Quinazoline derivatives and their medical applications

Abstract

Disclosed are quinazoline derivatives of formula (I), pharmaceutical compositions containing the derivatives, and their medical uses, in particular, their use as SOS1 inhibitors and their use in the preparation of drugs for treating or preventing diseases associated with SOS1.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to quinazoline derivatives and their application in medicine. Background Art

[0002] SOS1 is a guanine nucleotide exchange factor (GEF) that can interact with RAS proteins to convert GDP to GTP, or from an inactive state to an active state to send cell proliferation signals. RAS genes (including KRAS, NRAS, and HRAS) are the most commonly mutated oncogenes, and RAS gene mutations are present in approximately 30% of cancers. The RAS superprotein family belongs to the small GTPase protein family, which can bind and hydrolyze GTP to form GDP as a hydrolase. When RAS proteins bind to GDP, they are inactive, but they separate slowly after binding; SOS1 can catalyze the dissociation of GDP, allowing RAS proteins to bind to GTP and be activated, and promote cell survival, proliferation, and cytokine release through multiple downstream signaling pathways such as MAPK, PI3K, and Ral-GEFs (Liu et al., 2019). Published data show that SOS1 is essential for KRAS mutations to cause cancer (Jeng et al., 2012). Inhibiting SOS1 levels reduces the proliferation rate and survival rate of KRAS mutant tumor cells.

[0003] In addition, SOS1 is involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS mutations. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated receptor tyrosine kinases. SOS1 is localized on the cell membrane, close to RAS family proteins, enabling SOS1 to promote RAS family protein activation.

[0004] Abnormal SOS1 is also associated with cancer. SOS1 mutations have been found in embryonic rhabdomyosarcoma, testicular Sertoli cell tumor, cutaneous granular cell tumor, and lung adenocarcinoma. At the same time, SOS1 overexpression has also been reported in bladder cancer and prostate cancer.

[0005] Currently, there is no approved therapy for SOS1 inhibitors, which is still an unmet clinical need in the field of tumors. Therefore, there is still a need to develop safe and effective SOS1 inhibitors to better meet the clinical needs of patients. Summary of the invention

[0006] One of the purposes of one or more embodiments of the present application is to provide a novel quinazoline derivative or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which can be used to inhibit SOS1.

[0007] One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug, or pharmaceutically acceptable salt thereof:

[0008]

[0009] X is -(OCR 2 R 3 CR 4 R 5 ) x -, wherein the O terminal is connected to Z, and the C terminal is connected to O; x is 0, 1 or 2;

[0010] Y is -(OCR 6 R 7 CR 8 R 9 ) y -, wherein the O terminal is connected to Z, and the C terminal is connected to O; y is 0, 1 or 2;

[0011] Z is -(CR 10 R 11 ) z -; z is 0, 1, 2, 3, 4 or 5;

[0012] The R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Each is independent of H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Cycloalkyl or C 1-6 Heterocycloalkyl;

[0013] Optionally, each R 2 With R 3 , each R 4 With R 5, each R 6 With R 7 , each R 8 With R 9 , each R 10 With R 11 Any group of carbon atoms connected to it forms a C 1-6 Cycloalkyl or C 1-6 Heterocycloalkyl, the C 1-6 Heterocycloalkyl contains 1 or 2 oxygen atoms;

[0014] Optionally, the R 2 or R 3 and R 4 or R 5 The two carbon atoms or R 6 or R 7 and R 8 or R 9 The two carbon atoms connected to it form C 1-6 Cycloalkyl or C 1-6 Heterocycloalkyl, the C 1-6 Heterocycloalkyl contains 1 or 2 oxygen atoms;

[0015] Each R 1 are the same or different and are independently halogen, amino, C 1-6 Alkyl, C 1-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 1-6 The cycloalkyl group is optionally substituted with one or more substituents selected from hydroxy and halogen;

[0016] n is 1, 2 or 3.

[0017] In one or more embodiments, x is 0, 1, or 2; y is 0, 1, or 2; and z is 2, 3, 4, or 5.

[0018] In one or more embodiments, x is 0, y is 0, z is 2, x is 0, y is 0, z is 3, x is 0, y is 0, z is 4, x is 0, y is 0, z is 5, x is 1, y is 1, z is 2, x is 0, y is 1, z is 2, x is 1, y is 0, z is 2, x is 1, y is 2, z is 2, or x is 2, y is 1, z is 2.

[0019] In one or more embodiments, the R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 Each is independently H or C 1-6 alkyl.

[0020] One or more embodiments of the present application provide a compound or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug, or pharmaceutically acceptable salt thereof:

[0021]

[0022]

[0023] One or more embodiments of the present application provide a compound or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug, or pharmaceutically acceptable salt thereof:

[0024]

[0025]

[0026] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0027] (1) The compounds described in the present application or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their solvates, metabolites, cocrystals, prodrugs or pharmaceutically acceptable salts;

[0028] (2) optionally one or more other active ingredients; and

[0029] (3) Pharmaceutically acceptable carriers and / or excipients.

[0030] One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt, or the composition of the present application in the preparation of a medicament for treating or preventing cancer or tumors.

[0031] In one or more embodiments, the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granular cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

[0032] One or more embodiments of the present application provide the use of the compound described in the present application or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt, or the composition described in the present application in the preparation of an SOS1 inhibitor.

[0033] One or more embodiments of the present application provide a compound of the present application or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt, or use of the composition described herein in the preparation of a drug for treating or preventing a disease associated with SOS1.

[0034] One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application, as a drug.

[0035] One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in treating or preventing cancer or tumors.

[0036] In one or more embodiments, the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granular cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

[0037] One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application, which serves as an SOS1 inhibitor.

[0038] One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application, for treating or preventing a disease associated with SOS1.

[0039] One or more embodiments of the present application provide a method for treating or preventing cancer or tumors, which comprises administering to a subject in need thereof a compound of the present application or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, cocrystals, prodrugs or pharmaceutically acceptable salts, or a composition of the present application.

[0040] In one or more embodiments, the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granular cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

[0041] One or more embodiments of the present application provide a method for treating or preventing a disease associated with SOS1, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application.

[0042] One or more embodiments of the present application provide a method for inhibiting SOS1, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, cocrystal, prodrug or pharmaceutically acceptable salt thereof, or a composition of the present application.

[0043] In one or more embodiments, the disease associated with SOS1 is cancer or tumor.

[0044] In one or more embodiments, the disease associated with SOS1 is embryonic rhabdomyosarcoma, testicular Sertoli cell tumor, cutaneous granular cell tumor, lung adenocarcinoma, bladder cancer or prostate cancer. DETAILED DESCRIPTION OF THE INVENTION

[0046] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0047] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0048] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0049] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0050] "Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propene-2-yl, butene-2-yl, butene-2-yl, pentene-2-yl, pentene-4-yl, hexene-2-yl, hexene-3-yl, heptene-2-yl, heptene-3-yl, heptene-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0051] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and further preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyne-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl may optionally be further substituted with one or more substituents.

[0052] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5-12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, and non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.

[0053] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5-8 membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

[0054] "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl" above; when it is a non-aromatic ring, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclic group" or "carbocycle" is optionally further substituted by one or more substituents.

[0055] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thiinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiinyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furan ... pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 .1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0056] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4-12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic ring system, and the ring carbon atoms are preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl, etc. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0057] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" may be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom; "heterocycloalkyl" may be a bridged ring or a spiro ring. Non-limiting examples of “heterocycloalkyl” include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0058] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 Rq5 , =NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, and wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 , R q3 Select from H or C 1-6 Alkyl; wherein R q4 , R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O) 2 NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , where the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0059] Halogens include F, Cl, Br and I.

[0060] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0061] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0062] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0063] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0064] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0065] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0066] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0067] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group. DETAILED DESCRIPTION

[0068] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0069] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard was tetramethylsilane (TMS);

[0070] MS was determined using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0071] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0072] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0073] Example 2

[0074] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 2)

[0075] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0076]

[0077] first step:

[0078] 2-Methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4(3H)-one (2A)

[0079] 2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

[0080] Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL N, N-dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction bottle, and stirred at 80°C for 1 hour, and then a 50 mL N, N-dimethylformamide solution of diethylene glycol bis-p-toluenesulfonate (12.4 g, 3 mmol, 1 equiv) was slowly added dropwise, and stirring was continued for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, 20 mL of water was added, and 3×30 mL of dichloromethane was extracted, the organic phases were combined, dried over sodium sulfate, the solvent was removed by rotary evaporation, and compound 2A (white solid, 477 mg, yield 60%) was obtained by column chromatography.

[0081] 1H NMR (400 MHz, DMSO-d 6 ): δ(ppm)12.06(s,1H),7.96(s,1H),7.64(s,1H),7.18(s,1H),4.57-4.55(m,2H),4.32-4.30(m,2H),3.84-3.83(m,4H),2.30(s,3H).

[0082] LC-MS m / z(ESI)=263.1[M+1].

[0083] Step 2:

[0084] 2-Methyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (2B)

[0085] 2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl2,4,6-triisopropylbenzenesulfonate

[0086] Compound 2A (477 mg, 1.82 mmol, 1 equiv) and 2,4,6-triisopropylbenzenesulfonyl chloride (1.1 g, 3.64 mmol, 2 equiv) were added to a 25 mL reaction tube, nitrogen was replaced three times, triethylamine (756 μL, 5.64 mmol, 3 equiv), 4-dimethylaminopyridine (48 mg, 0.4 mmol) and dichloromethane (15 mL) were added, and the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, the solvent was removed by rotary evaporation, and compound 2B (white solid, 600 mg, yield 62%) was obtained by column chromatography.

[0087] 1 H NMR (400 MHz, DMSO-d 6 ): δ(ppm)7.51(s,1H),7.43(s,1H),7.35(s,2H),4.57-4.55(m,2H),4.32-4.30(m, 2H),4.25-4.17(m,2H),3.84-3.83(m,4H),2.96(p,1H),2.42(s,3H),1.20(t,18H).

[0088] LC-MS m / z(ESI)=529.2[M+1].

[0089] Step 3:

[0090] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 2)

[0091] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0092] Compound 2B (50 mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (23 mg, 1.2 equiv), triethylamine (0.1 mL), and dimethyl sulfoxide (2 mL) were added to a 25 mL reaction tube and stirred at 90° C. After the reaction, the solvent was distilled off under reduced pressure, and compound 2 (white solid, 35 mg, yield 82%) was obtained by column chromatography.

[0093] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.40-7.34(m,2H),7.06(s,1H),6.92(s,1H),6.79(s,1H),5.90(br,1H),5.6 1-5.56(m,1H),4.47(t,2H),4.38(d,2H),3.91-3.90(m,6H),2.57(s,3H),1.66(d,3H).

[0094] LC-MS m / z(ESI)=449.2[M+1].

[0095] Example 3

[0096] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 3)

[0097] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane- 1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0098]

[0099] first step:

[0100] 2'-Methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'(3'H)-one (3A)

[0101] 2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'(3'H)-one

[0102] Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL of dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction bottle, stirred at 80 ° C for 1 hour, and then a 50 mL dimethylformamide solution of cyclopropane-1,1-diylbis(methylene)bis(4-toluenesulfonate) (1.23 g, 3 mmol, 1 equiv) was slowly added dropwise, and stirring was continued for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, 20 mL of water was added, and 3×30 mL of dichloromethane was extracted. The organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 3A, which was directly used in the next step (yellow solid, 550 mg, yield 71%).

[0103] 1 H NMR (400 MHz, DMSO-d 6 ): δ(ppm)12.07(s,1H),8.00(s,1H),7.58(s,1H),7.20(s,1H),4.14-4.06(m,2H),2.35(s,3H),0.65-0.63(m,4H). LC-MS m / z(ESI)=307.2[M+1].

[0104] LC-MS m / z(ESI)=259.1[M+1].

[0105] Step 2:

[0106] 2'-Methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxoepinephrine[2,3-g]quinazoline]-4'-yl 2,4,6-triisopropylbenzenesulfonate (3B)

[0107] 2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl 2,4,6-triisopropylbenzenesulfonate

[0108] Compound 3A (550 mg, 2.13 mmol, 1 equiv), 2,4,6-triisopropylbenzenesulfonyl chloride (1.28 g, 4.26 mmol, 2 equiv) were added to a 25 mL reaction tube, nitrogen was replaced three times, triethylamine (856 μL, 6.39 mmol, 3 equiv), 4-dimethylaminopyridine (48 mg, 0.4 mmol) and dichloromethane (15 mL) were added, and the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, the solvent was removed by rotary evaporation, and compound 3B (white solid, 656 mg, yield 59%) was obtained by column chromatography.

[0109] 1 H NMR (400 MHz, DMSO-d 6 ): δ(ppm)7.65(s,1H),7.23(s,1H),6.96(s,2H),4.60-4.53(m,2H),4.04-4.00 (m,4H),2.84-2.77(m,1H),2.56(s,3H),1.10-1.17(m,18H),0.64-0.63(m,4H).

[0110] LC-MS m / z(ESI)=525.3[M+1].

[0111] Step 3:

[0112] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 3)

[0113] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0114] Compound 3B (50 mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (23 mg, 1.2 equiv), triethylamine (0.1 mL), and dimethyl sulfoxide (2 mL) were added to a 25 mL reaction tube and stirred at 90° C. After the reaction, the solvent was distilled off under reduced pressure, and compound 3 (white solid, 30 mg, yield 70%) was obtained by column chromatography.

[0115] 1 H NMR (400 MHz, CDCl 3 )δ(ppm)7.35(s,1H),7.30(s,1H),7.06(s,1H),6.89(s,1H),6.79(s,1H),5.62-5.55 (m,2H),4.02-3.94(m,4H),3.88(br,2H),2.56(s,3H)1.63(d,3H),0.73-0.66(m,4H).

[0116] LC-MS m / z(ESI)=445.2[M+1].

[0117] Example 4

[0118] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 4)

[0119] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0120]

[0121]

[0122] first step:

[0123] 1-(2-(Benzyloxy)ethoxy)propan-2-ol (4B)

[0124] 1-(2-(benzyloxy)ethoxy)propan-2-ol

[0125] Benzyl glycol (4.5 g, 30 mmol, 3 equiv), 25 mL of dichloromethane and boron trifluoride etherate (42 mg, 0.3 mmol, 0.01 equiv) were added to a 100 mL reaction bottle, cooled to 0°C, and propylene oxide (580 mg, 10 mmol, 1 equiv) was slowly added dropwise. Stirring was continued for 1 hour after the addition was completed. After the reaction was completed, the solvent was removed by rotary evaporation, and compound 4B (colorless liquid, 1.42 g, yield 68%) was obtained by column chromatography.

[0126] 1 H NMR (400 MHz, DMSO-d 6 ): δ(ppm)7.35-7.30(m,5H),5.55(br,1H),4.62(s,1H),3.67-4.02(m,7H),1.21(d,3H).

[0127] LC-MS m / z(ESI)=211.2[M+1].

[0128] Step 2:

[0129] 1-(2-Hydroxyethoxy)propan-2-ol (4C)

[0130] 1-(2-hydroxyethoxy)propan-2-ol

[0131] Compound 4B (1.4 g, 6.7 mmol, 1 equiv), pyridinium p-toluenesulfonate (33 mg, 0.13 mmol, 0.02 equiv), vinyl ethyl ether (2.4 g, 33.5 mmol, 5 equiv), and dichloromethane (25 mL) were added to a 100 mL reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, 1 mL of triethylamine was added and the solvent was removed by rotary evaporation to obtain 1.9 g of crude product which was directly used in the next step.

[0132] Palladium hydroxide / carbon (380 mg, 20 wt%) was added to the reaction bottle in the previous step, and the reaction was stirred at 50°C under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through diatomaceous earth and the solvent was removed by rotary evaporation. Then 20 mL of hydrogen chloride ethyl acetate solution and 1 mL of water were added, and the mixture was stirred at room temperature for 5 minutes. The solvent was removed by rotary evaporation to obtain 780 mg of crude product 4C (colorless liquid, total yield of two steps 97%), which was directly used in the next step.

[0133] 1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) 5.01 (br, 2H), 3.61-4.89 (m, 7H), 1.12 (d, 3H).

[0134] LC-MS m / z(ESI)=121.1[M+1].

[0135] Step 3:

[0136] 1-(2-(p-Tolyloxy)ethoxy)propan-2-yl 4-toluenesulfonate (4D)

[0137] 1-(2-(tosyloxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate

[0138] Compound 4C (600 mg, 5 mmol, 1 equiv), p-toluenesulfonyl chloride (2.85 g, 15 mmol, 3 equiv), DMAP (1.83 g, 15 mmol, 3 equiv) and dichloromethane (20 mL) were added to a 100 mL reaction bottle and stirred overnight at room temperature. After the reaction, the mixture was washed with 20 mL of 2M hydrochloric acid solution and 20 mL of water, dried over sodium sulfate, and the solvent was removed by rotary evaporation. 4D (white solid, 1.75 g, yield 82%) was obtained by column chromatography.

[0139] 1 H NMR (600MHz, DMSO-d6): δ (ppm) 7.80-7.74 (m, 4H), 7.50-7.42 (m, 4H), 4.62-3.41 (m, 7H), 2.42 (s, 6H), 1.02 (d, 3H).

[0140] LC-MS m / z(ESI)=429.1[M+1].

[0141] Step 4:

[0142] 2,11-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4(3H)-one (4E)

[0143] 2,11-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

[0144] Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL of dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction bottle, stirred at 100 ° C for 1 hour, and then a 50 mL dimethylformamide solution of compound 4D (1.28 g, 3 mmol, 1 equiv) was slowly added dropwise, and stirring was continued at 120 ° C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 mL of water was added, and 3×30 mL of dichloromethane was extracted. The organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 4E, which was directly used in the next step (light brown solid, 391 mg, yield 47%).

[0145] 1 H NMR (600 MHz, DMSO-d 6 )δ12.07(s,1H),8.00(s,1H),7.58(s,1H),7.20(s,1H),4.51-3.46(m,7H),2.35(s,3H),1.03(d,3H).

[0146] LC-MS m / z(ESI)=277.1[M+1].

[0147] Step 5:

[0148] 2,7-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (4F)

[0149] 2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate

[0150] Compound 4E (391 mg, 1.41 mmol, 1 equiv) and 2,4,6-triisopropylbenzenesulfonyl chloride (850 mg, 2.82 mmol, 2 equiv) were added to a 25 mL reaction tube, and nitrogen was replaced three times. Triethylamine (567 μL, 4.23 mmol, 3 equiv), 4-dimethylaminopyridine (24 mg, 0.2 mmol) and dichloromethane 15 mL) were added, and the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, and the solvent was removed by rotary evaporation. Compound 4F (white solid, 540 mg, yield 71%) was obtained by column chromatography.

[0151] 1 H NMR (600 MHz, DMSO-d6 )δ.69(s,1H),7.10(s,1H),6.96(s,2H),4.60-3.46(m,9H),2.80(p,1H),2.52(s,3H),1.13(m,18H),1.05(d,3H).

[0152] LC-MS m / z(ESI)=543.3[M+1].

[0153] Step 6:

[0154] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 4)

[0155] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0156] Compound 4F (50 mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (22 mg, 1.2 equiv), triethylamine (0.1 mL), and dimethyl sulfoxide (2 mL) were added to a 25 mL reaction tube and stirred at 90° C. After the reaction, the solvent was distilled off under reduced pressure, and compound 4 (white solid, 30 mg, yield 65%) was obtained by column chromatography.

[0157] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.07-8.06(m,2H),7.05(s,1H),6.89(s,1H),6.84(s,1H),6.69(s,1H),5.55-5.49 (m,3H),4.56-4.53(m,1H),4.15-3.62(m,6H),2.34(s,3H),1.53(d,3H),1.03-1.01(m,3H).

[0158] LC-MS m / z(ESI)=463.2[M+1].

[0159] Example 5

[0160] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 5)

[0161] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0162]

[0163] first step:

[0164] (S)-1-(2-((6-hydroxy-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate (5B)

[0165] (S)-1-(2-((6-hydroxy-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate

[0166] Compound 1C (572 mg, 3 mmol, 1 equiv), 50 mL DMF and K were added to a 250 mL reaction bottle. 2 CO 3 (1.24 g, 9 mmol, 3 equiv), stirred at 50 ° C for 1 hour, 5A (compound 5A, 1.28 g, 3 mmol, 1 equiv) in 20 mL DMF solution was slowly added dropwise over 8 hours, 200 mL of water was added, and the mixed solvent of EA / MeOH = 95:5 was extracted several times, and the organic phases were combined, and Na 2 SO 4 After drying, the solvent was removed by rotary evaporation and slurrying with DCM / PE, 5B (light yellow solid, 510 mg, yield 38%) was obtained.

[0167] LC-MS m / z(ESI)=449.1[M+1].

[0168] Step 2:

[0169] (R)-2,7-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4(3H)-one (5C)

[0170] (R)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

[0171] Compound 5B (510 mg, 1.14 mmol, 1 equiv), 120 mL DMF and K were added to a 250 mL reaction bottle. 2 CO 3 (628 mg g, 4.55 mmol, 4 equiv), stirred at 100 °C, added 200 mL of water for 4 hours, extracted with DCM several times, combined the organic phases, and Na 2 SO 4 After drying, the solvent was removed by rotary evaporation and the compound 5C (white solid, 113 mg, yield 36%) was obtained by column chromatography.

[0172] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),7.60(s,1H),7.02(s,1H),5.11(ddd,J= 13.1, 8.9, 1.9Hz, 1H), 4.30–3.45 (m, 8H), 2.29 (s, 3H), 1.32 (d, J = 6.4Hz, 3H).

[0173] LC-MS m / z(ESI)=277.1[M+1].

[0174] Step 3:

[0175] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 5)

[0176] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0177] Compound 5C (50 mg), Carter condensation agent (1.5 equiv), 1,8-diazobispiro[5.4.0]undec-7-ene (2 equiv), DMF (2 mL) were added to a 25 mL reaction tube, and stirred at room temperature for 30 minutes, and then (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (22 mg, 1.2 equiv) was added and stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and compound 5 (white solid, 51 mg, yield 62%) was obtained by separation by preparative HPLC.

[0178] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=6.5Hz,2H),7.04(s,1H),6.85(d,J=10.7Hz,2H),6.69(d,J=2.1Hz,1H),5.55(s,3H),4.99(ddd,J=12.9,8.5,2.0H z,1H),4.38(ddd,J=9.3,6.4,2.8Hz,1H),4.08(dt,J=13.1,3.2Hz,1H),4. 00–3.47(m,5H),2.34(s,3H),1.54(d,J=7.3Hz,3H),1.37(d,J=6.4Hz,3H).

[0179] LC-MS m / z(ESI)=463.2[M+1]

[0180] Example 6

[0181] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 6)

[0182] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0183]

[0184] The same method as Example 5 was used for synthesis.

[0185] 1H NMR (400MHz, DMSO-d6) δ8.00(d,J=6.5Hz,2H),7.05(s,1H),6.88(d,J=10.7Hz,2H),6.73(d,J=2.1Hz,1H),5.52(s,3H ),4.99-4.90(m,1H),4.45-4.38(m,1H),4.03-3.47(m,6H),2.34(s,3H),1.54(d,J=7.3Hz,3H),1.35(d,J=6.4Hz,3H).

[0186] LC-MS m / z(ESI)=463.2[M+1].

[0187] Example 7

[0188] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxetane[2,3-g]quinazoline]-4'-amine (Compound 7)

[0189] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0190]

[0191] The same method as Example 3 was used for synthesis.

[0192] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.22(s,1H),6.87(d,1H),6.75(s,2H),5.2 (s,1H),5.15–5.03(m,1H),4.63(s,4H),4.55(s,4H),2.57(s,3H),1.59(d,3H).

[0193] LC-MS m / z(ESI)=461.2[M+1].

[0194] Example 8

[0195] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,9-trimethyl-8,9-dihydro-7H-[1,4]dioxoepinephrine[2,3-g]quinazolin-4-amine (Compound 8)

[0196] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,9-trimethyl-8,9-dihydro-7H-[1,4]dioxepino[2,3-g]quinazolin-4-amine

[0197]

[0198] The same method as Example 3 was used for synthesis.

[0199] 1 H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.58(s,1H),7.00(dt,1H),6.92(dq,2H),5.20(s,1H),5.15–5.03( m,1H),3.71(qd,2H),3.52(s,2H),2.54(s,3H),2.00(dt,1H),1.84(dt,1H),1.48(d,3H),1.33(dd,6H).

[0200] Example 9

[0201] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,11-trimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 9)

[0202] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,11-trimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0203]

[0204] The same method as Example 3 was used for synthesis.

[0205] 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=6.5Hz,2H),7.04(s,1H),6.85(d,J=10.7Hz,2H),6.69(d,J=2.1Hz,1H),5.55(s,3H),4.99(ddd,J=12.9,8.5,2.0 Hz,1H),4.38(ddd,J=9.3,6.4,2.8Hz,1H),4.08(dt,J=13.1,3.2Hz,1H), 4.00–3.47(m,5H),2.34(s,3H),1.54(d,J=7.3Hz,3H),1.42-1.35(m,6H).

[0206] LC-MS m / z(ESI)=477.2[M+1].

[0207] Example 10

[0208] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(trifluoromethyl)-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 10)

[0209] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(trifluoromethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0210]

[0211] The same method as Example 5 was used for synthesis.

[0212] 1 H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.60(s,1H),7.22–6.95(m,2H),6.87(dt,1H),5.06(qt,1H),4.9 9–4.81(m,3H),4.73(dt,1H),3.87–3.59(m,3H),3.52(dq,2H),3.18(s,1H),2.51(s,3H),1.48(d,3H).

[0213] LC-MS m / z(ESI)=517.2[M+1].

[0214] Embodiment 11

[0215] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 11)

[0216] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0217]

[0218] The same method as Example 4 was used to synthesize.

[0219] 1 H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.54(t,1H),7.27(s,1H),7.23–7.1 1(m,1H),6.09(s,2H),6.04–5.94(m,1H),5.01–4.76(m,1H),4.11(dt,1H) ,3.91(dt,1H),3.75(p,1H),3.70–3.59(m,2H),3.53(dt,1H),3.34(dd,1H ),3.15(s,1H),2.51(s,3H),1.72–1.47(m,2H),1.47(d,3H),0.88(t,3H).

[0220] LC-MS m / z(ESI)=477.2[M+1].

[0221] Example 12

[0222] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,10-trimethyl-7,8,9,10-tetrahydro-[1,4]dioxacyclohexane[2,3-g]quinazolin-4-amine (Compound 12)

[0223] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,10-trimethyl-7,8,9,10-tetrahydro-[1,4]dioxocino[2,3-g]quinazolin-4-amine

[0224]

[0225] The same method as in Example 3 was used to synthesize and Prep-HPLC was used to separate and obtain compound 12-1, compound 12-2, compound 12-3 and compound 12-4.

[0226] Compound 12-1: 1 H NMR(400MHz,DMSO-d6)δ7.56(q,1H),7.19(d,2H),6.09(s,2H),5.99(dt,1H),5.02–4.80(m,1H ),3.97(dp,2H),3.14(s,1H),2.51(s,3H),1.90–1.57(m,2H),1.56–1.34(m,5H),1.23(t,6H).

[0227] LC-MS m / z(ESI)=461.2[M+1].

[0228] Compound 12-2: 1 H NMR (400MHz, DMSO-d6) δ7.55(s,1H),7.50–7.38(m,1H),7.32–7.15(m,2H),6.20–5.96(m,3H),4.94–4. 73(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.89–1.61(m,2H),1.56–1.35(m,5H),1.24(dd,6H).

[0229] LC-MS m / z(ESI)=461.2[M+1].

[0230] Compound 12-3: 1 H NMR (400 MHz, DMSO-d 6 )δ7.55(s,1H),7.43(dd,1H),7.36–7.19(m,2H),6.19–5.96(m,3H),4.97–4.80(m,1H),3 .99(dh,2H),3.08(s,1H),2.51(s,3H),1.75(tdd,2H),1.61–1.30(m,5H),1.24(dd,6H).

[0231] LC-MS m / z(ESI)=461.2[M+1].

[0232] Compound 12-4: 1H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.52–7.40(m,1H),7.26(q,1H),7.20(s,1H),6.18–5.98(m,3H),5.01 –4.72(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.87–1.63(m,2H),1.51–1.35(m,5H),1.24(dd,6H).

[0233] LC-MS m / z(ESI)=461.2[M+1].

[0234] Example 13

[0235] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,8-trimethyl-7,8-dihydro-[1,4]dioxy[2,3-g]quinazolin-4-amine (Compound 13)

[0236] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,8-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine

[0237]

[0238] The same method as Example 3 was used for synthesis.

[0239] 1 H NMR(400MHz,DMSO-d6)δ7.46(d,2H),7.41–7.38(m,1H),7.29(q,1H),6.08(s,2H),6.08–6.01(m, 1H),4.97–4.82(m,1H),3.97(qd,2H),3.07(s,1H),2.51(s,3H),1.41(d,3H),1.37–1.26(m,6H).

[0240] LC-MS m / z(ESI)=433.2[M+1].

[0241] Embodiment 14

[0242] cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methyl-1,3,3a,5,6,14a-hexahydrofuran[3',4':8,9][1,4,7]trione[2,3-g]quinazolin-12-amine (Compound 14)

[0243] cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methyl-1,3,3a,5,6,14a-hexahydrofuro[3',4':8,9][1,4,7]trioxonino[2,3-g]quinazolin-12-amine

[0244]

[0245] The same method as in Example 5 was used to synthesize and Prep-HPLC was used to separate and obtain compound 14-1 and compound 14-2.

[0246] Compound 14-1: 1 H NMR(400MHz,DMSO-d6)δ7.53(s,1H),7.27(s,1H),7.14(d,1H),6.97(q,1H),6.96–6.77(m,1H),5.03–4.79(m,3H),4.41(q,1 H),4.13(dt,1H),4.00(dt,1H),3.96–3.82(m,2H),3.82–3.62(m,3H),3.50(td,2H),3.10(s,1H),2.51(s,3H),1.37(d,3H).

[0247] LC-MS m / z(ESI)=491.2[M+1].

[0248] Compound 14-2: 1H NMR (400MHz, DMSO-d6) δ7.72 (s, 1H), 7.33 (s, 1H), 7.22–7.08 (m, 1H), 6.97 (q, 1H), 6.88 (q, 1H), 5.03–4.75 (m, 3H), 4.34–3.31 (m, 10H), 3.13 (s, 1H), 2.51 (s, 3H), 1.37 (d, 3H).

[0249] LC-MS m / z(ESI)=491.2[M+1].

[0250] Embodiment 15

[0251] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 15)

[0252] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0253]

[0254] The same method as Example 5 was used for synthesis.

[0255] Compound 15: 1 H NMR (400 MHz, DMSO-d 6 )δ7.67(s,1H),7.51–7.37(m,1H),7.37–7.23(m,2H),6.11(s,2H),6.03(dt,1H),4.97–4.71(m,1H),4.07(ddd,1H),4.01–3.79(m ,2H),3.74–3.49(m,3H),3.34(dd,1H),3.08(s,1H),2.51(s,3H),1.85–1.68(m,1H),1.68–1.49(m,1H),1.38(d,3H),0.92(t,3H).

[0256] LC-MS m / z(ESI)=477.2[M+1].

[0257] Example 16

[0258] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 16)

[0259] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0260]

[0261] The same method as Example 5 was used for synthesis.

[0262] 1H NMR (400MHz, DMSO-d6) δ7.67(s,1H),7.43(q,1H),7.30(q,1H),7.20(s,1H),6.08(s,2H),6.04–5.98(m,1H),5.01–4. 73(m,1H),4.53(ddd,1H),3.96–3.26(m,6H),3.13(s,1H),2.51(s,3H),1.84–1.47(m,2H),1.37(d,3H),0.88(t,3H).

[0263] LC-MS m / z(ESI)=477.2[M+1].

[0264] Embodiment 17

[0265] cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-methyl-1,2,3,4,4a,6,7,15a-octahydrobenzo[8,9][1,4,7]trione[2,3-g]quinazolin-13-amine (Compound 17)

[0266] cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-methyl-1,2,3,4,4a,6,7,15a-octahydrobenzo[8,9][1,4,7]trioxonino[2,3-g]quinazolin-13-amine

[0267]

[0268] The same method as in Example 5 was used to synthesize and Prep-HPLC was used to separate and obtain compound 17-1 and compound 17-2.

[0269] Compound 17-1: 1 H NMR(400MHz,DMSO-d6)δ7.55(d,1H),7.50(s,1H),7.24(s,1H),7.19(q,1H),6.09(s,2H),5.99(td,1H),5.05–4.89(m,1H),4 .46(q,1H),4.16(dt,1H),4.01(s,0H),3.61–3.39(m,3H),3.16(s,1H),2.51(s,3H),2.00–1.86(m,1H),1.79–1.19(m,10H).

[0270] LC-MS m / z(ESI)=503.2[M+1].

[0271] Compound 17-2: 1 H NMR(400MHz, DMSO-d6)δ7.67(s,1H),7.51(dd,1H),7.31(s,1H),7.28–7.20(m,1H),6.09(s,2H),6.00(q,1H),5.01–4. 80(m,1H),4.14(dt,1H),3.92(dt,1H),3.62(dt,1H),3.55–3.34(m,3H),3.23(s,1H),2.51(s,3H),2.00–1.16(m,11H).

[0272] LC-MS m / z(ESI)=503.2[M+1].

[0273] Embodiment 18

[0274] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-isopropyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 18)

[0275] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-isopropyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0276]

[0277] The same method as Example 5 was used for synthesis.

[0278] 1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.40(dq,1H),7.29(d,2H),6.12(s,2H),6.03(dt,1H),4.97–4.82(m,1H),4.1 4(dt,1H),4.03–3.75(m,2H),3.75–3.40(m,4H),3.14(s,1H),2.51(s,3H),2.02(h,1H),1.38(d,3H),0.84(dd,6H).

[0279] LC-MS m / z(ESI)=491.2[M+1].

[0280] Embodiment 19

[0281] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 19)

[0282] (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0283]

[0284] The same method as Example 5 was used for synthesis.

[0285] 1 H NMR(400MHz,DMSO-d6)δ7.72(d,2H),7.32(dt,2H),6.10(s,2H),6.05–5.93(m,1H),4.83– 4.58(m,1H),4.05–3.78(m,3H),3.72–3.13(m,9H),2.51(s,3H),1.41(d,3H),1.08(t,3H).

[0286] LC-MS m / z(ESI)=507.2[M+1].

[0287] Embodiment 20

[0288] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 20)

[0289] (S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0290]

[0291] The same method as Example 5 was used for synthesis.

[0292] 1 H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.62(s,1H),7.50–7.34(m,1H),7.34–7.24(m,1H),6.11(s,2H),6.03(dd, 1H),4.95–4.76(m,1H),4.52(ddd,1H),3.95–3.19(m,10H),3.12(s,1H),2.51(s,3H),1.38(d,3H),1.08(t,3H).

[0293] LC-MS m / z(ESI)=507.2[M+1].

[0294] Embodiment 21

[0295] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 21)

[0296] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0297]

[0298] Compound 2A, Carter condensation agent (1.5 equiv), 1,8-diazobispiro[5.4.0]undec-7-ene, DMF were added to a 25 mL reaction tube, and the mixture was stirred at room temperature for 30 minutes, and then compound 21A (synthesized by the method reported in Advanced Synthesis and Catalysis, 2018, vol. 360, #21, p. 4104-4114, and then compound 21A was obtained by the method reported in WO2018115380A1) was added and stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and compound 21 (white solid) was obtained by preparative HPLC separation.

[0299] 1H NMR(400MHz,DMSO-d6)δ7.69(d,2H),7.43–7.28(m,1H),7.25–7.02(m,2H),4.82(dd,1H),4.65 (qd,1H),4.15(ddd,1H),3.86–3.12(m,7H),2.51(s,3H),2.37–2.16(m,1H),1.57–1.07(m,5H).

[0300] LC-MS m / z(ESI)=460.2[M+1].

[0301] Embodiment 22

[0302] (R)-2,2-difluoro-2-(3-(1-((2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 22)

[0303] (R)-2,2-difluoro-2-(3-(1-((2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol

[0304]

[0305] Compound 2A, Carter condensation agent (1.5 equiv), 1,8-diazobispiro[5.4.0]undec-7-ene, and DMF were added to a 25 mL reaction tube, and the mixture was stirred at room temperature for 30 minutes. Compound 22A (compound 22A was obtained by the method reported in WO2018115380A1) was added and stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and compound 22 (white solid) was obtained by preparative HPLC separation.

[0306] 1 H NMR(400MHz,DMSO-d6)δ7.66–7.22(m,6H),4.95–4.81(m,1H),4.62(d,1H),4.50–4.41(m,1H),4.2 0–3.98(m,2H),3.98–3.72(m,3H),3.65–3.44(m,2H),3.34–3.12(m,3H),2.51(s,3H),1.36(d,3H).

[0307] LC-MS m / z(ESI)=446.1[M+1].

[0308] Embodiment 24

[0309] N-((1R)-1-(3-(2,2-difluorocyclopropyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 24)

[0310] N-((1R)-1-(3-(2,2-difluorocyclopropyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0311]

[0312] The product was synthesized in the same manner as in Example 21.

[0313] 1 H NMR(400MHz,DMSO-d6)δ7.67(d,2H),7.56–7.08(m,4H),5.06–4.79(m,1H), 4.63–4.25(m,2H),4.00–3.04(m,7H),2.68–2.25(m,4H),1.67–0.89(m,5H).

[0314] LC-MS m / z(ESI)=442.2[M+1].

[0315] Embodiment 25

[0316] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-8,9,10,11-tetrahydro-7H-[1,4]dioxacyclo[2,3-g]quinazolin-4-amine (Compound 25)

[0317] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-8,9,10,11-tetrahydro-7H-[1,4]dioxonino[2,3-g]quinazolin-4-amine

[0318]

[0319] The same method as Example 5 was used for synthesis.

[0320] 1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.66(s,1H),7.15(t,1H),7.06–6.93(m,1H),6.87(dt,1H),5.02–4.7 2(m,3H),4.39(ddt,1H),4.18–3.81(m,3H),3.15(s,1H),2.51(s,3H),1.98(dddd,1H),1.81–1.30(m,8H).

[0321] LC-MS m / z(ESI)=447.2[M+1].

[0322] Embodiment 27

[0323] (R)-N-(1-(2-fluoro-3-(1-fluorovinyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 27)

[0324] (R)-N-(1-(2-fluoro-3-(1-fluorovinyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0325]

[0326] Compound A2, Carter condensation agent (1.5 equiv), 1,8-diazobispiro[5.4.0]undec-7-ene, and DMF were added to a 25 mL reaction tube, and the mixture was stirred at room temperature for 30 minutes. Compound 27A (compound 27A was obtained by the method reported in WO2018115380A1) was added and stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and compound 27 (white solid) was obtained by preparative HPLC separation.

[0327] 1 H NMR(400MHz,DMSO-d6)δ7.64(d,2H),7.35(td,1H),7.16–7.02(m,2H),4.97–4.7 2(m,2H),4.60(d,1H),4.47(d,1H),4.18–3.21(m,9H),2.51(s,3H),1.33(d,3H).

[0328] LC-MS m / z(ESI)=428.1[M+1].

[0329] Embodiment 28

[0330] (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 28)

[0331] (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0332]

[0333] The same method as Example 5 was used for synthesis.

[0334] 1 H NMR (400MHz, DMSO-d6) δ7.80(s,1H),7.59(s,1H),7.52–7.43(m,1H),7.30–7.15(m,2H),4.91–4.81(m,1H),4.58(dd d,1H),3.91(h,1H),3.78(ddd,1H),3.71–3.59(m,2H),3.48(ddd,1H),3.34–3.24(m,2H),2.51(s,3H),1.30(dd,6H).

[0335] LC-MS m / z(ESI)=448.2[M+1].

[0336] Embodiment 29

[0337] (S)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 29)

[0338] (S)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0339]

[0340] The same method as Example 5 was used for synthesis.

[0341] 1 H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.59–7.45(m,3H),7.23(t,1H),4.67–4.54(m,2H),3.92(h,1H),3.78(d dd,1H),3.70–3.60(m,2H),3.58(s,1H),3.48(ddd,1H),3.29(dd,1H),2.51(s,3H),1.41(d,3H),1.28(d,3H).

[0342] LC-MS m / z(ESI)=466.2[M+1].

[0343] Embodiment 30

[0344] (S)-N-((R)-1-(3-cyclopropyl-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 30)

[0345] (S)-N-((R)-1-(3-cyclopropyl-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0346]

[0347] The same method as Example 5 was used for synthesis.

[0348] 1 H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.59(s,1H),7.44–7.25(m,1H),7.25–7.03(m,2H),4.73–4.51(m,2H),4.0 0–3.21(m,7H),2.51(s,3H),2.29–2.15(m,1H),1.40(d,3H),1.28(d,3H),1.22–1.04(m,2H),1.01–0.77(m,2H).

[0349] LC-MS m / z(ESI)=438.2[M+1].

[0350] Embodiment 31

[0351] 2-(3-((R)-1-((S)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethane-1-ol (Compound 31)

[0352] 2-(3-((R)-1-(((S)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethan-1-ol

[0353]

[0354] The same method as Example 5 was used for synthesis.

[0355] 1 H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(s,1H),7.52–7.43(m,3H),7.34(ddd,1H),4. 84(q,1H),4.66–4.54(m,2H),4.19–3.01(m,9H),2.51(s,3H),1.37(d,3H),1.27(d,3H).

[0356] LC-MS m / z(ESI)=460.2[M+1].

[0357] Embodiment 32

[0358] (S)-2,7-Dimethyl-N-((R)-1-(naphthalen-2-yl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 32)

[0359] (S)-2,7-dimethyl-N-((R)-1-(naphthalen-2-yl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0360]

[0361] The same method as Example 5 was used for synthesis.

[0362] 1H NMR(400MHz,DMSO-d6)δ8.03–7.83(m,3H),7.80(d,2H),7.73(s,1H),7.69(d,1H),7.55(dtd,2H),4.92(q,1H), 4.13–3.89(m,2H),3.85(ddd,1H),3.77–3.49(m,3H),3.44–3.19(m,2H),2.51(s,3H),1.44(d,3H),1.29(d,3H).

[0363] LC-MS m / z(ESI)=430.2[M+1].

[0364] Embodiment 33

[0365] (7S)-N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 33)

[0366] (7S)-N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0367]

[0368] The same method as Example 5 was used for synthesis.

[0369] 1 H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.57(s,1H),7.40–7.31(m,1H),7.25–7.07(m,2H),4.82–4.40(m,2H),3.9 4(h,1H),3.77(ddd,1H),3.74–3.59(m,3H),3.47(ddd,1H),3.30(d,1H),2.61–2.19(m,4H),1.54–1.00(m,8H).

[0370] LC-MS m / z(ESI)=474.2[M+1].

[0371] Embodiment 34

[0372] (S)-2,7-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 34)

[0373] (S)-2,7-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0374]

[0375] The same method as Example 5 was used for synthesis.

[0376] 1 H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.49–7.28(m,3H),4.71(qd,1H),4.58(ddd,1H),4.03–3.52(m, 4H),3.48(ddd,1H),3.28(dd,1H),3.13(s,1H),2.51(s,3H),2.33(s,3H),1.39(d,3H),1.27(d,3H).

[0377] LC-MS m / z(ESI)=462.2[M+1].

[0378] Embodiment 35

[0379] (S)-2,7-Dimethyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trione[2,3-g]quinazolin-4-amine (Compound 35)

[0380] (S)-2,7-dimethyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine

[0381]

[0382] The same method as Example 5 was used for synthesis.

[0383] 1H NMR(400MHz,DMSO-d6)δ7.78(d,2H),7.60(s,1H),7.57–7.32(m,3H),4.89(q,1H),4.56(ddd,1H),3.90(h,1H) ,3.77(ddd,1H),3.72–3.57(m,2H),3.48(ddd,1H),3.34–3.18(m,2H),2.51(s,3H),1.37(d,3H),1.27(d,3H).

[0384] LC-MS m / z(ESI)=448.2[M+1].

[0385] Embodiment 36

[0386] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (Compound 36)

[0387] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0388]

[0389] Compound 3A was synthesized in the same manner as in Example 3. Compound 3A (50 mg), Carter condensation agent (1.5 equiv), 1,8-diazobispiro[5.4.0]undec-7-ene (2 equiv), and DMF (2 mL) were added to a 25 mL reaction tube. After stirring at room temperature for 30 minutes, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (44 mg, 1.2 equiv) was added and stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and compound 36 (white solid, 45 mg, yield 54%) was obtained by separation by preparative HPLC.

[0390] 1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.11(s,1H),7.67(t,1H),7.48(t,1H),7.37–7.23(m,2H), 7.10(d,1H),5.79–5.76(m,1H),4.03–3.93(m,4H),2.30(s,3H),1.56(d,3H),0.67–0.66(m,4H).

[0391] LC-MS m / z(ESI)=430.17[M+1].

[0392] Embodiment 37

[0393] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (Compound 37)

[0394] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0395]

[0396] Synthesized in the same manner as Example 36.

[0397] 1 H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.08(s,1H),7.68(s,1H),7.48(t,1H),7.26(dd,2H ),7.08(d,1H),5.76(p,1H),4.17–4.08(m,4H),2.29(s,3H),1.91(dq,6H),1.56(d,3H).

[0398] LC-MS m / z(ESI)=444.18[M+1].

[0399] Embodiment 38

[0400] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (Compound 38)

[0401] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0402]

[0403] Synthesized in the same manner as Example 36.

[0404] 1 H NMR(400MHz,DMSO-d6)δ8.30(d,1H),8.13(s,1H),7.66(t,1H),7.48(t,1H),7.36–7 .23(dd,2H),7.10(d,1H),5.77(p,1H),4.51–4.41(m,8H),2.30(s,3H),1.57(d,3H).

[0405] LC-MS m / z(ESI)=446.16[M+1].

[0406] Embodiment 39

[0407] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine (Compound 39)

[0408] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0409]

[0410] Synthesized in the same manner as Example 36.

[0411] 1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),7.92(d,1H),7.58(d,1H),7.48-7.23(m,3H),5.8 6(t,1H),4.19–4.01(m,4H),2.59(s,3H),2.53(s,3H),1.63(d,3H),0.70-0.66(m,4H).

[0412] LC-MS m / z(ESI)=444.18[M+1].

[0413] Embodiment 40

[0414] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 40)

[0415] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0416]

[0417] Synthesized in the same manner as Example 36.

[0418] 1 H NMR(400MHz,DMSO-d6)δ8.30(d,1H),8.06(d,1H),7.77(d,1H),7.51(dd,1H),7.33(t,1H),7.06( s,1H),5.68(p,1H),4.17-4.09(m,4H),2.62(d,3H),2.28(s,3H),1.97-1.86(m,3H),1.51(d,3H).

[0419] LC-MS m / z(ESI)=458.20[M+1].

[0420] Embodiment 41

[0421] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxetane[2,3-g]quinazoline]-4'-amine (Compound 41)

[0422] (R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0423]

[0424] Synthesized in the same manner as Example 36.

[0425] 1 H NMR(400MHz,DMSO-d6)δ8.32(d,1H),8.10(S,1H),7.76(d,1H),7.51(d,1H),7.51(dd,1H),7.33(t,1H), 7.09(s,1H),5.68(p,4H),4.97-4.40(m,8H),2.61(d,3H),2.28(s,3H),1.97-1.86(m,3H),1.52(d,3H).

[0426] LC-MS m / z(ESI)=460.18[M+1].

[0427] Embodiment 42

[0428] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxetane[2,3-g]quinazoline]-4'-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 42)

[0429] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol

[0430]

[0431] Synthesized in the same manner as Example 36.

[0432] 1H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.03(s,1H),7.63(d,1H),7.56(dt,1H),7.43-7.34(m, 2H),7.02(s,1H),5.60(dt,2H),4.55–4.31(m,8H),3.68(td,2H),2.30(d,3H),1.52(dd,3H).

[0433] LC-MS m / z(ESI)=458.19[M+1].

[0434] Embodiment 43

[0435] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 43)

[0436] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenl)ethan-1-ol

[0437]

[0438] Synthesized in the same manner as Example 36.

[0439] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.03(s,1H),7.63(d,1H),7.56(dt,1H),7.43-7.34(m,2H),7 .07(s,1H),5.73(s,4H),5.62(dt,2H),3.83(td,2H),2.34(s,3H),1.97-1.85(m,6H),1.56(d,3H).

[0440] LC-MS m / z(ESI)=456.20[M+1].

[0441] Embodiment 44

[0442] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxoepinephrine[2,3-g]quinazoline]-4'-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 44)

[0443] (R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol

[0444]

[0445] Synthesized in the same manner as Example 36.

[0446] 1 H NMR (400 MHz, DMSO-d 6 )δ8.19(d,1H),8.07(s,1H),7.64(d,1H),7.57(d,1H),7.42(t,1H),7.36(dt,1H),7.10(s, 1H),5.63(dt,2H),4.08–3.90(m,4H),3.83(td,2H),2.35(s,3H),1.57(d,3H),0.66(d,4H).

[0447] LC-MS m / z(ESI)=443.19[M+1].

[0448] Embodiment 45

[0449] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxetane[2,3-g]quinazoline]-4'-amine (Compound 45)

[0450] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0451]

[0452] Synthesized in the same manner as Example 36.

[0453] 1 H NMR(400MHz,DMSO-d6)δ8.19(d,1H),8.13(d,1H),7.41(td,1H),7.18–7.04(m,3H),5.88–5. 57(m,1H),4.65–4.38(m,8H),3.03(ddd,1H),2.30(d,3H),2.11–1.86(m,2H),1.54(dd,3H).

[0454] LC-MS m / z(ESI)=472.18[M+1].

[0455] Embodiment 46

[0456] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 46)

[0457] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0458]

[0459] Synthesized in the same manner as Example 36.

[0460] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.08(d,1H),7.40(ddd,1H),7.21–7.01(m,3H),6.00–5 .57(m,1H),4.24–3.99(m,4H),3.03(ddd,1H),2.29(d,3H),2.09–1.81(m,8H),1.54(dd,3H).

[0461] LC-MS m / z(ESI)=470.20[M+1].

[0462] Embodiment 47

[0463] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 47)

[0464] N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine

[0465]

[0466] Synthesized in the same manner as Example 36.

[0467] 1 H NMR(400MHz,DMSO-d6)δ8.20(d,1H),8.12(d,1H),7.42(ddt,1H),7.12(dt,3H),5.79(dt,1H) ,4.08–3.83(m,4H),3.02(td,1H),2.31(d,3H),2.11–1.86(m,2H),1.54(d,3H),0.66(d,4H).

[0468] LC-MS m / z(ESI)=456.18[M+1].

[0469] Biological experiments

[0470] 1. H358 cell proliferation experiment

[0471] Use a nanoliter pipetting system (Labcyte, Echo 550) to add the gradient diluted test compound to a 384-well cell culture plate (Corning, CLS3830-50EA) and set up duplicate wells. Add an equal volume of culture medium to the positive control group, and add an equal volume of DMSO to the negative control group, and centrifuge at 1000rpm for 1 minute at room temperature. Inoculate NCI-H358 cells (ATCC, CRL-5807) into the 384 culture plate containing the compound, add an equal volume of cells to the negative control group, and only add an equal volume of culture medium to the positive control group. Centrifuge at 1000rpm for 1 minute at room temperature, and the final DMSO concentration of the final compound is 0.5%. Place at 37°C, 5% CO 2 Incubate in a constant temperature incubator for 72 hours. Add 20 μL / well 3D (Promega, G9683) was transferred to a 384-well cell culture plate, shaken at 320 rpm for 20 min in the dark, and incubated at room temperature for 2 h in the dark.

[0472] The luminescence value was read using an Envision multifunctional enzyme label (Perkin Elmer, Envision 2104). The IC value of the compound was obtained using the following nonlinear fitting formula using XLFIT software: 50 (half inhibitory concentration):

[0473] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0474] X: log value of compound concentration

[0475] Y: Inhibition rate (%)

[0476] Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0477] For the ability of the compounds of the present application to inhibit the proliferation of NCI-H358 cells, the measured IC 50 See Table 1 (A represents the measured IC 50 ≤0.5μM; B indicates the measured IC 50 Between 0.5 μM and 1 μM; C represents the measured IC 50 Between 1μM and 10μM.

[0478] Table 1 Results of NCI-H358 3D cell proliferation assay

[0479] Compound No. <![CDATA[NCI-H358 IC 50 ]]> Compound No. <![CDATA[NCI-H358 IC 50 ]]> Compound 2 A Compound 17-1 C Compound 3 A Compound 19 C Compound 4 A Compound 20 C Compound 5 A Compound 21 C Compound 5 A Compound 22 A Compound 6 A Compound 24 C Compound 7 A Compound 25 A Compound 8 A Compound 27 B Compound 9 A Compound 28 A Compound 10 A Compound 29 A Compound 11 B Compound 30 B Compound 12-1 C Compound 31 A Compound 12-2 C Compound 32 B Compound 12-3 B Compound 33 A Compound 12-4 B Compound 34 A Compound 13- B Compound 35 A Compound 14 A Compound 15 C Compound 16 C

[0480] The results show that the compounds of the present application can effectively inhibit the proliferation of NCI-H358 cells.

[0481] 2. Test the interaction between KRAS-G12C protein and SOS1 protein

[0482] 1) Preparation of 1X buffer (prepared and used immediately): Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 0.05%.

[0483] 2) Dilute the compound into 2% working solution with 1X buffer, add 5uL / well to the corresponding wells, and centrifuge at 1000 rpm for 1 minute.

[0484] 3) Preparation of His-SOS1 cat 4X working solution: Dilute SOS1 (5uM) with 1X buffer to a final concentration of 24nM working solution, take 2.5uL / well and add it to the corresponding wells. Blank wells do not contain SOS1 protein. Incubate at room temperature for 30 minutes.

[0485] 4) Preparation of KRAS(G12C)+MAb Anti GST-Eu cryptate+MAb Anti 6HIS-XL665 4X working solution: Dilute KRAS(G12C), MAb Anti GST-Eu cryptate and MAb Anti 6HIS-XL665 (400ng / uL) with 1X buffer, where the final concentration of KRAS(G12C) protein is 80nM, the final concentration of MAb Anti GST-Eu cryptate is 1ng / uL, and the final concentration of MAb Anti 6HIS-XL665 (400ng / uL) is 8ng / uL.

[0486] 5) After the incubation, take 2.5uL / well of the above mixed solution and add it to the corresponding wells. Centrifuge at 1000 rpm for 1 minute. The final concentrations of the components in the system are as follows:

[0487] DMSO 0.01 His-SOS1 cat 6nM KRAS(G12C) 20nM MAb Anti 6HIS-XL665 2ng / uL MAb Anti GST-Eu cryptate 0.25ng / uL

[0488] 6) After sealing the membrane, incubate at 25°C for 1 hour.

[0489] 7) Reading: Excitation is 320nm, emission is 615nm, 665nm.

[0490] 8) Calculate the IC of the compound using Graphpad Prism 50 .

[0491] The ability of the compounds of the present invention to inhibit the interaction between KRAS-G12C protein and SOS1 protein was measured by IC 50 See Table 2 (A represents the measured IC 50 ≤0.2μM; B indicates the measured IC 50 Between 0.2μM and 0.5μM; C represents the measured IC 50 Between 0.5μM and 1μM.

[0492] Table 2 IC of the ability to inhibit the interaction between KRAS-G12C protein and SOS1 protein 50

[0493] Compound No. <![CDATA[SOS1:KRAS-G12C IC 50 ]]> Compound No. <![CDATA[SOS1:KRAS-G12C IC 50 ]]> Compound 3 A Compound 42 A Compound 5 A Compound 43 A Compound 6 A Compound 44 A Compound 36 B Compound 45 C Compound 37 C Compound 38 A Compound 41 C

[0494] The results show that the IC value of the compound of the present application for inhibiting the interaction between KRAS-G12C protein and SOS1 protein is 50 <1μM.

[0495] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. Compound or pharmaceutically acceptable salt thereof:

2. Compound or pharmaceutically acceptable salt thereof:

3. A pharmaceutical composition comprising: (1) The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof; (2) optionally one or more other active ingredients; and (3) Pharmaceutically acceptable carriers and / or excipients.

4. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the composition according to claim 3 in the preparation of a medicament for treating or preventing non-small cell lung cancer.

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