((1-((4-(methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-1- benzo[b]thiophen-2-yl)carbamate

[0388] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- (methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)- 1- benzo[b]thiophene-2-yl)carbamate (270 mg, 53.3% yield) was obtained as a yellow solid. LCMS: m / z 847.4 [M+H]

[0389] LCMS: m / z 847.4 [M+H] + .

[0390] Step five: synthesis of 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)- 2-((1-((4-(methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin- 7-yl)-1- benzo[b]thiophene-3-carbonitrile

[0391] N-(3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- (methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7- yl)-1-benzo[b]thiophene-2-yl)carbamic acid tert-butyl ester (270 mg, 319 pmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) at 0 °C and stirred at 20 °C for 1 h. The reaction was monitored by LCMS, and the reaction was quenched with sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to give 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((1-((4- (methoxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)-1- benzo[b]thiophene-3-carbonitrile (109.1 mg, 45.8% yield) as a white solid.

[0392] LCMS: m / z 747.3 [M+H] + .

[0393] 1 H NMR (400 MHz, (CD3)2SO) d = 8.89 (s, 1H), 8.06 (s, 2H), 7.27-7.20 (m, 1H), 7.17-7.10 (m, 1H), 5.30 (s, 1H), 4.31-4.21 (m, 3H), 4.14-4.03 (m, 2H), 3.97-3.89 (m, 2H), 3.74-3.66 (m, 1H), 3.62-3.53 (m, 2H), 3.19 (s, 3H), 3.10 (d, J = 6.4 Hz, 2H), 2.96-2.87 (m, 2H), 2.32-2.22 (m, 2H), 1.85-1.76 (m, 2H), 1.60-1.52 (m, 2H), 1.49-1.40 (m, 1H), 1.13 (s, 3H), 1.12-1.02 (m, 2H), 0.65-0.59 (m, 2H), 0.41-0.35 (m, 2H) ppm.

[0394] Example 45: 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl-1- benzo[b]thiophene-3-carbonitrile

[0395] The synthesis of Example 45 (Compound 45) is mainly divided into the synthesis of fragment 45c, and the synthesis of Example 45 itself, the specific route is as follows:

[0396] The synthesis route of fragment 45c is as follows:

[0397] Step one: synthesis of methyl 1-(4-(fluoromethyl)piperidine-1-carbonyl)cyclopropane-1- carboxylate

[0398] Dissolve 4-(fluoromethyl)piperidin-1-yl hydrochloride (500 mg, 3.25 mmol), N,N- diisopropylethylamine (969 mg, 7.50 mmol) in dichloromethane (5 mL), then slowly drop 1-(chlorocarbonyl)cyclopropane-1-carboxylate (530 mg, 3.26 mmol) at 0 °C, finally react for 2 hours at 0 °C under nitrogen protection, monitor the reaction end by LCMS, quench with water at 0 °C, extract with ethyl acetate, wash with brine, dry over sodium sulfate, filter, concentrate. The crude product is column chromatographed to obtain methyl 1-(4-(fluoromethyl)piperidine-1-carbonyl)cyclopropane-1-carboxylate (700 mg, 88.3% yield).

[0399] LCMS: m / z 244.2 [M+H] + .

[0400] Step two: synthesis of (1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methanol

[0401] Dissolve methyl 1-(4-(fluoromethyl)piperidine-1-carbonyl)cyclopropane-1-carboxylate (700 mg, 2.88 mmol) in tetrahydrofuran (10 mL), then slowly drop lithium aluminum hydride (2.5 M, 2.30 mL, 5.75 mmol) at 0 °C, finally react for 2 hours at 0 °C under nitrogen protection, monitor the reaction end by LCMS, quench with sodium sulfate decahydrate, filter, concentrate. The crude product is column chromatographed to obtain colorless oil (1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methanol (510 mg, 88.0% yield).

[0402] LCMS: m / z 202.2 [M+H] + .

[0403] The synthesis route of Example 45 (Compound 45) is as follows, starting from the intermediate 1J of Example 1:

[0404] Step three: synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol

[0405] To a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (500 mg, 1.1 mmol), (1-((4-(fluoromethyl)piperidin-1- yl)methyl)cyclopropyl)methanol (478 mg, 2.37 mmol), N,N-diisopropyl ethylamine (512 mg, 3.96 mmol) in dry dioxane (5 ml) was heated at 120 °C for 12 h under nitrogen. The reaction was monitored by LCMS. The mixture was concentrated and purified by prep-HPLC to give 4-(7-bromo-8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol (410 mg, 58.2% yield) as a white solid.

[0406] LCMS: m / z 625.1 [M+H] + .

[0407] Step four: synthesis of N-(3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6- (trifluoromethyl)quinazolin-7-yl)-1-benzothiophen-2-yl)aminotert-butyl

[0408] Under nitrogen protection, 4-(7-bromo-8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazapyridine-heptane-6-ol (390 mg, 626 μmol), N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1-benzothiophene-2-yl)carbamate tert-butyl ester (523 mg, 1.25 mmol), cesium carbonate (612 mg, 1.88 mmol), and bis(diphenylphosphine phenyl ether)palladium(II) dichloride (134 mg, 188 μmol) were dissolved in dioxane (10 mL), and then purged with nitrogen three times. The mixture was reacted at 110 °C under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS until it ended. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by prep-HPLC to give a yellow solid: N-(3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazapyridine-heptane-4-yl)-6-(trifluoromethyl)quinazolin-7-yl)-1-benzothiophene-2-yl)aminotert-butyl ester (210 mg, 40.2% yield).

[0409] LCMS: m / z 835.4 [M+H] + .

[0410] Step 5: Synthesis of 2-amino-7-fluoro-4(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-yl)-6-(trifluoromethyl)quinazolin-7-yl-1-benzo[b]thiophene-3-onitrile

[0411] N-(3-cyano-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-1-benzothiophen-2-yl)amino tert-butyl carbamate (160 mg, 192 pmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at 0 °C, then stirred at 20 °C for 2 hours. The reaction was monitored by LCMS, and the reaction was quenched with sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 2-amino-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-1-benzo[b]thiophene-3-carbonitrile (9.60 mg, 6.61% yield) as a white solid.

[0412] LCMS: m / z 715.3 [M+H] + .

[0413] 1 H NMR (400 MHz, (CD3)2SO) d = 8.88 (s, 1H), 8.05 (s, 2H), 7.24 (dd, J1= 5.2, J2= 8.3 Hz, 1H), 7.17-7.10 (m, 1H), 5.30 (s, 1H), 4.31-4.26 (m, 3H), 4.16 (d, J = 5.4 Hz, 1H), 4.13-4.02 (m, 2H), 3.99-3.88 (m, 2H), 3.75-3.69 (m, 1H), 3.61-3.50 (m, 3H), 2.95 (br t, J = 9.6 Hz, 2H), 2.34-2.28 (m, 2H), 1.84 (br t, J = 11.0 Hz, 2H), 1.57 (br d, J = 10.4 Hz, 2H), 1.25-1.12 (m, 6H), 0.68-0.58 (m, 2H), 0.44-0.34 (m, 2H) ppm.

[0414] Example 46: 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0415] The synthesis of Example 46 (Compound 46) is mainly divided into the synthesis of fragment 46d, and the synthesis of Example 46 itself, the specific route is as follows:

[0416] The synthesis route of fragment 46d is as follows:

[0417] Step one: synthesis of methyl 1-(chloroacyl)cyclopropane-1-carboxylate

[0418] 1-(methylcarboxylate)cyclopropane-1-carboxylic acid (1.00 g, 6.94 mmol), N,N- dimethylformamide (25.3 mg, 346 μmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (1.32 g, 10.4 mmol) was slowly added, and the reaction was reacted at 20 °C for 2 hours. TLC plate monitoring reaction to end. The reaction liquid was concentrated to obtain yellow oily compound methyl 1-(chloroacyl)cyclopropane-1-carboxylate (1.10 g, 97.5% yield).

[0419] Step two: synthesis of methyl 1-(4-methoxy-4-methylpiperidine-1-carbonyl)cyclopropane-1- carboxylate

[0420] 4-methoxy-4-methylpiperidine (1.00 g, 6.04 mmol), diisopropylethylamine (1.53 g, 15.0 mmol) was dissolved in dichloromethane (10 mL), 1-(chloroacyl)cyclopropane-1- carboxylate (1.08 g, 6.64 mmol) in dichloromethane (10 mL) was added at 0 °C, and the reaction was reacted at 20 °C for 2 hours. LCMS monitoring reaction to end. The reaction liquid was quenched with water and extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain yellow oily compound methyl 1-(4-methoxy-4-methylpiperidine-1-carbonyl)cyclopropane-1-carboxylate (1.50 g, 97.3% yield).

[0421] 1 H NMR (400 MHz, CDCl3) δ = 4.26-4.13 (m, 1H), 3.73 (s, 3H), 3.64 (br d, J = 13.6 Hz, 1H), 3.42-3.30 (m, 1H), 3.22 (s, 3H), 3.10-3.02 (m, 1H), 1.88-1.71 (m, 2H), 1.52-1.39 (m, 4H), 1.36-1.29 (m, 2H), 1.18 (s, 3H) ppm.

[0422] Step three: synthesis of (1-((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methanol

[0423] To a solution of methyl 1-(4-methoxy-4-methylpiperidine-1-carbonyl)cyclopropane-1- carboxylate (1.40 g, 5.48 mmol) in tetrahydrofuran (14 mL) was added lithium aluminum hydride (374 mg, 9.87 mmol) in portions at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction was monitored by TLC. The reaction was quenched with sodium sulfate decahydrate and filtered to concentrate. The residue was purified by column chromatography to give compound (1-((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methanol (1.00 g, 85.4% yield) as colorless oil.

[0424] 1 H NMR (400 MHz, CDC13) δ = 6.05 (br s, 1H), 3.54 (s, 2H), 3.17 (s, 3H), 2.79 (br s, 2H), 2.49 (s, 2H), 2.31 (s, 2H), 1.78 (br d, J = 13.4 Hz, 2H), 1.60-1.45 (m, 2H), 1.14 (s, 3H), 0.53-0.46 (m, 2H), 0.39-0.32 (m, 2H) ppm.

[0425] The synthesis route of Example 46 (Compound 46) is as follows, starting from Intermediate 1J of Example 1:

[0426] Step Four: Synthesis of 4-(7-bromo-8-fluoro-2-((1-((4-methoxy-4-methylpiperidin-1- yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol

[0427] To a solution of 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (400 mg, 904 pmol) in DMSO (10 mL) was added 1-((4- methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methanol (771 mg, 3.62 mmol) and N,N- diisopropylethylamine (350 mg, 2.71 mmol) and the reaction mixture was stirred at 100 °C for 12 h. The reaction was monitored by LCMS till completion. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by prep-HPLC to get 4-(7-bromo-8-fluoro-2-((1-((4-methoxy-4- methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-1,4-oxazepan-6-ol (420 mg, 73.0% yield) as yellow oil.

[0428] LCMS: m / z 635.3 [M+H] + .

[0429] Step five: Synthesis of tert-butyl ((3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-yl)-2-(((((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-2-yl)carbamate

[0430] Step 1: Synthesis of tert-butyl 4-(7-bromo-8-fluoro-2-((1-((4-methoxy-4- methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)- 6-methyl-1,4-oxazepan-6-ol

[0431] LCMS: m / z 847 [M+H] + .

[0432] Step 1: Synthesis of tert-butyl 4-(7-bromo-8-fluoro-2-((1-((4-methoxy-4- methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)- 6-methyl-1,4-oxazepan-6-ol

[0433] To a solution of tert-butyl ((3-cyano-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)-benzo[b]thiophen-2-yl)aminoformate (120 mg, 141 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), the reaction was stirred at 20 °C for 2 hours. The reaction was monitored to completion by LCMS, the reaction was adjusted to basic and extracted, dried, filtered and concentrated. Purification by prep-HPLC gave compound 2-amino-7-fluoro-4-(8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-(((((4-methoxy-4-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(trifluoromethyl)quinolin-7-yl)benzo[b]thiophene-3-carbonitrile (49.0 mg, 69.9% yield) as a white solid.

[0434] LCMS: m / z 747 [M+H] + .

[0435] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.89 (s, 1H), 8.06 (s, 2H), 7.30-7.07 (m, 2H), 5.31 (s, 1H), 4.35-4.20 (m, 3H), 4.14-4.02 (m, 2H), 4.00-3.88 (m, 2H), 3.77-3.65 (m, 1H), 3.62-3.52 (m, 2H), 3.04 (s, 3H), 2.49-2.48 (m, 2H), 2.36-2.17 (m, 4H), 1.60 (br d, J = 13.0 Hz, 2H), 1.39 (br d, J = 1.8 Hz, 2H), 1.14 (s, 3H), 1.02 (s, 3H), 0.63 (s, 2H), 0.40 (br s, 2H) ppm.

[0436] Example 47: 4-(2-((((((2R)-4-methoxy-2-methylpiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0437] The synthesis of Example 47 (Compound 47) is mainly divided into the synthesis of fragment 47d, and the synthesis of Example 47 itself, which is shown in the specific route as follows:

[0438] The synthetic route of fragment 47d is as follows:

[0439] Step one: synthesis of 1-(chloroacyl)cyclopropane-1-carboxylate methyl ester

[0440] 1-(Methylcarboxylate)cyclopropane-1-carboxylic acid (3.00 g, 20.8 mmol), N,N- dimethylformamide (76.0 mg, 1.04 mmol) were dissolved in dichloromethane (30 mL), oxalyl chloride (3.96 g, 31.2 mmol) was added slowly, the reaction was reacted at 25 °C for 2 hours. TLC plate monitoring reaction end. The reaction liquid was concentrated to obtain yellow oily compound 1-(chloroacyl)cyclopropane-1-carboxylate methyl ester (3.30 g, 97.5% yield).

[0441] Step two: synthesis of 4-methoxy-2-methylpiperidine

[0442] 4-Methoxy-2-methylpyridine (10.0 g, 81.2 mmol) was sent to the fluid chemistry platform operation, after palladium / carbon catalytic hydrogenation, the reaction liquid was concentrated to obtain yellow oily compound 4-methoxy-2-methylpiperidine (10.3 g, 49.0% yield).

[0443] LCMS: m / z 130 [M+H] + .

[0444] Step three: synthesis of 1-((2R)-4-methoxy-2-methylpiperidine-1-carbonyl)cyclopropane-1- carboxylate methyl ester

[0445] 4-Methoxy-2-methylpiperidin-1-yl (10.0 g, 60.3 mmol), triethylamine (21.3 g, 211 mmol) were dissolved in dichloromethane (100 mL), 1-(chloroacyl)cyclopropane-1-carboxylate methyl ester (10.7 g, 66.4 mmol) was added to dichloromethane (50 mL) at 0 °C, the reaction was reacted at 20 °C for 2 hours. LCMS monitoring reaction end. The reaction liquid was quenched with water and extracted with dichloromethane, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, purified by column chromatography and SFC resolution to obtain yellow oily compound Peak 1: 1-((2S)-4-methoxy-2-methylpiperidine-1-carbonyl)cyclopropane-1-carboxylate methyl ester (4.60 g, 43.4% yield).

[0446] LCMS: m / z 256.1 [M+H] + .

[0447] SFC: ee% = 98.8%

[0448] Yellow oil Compound Peak 2: 1-((2R)-4-methoxy-2-methylpiperidin-1- yl) cyclopropane-1-carboxylate (3.40 g, 32.0% yield)

[0449] LCMS: m / z 256.1 [M+H] + .

[0450] SFC: ee% = 98.4%

[0451] Step four: Synthesis of (((2R)-4-methoxy-2-methylpiperidin-1- yl)methyl)cyclopropyl)methanol

[0452] Peak 2: 1-((2R)-4-methoxy-2-methylpiperidin-1-yl) cyclopropane-1-carboxylate (2.00 g, 7.83 mmol) was dissolved in tetrahydrofuran (20 mL) and lithium aluminium hydride (535 mg, 14.1 mmol) was added portion wise at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction was monitored by TLC plate. The reaction was quenched with sodium sulphate decahydrate and filtered and concentrated. Purification by column chromatography gave (((2R)-4-methoxy-2-methylpiperidin-1- yl)methyl)cyclopropyl)methanol (1.20 g, 71.2% yield) as yellow oil.

[0453] 1 H NMR (400 MHz, CDC13) δ = 5.74 (br s, 1H), 4.04 (d J = 1.6, J2= 11.4 Hz, 1H), 3.60 (td J = 3.6, 12.0 Hz, 1H), 3.51 (br d J = 12.8 Hz, 1H), 3.34 (s, 3H), 3.23 - 3.12 (m, 1H), 3.02 (br d J = 11.0 Hz, 1H), 2.20 (br s, 1H), 2.08 - 1.86 (m, 3H), 1.71 - 1.55 (m, 2H), 1.52 - 1.38 (m, 1H), 1.22 (d J = 6.2 Hz, 3H), 0.83 - 0.71 (m, 1H), 0.58 - 0.45 (m, 1H), 0.30 - 0.13 (m, 2H) ppm.

[0454] The synthesis route of Example 47 (Compound 47) is as follows, starting from Intermediate 1J of Example 1:

[0455] Step five: synthesis of 4-(2-((((((2R)-4-methoxy-2-methylpiperidin-l- yl)methyl)cyclopropyl)methyl)oxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin- 4-yl)-6-methyl-l,4-oxazepan-6-ol

[0456] ((((2R)-4-methoxy-2-methylpiperidin-l-yl)methyl)cyclopropyl)methanol (651 mg, 3.05 mmol), 4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6- methyl-l,4-oxazepan-6-ol (450 mg, 1.02 mmol), N,N-diisopropylethylamine (328 mg, 2.54 mmol) were dissolved in dioxane (12 mL) and stirred at 100 °C for 12 h. The reaction was monitored by LC-MS. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The compound 4-(2-((((((2R)-4-methoxy-2-methylpiperidin-l- yl)methyl)cyclopropyl)methyl)oxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4- yl)-6-methyl-l,4-oxazepan-6-ol (380 mg, 58.7% yield) was obtained as a yellow solid after purification by prep-HPLC.

[0457] LCMS: m / z 637.3 [M+H] + .

[0458] Step six: synthesis of methyl 2-methylprop-2-yl((4-(2-(((((2R)-4-methoxy-2- methylpiperidin-l-yl)methyl)cyclopropyl)methyl)oxy)-8-fluoro-4-(6-hydroxy-6- methyl-l,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)amino)carbamate

[0459] Step 1: Synthesis of tert-butyl N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-benzothiophene-2-yl)carbamate

[0460] LCMS: m / z 847.4 [M+H] + .

[0461] Step 7: Synthesis of 4-(2-((((((2R)-4-methoxy-2-methylpiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0462] To a solution of methyl 2-methylprop-2-yl ((4-(2-(((((2R)-4-methoxy-2- methylpiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-8-fluoro-4-(6-hydroxy-6- methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-3-cyano-7-fluoro- benzo[b]thiophen-2-yl)amino)carbamate (230 mg, 271 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the reaction was stirred at 20 °C for 2 hours. The reaction was monitored to completion by LCMS and the reaction was basified and extracted, dried, filtered and concentrated. Purification by prep-HPLC gave the compound as a yellow solid: 4-(2-((((((2R)-4-methoxy-2-methylpiperidin-1-yl)methyl)cyclopropyl)methyl)oxy)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinolin-7-yl)-2-amino-7-fluoro-benzo[b]thiophene-3-carbonitrile (25.0 mg, 23.6% yield).

[0463] LCMS: m / z 747.2 [M+H] + .

[0464] 1 H NMR (400 MHz, (CD3)2SO) δ = 8.87 (s, 1H), 8.04 (br s, 2H), 7.36 - 6.97 (m, 2H), 5.29 (s, 1H), 4.60 (br d, J = 10.4 Hz, 1H), 4.35 - 4.17 (m, 1H), 4.12 - 3.83 (m, 5H), 3.75 - 3.65 (m, 1H), 3.63 - 3.47 (m, 2H), 3.28 (s, 1H), 3.24 - 3.14 (m, 4H), 3.09 - 3.01 (m, 1H), 2.16 - 1.99 (m, 1H), 1.92 - 1.72 (m, 3H), 1.44 (br d, J = 12.8 Hz, 1H), 1.29 - 1.19 (m, 1H), 1.12 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.89 - 0.79 (m, 1H), 0.72 - 0.61 (m, 1H), 0.59 - 0.41 (m, 2H), 0.39 - 0.25 (m, 1H) ppm.

[0465] To confirm the technical effects achieved by the compounds of the present application have close relationship with the aforementioned fixed structure, the present application provides the following comparative example compounds.

[0466] Comparative Example 1: 2-amino-4-(6-chloro-2-(((R)-2,2-difluoro-1- (morpholinomethyl)cyclopropyl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7- yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0467] LCMS: m / z 677.2 [M+H] + .

[0468] 1 H NMR (400 MHz, CD3Cl) δ = 7.85 (d, J = 1.8 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.07 - 7.02 (m, 1H), 5.39 (s, 2H), 4.84 - 4.75 (m, 1H), 4.49 - 4.41 (m, 1H), 4.16 - 4.05 (m, 4H), 4.01 - 3.99 (m, 2H), 3.92 - 3.83 (m, 2H), 3.72 - 3.63 (m, 4H), 3.07 - 0.69 (m, 10H) ppm.

[0469] The compound of Comparative Example 1 is the compound of Example 31 in WO2024044667, which can be prepared by referring to the method provided in the document. Compared with the fixed structure of the compound of the present application, the compound does not have a trifluoromethyl substituent on the quinazoline ring, but uses a chlorine substituent at the corresponding position; in addition, the compound also does not have the structure of "piperidinylmethylcyclopropyl" in the fixed structure of the compound of the present application.

[0470] Comparative Example 2: 2-amino-4-(6-chloro-2-(((R)-2,2-difluoro-1- (piperidin-1-ylmethyl)cyclopropyl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7- yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0471] LCMS: m / z 675.2 [M+H] + .

[0472] 1H NMR (400 MHz, (CD3)2SO) d = 8.48 (s, 1H), 7.98 (s, 2H), 7.20 (dd, 1H), 7.07-6.94 (m, 1H), 4.31-4.20 (m, 3H), 4.12-3.99 (m, 2H), 3.93-3.85 (m, 1H), 3.74-3.62 (m, 2H), 3.58-3.48 (m, 2H), 2.40-2.22 (m, 6H), 1.69 (m, 2H), 1.55-1.41 (m, 4H), 1.34 (d, 2H), 0.98-0.72 (m, 2H).

[0473] The compound of Comparative Example 2 differs from the compound of Comparative Example 1 only in that the morpholinyl group is replaced by a piperidinyl group, which can be prepared by selecting appropriate starting materials according to the method for preparing Comparative Example 1. Compared with the fixed structure of the compound of the present application, this compound does not have a trifluoromethyl substituent on the quinazoline ring, but uses a chlorine substituent at the corresponding position.

[0474] Comparative Example 3: 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile:

[0475] LCMS: m / z 663.2 [M+H] + .

[0476] 1 H NMR (400 MHz, CD3Cl) d = 8.11 (s, 1H), 7.19 (dd, J = 8.3 Hz, 1H), 6.99 (dd, J = 9.1, 8.5 Hz, 1H), 5.68 (br s, 2H), 5.33 - 5.19 (m, 1H), 4.26 (d, J = 10.3 Hz, 1H), 4.17 - 3.98 (m, 7H), 3.89 - 3.86 (m, 2H), 3.28 - 3.11 (m, 3H), 3.00 - 2.94 (m, 1H), 2.27 - 2.13 (m, 5H), 1.98 - 1.80 (m, 3H).

[0477] The compound of Comparative Example 3 is the compound of Example 35 in WO2024044667, which can be prepared according to the method provided in the document. This compound does not have the structure of “piperidinylmethylcyclopropyl” in the fixed structure of the compound of the present application.

[0478] Test Example

[0479] The following test examples give biological activity and solubility data for the foregoing example and control compounds.

[0480] Test Example 1: MIA PaCa-2 Cell Proliferation Assay

[0481] The human pancreatic cancer cell line MIA PaCa-2 (ATCC, CRL-1420) is a KRAS G12C mutant cell line. MIA PaCa-2 cells were cultured in DMEM media containing 15% fetal bovine serum and grown in a humidified incubator at 37°C with 5% CO2.

[0482] The number of viable cells in culture was determined according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat #G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96-well plate and incubated at 37°C in a 5% CO2humidified incubator overnight. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96-well culture plate to lyse the cells and mixed gently. Subsequently, the luminescent signal was measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and by calculation of the compound concentration required for 50% inhibition. 50

[0483] Test Example 2: AsPC-1 Cell Proliferation Assay

[0484] The human pancreatic cancer cell line AsPC-1 (purchased from ATCC, CRL-1682) is a KRAS G12D mutant cell line. AsPC-1 cells were cultured in RPMI 1640 media containing 10% fetal bovine serum and grown in a humidified incubator at 37°C with 5% CO2.

[0485] ​The number of viable cells in culture was determined according to the protocol described in the Promega Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat #G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96 well plate and incubated overnight at 37°C in a 5% C02humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96 well culture plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and calculated as the concentration of compound required to inhibit the luminescent signal by 50%. 50

[0486] Test Example 3: SW480 Cell Proliferation Assay

[0487] The human colorectal carcinoma cell line SW480 (ATCC, CCL-228) is a KRAS G12V mutant cell line. SW480 cells were cultured in RPMI 1640 media containing 10% fetal bovine serum and grown at 37°C in a humidified incubator with 5% C02.

[0488] The number of viable cells in culture was determined according to the protocol described in the Promega Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat #G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96 well plate and incubated overnight at 37°C in a 5% C02humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96 well culture plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and calculated as the concentration of compound required to inhibit the luminescent signal by 50%. 50

[0489] ​​The activity data of each compound obtained in Test Example 1, Test Example 2 and Test Example 3 to inhibit KRAS G12C, KRAS G12D and KRAS G12V are shown in Table 1.

[0490] Table 1

[0491] Note 1: AMG510 (Cat No: HY-114277), MRTX849 (Cat No: HY-130149) and MRTX1133 (Cat No: HY-134813) were purchased from MedChemExpress.

[0492] Note 2: - means not detected.

[0493] Test Example 4: In vitro kinetic solubility experiment

[0494] 50 mM phosphate buffer (PB) at pH 7.4, test compounds and control compounds at 10 mM concentration were configured in turn.

[0495] 10 μL of 10 mM DMSO stock solution of test compounds and control compounds were added to the lower cavity of the vial, respectively, and then 490 μL of 50 mM PB (pH 7.4) solution was added to the vial. After mixing, the solubility sample was vortexed for at least 2 minutes, and then the vial was continued to be shaken at 800 rpm on a shaker at room temperature for 24 hours. After the end, the solubility sample was centrifuged at 4000 rpm at room temperature for 20 minutes, and the supernatant was compressed. The filtrate was prepared, injected into the UPLC-UV system, and the concentration was calculated using the standard curve. The chromatographic conditions used are as follows: Chromatographic column (ACQUTY UPLC BEH C18 1.7 μm 50 mm);

[0496] Mobile phase A: 0.1% TFA and 5 mM NH4OAc in water / ACN (v:v, 95:5);

[0497] Mobile phase B: 0.1% TFA and 5 mM NH4OAc in water / ACN (v:v, 5:95);

[0498] The in vitro kinetic solubility experiment data of the compounds obtained in Test Example 4 are shown in Table 2.

[0499] Table 2

[0500] ​

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: wherein each R1is independently selected from the group consisting of deuterium, halogen (e.g., F, CI, Br, etc.), cyano, amino, hydroxyl, deuterated hydroxyl, nitro, carboxyl, -N(R4)2, -C(=0)N(R4)2, -NHC(=0)R4, -S-R4, -S(=0)2R7, -NHS(=0)2R7, -S(=0)2NHR4, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g., -CF3), C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl (e.g., cyclopropyl), mono-C 1-6 alkylamino, di-C 1-6 alkylamino, aminoacyl, mono-C 1-6 alkylaminoacyl, di-C 1-6 alkylaminoacyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or alkoxy is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, nitro, carboxyl, -CF3, C 1-4 alkyl, or C 1-4 alkoxy; when n > 1, R1may be the same or different; n is 0, 1, 2, 3, 4 or 5; R2is selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, deuterated hydroxyl, nitro, C 1- 4alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 2-4 alkynyl, C 2-4 alkenyl, C 1-4 alkylcyano, C 3-6 cycloalkyl, C 1-4 haloalkyl (such as -CF3), C 1-4 haloalkoxy (such as -OCF3, -OCHF2, and the like), aminoacyl, mono C 1-6 alkylaminoacyl, di C 1-6 alkylaminoacyl; R2may be the same or different when m > 1; m is 0, 1 or 2; R3is selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, deuterated hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g., -CF3), C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl (e.g., cyclopropyl), -N(R5)2, -C(=O)N(R5)2, -C(=O)NHR5, -NHC(=O)R5, -S-R5, -S(=O)2R7, -NR5S(=O)2R7, -S(=O)2N(R5)2, -S(=O)2NHR5, -NR5C(=O)-C 1-6 alkyl, -NR5C(=O)-3- to 8-membered heterocyclyl, -(CH2) k NHC(=O)-C 1-6 alkyl, -(CH2) k NHC(=O)-3- to 8-membered heterocyclyl, -NR5C(=O)-C 6-10 aryl, -NR5C(=O)-C 6-10 heteroaryl, -N(R5)(R6), -(CH2) k N(R5)(R6), -(CH2) k NH(R5), -(CH2) k OC(=O)N(R5)(R6), -C(=O)N(R5)(R6), -NHC(=NH)NH2, =CH2; said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, or =CH2is optionally substituted with 1 to 4 substituents independently selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, nitro, carboxyl, -CF3, C 1-4 alkyl, or C 1-4 alkoxy; when p is greater than 1, R3may be the same or different; or when p is greater than or equal to 2, 2 R3groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (preferably cyclopropyl); R4is selected from hydrogen, deuterium, or deuterated or non-deuterated C 1-6 alkyl, C 1-6 haloalkyl; R5and R6are each independently selected from the group consisting of hydrogen, deuterium, deuterated or non-deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1- 6haloalkyl; R7is selected from deuterated or non-deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or amino; p is 0, 1, 2, 3, 4 or 5; k is 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein, selected from the group consisting of:

3. The compound according to claim 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein, selected from the group consisting of:

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein, selected from the group consisting of:

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein, selected from the group consisting of:

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein, selected from the group consisting of:

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the compounds in the following table:

8. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of a disease, which is a cancer, such as pancreatic cancer.

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