CN116249529A

CN116249529A - Quinazoline derivative and application thereof in medicine

Info

Publication number: CN116249529A
Application number: CN202180063168.5A
Authority: CN
Inventors: 周锡兵; 魏用刚; 张靖; 楚洪柱; 孙毅
Original assignee: Chengdu Baiyu Pharmaceutical Co Ltd
Current assignee: Kangbaida Sichuan Biopharmaceutical Technology Co ltd
Priority date: 2020-12-30
Filing date: 2021-12-27
Publication date: 2023-06-09
Also published as: WO2022143533A1

Abstract

Quinazoline derivatives of formula (I), pharmaceutical compositions containing them and their use in medicine, in particular as SOS1 inhibitors and in the manufacture of a medicament for the treatment or prophylaxis of SOS 1-related diseases,

Description

Quinazoline derivative and application thereof in medicine

Technical Field

the invention belongs to the field of pharmaceutical chemistry, and particularly relates to quinazoline derivatives and application thereof in medicines.

Background

SOS1 is a guanine nucleotide exchange factor (GEF) that interacts with RAS proteins to convert GDP to GTP, or from an inactive state to an active state to signal cell proliferation. RAS genes (including KRAS, NRAS and HRAS) are oncogenes that are most commonly mutated, with RAS gene mutations occurring in approximately 30% of cancers. The RAS superfamily of proteins belongs to the small GTPase (small GTPase) family of proteins, which bind as hydrolases and hydrolyze GTP to form GDP. Inactive when RAS protein binds to GDP, but separates slowly after binding; SOS1 catalyzes the dissociation of GDP, enables RAS proteins to be activated in combination with GTP, and promotes cell survival, proliferation, cytokine release, etc. through multiple downstream signaling pathways such as MAPK, PI3K, and Ral-GEFs (Liu et al, 2019). Published data indicate that SOS1 is critical for KRAS mutation-initiated cancer (Jeng et al 2012). Inhibition of SOS1 levels reduced proliferation rate and survival of KRAS mutated tumor cells.

Furthermore, SOS1 is involved in activation of RAS family protein signals in cancer by 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 located on the cell membrane, close to the RAS family proteins, enabling SOS1 to promote RAS family protein activation.

SOS1 abnormalities are also associated with cancer. SOS1 mutations were found in embryonal rhabdomyosarcoma, testicular support cell tumors, granuloma of the skin, and lung adenocarcinoma. Meanwhile, SOS1 overexpression has been reported in bladder cancer and prostate cancer.

At present, no therapy for SOS1 inhibitors is available, and the clinical demands of the tumor field are not satisfied. Thus, there remains a need to develop safe and effective SOS1 inhibitors to better meet the clinical needs of patients.

Disclosure of Invention

It is an object of one or more embodiments of the present application to provide novel quinazoline derivatives or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are useful for inhibiting SOS1.

One or more embodiments of the present application provide compounds of formula (I) or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:

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;

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;

z is- (CR) ¹⁰ R ¹¹ ) _z -; z is 0, 1, 2, 3, 4 or 5;

the R is ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ Each independently H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Cycloalkyl or C _1-6 A heterocycloalkyl group;

optionally, each R ² And R is R ³ Each R is ⁴ And R is R ⁵ Each R is ⁶ And R is R ⁷ Each R is ⁸ And R is R ⁹ Each R is ¹⁰ And R is R ¹¹ Form C with any group of carbon atoms to which it is attached _1-6 Cycloalkyl or C _1-6 Heterocycloalkyl, said C _1-6 Heterocycloalkyl contains 1 or 2 oxygen atoms;

optionally, the R ² Or R is ³ And R is ⁴ Or R is ⁵ To which two carbon atoms or R are attached ⁶ Or R is ⁷ And R is ⁸ Or R is ⁹ To which two carbon atoms are attached to form C _1-6 Cycloalkyl or C _1-6 Heterocycloalkyl, said C _1-6 Heterocycloalkyl contains 1 or 2 oxygen atoms;

each R is ¹ Identical or different, each independently of the other is halogen, amino, C _1-6 Alkyl, C _1-6 Cycloalkyl, wherein said C _1-6 Alkyl and C _1-6 Cycloalkyl is optionally substituted with one or more substituents selected from hydroxy and halogen;

n is 1, 2 or 3.

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.

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.

In one or more embodiments, the R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ Each independently is H or C _1-6 An alkyl group.

One or more embodiments of the present application provide a compound or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof:

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

(1) A compound described herein or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof;

(2) Optionally one or more other active ingredients; and

(3) Pharmaceutically acceptable carriers and/or excipients.

One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, in the manufacture of a medicament for treating or preventing cancer or tumor.

In one or more embodiments, the cancer or tumor is an embryonic rhabdomyosarcoma, testicular support cell tumor, skin granuloma cell tumor, lung adenocarcinoma, bladder cancer, or prostate cancer.

One or more embodiments of the present application provide for the use of a compound described herein, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition described herein, in the preparation of an SOS1 inhibitor.

One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition described herein, in the manufacture of a medicament for treating or preventing a disease associated with SOS 1.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as an SOS1 inhibitor.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of a disease associated with SOS 1.

One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application.

One or more embodiments of the present application provide a method of 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, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application.

One or more embodiments of the present application provide a method of inhibiting SOS1 comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application.

In one or more embodiments, the SOS 1-related disease is cancer or tumor.

In one or more embodiments, the SOS 1-associated disease is embryonal rhabdomyosarcoma, testicular support cell tumor, granuloma of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

Detailed Description

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C、 ¹³ C and C ¹⁴ Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur include ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen include ¹⁴ N and ¹⁵ isotopes of N, fluorine include ¹⁷ F and F ¹⁹ Isotopes of F, chlorine include ³⁵ Cl and Cl ³⁷ Isotopes of Cl, bromine include ⁷⁹ Br and ⁸¹ Br。

"alkyl" refers to a straight or branched chain 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, still more 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 optionally be further substituted with 1 or more substituents.

"alkoxy" refers to a group formed by substitution of at least 1 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-hexoxy, cyclopropoxy and cyclobutoxy. The alkyl group is as defined above for the "alkyl" group.

"alkenyl" means an alkenyl group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl group may optionally be further substituted with 1 or more substituents.

"alkynyl" refers to alkynyl groups containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, straight or branched chain unsaturated aliphatic hydrocarbon groups consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably alkynyl groups of 2 to 8 carbon atoms, even more preferably alkynyl groups 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-dimethylbutyyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodyn-4-yl. The alkynyl group may be optionally further substituted with one or more substituents.

"aryl" refers to a substituted or unsubstituted aromatic ring that may be a 5 to 8 membered (e.g., 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system that may be a bridged or spiro ring, non-limiting examples include phenyl, naphthyl. The aryl group may optionally be further substituted with 1 or more substituents.

"heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 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 5 to 8 membered heteroaryl, with 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring being oxidizable to various oxidation states. Heteroaryl groups may be attached to a heteroatom or carbon atom, and heteroaryl groups may be bridged or spiro, non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted with 1 or more substituents.

"carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, the definition is the same as for "aryl" above; when non-aromatic, it may be a 3 to 10 membered (e.g., 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,

The "carbocyclyl" or "carbocycle" is optionally further substituted with 1 or more substituents.

"heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic heterocycle, which, when aromatic, is as defined above for "heteroaryl"; when a non-aromatic heterocycle, it may be a 3 to 10 membered (e.g. 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 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, preferably 3 to 8 membered heterocyclyl. 1 to 4 (e.g., 1,2,3, 4) N, S optionally substituted by "heterocyclyl" or a ring of "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or carbon atom; "heterocyclyl" or "heterocycle" may be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" include epoxy ethyl, epoxy propyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, oxepinyl, thiepanyl, oxazepine, diazanyl, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thialkyl, 1, 3-dithianyl, dihydrofuranyl, dithianyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxapentyl, pyrazolinyl, dithianyl, dithiadienyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [ 2.2.2.2 ] hexyl, 3H-indolylquinolizinyl, N-pyridyl urea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1] octyl, azabicyclo [5.2.0] nonyl, oxatricyclic [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 1 or more substituents.

"cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system, the ring carbon atoms preferably being 3 to 10 carbon atoms, 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-cyclohexanedienyl, cycloheptatrienyl, and the like. When cycloalkyl is substituted, it may optionally be further substituted with 1 or more substituents.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring radical which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 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 3 to 8 membered heterocyclyl. Optionally substituted 1, 2 or 3N, S of the "heterocycloalkyl" rings can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or carbon atom; "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxy ethyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, piperidinyl, piperdinyl, 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.

When "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" described above is substituted, it may optionally be further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, cl, br, I, hydroxy, 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 R _q5 、＝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 alkynyl groups, and wherein said substituents 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 Cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, F, cl, br, I, C _1-6 Alkyl, C _1-6 Alkoxy, -NR _q4 R _q5 Or = O; r is R _q1 Selected from C _1-6 Alkyl, C _1-6 Alkoxy or C _6-10 An aryl group; r is R _q2 、R _q3 Selected from H or C _1-6 An alkyl group; wherein R is _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 Wherein said C _1-6 The alkyl group optionally being further substituted by 1 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 Substituted by a substituent of heterocycloalkyl; or R is _q4 And R is R _q5 And the N atom forms a 3 to 8 membered heterocyclic ring which may contain 1 or more heteroatoms selected from N, O or S.

Halogen includes F, cl, br and I.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance that is 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 disintegrating agents.

"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.

"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally alkyl-substituted heterocyclyl" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group.

Detailed Description

The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using a Bruker Avance III and Bruker Avance 300 magnetonucleate, with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS);

agilent 6120B (ESI) and Agilent 6120B (APCI) for MS measurement;

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;

column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.

Example 2

(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)

(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

The first step:

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

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

To a 500mL reaction flask, 50mL of a solution of Compound 1C (578mg, 3mmol,1 equiv), 250mL of N, N-dimethylformamide, and potassium carbonate (1.24 g,9mmol,3 equiv) were added, and after the reaction was stirred at 80℃for 1 hour, 50mL of a solution of diethylene glycol bis-p-toluenesulfonate (12.4 g,3mmol,1 equiv) was slowly added dropwise, and stirring was continued for 1 hour after completion of the dropwise addition. After the completion of the reaction, the solvent was distilled off under reduced pressure, 20mL of water was added, 3X 30mL of methylene chloride was extracted, the organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation, and the compound 2A (white solid, 477mg, yield 60%) was obtained by column chromatography separation.

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝263.1[M+1]。

And a second step of:

2-methyl-7, 8,10, 11-tetrahydro- [1,4,7] trion-o [2,3-g ] quinazolin-4-yl 2,4, 6-triisopropylbenzenesulfonate (2B)

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

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

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝529.2[M+1]。

And a third step of:

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

¹ H NMR(400MHz,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),5.61-5.56(m,1H),4.47(t,2H),4.38(d,2H),3.91-3.90(m,6H),2.57(s,3H),1.66(d,3H)。

LC-MS m/z(ESI)＝449.2[M+1]。

Example 3

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

(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

The first step:

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

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

To a 500mL reaction flask, 50mL of a solution of cyclopropane-1, 1-diylbis (methylene) bis (4-toluenesulfonate) (1.23 g,3mmol,1 equiv) in dimethylformamide and potassium carbonate (1.24 g,9mmol,3 equiv) were added, and after the reaction was stirred at 80℃for 1 hour, 50mL of dimethylformamide was slowly added dropwise, and stirring was continued for 1 hour after completion of the dropwise addition. After completion of the reaction, the solvent was distilled off under reduced pressure, 20mL of water was added, 3×30mL of dichloromethane was extracted, the organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to give compound 3A which was used directly in the next step (yellow solid, 550mg, yield 71%).

¹ H NMR(400MHz,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]。

LC-MS m/z(ESI)＝259.1[M+1]。

And a second step of:

2' -methyl-7 ' H,9' H-spiro [ cyclopropane-1, 8' - [1,4] dioxaepinephrine [2,3-g ] quinazoline ] -4' -yl 2,4, 6-triisopropylenesulfonate (3B)

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

To a 25mL reaction tube was added compound 3A (550 mg,2.13mmol,1 equiv), 2,4, 6-triisopropylbenzenesulfonyl chloride (1.28 g,4.26mmol,2 equiv), nitrogen was purged three times, triethylamine (856. Mu.L, 6.39mmol,3 equiv), 4-dimethylaminopyridine (48 mg,0.4 mmol) and dichloromethane (15 mL), and the reaction was stirred overnight at room temperature. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was washed, dried over sodium sulfate, and the solvent was removed by rotary evaporation, followed by column chromatography to give compound 3B (white solid, 656mg, yield 59%).

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝525.3[M+1]。

And a third step of:

(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

To a 25mL reaction tube was added compound 3B (50 mg), (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (23 mg,1.2 equiv), triethylamine (0.1 mL), dimethyl sulfoxide (2 mL), and the mixture was stirred at 90 ℃. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the compound 3 was isolated by column chromatography (white solid, 30mg, yield 70%).

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝445.2[M+1]。

Example 4

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

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

The first step:

1- (2- (benzyloxy) ethoxy) propan-2-ol (4B)

1-(2-(benzyloxy)ethoxy)propan-2-ol

To a 100mL reaction flask was added benzyl glycol (4.5 g,30mmol,3 equiv), 25mL dichloromethane and boron trifluoride diethyl etherate (42 mg,0,3mmol,0.01 equiv), cooled to 0deg.C, propylene oxide (580 mg,10mmol,1 equiv) was slowly added dropwise, and stirring was continued for 1 hour after completion of the dropwise addition. After the completion of the reaction, the solvent was removed by rotary evaporation, and the compound 4B (colorless liquid, 1.42g, yield 68%) was obtained by column chromatography.

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝211.2[M+1]。

And a second step of:

1- (2-hydroxyethoxy) propan-2-ol (4C)

1-(2-hydroxyethoxy)propan-2-ol

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

Palladium hydroxide/carbon (380 mg,20 wt%) was added to the reaction flask of the previous step, and the mixture was stirred under a hydrogen atmosphere at 50℃to effect a reaction, and after the completion of the reaction, the mixture was filtered through celite and the solvent was removed by rotary evaporation. Then, 20mL of ethyl hydrogen chloride acetate solution and 1mL of water were added, and stirred at room temperature for 5 minutes, and the solvent was removed by rotary evaporation to give 4C 780mg (colorless liquid, 97% of the total yield of the two steps) of the crude product, which was used directly in the next step.

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

LC-MS m/z(ESI)＝121.1[M+1]。

And a third step of:

1- (2- (Paraphthoxy) ethoxy) propan-2-yl 4-toluenesulfonate (4D)

1-(2-(tosyloxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate

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

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)。

LC-MS m/z(ESI)＝429.1[M+1]。

Fourth step:

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

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

To a 500mL reaction flask, 250mL dimethylformamide and potassium carbonate (1.24 g,9mmol,3 equiv) were added, and after stirring at 100℃for 1 hour, a 50mL dimethylformamide solution of compound 4D (1.28 g,3mmol,1 equiv) was slowly added dropwise, and stirring was continued at 120℃for 2 hours after completion of the dropwise addition. After completion of the reaction, the solvent was distilled off under reduced pressure, 20mL of water was added, 3×30mL of dichloromethane was extracted, the organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to give compound 4E which was used directly in the next step (pale brown solid, 391mg, yield 47%).

¹ H NMR(600MHz,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)。

LC-MS m/z(ESI)＝277.1[M+1]。

Fifth step:

2, 7-dimethyl-7, 8,10, 11-tetrahydro- [1,4,7] trion-o [2,3-g ] quinazolin-4-yl 2,4, 6-triisopropylbenzenesulfonate (4F)

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

To a 25mL reaction tube was added compound 4E (399mg, 1.41mmol,1 equiv), 2,4, 6-triisopropylbenzenesulfonyl chloride (850 mg,2.82mmol,2 equiv), nitrogen was purged three times, triethylamine (567. Mu.L, 4.23mmol,3 equiv), 4-dimethylaminopyridine (24 mg,0.2 mmol) and dichloromethane 15 mL), and the reaction was stirred overnight at room temperature. After the reaction was completed, the saturated sodium bicarbonate solution was washed, dried over sodium sulfate, and the solvent was removed by rotary evaporation, followed by column chromatography to give compound 4F (white solid, 540mg, yield 71%).

¹ H NMR(600MHz,DMSO-d ₆ )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)。

LC-MS m/z(ESI)＝543.3[M+1]。

Sixth step:

(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)

To a 25mL reaction tube was added compound 4F (50 mg), (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (22 mg,1.2 equiv), triethylamine (0.1 mL), dimethyl sulfoxide (2 mL), and the reaction was stirred at 90 ℃. After the completion of the reaction, the solvent was removed by distillation under the reduced pressure, and the compound 4 was isolated by column chromatography (white solid, 30mg, yield 65%).

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝463.2[M+1]。

Example 5

(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)

(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

The first step:

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

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

Into a 250mL reaction flask was charged compound 1C (578mg, 3mmol,1 equiv), 50mL DMF and K ₂ CO ₃ (1.24 g,9mmol,3 equiv) and after stirring at 50 ℃ for 1 hour, a solution of 5A (compound 5A,1.28g,3mmol,1 equiv, obtained by the same method as compound 4D using (S) -propylene oxide as starting material) in 20mL of DMF was slowly added dropwise over 8 hours, 200mL of water was added, EA/meoh=95: 5, mixing the solvent extracts for multiple times, combining organic phases, na ₂ SO ₄ Drying, rotary evaporation of the solvent and beating with DCM/PE gave 5B (pale yellow solid, 510mg, 38% yield).

LC-MS m/z(ESI)＝449.1[M+1]。

And a second step of:

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

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

Into a 250mL reaction flask was charged compound 5B (510 mg,1.14mmol,1 equiv), 120mL DMF and K ₂ CO ₃ (628mg g,4.55mmol,4equiv), stirring at 100deg.C, adding 200mL of water for 4 hr, extracting with DCM for several times, mixing the organic phases, na ₂ SO ₄ Drying, rotary evaporation of the solvent gave compound 5C (white solid, 113mg, 36% yield) by column chromatography.

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)。

LC-MS m/z(ESI)＝277.1[M+1]。

And a third step of:

To a 25mL reaction tube was added compound 5C (50 mg), a Kate condensing agent (1.5 equiv), 1, 8-diazabicyclo [5.4.0] undec-7-ene (2 equiv), DMF (2 mL), and after stirring at room temperature for 30 minutes, (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (22 mg,1.2 equiv) was added and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and compound 5 (white solid, 51mg, yield 62%) was obtained by separation by preparative HPLC.

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＝12.9,8.5,2.0Hz,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)。

LC-MS m/z(ESI)＝463.2[M+1]

Example 6

(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)

(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

Synthesized in the same manner as in example 5.

¹ H 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)。

LC-MS m/z(ESI)＝463.2[M+1]。

Example 7

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

(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

Synthesized in the same manner as in example 3.

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)。

LC-MS m/z(ESI)＝461.2[M+1]。

Example 8

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

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

Synthesized in the same manner as in example 3.

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)。

Example 9

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)

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

Synthesized in the same manner as in example 3.

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＝12.9,8.5,2.0Hz,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)。

LC-MS m/z(ESI)＝477.2[M+1]。

Example 10

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)

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

Synthesized in the same manner as in example 5.

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),4.99–4.81(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)。

LC-MS m/z(ESI)＝517.2[M+1]。

Example 11

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

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

Synthesized in the same manner as in example 4.

¹ H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.54(t,1H),7.27(s,1H),7.23–7.11(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)。

LC-MS m/z(ESI)＝477.2[M+1]。

Example 12

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

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

Synthesized in the same manner as in example 3, compound 12-1, compound 12-2, compound 12-3 and compound 12-4 were obtained by separation using Prep-HPLC.

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)。

LC-MS m/z(ESI)＝461.2[M+1]。

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)。

LC-MS m/z(ESI)＝461.2[M+1]。

compound 12-3: ¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝461.2[M+1]。

compound 12-4: ¹ H 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)。

LC-MS m/z(ESI)＝461.2[M+1]。

example 13

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

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

Synthesized in the same manner as in example 3.

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)。

LC-MS m/z(ESI)＝433.2[M+1]。

Example 14

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

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

Synthesized in the same manner as in example 5, compound 14-1 and compound 14-2 were obtained by separation using Prep-HPLC.

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,1H),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)。

LC-MS m/z(ESI)＝491.2[M+1]。

compound 14-2:1H NMR (400 MHz, DMSO-d 6) delta 7.72 (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).

LC-MS m/z(ESI)＝491.2[M+1]。

Example 15

(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)

(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

Synthesized in the same manner as in example 5.

Compound 15: ¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝477.2[M+1]。

example 16

(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)

(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

Synthesized in the same manner as in example 5.

¹ H 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)。

LC-MS m/z(ESI)＝477.2[M+1]。

Example 17

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

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

Synthesized in the same manner as in example 5, compound 17-1 and compound 17-2 were obtained by separation using Prep-HPLC.

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)。

LC-MS m/z(ESI)＝503.2[M+1]。

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)。

LC-MS m/z(ESI)＝503.2[M+1]。

example 18

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)

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

Synthesized in the same manner as in example 5.

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),4.14(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)。

LC-MS m/z(ESI)＝491.2[M+1]。

Example 19

(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)

(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

Synthesized in the same manner as in example 5.

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)。

LC-MS m/z(ESI)＝507.2[M+1]。

Example 20

(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)

(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

Synthesized in the same manner as in example 5.

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)。

LC-MS m/z(ESI)＝507.2[M+1]。

Example 21

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)

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

To a 25mL reaction tube was added compound 2A, a Kate condensing agent (1.5 equiv), 1, 8-diazabicyclo [5.4.0] undec-7-ene, DMF, and after 30 minutes of stirring reaction at room temperature, compound 21A (synthesized as reported in Advanced Synthesis and Catalysis,2018, vol.360, #21, p.4104-4114, then compound 21A was obtained as reported in WO2018115380A 1) and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and compound 21 (white solid) was obtained by separation by preparative HPLC.

¹ H 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)。

LC-MS m/z(ESI)＝460.2[M+1]。

Example 22

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

(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

To a 25mL reaction tube was added compound 2A, a Kate condensing agent (1.5 equiv), 1, 8-diazabicyclo [5.4.0] undec-7-ene, DMF, and after 30 minutes of stirring reaction at room temperature, compound 22A (compound 22A was obtained as reported in WO2018115380A 1) was added, and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and compound 22 (white solid) was obtained by separation by preparative HPLC.

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),4.20–3.98(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)。

LC-MS m/z(ESI)＝446.1[M+1]。

Example 24

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)

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

Synthesized in the same manner as in example 21.

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)。

LC-MS m/z(ESI)＝442.2[M+1]。

Example 25

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

(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

Synthesized in the same manner as in example 5.

¹ H 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),5.02–4.72(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)。

LC-MS m/z(ESI)＝447.2[M+1]。

Example 27

(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)

(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

To a 25mL reaction tube was added compound A2, a Kate condensing agent (1.5 equiv), 1, 8-diazabicyclo [5.4.0] undec-7-ene, DMF, and after 30 minutes of stirring reaction at room temperature, compound 27A (compound 27A was obtained as reported in WO2018115380A 1) was added and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and compound 27 (white solid) was obtained by separation by preparative HPLC.

¹ H NMR(400MHz,DMSO-d6)δ7.64(d,2H),7.35(td,1H),7.16–7.02(m,2H),4.97–4.72(m,2H),4.60(d,1H),4.47(d,1H),4.18–3.21(m,9H),2.51(s,3H),1.33(d,3H)。

LC-MS m/z(ESI)＝428.1[M+1]。

Example 28

(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)

(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

Synthesized in the same manner as in example 5.

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(ddd,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)。

LC-MS m/z(ESI)＝448.2[M+1]。

Example 29

(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)

(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

Synthesized in the same manner as in example 5.

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(ddd,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)。

LC-MS m/z(ESI)＝466.2[M+1]。

Example 30

(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)

(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

Synthesized in the same manner as in example 5.

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),4.00–3.21(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)。

LC-MS m/z(ESI)＝438.2[M+1]。

Example 31

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

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

Synthesized in the same manner as in example 5.

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)。

LC-MS m/z(ESI)＝460.2[M+1]。

Example 32

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

(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

Synthesized in the same manner as in example 5.

¹ H 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)。

LC-MS m/z(ESI)＝430.2[M+1]。

Example 33

(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)

(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

Synthesized in the same manner as in example 5.

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),3.94(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)。

LC-MS m/z(ESI)＝474.2[M+1]。

Example 34

(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)

(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

Synthesized in the same manner as in example 5.

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)。

LC-MS m/z(ESI)＝462.2[M+1]。

Example 35

(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)

(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

Synthesized in the same manner as in example 5.

¹ H 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)。

LC-MS m/z(ESI)＝448.2[M+1]。

Example 36

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

(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

Compound 3A was synthesized in the same manner as in example 3, and Compound 3A (50 mg), a Kate condensing agent (1.5 equiv), 1, 8-diazabicyclo [5.4.0] undec-7-ene (2 equiv), DMF (2 mL) was added to a 25mL reaction tube, and after stirring reaction at room temperature for 30 minutes, (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (44 mg,1.2 equiv) was added thereto and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and compound 36 (45 mg, yield 54%) was obtained by separation by preparative HPLC.

¹ H 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)。

LC-MS m/z(ESI)＝430.17[M+1]。

Example 37

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ' H,9' H-spiro [ cyclobutane-1, 8' - [1,4] dioxine [2,3-g ] quinazolin ] -4' -amine (compound 37)

(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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝444.18[M+1]。

Example 38

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ' H,9' H-spiro [ oxetane-3, 8' - [1,4] dioxine [2,3-g ] quinazolin ] -4' -amine (compound 38)

(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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝446.16[M+1]。

Example 39

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

(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

Synthesized in the same manner as in example 36.

¹ H NMR(400MHz,DMSO-d6)δ8.58(d,1H),7.92(d,1H),7.58(d,1H),7.48-7.23(m,3H),5.86(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)。

LC-MS m/z(ESI)＝444.18[M+1]。

Example 40

(R) -2' -methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -7' H,9' H-spiro [ cyclobutane-1, 8' - [1,4] dioxacetirizine [2,3-g ] quinazolin ] -4' -amine (compound 40)

(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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝458.20[M+1]。

Example 41

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

(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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝460.18[M+1]。

Example 42

(R) -2, 2-difluoro-2- (3- (1- ((2 ' -methyl-7 ' H,9' H-spiro [ oxetan-3, 8' - [1,4] dioxacimine [2,3-g ] quinazolin ] -4' -yl) amino) ethyl) phenyl) ethane-1-ol (compound 42)

(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

Synthesized in the same manner as in example 36.

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),7.02(s,1H),5.60(dt,2H),4.55–4.31(m,8H),3.68(td,2H),2.30(d,3H),1.52(dd,3H)。

LC-MS m/z(ESI)＝458.19[M+1]。

Example 43

(R) -2, 2-difluoro-2- (3- (1- ((2 ' -methyl-7 ' H,9' H-spiro [ cyclobutane-1, 8' - [1,4] dioxacimine [2,3-g ] quinazolin ] -4' -yl) amino) ethyl) phenyl) ethane-1-ol (compound 43)

(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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝456.20[M+1]。

Example 44

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

(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

Synthesized in the same manner as in example 36.

¹ H NMR(400MHz,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)。

LC-MS m/z(ESI)＝443.19[M+1]。

Example 45

N- ((1R) -1- (3- (2, 2-difluorocyclopropyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ' H,9' H-spiro [ oxetan-3, 8' - [1,4] dioxazepine [2,3-g ] quinazolin ] -4' -amine (compound 45)

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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝472.18[M+1]。

Example 46

N- ((1R) -1- (3- (2, 2-difluorocyclopropyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ' H,9' H-spiro [ cyclobutane-1, 8' - [1,4] dioxazipine [2,3-g ] quinazolin ] -4' -amine (compound 46)

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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝470.20[M+1]。

Example 47

N- ((1R) -1- (3- (2, 2-difluorocyclopropyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ' H,9' H-spiro [1,8' - [1,4] dioxazipine [2,3-g ] quinazolin ] -4' -amine (compound 47)

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

Synthesized in the same manner as in example 36.

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)。

LC-MS m/z(ESI)＝456.18[M+1]。

Biological assay

1. Proliferation assay of H358 cells

The gradient diluted test compounds were added to 384 well cell culture plates (Corning, CLS3830-50 EA) using a nanoliter pipetting system (Labcyte, echo 550) and multiple wells were set. The positive control group was added with an equal volume of medium, the negative control group was added with an equal volume of DMSO, and centrifuged at 1000rpm at room temperature for 1 minute. NCI-H358 cells (ATCC, CRL-5807) were inoculated into 384 plates containing the compound, the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of medium alone. Centrifugation at 1000rpm at room temperature for 1 min, final compound DMSO concentration of 0.5%, and standing at 37deg.C, 5% CO ₂ Incubate at constant temperature for 72 hours. By adding 20. Mu.L/well

3D (Promega, G9683) to 384 well cell culture plates, shake for 20 min at 320rpm in the dark and incubate for 2 hours at room temperature in the dark.

Luminescence values were read using an Envision multifunctional enzyme-labeled (Perkin Elmer, envision 2104) instrument. IC for obtaining compounds using XLFIT software with the following nonlinear fitting equation ₅₀ (half inhibition concentration):

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

log of compound concentration

Inhibition ratio (Y) (%)

Inhibition (%) =100× (negative control mean-compound read)/(negative control mean-positive control mean)

IC measured for the ability of the compounds of the present application to inhibit proliferation of NCI-H358 cells ₅₀ See Table 1 (A for measured IC ₅₀ Less than or equal to 0.5 mu M; b represents the measured IC ₅₀ Between 0.5 μm and 1 μm; c represents the measured IC ₅₀ Between 1 μm and 10 μm.

TABLE 1 NCI-H358 3D cell proliferation assay results

Numbering of compounds	NCI-H358 IC ₅₀	Numbering of compounds	NCI-H358 IC ₅₀
Compound 2	A	Compounds of formula (I)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	Compounds of formula (I)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

The results show that the compounds can well inhibit proliferation of NCI-H358 cells.

2. Test of interaction experiments between KRAS-G12C protein and SOS1 protein

1) 1X buffer formulation (as-prepared): hepes 5mM; 150mM NaCl; EDTA 10mM; igepal 0.0025%; KF:100mM; DTT 1mM; BSA 0.05%.

2) The compound was diluted to 2% working solution with 1 Xbuffer, 5 uL/well was added to the corresponding well, 1000 revolutions, and centrifuged for 1 min.

3) His-SOS1 cat 4X working solution is prepared: SOS1 (5 uM) was diluted with 1 Xbuffer to a final concentration of 24nM working solution, 2.5 uL/well was added to the corresponding well and Blank wells were incubated at room temperature for 30min without SOS1 protein.

4) KRAS (G12C) +MAb Anti GST-Eucryptate+MAb Anti 6HIS-XL665 4X working solution is prepared: KRAS (G12C), MAb Anti GST-Eucryptate and MAb Anti 6HIS-XL665 (400 ng/uL) were diluted with 1 Xbuffer, wherein the final concentration of KRAS (G12C) protein was 80nM,MAb Anti GST-Eucryptate was 1ng/uL and the final concentration of MAb Anti 6HIS-XL665 (400 ng/uL) was 8ng/uL.

5) After the incubation, 2.5 uL/well of the above mixture was added to the corresponding well, and the mixture was centrifuged at 1000 rpm for 1 minute, at which time the final concentrations of the components in the system were as follows:

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

6) After sealing the membrane, the membrane is incubated at 25 ℃ for 1 hour.

7) Reading: excitation (excitation) was 320nm and luminescence (emission) was 245 nm,665nm.

8) IC of the compound was calculated using Graphpad Prism ₅₀ 。

The ability of the compounds of the invention to inhibit the interaction between KRAS-G12C protein and SOS1 protein, IC measured ₅₀ See Table 2 (A for measured IC ₅₀ Less than or equal to 0.2 mu M; b represents the measured IC ₅₀ Between 0.2 μm and 0.5 μm; c represents the measured IC ₅₀ Between 0.5 μm and 1 μm.

TABLE 2 IC inhibiting the interaction ability between KRAS-G12C protein and SOS1 protein ₅₀

Numbering of compounds	SOS1:KRAS-G12C IC ₅₀	Numbering of compounds	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

The results indicate that the compounds of the present application inhibit the ability of the IC to interact between KRAS-G12C protein and SOS1 protein ₅₀ ＜1μM。

While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims

A compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof:

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;

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;

z is- (CR) ¹⁰ R ¹¹ ) _z -; z is 0, 1, 2, 3, 4 or 5;

the R is ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ Each independently H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Cycloalkyl or C _1-6 A heterocycloalkyl group;

optionally, each R ² And R is R ³ Each R is ⁴ And R is R ⁵ Each R is ⁶ And R is R ⁷ Each R is ⁸ And R is R ⁹ Each R is ¹⁰ And R is R ¹¹ Form C with any group of carbon atoms to which it is attached _1-6 Cycloalkyl or C _1-6 Heterocycloalkyl, said C _1-6 Heterocycloalkyl contains 1 or 2 oxygen atoms;

each R is ¹ Identical or different, each independently of the other is halogen, amino, C _1-6 Alkyl, C _1-6 Cycloalkyl, wherein said C _1-6 Alkyl and C _1-6 Cycloalkyl is optionally substituted with one or more substituents selected from hydroxy and halogen;

n is 1, 2 or 3.
The compound of claim 1, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, wherein

x is 0, 1 or 2;

y is 0, 1 or 2; and

z is 2, 3, 4 or 5.
The compound of claim 1, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, wherein

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, and z is 2.
The compound of claim 1, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, wherein said R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ Each independently is H or C _1-6 An alkyl group.
A compound or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof:
A compound or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof:
a pharmaceutical composition comprising:

(1) The compound of any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof;

(2) Optionally one or more other active ingredients; and

(3) Pharmaceutically acceptable carriers and/or excipients.
Use of a compound according to any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition according to claim 7, in the manufacture of a medicament for the treatment or prevention of cancer or tumor; preferably, the cancer is embryonal rhabdomyosarcoma, testicular support cell tumor, skin granuloma, lung adenocarcinoma, bladder cancer, or prostate cancer.
Use of a compound according to any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or a composition according to claim 7, for the preparation of an SOS1 inhibitor.
Use of a compound according to any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or a composition according to claim 7, for the preparation of a medicament for the treatment or prophylaxis of a SOS 1-related disease.