CN112979664A

CN112979664A - Oxygen-containing heterocyclic compound, preparation method and application thereof

Info

Publication number: CN112979664A
Application number: CN202011077052.0A
Authority: CN
Inventors: 许祖盛; 楼杨通; 谢铁刚
Original assignee: Shanghai Yingli Pharmaceutical Co Ltd
Current assignee: Shanghai Yingli Pharmaceutical Co Ltd
Priority date: 2019-12-02
Filing date: 2020-10-10
Publication date: 2021-06-18
Anticipated expiration: 2040-10-10
Also published as: CN112979664B; TW202128702A

Abstract

The invention discloses an oxygen-containing heterocyclic compound, and a preparation method and application thereof. The invention provides an oxygen-containing heterocyclic compound shown as a formula I, a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotopic compound thereof, and the oxygen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by Ras.

Description

Oxygen-containing heterocyclic compound, preparation method and application thereof

Technical Field

The invention relates to an oxygen-containing heterocyclic compound, a preparation method and application thereof.

Background

Ras (Rat sarcoma viral oncogene, murine sarcoma virus oncogene) was first discovered in Rat sarcomas. There are three members of the mammalian ras gene family, H-ras, K-ras, and N-ras, in which the fourth exon of K-ras has two variants, A and B. Ras genes are widely present in various eukaryotes such as mammals, Drosophila, fungi, nematodes and yeasts, and are expressed to varying degrees in different tissues, wherein H-Ras is mainly expressed in skin and skeletal muscle, K-Ras is mainly expressed in colon and thymus, and N-Ras is expressed to a high degree in testis. Ras protein is used as a molecular switch in the cell signal transduction process, and regulates and controls signal transduction by combining with GTP/GDP for switching, thereby regulating the life processes of cell proliferation, differentiation, aging, apoptosis and the like.

Ras mutations are closely associated with the development and progression of tumors. Ras is mutated in more than 30% of human tumors and is considered one of the most powerful cancer drivers. Ras proto-oncogene mutation is mainly performed by means of point mutation. More than 150 different Ras point mutations have been found, with mutations at glycine 12 and 13 and glutamine 61 being the most common.

For decades, efforts have been made to develop small molecule inhibitors targeting Ras, but no relevant drugs have yet been on the market. Scientists have long desired to develop competitive inhibitors of GTP that act directly on Ras proteins. However, it has not been successful because of the strong affinity between GTP and Ras (pmol/L scale), the high GTP concentration in cells (0.5mM), and the lack of a pocket in the RAS protein structure for small molecule binding. In recent years, people using K-Ras G12C mutant allosteric site for drug development has been advanced. In 2013, a research group reported the discovery of a K-Ras G12C small molecule inhibitor (Nature,2013,503, 548-551). They identified a novel binding pocket located below the region of molecular switch II from the K-Ras G12C mutant, to which these inhibitors bound and form covalent bonds with nearby Cys12, thereby selectively inhibiting activation of K-Ras G12C. Other researchers have reported KRAS inhibitors with cellular activity (Science,2016,351, 604-608). Currently, drugs are in clinical development stage, and a compound AMG510 from Amgen starts a clinical test in 2018, and is the first small-molecule inhibitor directly targeting KRAS to enter the clinic.

In conclusion, through continuous efforts for decades, people gradually deepen the understanding of Ras, but a compound capable of being used for medicine is not developed successfully so far, and a compound with a better inhibitory effect on Ras is searched, so that the method is still a research hotspot and difficulty in the field of new medicine development.

Disclosure of Invention

The technical problem to be solved by the invention is that no effective medicine as Ras inhibitor is used for clinical treatment in the prior art, therefore, the invention provides an oxygen-containing heterocyclic compound, a preparation method and application thereof, and the oxygen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by Ras.

The present invention solves the above-mentioned problems by the following technical means.

The invention provides an oxygen-containing heterocyclic compound shown as a formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotopic compound thereof:

wherein R is¹Is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N;

R^1-6And R^1-7Independently halogen, hydroxy, -C (═ O) R⁶⁵、-NR⁶³R⁶⁴、-C(＝O)OR⁶⁶、-C(＝O)NR⁶⁹R⁶¹⁰、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl, 5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O and N, and C_6-20Aryl, 5-to 7-membered heteroaryl containing 1 or 2 heteroatoms, which is one or more of O and N, and one or more R^1-6-1Substituted C_1-6Alkyl, by one or more R^1-6-2Substituted C_1-6Alkoxy, by one or more R^1-6-3Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-4Substituted '5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms which are one or more of O and N', substituted with one or more R^1-6-5Substituted C_6-20Aryl, or, by one or more R^1-6-6Substituted 5-7 membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are one or more of O and N;

R^1-6-1、R^1-6-2、R^1-6-3、R^1-6-4、R^1-6-5and R^1-6-6Independently cyano, halogen, hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, -C (═ O) R^65-2、-NR^63-2R^64-2、-C(＝O)OR^66-2or-C (═ O) NR^69-2R^610-2；

R⁶⁵、R^65-2、R⁶³、R^63-2、R⁶⁴、R^64-2、R⁶⁶、R^66-2、R⁶⁹、R^69-2、R⁶¹⁰And R^610-2Independently is hydrogen or C_1-6An alkyl group;

m is 0, 1 or 2;

R⁵independent of each otherGround is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl, or substituted by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently is C _3-10Cycloalkyl, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N, and one or more R^d16Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^d15Substituted 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one OR more of O and N, -OR^d、-SR^d1、-NR^e1R^e2or-C (═ O) NR^e3R^e4；

R^d15And R^d16Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C_1-6Alkoxy, halogen, -NR^e5R^e6or-C (═ O) NR^e7R^e8；

R^d、R^d1、R^e1、R^e2、R^e3And R^e4Independently of one another is hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N, or substituted with one or more R^1-8-2Substituted C_1-6An alkyl group;

R^1-8-1and R^1-8-2Independently cyano, halogen, hydroxy, C_1-6Alkoxy, -C (═ O) R^e9、-NR^e10R^e11、-C(＝O)OR^e12or-C (═ O) NR^e13R^e14；

R^e5、R^e6、R^e7、R^e8、R^e9、R^e10、R^e11、R^e12、R^e13And R^e14Independently is hydrogen or C_1-6An alkyl group;

the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic, bridged or spiro;

g is N, C or CH;

n is 0, 1, 2 or 3;

R⁴independently is C_1-6Alkyl, by one or more R^4-1Substituted C_1-6Alkyl, oxo, -C (═ O) OR^4aor-C (═ O) NR^4bR^4c；

R^4-1Independently halogen, cyano, hydroxy, C _1-6Alkoxy, -NR⁴ⁱR^4j、-C(＝O)OR^4dor-C (═ O) NR^4eR^4f；R^4d、R^4e、R^4f、R⁴ⁱAnd R^4jIndependently is hydrogen or C_1-6An alkyl group;

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R²is CN, -C (═ O) -C (R)^a)＝C(R^b)(R^f)、-C(＝O)-C≡CR^f、-S(＝O)₂-C(R^a)＝C(R^b)(R^f) or-S (═ O)₂-C≡CR^f；

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

R^band R^fIndependently of one another is hydrogen, deuterium, C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, or, substituted with one or more R^b-1Substituted C_1-6An alkyl group;

R^b-1independently of one another is halogen, hydroxy, C_1-6Alkoxy, or, -NR^10jR^10k；

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N connected therewith to form a compound containing 1 to 3 hetero atoms of one of O and NOr a plurality of 4-to 10-membered heterocycloalkyl groups.

In a certain embodiment, in the oxygen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, some groups have the following definitions, and the definitions of the groups not mentioned are as described in any of the embodiments of the present invention (hereinafter, this paragraph is simply referred to as "in a certain embodiment"), the oxygen-containing heterocyclic compound represented by formula I,

wherein R is¹Is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R ^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N;

m is 0, 1 or 2;

R⁵independently is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²、R³³And R³⁴Independently by one or more R ^31-1Substituted C_1-6An alkyl group;

R^31-1independently is C_3-10Cycloalkyl, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N, and one or more R^d16Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^d15Substituted 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one OR more of O and N, -OR^d、-SR^d1、-NR^e1R^e2or-C (═ O) NR^e3R^e4；

R^d、R^d1、R^e1、R^e2、R^e3And R^e4Independently of one another is hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl, 4-10 membered hetero having 1-3 hetero atoms of one or more of O and NCycloalkyl ", or, substituted by one or more R^1-8-2Substituted C_1-6An alkyl group;

g is N, C or CH;

n is 0, 1, 2 or 3;

R⁴independently is C_1-6Alkyl, by one or more R^4-1Substituted C_1-6Alkyl, oxo, -C (═ O) OR ^4aor-C (═ O) NR^4bR^4c；

R^4-1Independently halogen, cyano, hydroxy, C_1-6Alkoxy, -NR⁴ⁱR^4j、-C(＝O)OR^4dor-C (═ O) NR^4eR^4f；R^4d、R^4e、R^4f、R⁴ⁱAnd R^4jIndependently is hydrogen or C_1-6An alkyl group;

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)、-C(＝O)-C≡CR^f、-S(＝O)₂-C(R^a)＝C(R^b)(R^f) or-S (═ O)₂-C≡CR^f；

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

R^band R^fIndependently hydrogen, deuterium,C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N connected therewith to form a "4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms which are one or more of O and N".

In one aspect:

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N;

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R¹ ^-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently a halogen.

In one aspect:

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N; e.g. C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, or substituted with one or more R^1-6Substituted C_6-20An aryl group;

R^1-6and R^1-7Independently of one another, halogen, C_1-6Alkyl, or substituted by one or more R^1-6-1Substituted C_1-6An alkyl group;

R^1-6-1independently a halogen.

In one aspect:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6independently of one another, halogen, C_1-6Alkyl, or substituted by one or more R^1-6-1Substituted C_1-6An alkyl group;

R^1-6-1independently a halogen.

In one aspect:

m is 0.

In one aspect:

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R^31-1independently by one or more R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR ^e1R^e2；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-SR³²；

R³²Is represented by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently is-NR^e1R^e2；

R^e1And R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently by one or more R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR^e1R^e2；

R^d15Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C_1-6Alkoxy, halogen, -NR^e5R^e6or-C (═ O) NR^e7R^e8；

R^1-8-1Independently is halogen; r^e5、R^e6、R^e7And R^e8Independently is hydrogen or C_1-6An alkyl group;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-NR³³R³⁴；

R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group; e.g. H or C_1-6An alkyl group;

R^d15Independently is C_1-6An alkyl group;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R³¹And R ³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group; e.g. H or C_1-6An alkyl group;

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R^31-1independently is one orPlural R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR^e1R^e2；

R^e1、R^e2And R^d15Independently is C_1-6An alkyl group.

In one aspect:

the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic or spiro; such as a single ring;

G is N, C or CH.

In one aspect:

the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic;

g is N.

In one aspect:

n is 0 or 1;

R⁴independently is C_1-6Alkyl, or substituted by one or more R^4-1Substituted C_1-6An alkyl group;

R^4-1independently is hydroxy, cyano, or, -C (═ O) NR^4eR^4f；R^4eAnd R^4fIndependently is hydrogen or C_1-6An alkyl group; such as hydrogen.

In one aspect:

n is 0 or 1;

R⁴independently by one or more R^4-1Substituted C_1-6An alkyl group;

R^4-1independently is-C (═ O) NR^4eR^4f；R^4eAnd R^4fIndependently is hydrogen or C_1-6An alkyl group; such as hydrogen.

In one aspect:

n is 0 or 1;

R^4-1independently a hydroxyl group or a cyano group.

In one aspect:

n is 0 or 1;

R^4-1independently a hydroxyl group.

In one aspect:

n is 0 or 1;

R^4-1independently a cyano group.

In one aspect:

R²is CN, -C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O)₂-C(R^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^bAnd R^fIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, or, substituted with one or more R^b-1Substituted C_1-6An alkyl group;

R^b-1independently is-NR^10jR^10k；

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N attached to it together form a "4-to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms, which is one or more of O and N".

In one aspect:

R²is CN or-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently is hydrogen;

R^band R^fIndependently of one another is hydrogen, C_1-6alkyl-C (═ O) -.

In one aspect:

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O)₂-C(R^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^band R^fIndependently of one another is hydrogen, C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group;

In one aspect:

R^aIndependently hydrogen or halogen;

R^b-1independently is-NR^10jR^10k；

R^10jAnd R^10kIndependently is hydrogen or C _1-6Alkyl, or, R^10j、R^10kAnd N attached to it together form a "4-to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms, which is one or more of O and N".

In one aspect:

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or moreR is^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N;

R^1-6and R^1-7Independently of one another, halogen, C_1-6Alkyl, by one or more R^1-6-1Substituted C_1-6An alkyl group; r^1-6-1Independently is halogen;

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group; e.g. H or C_1-6An alkyl group;

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic or spiro;

G is N, C or CH;

n is 0 or 1;

R^4-1independently cyano, hydroxy or-C (═ O) NR^4eR^4f；R^4eAnd R^4fIndependently is hydrogen or C_1-6An alkyl group;

R^aIndependently hydrogen or halogen;

In one aspect:

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R¹ ^-6-1Substituted C_1-6Alkyl, or substituted by one or more R ^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^31-1independently of each otherIs represented by one or more R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR^e1R^e2；

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^4-1independently cyano or hydroxy;

R^aIndependently hydrogen or halogen;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N linked thereto together form " A 4-6 membered heterocycloalkyl group containing 1-3 heteroatoms, the heteroatoms being one or more of O and N.

In one aspect:

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；R^aIndependently hydrogen or halogen; r^bAnd R^fIndependently is hydrogen or C_1-6An alkyl group.

In one aspect:

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R¹ ^-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C_1-6Alkoxy, halogen, -NR^e5R^e6or-C (═ O) NR ^e7R^e8；

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^4-1independently is cyano;

R^aIndependently hydrogen or halogen;

In one aspect:

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted "containing 1 to 4 heteroatoms, the heteroatoms being O, S and5-12 membered heteroaryl of one or more of N; e.g. C _6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, or substituted with one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R⁴independently by one or more R^4-1Substituted C_1-6An alkyl group;

R^4-1independently cyano or-C (═ O) NR^4eR^4f；R^4eAnd R^4fIndependently is hydrogen or C_1-6An alkyl group;

R²is CN, -C (═ O) -C(R^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^band R^fIndependently of one another is hydrogen, C_1-6Alkyl, or, C_1-6alkyl-C (═ O) -.

In one aspect:

R¹Is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^band R^fIndependently is hydrogen or C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group;

R^b-1independently is-NR^10jR^10k；

In one aspect:

R¹Is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^e1、R^e2And R^d15Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^band R^fIndependently is hydrogen or C_1-6An alkyl group.

In one aspect:

the structure of the oxygen-containing heterocyclic compound shown in the formula I is as follows:

or "

And

in a molar ratio such as 1: 1".

In one aspect: the structure of the oxygen-containing heterocyclic compound shown in the formula I is as follows:

in one aspect:

when said R is¹Is C_6-20When aryl, said C_6-20Aryl may be phenyl or naphthyl, and may also be phenyl or 1-naphthyl.

In one aspect:

when said R is¹In the case of the "5-to 12-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N", the "5-to 12-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N" may be a "9-to 10-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N", and may be a "1-membered heteroaryl group containing 1 hetero atom",9-to 10-membered heteroaryl with one of the heteroatoms O, S and N, and optionally isoquinolinyl and optionally

In one aspect:

when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said C_6-20Aryl may be phenyl or naphthyl, and may also be phenyl or 1-naphthyl.

In one aspect:

when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, the plurality may be 2 or 3.

In one aspect:

when said R is^1-6When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, and may also be fluorine or chlorine.

In one aspect:

when said R is^1-6Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When an alkyl group is used, the number of the alkyl groups may be 2 or 3.

In one aspect:

when said R is^1-6-1When independently halogen, said halogenThe element can be fluorine, chlorine, bromine or iodine, and also can be fluorine.

In one aspect:

when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said is substituted by one or more R^1-6-1Substituted C_1-6The alkyl group may be trifluoromethyl.

In one aspect:

when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said is substituted by one or more R^1-6Substituted C_6-20Aryl is

Or

In one aspect:

Or

In one aspect:

when said R is³³Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, or may be a methyl, ethyl, n-propyl or isopropyl group.

In one aspect:

when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, or may be a methyl, ethyl, n-propyl or isopropyl group.

In one aspect:

when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When an alkyl group is used, the number of the alkyl groups may be 2 or 3.

In one aspect:

when said R is^31-1Independently by one or more R^d15When the substituted "4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms and one or more of O and N as a hetero atom" is used, the "4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms and one or more of O and N as a hetero atom" may be a "5-to 7-membered heterocycloalkyl group containing 1 to 3 hetero atoms and one or more of O and N as a hetero atom", or a "5-to 7-membered heterocycloalkyl group containing 1 hetero atom and one or more of O and N as a hetero atom", and may further be a tetrahydropyrrole, or a tetrahydropyrrole-2-yl group.

In one aspect:

when said R is^31-1Independently by one or more R^d15When the substituted "4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms which are one or more of O and N" is used, the number of the hetero atoms may be 2 or 3.

In one aspect:

when said R is^d15Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^d15When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, and may also be fluorine.

In one aspect:

when said R is^e1And R^e2Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, and may also be a methyl or ethyl group.

In one aspect:

when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said is substituted by one or more R^31-1Substituted C_1-6The alkyl group can be

Or

In one aspect:

when the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms, the 4-12 membered heterocyclic ring containing 1-4N atoms may be a 6-9 membered heterocyclic ring containing 1-2N atoms, or may be a 6-9 membered heterocyclic ring containing 1-2N atoms

Or

Its upper end and R²And (4) connecting.

In one aspect:

the structure of the oxygen-containing heterocyclic compound shown as the formula I is as follows:

in one aspect:

When said R is⁴Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4Alkyl, which may be methyl, ethyl, n-propyl,Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also methyl.

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When an alkyl group is used, the number of the alkyl groups may be 2 or 3.

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group can be hydroxymethyl, cyanomethyl or

For example cyanomethyl or

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group can be

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C _1-6The alkyl group may be hydroxymethyl or cyanomethyl.

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group may be a hydroxymethyl group.

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group may be cyanomethyl.

In one aspect:

when said R is^aWhen independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, and may also be fluorine.

In one aspect:

when said R is^bAnd R^fIndependently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^bAnd R^fIndependently is C_1-6When alkyl-C (═ O) -, said C_1-6C in alkyl-C (═ O) -)_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^bAnd R^fIndependently by one or more R ^b-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When an alkyl group is used, the number of the alkyl groups may be 2 or 3.

In one aspect:

when said R is^10jAnd R^10kIndependently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is^10jAnd R^10kAnd N connected with the N to form a 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms and one or more of O and N, the 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms and one or more of O and N may be a 5-to 6-membered heterocycloalkyl containing 2 hetero atoms and one or more of O and N

In one aspect:

said R²Can be CN,

Or

In one aspect:

said R²Can be CN,

In one aspect:

said R²(may be)

Or

In one aspect:

Said R²(may be)

Or

In a certain embodiment, the oxygen-containing heterocyclic compound represented by formula I has any one of the following structures:

in a certain embodiment, the oxygen-containing heterocyclic compound shown in formula I is any one of the following compounds:

compounds with a retention time of 0.92min under the following conditions

SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.74min under the following conditions

Equipment SFC methodd Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 0.97min under the following conditions

SFC Method Station (Thar, Waters); chromatographic column AD-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂ETOH (0.5% TEA) 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 2.40min under the following conditions

SFC Method Station (Thar, Waters); chromatographic column AD-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO ₂ETOH (0.5% TEA) 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

a compound having a retention time of 0.97min under the following conditions:

SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂Methyl alcohol (0.1% TEA) 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 1.94min under the following conditions

compounds with a retention time of 1.22min under the following conditions

SFC Method Station (Thar, Waters); column CHIRALCEL OJ-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 1.0 ml/min; the wavelength is 214 nm; back pressure of 120 bar;

compound with retention time of 2.67min under the following conditions

Compound with retention time of 3.26min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column R, R-WHELK-O14.6 x 100mm,5 μm (REGIS); the column temperature is 40 ℃; mobile phase of CO₂(MeOH/ACN ═ 3:2 (0.1% TEA)) ═ 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 4.16min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column R, R-WHELK-O14.6 x 100mm,5 μm (REGIS); the column temperature is 40 ℃; mobile phase of CO₂(MeOH/ACN ═ 3:2 (0.1% TEA)) ═ 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; the back pressure was 120 bar.

Compounds with a retention time of 1.36min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; the back pressure was 120 bar.

A combination with a retention time of 2.77min under the following conditionsArticle (A)

Compounds with a retention time of 1.17min under the following conditions

Compound with retention time of 2.76min under the following conditions

Compounds with a retention time of 0.78min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; the back pressure was 120 bar.

Compound with retention time of 2.42min under the following conditions

In the followingCompound with retention time of 0.79min under condition

Instrument SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO ₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; the back pressure was 120 bar.

Compounds with a retention time of 2.29min under the following conditions

Compounds with a retention time of 1.45min under the following conditions

Compounds with a retention time of 2.81min under the following conditions

the invention also provides a preparation method of the oxygen-containing heterocyclic compound shown in the formula I, which is a route I or a route II:

route one

Wherein R is¹、R²、R³、R⁴G, n and Y are as defined above, X₁Is a leaving group (e.g., OTf, Cl) and Alk is an alkyl group (e.g., C)_1～6Alkyl), PG is an amino protecting group (e.g., Boc, Cbz);

on the second route, the first route is,

wherein R is¹、R²、R³、R⁴G, n and Y are as defined above, X₃PG is an amino protecting group (e.g., Boc, Cbz) for a leaving group (e.g., OTf, Cl).

The detailed description of route one can be as follows: aldehyde compound A1 is condensed with acetoacetate to obtain compound A2, A2 is condensed with DMF-DMA to obtain compound A3, A3 is reduced to A4, A4 forms ring to form A5, hydroxyl in A5 is converted to leaving group to obtain A6, A6 is converted to A7 by nucleophilic substitution or coupling, A7 is oxidized to obtain A8, A8 is further converted to A9, A9 is deprotected, and is further converted to A11.

The detailed description of the second route can be as follows: compound a5 is protected by Bn, C1 is oxidized to obtain C2, C2 is converted to C3 by nucleophilic substitution, C3 is deprotected to C4, hydroxyl in C4 is converted to leaving group to obtain C5, C5 is converted to a9 by nucleophilic substitution or coupling, a9 is deprotected, and further converted to a 11.

Each strip described in the inventionThe conditions and procedures used for the chemical reactions involved in the schemes can be carried out with reference to those conventional in the art, in particular to the literature: larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis,3 ^rdEd, John Wiley and Sons (1999); l.fieser and m.fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.

The present application is incorporated herein by reference in its entirety. The compound obtained by the above method can be further modified at the peripheral position by referring to the related methods of the above documents to obtain another target compound of the present invention.

The invention also provides a compound shown as formula A5, A6, A7, A8, A9, A10, C1, C2, C3, C4 or C5;

wherein R is¹、R³、R⁴G, Y and n are as defined above;

X¹and X³Independently a leaving group (e.g., OTf, Cl) and PG an amino protecting group (e.g., Boc, Cbz).

In one embodiment, the compound of formula a5, a6, a7, A8, a9, a10, C1, C2, C3, C4, or C5 can be any of the following:

the invention also provides a pharmaceutical composition comprising the substance A and pharmaceutic adjuvants; the substance A is the oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotopic compound thereof.

The invention also provides an application of the substance A in preparing the RAS inhibitor, wherein the substance A is the oxygen-containing heterocyclic compound shown as the formula I, the pharmaceutically acceptable salt, the stereoisomer, the tautomer or the isotopic compound thereof.

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

The invention also provides the use of a substance A in the manufacture of a medicament for the treatment or prevention of a RAS mediated disease;

the substance A is the oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotopic compound thereof.

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

Such RAS mediated diseases as cancer. Such as one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

The invention also provides the use of a substance A in the manufacture of a medicament for the treatment or prophylaxis of cancer;

Such as one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

The invention provides an oxygen-containing heterocyclic compound shown as a formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, crystal form thereof, stereoisomer thereof, tautomer thereof or isotope compound thereof:

R^1-6and R^1-7Independently halogen, hydroxy, -C (═ O) R⁶⁵、-NR⁶³R⁶⁴、-C(＝O)OR⁶⁶、-C(＝O)NR⁶⁹R⁶¹⁰、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, containing 1 or 2Heteroatom, 5-7 membered heterocycloalkyl group' of which heteroatom is one or more of O and N, C_6-20Aryl, 5-to 7-membered heteroaryl containing 1 or 2 heteroatoms, which is one or more of O and N, and one or more R^1-6-1Substituted C_1-6Alkyl, by one or more R^1-6-2Substituted C_1-6Alkoxy, by one or more R^1-6-3Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-4Substituted '5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms which are one or more of O and N', substituted with one or more R^1-6-5Substituted C_6-20Aryl, or, by one or more R^1-6-6Substituted 5-7 membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are one or more of O and N;

m is 0, 1 or 2;

R⁵independently is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R ^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl, or substituted by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently isC_3-10Cycloalkyl, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N, and one or more R^d16Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^d15Substituted 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one OR more of O and N, -OR^d、-SR^d1、-NR^e1R^e2or-C (═ O) NR^e3R^e4；

g is N, C or CH;

n is 0, 1, 2 or 3;

R⁴independently is C _1-6Alkyl, by one or more R^4-1Substituted byC_1-6Alkyl, oxo, -C (═ O) OR^4aor-C (═ O) NR^4bR^4c；

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

In a certain embodiment, in the oxygen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, some groups have the following definitions, and definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter, referred to as "in a certain embodiment" in this paragraph), the oxygen-containing heterocyclic compound represented by formula I,

R^1-6-1、R^1-6-2、R^1-6-3、R^1-6-4、R^1-6-5and R^1-6-6Independently cyano, halogen, hydroxy, C _1-6Alkoxy radical, C_1-6Alkyl, -C (═ O) R^65-2、-NR^63-2R^64-2、-C(＝O)OR^66-2or-C (═ O) NR^69-2R^610-2；

m is 0, 1 or 2;

R⁵independently is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group;

G is N, C or CH;

n is 0, 1, 2 or 3;

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

R^band R^fIndependently of one another is hydrogen, deuterium, C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N common form connected therewithTo form 4-10 membered heterocycloalkyl containing 1-3 heteroatoms, the heteroatoms being one or more of O and N.

In one aspect:

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C _3-10Cycloalkyl radicals, substituted by one or more R¹ ^-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently a halogen.

In one aspect:

R^1-6-1independently a halogen.

In one aspect:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently a halogen.

In one aspect:

m is 0.

In one aspect:

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl, or substituted by one or more R ^31-1Substituted C_1-6An alkyl group;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-SR³²；

R³²Is represented by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently is-NR^e1R^e2；

R^e1And R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-NR³³R³⁴；

R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R ^31-1Substituted C_1-6An alkyl group; e.g. H or C_1-6An alkyl group;

R^d15Independently is C_1-6An alkyl group;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R³¹And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group; e.g. H or C_1-6An alkyl group;

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group.

In one aspect:

R³is-NR³³R³⁴；

R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group;

R^31-1independently by one or more R ^d15Substituted 5-7 membered ring containing 1-3 hetero atoms of one or more of O and NHeterocycloalkyl ";

R^d15independently is C_1-6An alkyl group.

In one aspect:

R³is-OR³¹or-NR³³R³⁴；

R^e1、R^e2And R^d15Independently is C_1-6An alkyl group.

In one aspect:

g is N, C or CH.

In one aspect:

g is N.

In one aspect:

n is 0 or 1;

In one aspect:

n is 0 or 1;

R⁴independently by one or more R^4-1Substituted C_1-6An alkyl group;

In one aspect:

n is 0 or 1;

R^4-1independently a hydroxyl group or a cyano group.

In one aspect:

n is 0 or 1;

R^4-1independently a hydroxyl group.

In one aspect:

n is 0 or 1;

R^4-1independently a cyano group.

In one aspect:

R^aIndependently hydrogen or halogen;

R^b-1independently is-NR^10jR^10k；

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N common form connected therewithTo form 4-6 membered heterocycloalkyl containing 1-3 heteroatoms, the heteroatoms being one or more of O and N.

In one aspect:

R²is CN or-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently is hydrogen;

R^band R^fIndependently of one another is hydrogen, C_1-6alkyl-C (═ O) -.

In one aspect:

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O) ₂-C(R^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

In one aspect:

R^aIndependently hydrogen or halogen;

R^b-1independently is-NR^10jR^10k；

In one aspect:

R^1-6and R^1-7Independently of one another, halogen, C _1-6Alkyl, by one or more R^1-6-1Substituted C_1-6An alkyl group; r^1-6-1Independently is halogen;

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^aIndependently hydrogen or halogen;

In one aspect:

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R¹ ^-6-1Substituted C_1-6Alkyl, orBy one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^1-8-1Independently is halogen; r^e5、R^e6、R^e7And R^e8Independently is hydrogen or C _1-6An alkyl group;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^4-1independently cyano or hydroxy;

R^aIndependently hydrogen or halogen;

In one aspect:

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^4-1independently is cyano;

R^aIndependently hydrogen or halogen;

R^band R^fIndependently of one another is hydrogen, C_1-6Alkyl, or substituted by one or more R^b-1Substituted C _1-6An alkyl group;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd withThe N groups connected to each other form a 4-to 6-membered heterocycloalkyl group containing 1 to 3 hetero atoms, which is one or more of O and N.

In one aspect:

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R⁴independently by one or more R^4-1Substituted C_1-6An alkyl group;

R²is CN, -C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

In one aspect:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

G is N;

n is 0 or 1;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^b-1independently is-NR^10jR^10k；

In one aspect:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^31-1independently by one or more R^d15Substituted "containing 1-3 hetero atomsAn atom, a 5-to 7-membered heterocycloalkyl group in which the heteroatom is one or more of O and N, or-NR^e1R^e2；

R^e1、R^e2And R^d15Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R⁴independently is C _1-6Alkyl, or substituted by one or more R^4-1Substituted C_1-6An alkyl group;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^band R^fIndependently is hydrogen or C_1-6An alkyl group.

In one aspect:

or "

And

in a molar ratio such as 1: 1".

in one aspect:

when said R is¹Is C_6-20When aryl, said C_6-20Aryl radicalsIt may be phenyl or naphthyl, and may also be phenyl or 1-naphthyl.

In one aspect:

when said R is¹In the case of a "5-to 12-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N", the "5-to 12-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N" may be a "9-to 10-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from O, S and N", or may be a "9-to 10-membered heteroaryl group containing 1 hetero atom and one or more hetero atoms selected from O, S and N", or may be an isoquinolinyl group, or may be an "5-to 12-membered heteroaryl group containing 1 to 4 hetero atoms and one or more hetero atoms selected from 3578 and N", or may be a "9-to 10-membered heteroaryl group containing 1 hetero atom and one or more

In one aspect:

when said R is¹Is represented by one or more R^1-6Substituted C _6-20When aryl, said C_6-20Aryl may be phenyl or naphthyl, and may also be phenyl or 1-naphthyl.

In one aspect:

when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4Alkyl, in turn, can beMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also methyl.

In one aspect:

when said R is^1-6-1When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, and may also be fluorine.

In one aspect:

Or

In one aspect:

Or

In one aspect:

when said R is³³Independently of each otherIs C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, or may be a methyl, ethyl, n-propyl or isopropyl group.

In one aspect:

when said R is³¹、R³³And R³⁴Independently by one or more R ^31-1Substituted C_1-6When an alkyl group is used, the number of the alkyl groups may be 2 or 3.

In one aspect:

Or

In one aspect:

Or

Its upper end and R²And (4) connecting.

In one aspect:

in one aspect:

when said R is⁴Independently is C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

when said R is⁴Independently by one or more R ^4-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

For example cyanomethyl or

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted byC_1-6The alkyl group can be

In one aspect:

when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group may be hydroxymethyl or cyanomethyl.

In one aspect:

when said R is⁴Independently by one or more R ^4-1Substituted C_1-6When alkyl, said is substituted by one or more R⁴ ^-1Substituted C_1-6The alkyl group may be cyanomethyl.

In one aspect:

when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When alkyl, said C_1-6The alkyl group may be C_1-4The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

In one aspect:

In one aspect:

said R²Can be CN,

Or

In one aspect:

said R²Can be CN,

In one aspect:

said R²(may be)

Or

In one aspect:

said R²(may be)

Or

compounds with a retention time of 0.92min under the following conditions

SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO ₂/MeOH(0.1％TEA) 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.74min under the following conditions

compounds with a retention time of 0.97min under the following conditions

compounds with a retention time of 2.40min under the following conditions

a compound having a retention time of 0.97min under the following conditions:

Compounds with a retention time of 1.94min under the following conditions

SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); columnThe temperature is 40 ℃; mobile phase of CO₂Methyl alcohol (0.1% TEA) 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 1.22min under the following conditions

compound with retention time of 2.67min under the following conditions

compound with retention time of 3.26min under the following conditions

compound with retention time of 4.16min under the following conditions

compounds with a retention time of 1.36min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.77min under the following conditions

compounds with a retention time of 1.17min under the following conditions

compound with retention time of 2.76min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO ₂MeOH (0.1% TEA) ═ 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 0.78min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.42min under the following conditions

compounds with a retention time of 0.79min under the following conditions

compounds with a retention time of 2.29min under the following conditions

Compounds with a retention time of 1.45min under the following conditions

compounds with a retention time of 2.81min under the following conditions

route one

Wherein R is¹、R²、R³、R⁴G, n and Y are as defined above, X₁Is a leaving group (e.g., OTf, Cl), etc., Alk is an alkyl group (e.g., C)_1～6Alkyl), PG is an amino protecting group (e.g., Boc, Cbz);

on the second route, the first route is,

The conditions and procedures used for the chemical reactions involved in the various reaction schemes described in the present invention can be carried out with reference to the conditions and procedures of such reactions that are conventional in the art, in particular with reference to the literature: larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis,3^rdEd, John Wiley and Sons (1999); l.fieser and m.fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.

wherein R is¹、R³、R⁴G, Y and n are as defined above;

the invention also provides a pharmaceutical composition comprising the substance A and pharmaceutic adjuvants; the substance A is the oxygen-containing heterocyclic compound shown as the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, crystal form thereof or isotope compound thereof.

The invention also provides an application of the substance A in preparing the RAS inhibitor, wherein the substance A is the oxygen-containing heterocyclic compound shown as the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, crystal form thereof or isotopic compound thereof.

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

The substance A is the oxygen-containing heterocyclic compound shown as the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, crystal form thereof or isotope compound thereof.

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

The invention also provides a method of inhibiting RAS comprising administering to a patient a therapeutically effective amount of substance a;

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

The invention also provides a method of treatment or prevention of a RAS-mediated disease comprising administering to a patient a therapeutically effective amount of substance a;

Said RAS such as KRAS G12C, HRAS G12C or NRAS G12C mutation; such as KRAS G12C.

The present invention also provides a method of treating or preventing cancer, which comprises administering to a patient a therapeutically effective amount of substance a;

The term "plurality" means 2, 3, 4 or 5.

The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.

The terms "pharmaceutically acceptable salt" and "solvate" of the "solvate of a pharmaceutically acceptable salt" as used herein refer to a compound of the invention formed by combining 1 with 2 prepared from a relatively nontoxic, pharmaceutically acceptable acid or base, with a stoichiometric or non-stoichiometric amount of a solvent, as described above. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

The term "stereoisomer" refers to an isomer caused by the same order of connection of atoms or groups of atoms to each other in a molecule but different in spatial arrangement, such as cis-trans isomer, optical isomer or atropisomer, etc. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like.

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. For example, acetone and 1-propen-2-ol can be converted to each other by the rapid movement of hydrogen atoms on oxygen and on the alpha-carbon.

The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist.

The term "isotopic compound" means that one or more atoms in the compound are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36 Cl). Isotopically-labeled compounds of the present invention can generally be prepared by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent according to the procedures described herein.

When any variable (e.g. R)^1-6) In the definition of a compound, the occurrence at each position of the variable is defined multiple times independently of the occurrence at the remaining positions, and their meanings are independent of each other and independent of each other. Thus, if a group is substituted by 1, 2 or 3R ^1-6Substituted by radicals, i.e. the radical may be substituted by up to 3R^1-6Substituted in the position R^1-6Definition and rest ofPut R^1-6Are defined independently of each other. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term "alkoxy" refers to the group-O-R^XWherein R is^XIs an alkyl group as defined above.

The term "cycloalkyl" refers to a saturated monocycloalkyl group, preferably having from 3 to 7 ring carbon atoms, more preferably from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocycloalkyl" refers to a saturated monocyclic group having a heteroatom, preferably a 3-7 membered saturated monocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1, 1-dioxo-thiomorpholin-4-yl.

The term "saturated heterocycle" refers to a saturated cyclic group having a heteroatom, which may be monocyclic, bridged, or spiro. Monocyclic "saturated heterocycles" are "heterocycloalkyl" as described above.

The term "partially saturated heterocycle" refers to a partially saturated cyclic group having heteroatoms, which are neither fully saturated nor aromatic, and which may be monocyclic, bridged, or spiro. Examples of "partially saturated heterocycles" are: pyran ring, 1,2,5, 6-tetrahydropyridine.

The term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromatic character. Such as phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing heteroatoms, each ring having aromatic character; preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1,2 or 3 members independently selected from nitrogen, oxygen or sulphur, for example furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl and the like.

The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition)

The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of skill in the art.

The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.

The positive progress effects of the invention are as follows: the oxygen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by Ras.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the present invention, room temperature means ambient temperature, and is 10 ℃ to 35 ℃. Overnight means 8-15 hours. Reflux refers to the reflux temperature of the solvent at atmospheric pressure.

The following is a list of abbreviations used in the examples:

DMF N, N-dimethylformamide

HATU 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

DIPEA diisopropylethylamine

Pd(PPh₃)₄Tetratriphenylphosphine palladium

Pd(dppf)Cl₂[1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex

LiHMDS bis- (trimethylsilyl) aminolithium

MCPBA m-chloroperoxybenzoic acid

EXAMPLE 1 synthetic route to Compound 1

Synthesis of Compound 1-f

To a solution of the compound 4-carbonyl-tetrahydropyran-3-carboxylic acid ethyl ester (1g, 5.81mmol) in methanol (20mL) was added 2-methyl-2-mercaptourea sulfate (1.45g, 10.43mmol) and sodium methoxide (1.57g, 29.07mmol), respectively, in an ice-water bath. After the addition, the reaction mixture was stirred at room temperature for 3 hours. LCMS monitors incomplete, byproduct formation, pH 5 with 1M dilute hydrochloric acid, 30mL water and 30mL ethyl acetate, respectively, stirring for 10 minutes. The mixture was filtered to give compound 1-f (684mg, 59%) as a white solid. LC-MS (ESI) M/z 199.1[ M + H ]]⁺.

Synthesis of Compound 1-e

1-f (684mg, 3.45mmol) was dissolved in dichloromethane (20mL) at room temperature and DIPEA (1.14mL, 6.91mmol) was added. While the ice-water bath was cooling, trifluoromethanesulfonic anhydride (0.871mL, 5.18mmol) was added dropwise with stirring. After the addition, stirring was continued for 1 hour under ice-water bath. LCMS monitored reaction completion, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30mL 4), dried, concentrated, and passed through silica gel column to afford compound 1-e (996mg, 87%) as a light brown oil. LC-MS (ESI) where M/z is 331.2[ M + H ] ]⁺.

Synthesis of Compound 1-d

1-e (400mg, 1.21mmol) was dissolved in DMF (15mL) at room temperature, and the compound (S) -benzyl 2-cyanomethylpiperazine-1-carboxylate hydrochloride (429mg, 1.45mmol) and DIPEA (0.6mL, 3.64mmol) were added, respectively. The reaction solution was replaced with nitrogen gas 3 times, heated to 100 ℃ under nitrogen protection, and stirred for 1 hour. The reaction was monitored by LCMS for completion, and the reaction was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50mL × 3). The organic layer was washed three times with saturated brine, dried, concentrated and passed through a silica gel column to give compound 1-d (522mg, 98%) as a white solid. LC-MS (ESI) where M/z is 440.4[ M + H ]]⁺.

Synthesis of Compound 1-c

1-d (522mg, 1.19mmol) was dissolved in ethyl acetate (30mL) at room temperature, and MCPBA (601.5mg, 2.97mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 1 hour. TLC monitored the reaction was complete, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50mL × 2), dried, concentrated, and passed through a silica gel column to afford compound 1-c (552mg, 99%) as a white solid. LC-MS (ESI) M/z 472.4[ M + H ]]⁺.

Synthesis of Compound 1-b

1-c (552mg, 1.17mmol) was dissolved in toluene (15mL) and N-methyl-L-prolinol (243.7. mu.L, 2.05mmol) and sodium tert-butoxide (225mg, 2.34mmol) were added, respectively, with cooling in an ice-water bath. After the addition, stirring was continued for 30 minutes in an ice-water bath under nitrogen protection. TLC monitored the reaction completion, quenched with water, extracted twice with ethyl acetate, dried, concentrated, and passed through a silica gel column to give compound 1-b (443mg, 75%) as a white solid. LC-MS (ESI) M/z 507.5[ M + H ] ]⁺.

Synthesis of Compound 1-a

1-b (150mg, 0.296mmol) was dissolved in ethyl acetate (30mL), 10% palladium on carbon (450mg) was added, the mixture was replaced with hydrogen three times, and the reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. TLC monitored the reaction completion, filtered through celite, washed with methanol, and spun dry to give 1-a (74mg, 67%) as a white solid which was used in the next reaction without further purification. LC-MS (ESI) 373.4[ M + H ]]⁺.

Synthesis of Compound 1

To a solution of 1-a (74mg, 0.199mmol) in dichloromethane (30mL) was added DIPEA (164. mu.L, 0.995mmol) and acryloyl chloride (24. mu.L, 0.298mmol), respectively, at room temperature. The reaction was allowed to react overnight at room temperature under nitrogen, LCMS monitored for reaction completion, quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (30mLx 3). The organic phase was dried, spun dry and purified by preparative TLC (DCM: MeOH ═ 10:1) to give compound 1(20mg, 24%) as a white solid. LC-MS (ESI) M/z 427.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ6.65-6.50(m,1H),6.41-6.24(m,1H),6.16-5.69(m,1H),4.78-4.67(m,1H),4.67-4.52(m,2H),4.38(dd,1H,J＝11.6Hz,J＝4.8Hz),4.12-3.93(m,3H),3.59-3.48(m,2H),3.36(dd,2H,J＝14Hz,J＝3.6Hz),3.26-3.00(m,4H),2.95-2.81(m,3H),2.77(s,3H),2.73-2.58(m,2H),2.26-1.88(m,4H).

EXAMPLE 2 synthetic route to Compound 2

Synthesis of Compound 2-h

NaH (60%, 3.6g, 90.0mmol) was added to THF (100mL) at room temperature, and methyl acetoacetate (10.4g, 90.0mmol) was added under nitrogen at room temperature. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 36mL, 90.0mmol) was added dropwise at-15 ℃ to-10 ℃, after the addition, the reaction mixture was stirred at this temperature for 30 minutes, a solution of 2-trifluoromethylbenzaldehyde (5.2g, 29.9mmol) in THF (10mL) was added dropwise, and after the addition, the mixture was stirred at low temperature (-10 ℃ to 0 ℃) for 2 hours. The reaction was quenched by addition of saturated ammonium chloride solution (100mL), extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column (EA/PE ═ 1/3) to give compound 2-h (5.8g, 67%) as a pale yellow liquid, which was directly charged into the next reaction.

Synthesis of Compound 2-g

Add DMF-DMA (3.2mL, 24.1mmol) to a solution of compound 2-h (5.8g, 20.0mmol) in DCM (120mL) at room temperature under nitrogen. After the addition was complete, the mixture was stirred at room temperature for 45 minutes. Adding BF₃·Et₂O (3.2mL, 25.4mmol), and stirring was continued at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (200mL) and successively with saturated NaHCO₃The solution (400mL) was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was dissolved in THF (60mL), a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (30.0mL, 30.0mmol) was added dropwise at-78 deg.C under nitrogen, and the mixture was stirred at this temperature for 1 hour. The reaction was quenched by addition of saturated ammonium chloride (200mL) and ethyl acetate(100mL x 3) extraction, the organic phase was washed with saturated brine (100mL x 2) and concentrated to give compound 2-g (3.8g, 63%) as a yellow oil. LC-MS (ESI) 303.1[ M +1 ]]⁺.

Synthesis of Compound 2-f

Sodium methoxide (2.7g, 50.0mmol) and urea 2-methyl-2-mercaptosulfate (2.5g, 8.4mmol) were added to methanol (100mL) 2-g (3.0g, 10.0mmol) in this order under nitrogen in an ice-water bath. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The pH was adjusted to 5 with 1M dilute hydrochloric acid, and a solid precipitated and was filtered to give compound 2-f (1.7g, 50%) as a pale yellow solid. LC-MS (ESI) M/z 343.0[ M +1 ] ]⁺.

Synthesis of Compound 2-e

To 2-f (1.7g, 5.0mmol) in dichloromethane (40mL) under ice-water bath nitrogen was added DIPEA (2.1mL, 12.3mmol) and trifluoromethanesulfonic anhydride (1.0mL, 6.3mmol) in that order. After the addition was complete, the mixture was stirred at 0 ℃ for 2 hours. Add saturated sodium bicarbonate solution (50mL) to quench, extract with DCM (50mL × 2), concentrate to give compound 2-e (1.5g) which is directly charged to the next reaction. LC-MS (ESI) M/z 474.9[ M +1 ]]⁺.

Synthesis of Compound 2-d

Compound 2-e (1.5g, 3.2mmol) was dissolved in DMF (10mL) at room temperature and DIPEA (0.9mL, 5.6mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (0.8g, 2.8mmol) was added in that order. After the mixture was stirred at 100 ℃ for 1 hour, water (100mL) was added and quenched, extracted with ethyl acetate (80mL × 2), concentrated, and the crude product was purified by flash column separation (EA/PE ═ 1/1) to give compound 2-d (0.93g, 50%) as a white solid. LC-MS (ESI) M/z 584.0[ M +1 ]]⁺.

Synthesis of Compound 2-c

Compound 2-d (0.4g, 0.69mmol) was dissolved in ethyl acetate (20mL) and MCPBA (0.23g, 1.4mmol) was added at room temperature. After the mixture was stirred at room temperature for 1 hour, it was quenched by addition of saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50mL × 2), the organic phase was concentrated and the crude product was purified by flash column separation (DCM/MeOH ═ 9/1) to give compound 2-c (0.33g, 78%) as a white solid. LC-MS (ESI) m/z ＝616.0[M+1]⁺.

Synthesis of Compound 2-b

To compound 2-c (0.33g, 0.54mmol) in toluene (15mL) was added sequentially N-methyl-L-prolinol (0.1mL, 0.9mmol), t-BuONa (0.1g, 0.9mmol) with cooling in an ice-water bath. After stirring the mixture under nitrogen in an ice-water bath for 0.5 h, quench with water (10mL), extract with ethyl acetate (30mL × 2), concentrate the organic phase and purify the crude product by flash column separation (MeOH/DCM ═ 1/9) to give compound 2-b (0.26g, 74%) as a white solid. LC-MS (ESI) M/z 651.3[ M +1 ]]⁺.

Synthesis of Compound 2-a

Compound 2-b (0.26g, 0.4mmol) was dissolved in methanolic ammonia (7M, 50mL) and cooled to-78 ℃ and then replaced with nitrogen 2 times, followed by addition of Pd/C (70mg) and replacement with hydrogen 3 times. The reaction solution was warmed to room temperature and stirred under hydrogen for 2 hours. The reaction mixture was filtered and concentrated to obtain compound 2-a (0.16g, 77%). LC-MS (ESI) M/z 517.2[ M +1 ]]⁺.

Synthesis of Compound 2

Compound 2-a (0.12g, 0.23mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (75. mu.L, 0.45mmol) and acryloyl chloride (25. mu.L, 0.23mmol) were added in that order. After the mixture was stirred at room temperature under nitrogen for 20 hours, it was quenched by addition of water (10mL) and extracted with DCM (50mL × 3). The organic phase was concentrated and the crude product was purified by flash column separation (MeOH/DCM ═ 1/9) to give compound 2(58mg, 44%) as a white solid. LC-MS (ESI) M/z 571.3[ M +1 ] ]⁺；¹H NMR(500MHz,CD₃OD):δ7.84(d,1H,J＝7.5Hz),7.68-7.76(m,2H),7.53(t,1H,J＝7.5Hz),6.73-6.97(m,1H),6.30(d,1H,J＝16.5Hz),5.85(d,1H,J＝9.5Hz),5.21(t,1H,J＝11.0Hz),4.99-5.02(m,2H),4.25-4.43(m,2H),4.06-4.16(m,1H),3.80-3.96(m,1H),3.43-3.80(m,2H),3.20-3.33(m,1H),2.97-3.19(m,4H),2.81-2.95(m,2H),2.70-2.83(m,1H),2.53(d,3H,J＝4.5Hz),2.32-2.45(m,1H),2.06-2.15(m,1H),1.79-1.90(m,2H),1.68-1.77(m,1H),1.31-1.39(m,1H).

Synthesis of Compounds 2-1 and 2-2

Purification of compound 2(29mg, 0.05mmol) by manual resolution gave compound 2-1(10mg, 34%) as a white solid and compound 2-2(10mg, 34%) as a white solid.

2-1:LC-MS(ESI):m/z＝571.2[M+1]⁺；¹H NMR(400MHz,CDCl₃):δ7.75(d,1H,J＝7.6Hz),7.67(d,1H,J＝7.6Hz),7.63(t,1H,J＝8.0Hz),7.44(t,1H,J＝8.0Hz),6.54-6.65(m,1H),6.38(dd,1H,J＝16.4,1.6Hz),5.83(d,1H,J＝10.0Hz),5.14(dd,1H,J＝10.8,3.2Hz),4.88(d,1H,J＝14.0Hz),4.80(d,1H,J＝13.6Hz),4.51-5.12(m,2H),4.37(dd,1H,J＝10.8,5.2Hz),4.18(dd,1H,J＝10.8,6.4Hz),3.84-4.10(m,1H),3.70-3.83(m,1H),3.32-3.64(m,1H),2.75-3.27(m,6H),2.63-2.72(m,1H),2.48(s,3H),2.25-2.32(m,1H),1.98-2.10(m,1H),1.69-1.90(m,3H),1.28-1.39(m,1H).

2-2:LC-MS(ESI):m/z＝571.2[M+1]⁺；¹H NMR(400MHz,CDCl₃):δ7.76(d,1H,J＝7.6Hz),7.67(d,1H,J＝7.6Hz),7.63(t,1H,J＝7.6Hz),7.44(t,1H,J＝7.6Hz),6.50-6.65(m,1H),6.39(dd,1H,J＝16.8,1.6Hz),5.83(d,1H,J＝11.2Hz),5.17(dd,1H,J＝12.0,4.0Hz),4.89(d,1H,J＝14.0Hz),4.78(d,1H,J＝13.2Hz),4.46-5.11(m,2H),4.39(dd,1H,J＝10.4,4.8Hz),4.16(dd,1H,J＝10.4,6.4Hz),3.94-4.01(m,1H),3.62-3.84(m,1H),3.38-3.56(m,1H),2.59-3.16(m,7H),2.47(s,3H),2.24-2.33(m,1H),1.98-2.10(m,1H),1.69-1.89(m,3H),1.28-1.38(m,1H).

EXAMPLE 3 Synthesis of Compound 3

Synthesis of Compound 3-i

NaH (60%, 3.0g, 75.0mmol) was added to THF (100mL) at room temperature, and methyl acetoacetate (8mL, 77.0mmol) was added under nitrogen at room temperature. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 30.8mL, 77.0mmol) was added dropwise at-15 ℃ to-10 ℃. After the addition was completed, the reaction mixture was stirred at this temperature for 30 minutes, and then a solution of compound 1-naphthaldehyde (4.0g, 25.6mmol) in THF (10mL) was added dropwise. After the addition, the mixture was stirred at low temperature (-10 ℃ C. -0 ℃ C.) for 2 hours. The reaction was quenched by addition of saturated ammonium chloride solution (100mL), extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column separation (EA/PE ═ 1/3) to give compound 3-i (4.5g, 64%) as a pale yellow liquid.

Synthesis of Compounds 3-h

Compound 3-i (3.3g, 12.1mmol) was dissolved in DCM (120mL) and DMF-DMA (1.6mL, 12.0mmol) was added under nitrogen at room temperature. After stirring the reaction solution at room temperature for 45 minutes, BF was added ₃·Et₂O (1.6mL, 12.7 mmol). The mixture is stirred at room temperature for 1 hour, diluted with 200mL of dichloromethane and the organic phase is successively diluted with saturated NaHCO₃The solution (400mL) was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column separation (EA/PE ═ 1/3) to give compound 3-h (3.0g, 88%) as a pale yellow liquid. LC-MS (ESI) M/z 283.1[ M +1 ]]⁺.

Synthesis of Compound 3-g

To a solution of compound 3-h (2.3g, 8.1mmol) in THF (60mL) at-78 deg.C under nitrogen was added dropwise a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1M, 8.3mL, 8.3 mmol). After the addition was complete, the mixture was stirred at this temperature for 1 hour, the reaction was quenched by addition of saturated ammonium chloride (20mL), extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated sodium chloride and concentrated to give the crude product which was purified by flash column separation (EA/PE ═ 1/4) to give compound 3-g (2.8g) as a yellow oil. LC-MS (ESI) M/z 285.1[ M +1 ]]⁺.

Synthesis of Compound 3-f

To a solution of 3-g (2.8g, 10.0mmol) of the compound in methanol (100mL) in an ice-water bath was added sodium methoxide (2.7g, 50.0mmol), 2-methyl-2-Mercaptosulfuric acid urea (2.6g, 8.8 mmol). After the addition was completed, the reaction solution was warmed to room temperature and stirred overnight. The pH was adjusted to 5 with 1M hydrochloric acid solution and the solid precipitated, filtered, washed with water (50mL x 3) and dried to give crude 3-f (1.3g, two steps 49%) as a pale yellow solid. LC-MS (ESI) 325.0[ M +1 ] ]⁺.

Synthesis of Compound 3-e

To a solution of compound 3-f (0.65g, 2.0mmol) in DCM (40mL) was added DIPEA (0.67mL, 4.1mmol), followed by trifluoromethanesulfonic anhydride (0.34mL, 2.1mmol) in an ice-water bath. After the addition was completed, the mixture was stirred in an ice-water bath for 2 hours, quenched by addition of saturated sodium bicarbonate solution (50mL), extracted with DCM (50mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3-e (0.62g) which was directly charged to the next reaction.

Synthesis of Compound 3-d

Compound 3-e (0.62g, 1.4mmol) was dissolved in DMF (10mL) at room temperature, followed by the addition of DIPEA (0.45mL, 2.8mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (0.41g, 1.4 mmol). After the addition was complete, the mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched by addition of water (100mL), extracted with ethyl acetate (80mL × 2), the organic phase washed with saturated brine (100mL × 3), concentrated, and the crude product was purified by flash column separation (EA/PE ═ 1/1) to give compound 3-d (0.5g, 44% yield over two steps) as a white solid. LC-MS (ESI) M/z 566.3[ M +1 ]]⁺.

Synthesis of Compound 3-c

Compound 3-d (0.5g, 0.9mmol) was dissolved in ethyl acetate (20mL) and MCPBA (0.46g, 2.7mmol) was added at room temperature. After the mixture was stirred at room temperature for 1 hour, saturated sodium bicarbonate solution (50mL) was added and quenched, extracted with ethyl acetate (50mL × 2), filtered, concentrated, and the crude product was purified by flash column separation (DCM/MeOH ═ 9/1) to give compound 3-c as a solid (0.38g, 72%).

Synthesis of Compound 3-b

To a solution of compound 3-c (0.38g, 0.63mmol) in toluene (15mL) under ice-water bath was added N-methyl-L-prolinol (0.1mL, 0.9mmol), t-BuONa (0.1g, 0.9mmol) in that order. After the addition, mixingAfter stirring under nitrogen in an ice-water bath for 0.5 h, quench with water (10mL), extract with ethyl acetate (30mL × 2), concentrate the organic phase and purify the crude product by flash column separation (MeOH/DCM ═ 1/9) to give compound 3-b (0.3g, 75%) as a white solid. LC-MS (ESI) M/z 633.3[ M +1 ]]⁺.

Synthesis of Compound 3-a

A solution of compound 3-b (0.13g, 0.2mmol) in methanolic ammonia (7M, 50mL) was cooled to-78 ℃ and replaced with nitrogen 2 times, 10% Pd-C (55mg) was added and replaced with hydrogen 3 times. The reaction solution was warmed to room temperature and stirred under hydrogen for 2 hours. The reaction mixture was filtered and concentrated to obtain compound 3-a (0.1g, 100%). LC-MS (ESI) M/z 499.3[ M +1 ]]⁺.

Synthesis of Compound 3

Compound 3-a (0.1g, 0.2mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (75. mu.L, 0.45mmol) and acryloyl chloride (25. mu.L, 0.23mmol) were added in that order. The mixture was stirred at room temperature under nitrogen overnight, quenched by addition of water (10mL), extracted with DCM (50mL × 3), the organic phase concentrated and the crude product purified by flash column separation (MeOH/DCM ═ 1/9) to give compound 3(8mg, 7%) as a white solid. LC-MS (ESI) M/z 553.3[ M +1 ] ]⁺；¹H NMR(500MHz,CD₃OD):δ8.07(d,1H,J＝7.5Hz),7.82(d,1H,J＝9.5Hz),7.78(d,1H,J＝8.5Hz),7.50-7.59(m,1H),7.36-7.48(m,3H),6.62-6.86(m,1H),6.19(d,1H,J＝17.0Hz),5.96-6.08(m,2H),5.73(d,1H,J＝9.5Hz),5.53(dd,1H,J＝4.5Hz,J＝11.0Hz),5.46(dd,1H,J＝2.5Hz,J＝9.0Hz),4.93-5.07(m,2H),4.67-4.76(m,1H),4.43-4.52(m,2H),4.35-4.42(m,1H),3.91-4.08(m,1H),3.28-3.64(m,1H),3.26-3.36(m,2H),3.09-3.18(m,2H),2.90-3.02(m,2H),2.78-2.86(m,1H),2.69(d,3H,J＝12.5Hz),2.06-2.18(m,1H),1.86-1.93(m,2H),1.73-1.77(m,1H).

Synthesis of Compounds 3-1 and 3-2

Compound 3(170mg) was synthesized according to the synthetic method for Compound 3, and purified by manual resolution to give Compound 3-1(40mg, 24%) as a white solid, and Compound 3-2(20mg, 12%) as a white solid.

3-1：LC-MS(ESI):m/z＝553.0[M+1]⁺；¹H NMR(400MHz,MeOD):δ8.06(d,1H,J＝7.6Hz),7.82(d,1H,J＝7.6Hz),7.76(d,1H,J＝8.4Hz),7.57(d,1H,J＝6.8Hz),7.38-7.44(m,3H),6.62-6.86(m,1H),6.19(d,1H,J＝16.0Hz),5.73(d,1H,J＝10.4Hz),5.51(dd,1H,J＝10.4,4.0Hz),5.02(d,1H,J＝13.6Hz),4.64-4.98(m,1H),4.37-4.59(m,1H),4.19-4.31(m,2H),3.93-3.06(m,1H),3.81-3.91(m,1H),3.57-3.74(m,1H),3.28-3.50(m,1H),2.89-3.16(m,5H),2.76-2.86(m,1H),2.66-2.75(m,1H),2.42(s,3H),2.24-2.33(m,1H),1.95-2.05(m,1H),1.68-1.78(m,2H),1.55-1.67(m,1H),1.21-1.28(m,1H).

3-2：LC-MS(ESI):m/z＝553.0[M+1]⁺；¹H NMR(400MHz,MeOD):δ8.07(d,1H,J＝8.0Hz),7.82(d,1H,J＝7.2Hz),7.76(d,1H,J＝8.0Hz),7.54(d,1H,J＝7.2Hz),7.37-7.44(m,3H),6.33-6.85(m,1H),6.19(d,1H,J＝16.4Hz),5.74(d,1H,J＝10.4Hz),5.50(dd,1H,J＝10.4,4.0Hz),4.97(d,1H,J＝14.0Hz),4.61-4.75(m,1H),4.37-4.57(m,1H),4.21-4.34(m,2H),4.14(d,1H,J＝13.6Hz),3.92-4.06(m,1H),3.70-3.81(m,1H),3.27-3.42(m,1H),2.89-3.17(m,6H),2.69-2.80(m,1H),2.46(s,3H),2.30-2.39(m,1H),1.96-2.12(m,1H),1.70-1.79(m,2H),1.60-1.69(m,1H),1.20-1.27(m,1H).

EXAMPLE 4 synthetic route to Compound 4

Synthesis of Compound 4-k

A solution of compound 1, 8-dibromonaphthalene (5g, 17.48mmol) in THF (40mL) was cooled to-78 deg.C and n-BuLi (2.5M, 7.5mL, 18.75mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred at-78 ℃ for 20 minutes, and methyl iodide (2.2mL, 35.2mmol) was added dropwise at-78 ℃. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then poured into 50mL of saturated brine, extracted with ethyl acetate (100mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column separation (PE) to afford compound 4-k (3.28g, 85% yield) as a white solid.¹H NMR(500MHz,CDCl₃):δ7.85(d,1H,J＝7.0Hz),7.80(d,1H,J＝7.5Hz),7.75-7.71(m,1H),7.40-7.33(m,2H),7.23(t,1H,J＝8.0Hz),3.15(s,3H).

Synthesis of Compound 4-j

A solution of compound 4-k (3.28g, 14.84mmol) in THF (110mL) was cooled to-78 deg.C and n-BuLi (2.5M, 12mL, 30mmol) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at-78 ℃ for 10 minutes, and then DMF (5.8mL, 74.55mmol) was added dropwise at-78 ℃. After the addition was completed, the reaction mixture was stirred at-78 ℃ for 30 minutes, warmed to room temperature and stirred for 2 hours, quenched with 20mL of a saturated ammonium chloride solution, then added to 100mL of a saturated sodium bicarbonate solution, extracted with ethyl acetate (100mL), and the organic phase was washed with a saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was isolated and purified by flash column (EA/PE ═ 1/10) to give compound 4-j (1.5g, 60% yield) as a white solid. LC-MS (ESI) 171.2[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ10.85(s,1H),7.97(dd,1H,J₁＝1.2Hz,J₂＝8Hz),7.89(dd,1H,J₁＝1.6Hz,J₂＝7.2Hz),7.74-7.69(m,1H),7.46(t,1H,J＝8Hz),7.42-7.36(m,2H),2.75(s,3H).

Synthesis of Compound 4-i

NaH (60%, 423mg, 10.58mmol) was added to 10mL of THF at room temperature. Methyl acetoacetate (950. mu.L, 8.82mmol) was added under nitrogen at room temperature. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 4.2mL, 10.5mmol) was added dropwise at-15 ℃ to-10 ℃. After the addition was complete, the mixture was held at this temperature for 30 minutes, and then a solution of compound 4-j (500mg, 2.94mmol) in THF (10mL) was added dropwise. After the addition was completed, the mixture was stirred at low temperature (-10 ℃ C. to 0 ℃ C.) for 2 hours, and then the reaction was quenched with a saturated ammonium chloride solution (100mL), followed by ethyl acetate (8)0mL 2) extraction. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (EA/DCM ═ 1/10) to give compound 4-i (806mg, 96% yield) as a white solid. LC-MS (ESI) M/z 309.1[ M + Na]⁺；¹H NMR(400MHz,CDCl₃):δ7.92(d,1H,J＝7.2Hz),7.81(dd,1H,J₁＝1.2Hz,J₂＝8.4Hz),7.77-7.72(m,1H),7.49(t,1H,J＝7.2Hz),7.39-7.33(m,2H),6.47(d,1H,J＝9.6Hz),3.76(s,3H),3.55(s,2H),3.10-2.92(m,3H),2.89(s,3H).

Synthesis of Compound 4-h

Compound 4-i (800mg, 2.79mmol) was dissolved in DCM (30mL) at room temperature and DMF-DMA (412. mu.L, 3.08mmol) was added under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 45 minutes, and BF was added thereto₃·Et₂O (390. mu.L, 3.08 mmol). After the addition was completed, the mixture was stirred at room temperature for 1 hour, and then diluted with 200mL of ethyl acetate. The organic phase is successively treated with saturated NaHCO ₃The solution (200mL) was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound 4-h (870 mg). The crude product was used in the next reaction without purification. LC-MS (ESI) with M/z 297.1[ M +1 ]]⁺.

Synthesis of Compound 4-g

Compound 4-h (770mg, 2.59mmol) was dissolved in THF (60mL) at room temperature, and a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1M, 2.6mL, 2.6mmol) was added dropwise at-78 deg.C under nitrogen. After the addition was completed, the mixture was stirred at-78 ℃ for 1 hour, and then a saturated ammonium chloride solution (50mL) was added to quench the reaction, extracted with ethyl acetate (100mL × 2), the organic layer was washed with a saturated saline solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was isolated and purified by flash column separation (PE/EA ═ 4/1) to give 4-g (670mg, 86% yield) of compound as a yellow oil. LC-MS (ESI) M/z 299.2[ M +1 ]]⁺.

Synthesis of Compound 4-f

Compound 4-g (670mg, 2.25mmol) was dissolved in methanol (50mL) at room temperature, followed by 0 ℃ under nitrogenSodium methoxide (608mg, 11.25mmol) and the compound 2-methyl-2-mercaptourea sulfate (563mg, 2.02mmol) were added. After the addition was complete, the mixture was warmed to room temperature and stirred for 20 hours. The reaction solution was adjusted to pH 5 with 1M dilute hydrochloric acid, a solid precipitated, filtered, the filter cake washed with water (5mL × 2), the solid collected and dried in vacuo to give crude 4-f (459mg, 60% yield) as a white solid. LC-MS (ESI) M/z 339.1[ M +1 ] ]⁺.

Synthesis of Compound 4-e

Compound 4-f (459mg, 1.36mmol) was dissolved in DCM (18mL) at room temperature, and DIPEA (673. mu.L, 4.08mmol), trifluoromethanesulfonic anhydride (343. mu.L, 2.04mmol) were added in that order under nitrogen in an ice-water bath. After the addition was complete, the reaction mixture was stirred for 2 hours in an ice-water bath, quenched with saturated sodium bicarbonate solution (50mL), extracted with DCM (50mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was isolated and purified by flash column (EA/PE ═ 1/10) to give compound 4-e (432mg, 68% yield) as a white solid. LC-MS (ESI) M/z 471.1[ M +1 ]]⁺.

Synthesis of Compound 4-d

Compound 4-e (430mg, 0.91mmol) was dissolved in DMF (10mL) at room temperature, followed by the addition of DIPEA (453 μ L, 2.75mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (324mg, 1.1mmol) in that order. After the addition was completed, the mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched with saturated brine (100mL), and extracted with ethyl acetate (80mL × 2). The organic phase was washed with saturated brine (100mL × 3), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column separation (EA/PE ═ 1/1) to give compound 4-d (470mg, 68% yield) as a white solid. LC-MS (ESI) M/z 580.3[ M +1 ] ]⁺.

Synthesis of Compound 4-c

Compound 4-d (200mg, 0.34mmol) was dissolved in ethyl acetate (20mL) at room temperature, and MCPBA (175mg, 0.86mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate,Filtration and concentration gave the crude product which was purified by flash column separation (EA/PE ═ 1/4) to give compound 4-c (210mg, 99% yield) as a white solid. LC-MS (ESI) M/z 612.3[ M +1 ]]⁺.

Synthesis of Compound 4-b

Compound 4-c (100mg, 0.16mmol) was dissolved in toluene (5mL) at room temperature, and the reaction was cooled to 0 ℃ and N-methyl-L-prolinol (34. mu.L, 0.29mmol) and t-BuONa (32mg, 0.33mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred under nitrogen in an ice-water bath for 0.5 h, quenched with water (10mL) and extracted with ethyl acetate (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/20) to give compound 4-b (97mg, 92% yield) as a white solid. LC-MS (ESI) M/z 647.4[ M +1 ]]⁺.

Synthesis of Compound 4-a

Compound 4-b (90mg, 0.14mmol) was dissolved in methanolic ammonia (7M, 50mL) at room temperature, the reaction was cooled to-78 ℃ and replaced with nitrogen 2 times, then 10% Pd-C (75mg) was added and replaced with hydrogen 3 times, the reaction was warmed to room temperature and stirred under hydrogen for 2 hours. The reaction mixture was filtered and concentrated to give compound 4-a (77mg, 99% yield) as a white solid. LC-MS (ESI) M/z 513.3[ M +1 ]]⁺.

Synthesis of Compound 4

Compound 4-a (77mg, 0.15mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (75. mu.L, 0.45mmol) and acryloyl chloride (25. mu.L, 0.23mmol) were added sequentially. After addition, the reaction mixture was stirred at room temperature under nitrogen for 20 hours, quenched with water (10mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 4(56mg, 66% yield) as a white solid. LC-MS (ESI) with M/z 567.3[ M +1 ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.78-7.65(m,3H),7.45-7.36(m,1H),7.31-7.26(m,2H),6.55-6.44(m,1H),6.35-6.27(m,1H),5.95-5.88(m,1H),5.75(d,1H,J＝10.4Hz),4.94-4.84(m,1H),4.81-4.59(m,2H),4.52-4.37(m,1H),4.22-4.11(m,1H),3.96-3.76(m,2H),3.68-3.58(m,1H),3.48-3.37(m,1H),3.24-2.88(m,5H),2.85(d,3H,J＝11.6Hz),2.78-2.58(m,2H),2.50(s,3H),2.40-2.27(m,1H),2.08-1.68(m,5H).

Synthesis of Compounds 4-1 and 4-2

Compound 4(140mg) was synthesized according to the synthetic method for Compound 4, and purified by manual resolution to give Compound 4-1(30mg, 21% yield) as a white solid, and Compound 4-2(40mg, 29% yield) as a white solid.

4-1：LC-MS(ESI):m/z＝567.3[M+H]⁺；¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝8Hz,1H),7.80–7.74(m,2H),7.47(t,J＝8Hz,1H),7.41–7.34(m,2H),6.65–6.50(m,1H),6.40(d,J＝16.4Hz,1H),6.01(dd,J＝8.8,3.6Hz,1H),5.84(d,J＝10.4Hz,1H),5.17–4.98(m,1H),4.87(d,J＝13.6Hz,1H),4.71(d,J＝13.2Hz,1H),4.43(dd,J＝10.8,4.8Hz,1H),4.21(dd,J＝10,6.4Hz,1H),4.03–3.38(m,3H),3.34–3.05(m,5H),3.03–2.97(m,1H),2.95(s,3H),2.84–2.70(m,2H),2.52(s,3H),2.34–2.29(m,1H),2.14–2.00(m,2H),1.92–1.82(m,2H),1.39–1.32(m,1H).

4-2：LC-MS(ESI):m/z＝567.3[M+H]⁺；¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝7.6Hz,2H),7.76(d,J＝6.4Hz,1H),7.51(t,J＝7.6Hz,1H),7.39–7.35(m,2H),6.68–6.52(m,1H),6.40(d,J＝16.4Hz,1H),6.01(dd,J＝10.4,2.8Hz,1H),5.84(d,J＝10Hz,1H),5.11–4.92(m,2H),4.80(d,J＝13.6Hz,1H),4.49–4.38(m,1H),4.23–4.15(m,1H),4.04–3.68(m,3H),3.58–3.45(m,1H),3.36–3.00(m,5H),2.92(s,3H),2.78–2.69(m,2H),2.51(s,3H),2.38–2.28(m,1H),2.16–2.01(m,2H),1.91–1.81(m,2H),1.38–1.33(m,1H).

EXAMPLE 5 synthetic route to Compound 5

Synthesis of Compound 5-b

Compound 4-c (100mg, 0.164mmol) was dissolved in toluene (5mL), and 2-dimethylaminoethanol (29. mu.L, 0.29mmol) and t-BuONa (32mg, 0.33mmol) were added sequentially with cooling in an ice-water bath. After stirring the mixture under nitrogen in an ice-water bath for 0.5 h, it was quenched with water (10mL) and extracted with ethyl acetate (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 5-b (100mg, 98% yield) as a white solid. LC-MS (ESI) M/z 621.4[ M +1 ]]⁺.

Synthesis of Compound 5-a

Compound 5-b (100mg, 0.161mmol) was dissolved in methanolic ammonia (7M, 50mL), cooled to-78 deg.C, and replaced with nitrogen 2 times, followed by addition of Pd-C (75 mg). Then, the reaction solution was replaced with hydrogen gas 3 times, warmed to room temperature, and stirred under hydrogen gas for 2 hours. The reaction mixture was filtered and concentrated to give compound 5-a (80mg, 97% yield) as a white solid. LC-MS (ESI) M/z 487.3[ M +1 ]]⁺.

Synthesis of Compound 5

Compound 5-a (80mg, 0.165mmol) was dissolved in DCM (10mL) at room temperature, followed by the addition of DIPEA (82. mu.L, 0.495mmol) and acryloyl chloride (30. mu.L, 0.25 mmol). After the mixture was stirred at room temperature under nitrogen for 20 h, quenched with water (10mL), extracted with DCM (50mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by flash column separation (MeOH/DCM ═ 10%) to give compound 5(55mg, 62% yield) as a white solid. LC-MS (ESI) M/z 541.3[ M +1 ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.88-7.65(m,3H),7.56-7.40(m,1H),7.38-7.12(m,2H),6.68-6.25(m,2H),6.05-5.66(m,2H),5.44-4.54(m,3H),4.44(s,2H),4.05-3.79(m,2H),3.77-3.33(m,3H),3.29-2.99(m,4H),2.91(d,3H,J＝12.4Hz),2.83-2.56(m,3H),2.36(s,6H).

EXAMPLE 6 synthetic route to Compound 6

Synthesis of Compound 6-b

Compound 4-c (62mg, 0.10mmol) was dissolved in toluene (5mL), and 2-diethylaminoethanol (24. mu.L, 0.18mmol) and t-BuONa (20mg, 0.20mmol) were added in this order under cooling in an ice-water bath. After stirring the mixture under nitrogen in an ice-water bath for 0.5 h, it was quenched with water (10mL) and extracted with ethyl acetate (25mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 6-b (65mg, 99% yield) as a white solid. LC-MS (ESI) M/z 649.4[ M +1 ]]⁺.

Synthesis of Compound 6-a

Compound 6-b (65mg, 0.1mmol) was dissolved in methanolic ammonia (7M, 50mL), cooled to-78 deg.C, and replaced with nitrogen 2 times, followed by addition of Pd/C (30 mg). The reaction solution was allowed to stand at room temperature for 3 times under hydrogen replacement, and stirred for 1 hour under hydrogen. The reaction mixture was filtered and concentrated to give compound 6-a (51mg, 99% yield) as a white solid. LC-MS (ESI) M/z 515.3[ M +1 ]]⁺.

Synthesis of Compound 6

Compound 6-a (51mg, 0.10mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (82. mu.L, 0.50mmol) and acryloyl chloride (13.6mg, 0.15mmol) were added in that order. After addition, the mixture was stirred at room temperature under nitrogen for 20 hours, quenched with water (10mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 6(50mg, 68% yield) as a white solid. LC-MS (ESI) M/z 569.3[ M +1 ] ]⁺；¹H NMR(400MHz,CDCl₃)δ7.85-7.71(m,3H),7.52-7.43(m,1H),7.39-7.31(m,2H),6.67-6.47(m,1H),6.42-6.24(m,1H),6.17-5.95(m,1H),5.85-5.66(m,1H),5.08-4.92(m,1H),4.89-4.66(m,4H),4.08-3.85(m,2H),3.80-3.53(m,2H),3.32-3.15(m,4H),3.12-2.97(m,6H),2.92(d,3H,J＝12.8Hz),2.85-2.62(m,2H),1.34-1.27(m,6H).

Synthesis of Compounds 6-1 and 6-2

Compound 6(40mg, 0.07mmol) was subjected to chiral resolution. Compound 6-1(12mg, 30% yield) was obtained as a white solid; compound 6-2(11mg, 28% yield) was obtained as a white solid.

6-1:LC-MS(ESI):m/z＝569.3[M+1]⁺；¹H NMR(500MHz,CDCl₃):δ7.83(d,1H,J＝8Hz),7.75(t,2H,J＝7Hz),7.45(t,1H,J＝8Hz),7.39-7.31(m,2H),6.63-6.49(m,1H),6.38(d,1H,J＝17Hz),6.00(dd,1H,J₁＝4Hz,J₂＝9.5Hz),5.81(d,1H,J＝11Hz),5.17-4.92(m,1H),4.86(d,1H,J＝14Hz),4.71(d,1H,J＝14Hz),4.39(t,2H,J＝6.5Hz),4.11-3.78(m,2H),3.70(d,1H,J＝12Hz),3.53-3.33(m,1H),3.25(dt,2H,J₁＝3.5Hz,J₂＝18.5Hz),3.17-3.03(m,2H),3.02-2.95(m,1H),2.94(s,3H),2.87(t,2H,J＝6.5Hz),2.83-2.71(m,1H),2.63(q,4H,J＝6.5Hz),1.06(t,6H,J＝7Hz).

6-2:LC-MS(ESI):m/z＝569.3[M+1]⁺；¹H NMR(500MHz,CDCl₃):δ7.87-7.79(m,2H),7.75(d,1H,J＝8Hz),7.49(t,1H,J＝7.5Hz),7.39-7.30(m,2H),6.65-6.48(m,1H),6.38(d,1H,J＝16.5Hz),5.99(dd,1H,J₁＝3.5Hz,J₂＝10.5Hz),5.82(d,1H,J＝10.5Hz),4.99(d,2H,J＝13.5Hz),4.78(d,1H,J＝14Hz),4.73-4.45(m,1H),4.38(t,2H,J＝6.5Hz),3.96(d,1H,J＝14Hz),3.92-3.78(m,1H),3.75-3.57(m,1H),3.55-3.36(m,1H),3.25(dd,1H,J₁＝3Hz,J₂＝18.5Hz),3.15-2.96(m,2H),2.91(s,3H),2.86(t,2H,J＝6.5Hz),2.80-2.66(m,2H),2.62(q,4H,J＝7Hz),1.05(t,6H,J＝7Hz).

EXAMPLE 7 synthetic route to Compound 7

Synthesis of Compound 7-b

Compound 4-c (62mg, 0.10mmol) was dissolved in toluene (5mL), and 3-dimethylamino-1-propanol (21. mu.L, 0.18mmol), t-BuONa (20mg, 0.20mmol) were added sequentially with cooling in an ice-water bath. After the mixture was stirred under nitrogen in an ice-water bath for 0.5 hour, it was warmed to room temperature and stirred for 20 hours, and then slowly heated to 100 ℃ and stirred for about 2 hours. The reaction was cooled to room temperature, quenched with water (50mL) and extracted with ethyl acetate (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 7-b (38mg, 60% yield) as a white solid. LC-MS (ESI) M/z 635.4[ M +1 ]]⁺.

Synthesis of Compound 7-a

Compound 7-b (38mg, 0.06mmol) was dissolved in methanolic ammonia (7M, 20mL), cooled to-78 deg.C, and replaced with nitrogen 2 times, followed by addition of Pd/C (20 mg). Then, the reaction solution was heated to room temperature by 3-fold replacement with hydrogen, stirred under hydrogen for 1 hour, filtered and concentrated to obtain compound 7-a (35mg, 99% yield) as a white solid. LC-MS (ESI) 501.3[ M +1 ] ]⁺.

Synthesis of Compound 7

Compound 7-a (35mg, 0.07mmol) was dissolved in DCM (10mL), and DIPEA (58. mu.L, 0.35mmol) and acryloyl chloride (10mg, 0.11mmol) were added in that order. After stirring the mixture at room temperature under nitrogen for 20 h, it was quenched with saturated sodium bicarbonate solution (20mL) and extracted with DCM (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 7(15mg, 38% yield) as a white solid. LC-MS (ESI) M/z 555.3[ M +1 ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.87-7.59(m,3H),7.53-7.41(m,1H),7.41-7.30(m,2H),6.63-6.48(m,1H),6.38(d,1H,J＝15.6Hz),6.19-6.05(m,1H),6.04-5.94(m,1H),5.82(d,1H,J＝10.4Hz),5.59-5.51(m,1H),5.10-4.91(m,1H),4.89-4.62(m,2H),4.42-4.23(m,2H),4.03-3.84(m,2H),3.76-3.58(m,1H),3.56-3.39(m,1H),3.31-3.20(m,2H),3.19-3.00(m,5H),2.77-2.60(m,2H),2.42(s,6H),2.13-2.02(m,2H).

EXAMPLE 8 Synthesis of Compound 8

Synthesis of Compound 8-g

Compound 4-f (338mg, 1.0mmoL) was dissolved in DMF (10mL) at room temperature, and potassium carbonate (207mg, 1.5mmoL) and benzyl bromide (132. mu.L, 1.1mmoL) were added sequentially. After stirring at room temperature for 3 hours, the reaction mixture was poured into 50mL of water and extracted with ethyl acetate (50mL × 2). The organic phase was washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was isolated and purified by flash column (PE/EA ═ 2/1) to give compound (mixture) 8-g (211mg, 49% yield) as a white solid. LC-MS (ESI) M/z 429.2[ M +1 ] ]⁺.

Synthesis of Compound 8-f

Compound 8-g (211mg, 0.49mmol) was dissolved in ethyl acetate (20mL) and MCPBA (250mg, 1.23mmol) was added at room temperature. After the mixture was stirred at room temperature for 3 hours, it was quenched with saturated sodium bicarbonate solution (50mL) and extracted with ethyl acetate (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (EA/PE ═ 1/1) to give compound 8-f (138mg, 61% yield) as a white solid. LC-MS (ESI) M/z 461.0[ M +1 ]]⁺.

Synthesis of Compound 8-e

Compound 8-f (138mg, 0.3mmol) was dissolved in toluene (10mL) and N-methyl-L-prolinol (65. mu.L, 0.54mmol) and t-BuONa (58mg, 0.6mmol) were added sequentially under ice-water bath conditions. After stirring the mixture under nitrogen in an ice-water bath for 0.5 h, it was quenched with water (30mL) and extracted with ethyl acetate (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 8-e (105mg, 70% yield) as a white solid. LC-MS (ESI) M/z 496.3[ M +1 ]]⁺.

Synthesis of Compound 8-d

Compound 8-e (105mg, 0.212mmol) was dissolved in methanol (30mL), cooled to-78 deg.C, and replaced with nitrogen 2 times, followed by addition of Pd/C (50 mg). Then, the reaction solution was cooled to room temperature by 3-fold replacement with hydrogen, and after stirring for 3 hours under hydrogen, the reaction solution was filtered and concentrated to obtain compound 8-d (91mg, 100% yield) as a white solid. The crude product was used directly in the next reaction without further purification. LC-MS (ESI) 406.1[ M +1 ] ]⁺.

Synthesis of Compound 8-c

Compound 8-d (91mg, 0.225mmol) was dissolved in DCM (10mL) and DIPEA (111. mu.L, 0.68mmol), trifluoromethanesulfonic anhydride (57. mu.L, 0.34mmol) were added sequentially under nitrogen in an ice-water bath. After stirring the mixture in an ice-water bath for 1 hour, it was quenched with saturated sodium bicarbonate solution (20mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 8-c (68mg, 56% yield) as a white solid. LC-MS (ESI) M/z 538.2[ M +1 ]]⁺.

Synthesis of Compound 8-b

Compound 8-c (66mg, 0.123mmol) was dissolved in DMF (5mL) at room temperature and DIPEA (61. mu.L, 0.37mmol), 1-Cbz-piperazine hydrochloride (38mg, 0.15mmol) were added sequentially. The mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched with saturated brine (50mL), and extracted with ethyl acetate (50mL × 2). The organic phase was washed with saturated brine (50mL × 3), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 8-b (62mg, 83 yield) as a white solid. LC-MS (ESI) M/z 608.2[ M +1 ] ]⁺.

Synthesis of Compound 8-a

Compound 8-b (62mg, 0.102mmol) was dissolved in methanol (20mL), cooled to-78 deg.C, and purged with nitrogen 2 times, followed by addition of Pd/C (30 mg). Then, the reaction solution was replaced with hydrogen gas 3 times, warmed to room temperature, and stirred under hydrogen gas for 1 hour. The reaction mixture was filtered and concentrated to give compound 8-a (45mg, 94% yield) as a white solid. The crude product was used directly in the next reaction without further purification. LC-MS (ESI) M/z 474.3[ M +1 ]]⁺.

Synthesis of Compound 8

Compound 8-a (45mg, 0.095mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (79. mu.L, 0.48mmol) and acryloyl chloride (13mg, 0.143mmol) were added in that order. After stirring the mixture at room temperature under nitrogen for 20 h, it was quenched with saturated aqueous sodium bicarbonate (20mL) and extracted with DCM (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was passed through PREP-TLC (MeOH/DCM ═ 1/10) to give compound 8(28mg, 56% yield) as a white solid. LC-MS (ESI) M/z 528.3[ M +1 ]]⁺；¹H NMR(400MHz,CDCl₃)δ7.89-7.64(m,3H),7.53-7.40(m,1H),7.40-7.16(m,2H),6.65-6.45(m,1H),6.40-6.21(m,1H),6.02-5.89(m,1H),5.79-5.66(m,1H),4.88-4.76(m,1H),4.74-4.60(m,1H),4.45-4.26(m,1H),4.22-4.05(m,1H),3.93-3.17(m,10H),3.13-2.99(m,2H),2.93(s,3H),2.85-2.55(m,2H),2.47(s,3H),2.38-2.25(m,1H),2.10-1.95(m,1H).

EXAMPLE 9 synthetic route to Compound 9

Synthesis of Compound 9-b

Compound 4-c (61mg, 0.1mmol) was dissolved in dioxane (5mL) at room temperature, followed by the addition of N, N-dimethyl-N' -methylethylenediamine (255 μ L, 2 mmol). After the reaction mixture was stirred at 110 ℃ under nitrogen for 24 hours, the reaction was cooled to room temperature and concentrated to dryness to give the crude product. The crude product was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 9-b (49mg, 78% yield) as a white solid. LC-MS (ESI) M/z 634.4[ M +1 ] ]⁺.

Synthesis of Compound 9-a

Compound 9-b (69mg, 0.11mmol) was dissolved in methanolic ammonia (7M, 50mL), cooled to-78 deg.C, and replaced with nitrogen 2 times, followed by addition of Pd/C (50 mg). Then, the reaction solution was replaced with hydrogen gas 3 times, warmed to room temperature, and stirred under hydrogen gas for 1 hour. The reaction mixture was filtered and concentrated to give compound 9-a (50mg, 99% yield) as a white solid. LC-MS (ESI) M/z 500.5[ M +1 ]]⁺.

Synthesis of Compound 9

Compound 9-a (50mg, 0.1mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (83. mu.L, 0.5mmol) and acryloyl chloride (15mg, 0.15mmol) were added sequentially. After stirring the mixture at room temperature under nitrogen for 20 h, it was quenched with saturated sodium bicarbonate solution (20mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 9(27mg, 49% yield) as a white solid. LC-MS (ESI) M/z 554.4[ M +1 ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.87-7.69(m,3H),7.55-7.42(m,1H),7.40-7.29(m,2H),6.67-6.45(m,1H),6.37(d,1H,J＝16.8Hz),5.96(d,1H,J＝7.2Hz),5.80(d,1H,J＝10.4Hz),5.20-4.39(m,3H),3.89(d,1H,J＝13.2Hz),3.81-3.65(m,2H),3.65-3.50(m,1H),3.44-3.25(m,1H),3.20-3.03(m,4H),3.01-2.85(m,5H),2.78-2.61(m,1H),2.58-2.41(m,2H),2.31(s,6H),2.14-1.83(m,4H).

EXAMPLE 10 synthetic route to Compound 10

Synthesis of Compound 4-a

Compound 4-a (61mg) was prepared according to the synthetic route for Compound 4.

Synthesis of Compound 10

Compound 4-a (61mg, 0.12mmol) was dissolved in DCM (10mL) at room temperature and DIPEA (99. mu.L, 0.6mmol), 2-butenoyl chloride (17. mu.L, 0.18mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen for 20 hours, and then Saturated sodium bicarbonate solution (20mL) was quenched and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 10(55mg, 78% yield) as a white solid. LC-MS (ESI) M/z 581.3[ M +1 ]]⁺；¹H NMR(500MHz,CDCl₃):δ7.87-7.68(m,3H),7.54-7.41(m,1H),7.40-7.29(m,2H),7.05-6.90(m,1H),6.30-6.18(m,1H),6.04-5.88(m,1H),5.12-4.91(m,1H),4.89-4.57(m,2H),4.44-4.29(m,1H),4.22-4.10(m,1H),4.02-3.76(m,2H),3.75-3.54(m,1H),3.51-3.34(m,1H),3.31-3.15(m,2H),3.15-2.99(m,3H),2.99-2.82(m,4H),2.81-2.56(m,3H),2.47(s,3H),2.35-2.13(m,1H),2.12-1.97(m,1H),1.91(s,3H),1.85-1.82(m,2H).

EXAMPLE 11 synthetic route to Compounds 11-1 and 11-2

Synthesis of Compound 11-d

To a solution of 4-e (220mg, 0.47mmol) and (S) -4-N-tert-butoxycarbonyl-2-methylpiperazine (112mg, 0.56mmol) in DMF (10mL) at room temperature was added DIPEA (121mg, 0.94 mmol). The reaction temperature was raised to 100 ℃ and stirred at this temperature for 1 hour. The reaction was cooled to room temperature, water was added, extracted with ethyl acetate (30mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was purified by flash column separation (EA: PE ═ 0:100 to 30:70) to give compound 11-d (173mg, 71%) as a white solid. LC-MS (ESI) with M/z 521.3[ M + H ]]⁺.

Synthesis of Compound 11-c

85% m-chloroperoxybenzoic acid (169mg, 0.83mmol) was added to a solution of 11-d (173mg, 0.33mmol) in ethyl acetate (10mL) while cooling on ice. The reaction was slowly warmed to room temperature, stirred for 3 hours, added with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was isolated and purified by flash column separation (EA: PE ═ 0:100 to 50:50) to give compound 11-c (154mg, 84%) as a white solid. LC-MS (ESI) m/z ═ m/z 553.2[M+H]⁺.

Synthesis of Compound 11-b

To a solution of 11-c (154mg, 0.28mmol) in toluene (6mL) was added a solution of N-methyl-L-prolinol (48mg, 0.42mmol) in toluene (4mL) and sodium tert-butoxide (53mg, 0.56mmol), respectively, at room temperature. After the mixture was stirred at room temperature for 3 hours, it was concentrated, water was added, extracted with ethyl acetate (30mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, spun dried, and the crude product was purified by flash column separation (DCM: MeOH ═ 10:1) to give compound 11-b (120mg, 73%) as a white solid. LC-MS (ESI) M/z 588.3[ M + H ]]⁺.

Synthesis of Compound 11-a

To a solution of 11-b (120mg, 0.2mmol) in dichloromethane (8mL) was added TFA (2mL) at room temperature. After the mixture was stirred at room temperature overnight, it was concentrated, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate (30mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried to give compound 11-a (70mg, 70%) as a white solid. LC-MS (ESI) M/z 488.0[ M + H ]]⁺.

Synthesis of Compounds 11-1 and 11-2

To a solution of 11-a (70mg, 0.14mmol) in dichloromethane (5mL) was added acryloyl chloride (19mg, 0.22mmol) and DIPEA (36mg, 0.28mmol), respectively, while cooling on ice. The reaction temperature was raised to room temperature and after stirring at room temperature for 2 h, concentrated, water was added, extracted with ethyl acetate (30mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, spun dry and the crude product was chirally resolved to give compound 11-1(25mg, 32%) and 11-2(20mg, 26%) as a white solid.

11-1:LC-MS(ESI):m/z＝542.3[M+H]⁺；¹H NMR(500MHz,CDCl₃):δ7.85(t,J＝8Hz,2H),7.78(dd,J＝8,2Hz,1H),7.50(t,J＝7.5Hz,1H),7.40–7.35(m,2H),6.66–6.53(m,1H),6.39(dd,J＝17,2Hz,1H),6.00(dd,J＝10,3.5Hz,1H),5.78(d,J＝9Hz,1H),4.85–4.80(m,1H),4.77–4.70(m,1H),4.43–4.16(m,3H),4.07–3.96(m,1H),3.77–3.57(m,1H),3.49–3.43(m,1H),3.32–3.24(m,2H),3.14–3.03(m,2H),2.96(s,3H),2.73–2.66(m,1H),2.49(s,3H),2.34–2.24(m,1H),2.11–2.02(m,1H),1.88–1.73(m,3H),1.37–1.31(m,1H),1.24–1.14(m,4H).

11-2:LC-MS(ESI):m/z＝542.3[M+H]⁺；¹H NMR(500MHz,CDCl₃):δ7.83(dd,J＝17,8Hz,2H),7.78(dd,J＝7,2Hz,1H),7.49(t,J＝7.5Hz,1H),7.40–7.35(m,2H),6.66–6.53(m,1H),6.39(dd,J＝17,1.5Hz,1H),6.00(d,J＝7.5Hz,1H),5.77(d,J＝9.5Hz,1H),4.88(d,J＝14Hz,1H),4.68(d,J＝13.5Hz,1H),4.45–4.34(m,1H),4.20–4.09(m,1H),4.00–3.88(m,1H),3.80–3.69(m,1H),3.62–3.44(m,1H),3.34–3.25(m,2H),3.14–3.03(m,3H),2.96(s,3H),2.73–2.65(m,1H),2.49(s,3H),2.34–2.24(m,1H),2.12–2.02(m,1H),1.88–1.72(m,3H),1.36–1.28(m,5H).

EXAMPLE 12 synthetic route to Compound 12

Synthesis of Compound 12-j

The compound 1-bromo-8-chloronaphthalene (500mg, 2.07mmol) was dissolved in THF (20mL), cooled to-78 deg.C, and n-BuLi (2.5M, 1.66mL, 4.14mmol) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at-78 ℃ for 10 minutes, and then DMF (800. mu.L, 10.35mmol) was added dropwise at-78 ℃. After the addition was completed, the reaction mixture was stirred at-78 ℃ for 30 minutes, warmed to room temperature and stirred for 2 hours, quenched with 50mL of a saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL. times.2). The organic phase was washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated,Filtering and concentrating to obtain a crude product. The crude product was isolated and purified by flash column separation (EA/PE ═ 1/10) to give compound 12-j (330mg, 84% yield) as a white solid. LC-MS (ESI) 191.0[ M + H ]]⁺；¹H NMR(400MHz,CDCL₃):δ11.31(s,1H),8.03(dd,1H,J₁＝1.2Hz,J₂＝8.4Hz),7.92(dd,1H,J₁＝1.2Hz,J₂＝7.2Hz),7.86(1H,J＝8.4Hz),7.70(dd,1H,J₁＝1.2Hz,J₂＝7.6Hz),7.59(t,1H,J＝7.6Hz),7.47(t,1H,J＝8Hz).

Synthesis of Compound 12-i

NaH (60%, 242mg, 6.05mmol) was added to 6mL of THF at room temperature. Methyl acetoacetate (543. mu.L, 5.04mmol) was then added under nitrogen at room temperature, and after the mixture was stirred for 30 minutes under nitrogen at room temperature, n-BuLi (2.5M, 2.4mL, 6.05mmol) was added dropwise at-15 ℃ to-10 ℃. After the addition was complete, the mixture was held at this temperature for 30 minutes, and then a solution of compound 12-j (320mg, 1.68mmol) in THF (10mL) was added dropwise. After the addition was completed, the mixture was stirred at low temperature (-10 ℃ C. to 0 ℃ C.) for 2 hours, and then the reaction was quenched with a saturated ammonium chloride solution (50mL), followed by extraction with ethyl acetate (50 mL. times.2). The organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (EA/DCM ═ 1/10) to give compound 12-i (510mg, 99% yield) as a white solid. LC-MS (ESI) M/z 329.1[ M + Na ] ]⁺；¹H NMR(400MHz,CDCl₃):δ8.06(d,1H,J＝6.4Hz),7.79(d,2H,J＝8Hz),7.58(dd,1H,J₁＝7.6Hz,J₂＝1.6Hz),7.53(t,1H,J＝7.6Hz),7.34(t,1H,J＝7.6Hz),6.91(dd,1H,J₁＝9.2Hz,J₂＝2.4Hz),3.74(s,3H),3.54(s,2H),3.36(dd,1H,J₁＝18Hz,J₂＝1.6Hz),3.24(d,1H,J＝3.6Hz),2.85-2.75(m,1H).

Synthesis of Compound 12-h

Compound 12-i (510mg, 1.66mmol) was dissolved in DCM (18mL) at room temperature, then DMF-DMA (245. mu.L, 1.83mmol) was added under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 45 minutes, and BF was added thereto₃.Et₂O(232μL，183 mmol). After the addition was completed, the mixture was stirred at room temperature for 1 hour, and then diluted with 100mL of ethyl acetate. The organic phase is successively treated with saturated NaHCO₃The solution (100mL), saturated brine (100mL × 2) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound 12-h (520 mg). The crude product was used in the next reaction without purification. LC-MS (ESI) M/z 317.1[ M +1 ]]⁺.

Synthesis of Compound 12-g

Compound 12-h (520mg, 1.64mmol) was dissolved in THF (20mL) at room temperature, then lithium tri-sec-butylborohydride (1M, 1.64mL, 1.64mmol) was added dropwise under nitrogen at-78 ℃. After addition was complete, the mixture was stirred at-78 ℃ for 1 hour, quenched with saturated ammonium chloride solution (50mL), extracted with ethyl acetate (50mL × 2), the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by flash column separation (PE/EA ═ 4/1) to give compound 12-g (338mg, 65% yield) as a yellow oil. LC-MS (ESI) M/z 319.0[ M +1 ] ]⁺.

Synthesis of Compound 12-f

Compound 12-g (338mg, 1.06mmol) was dissolved in methanol (20mL) at room temperature, followed by the addition of sodium methoxide (286mg, 5.3mmol), compound 2-methyl-2-mercaptourea sulfate (265mg, 0.954mmol) sequentially under nitrogen at 0 ℃. After the addition was complete, the mixture was warmed to room temperature and stirred for 20 hours. The reaction solution was adjusted to pH 5 with 1N dilute hydrochloric acid, the solid precipitated, filtered, the filter cake washed with water (5 mL. times.2), the solid collected and dried in vacuo to give crude 12-f (313mg) as a white solid. LC-MS (ESI) 359.1[ M +1 ]]⁺.

Synthesis of Compound 12-e

Compound 12-f (313mg, 0.87mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (431. mu.L, 2.61mmol), triflic anhydride (219. mu.L, 1.31mmol) were added sequentially under nitrogen in an ice-water bath. After the addition was complete, the reaction mixture was stirred for 2 hours in an ice-water bath, quenched with saturated sodium bicarbonate solution (50mL), extracted with DCM (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was quickly separatedColumn separation and purification (EA/PE ═ 1/10) gave compound 12-e (83mg, 2 steps, 16% yield) as a white solid. LC-MS (ESI) M/z 491.0[ M +1 ] ]⁺.

Synthesis of Compound 12-d

Compound 12-e (83mg, 0.169mmol) was dissolved in DMF (10mL) at room temperature, followed by the addition of DIPEA (84. mu.L, 0.507mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (59.9mg, 0.203mmol) in that order. After the addition was completed, the mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched with saturated brine (50mL), and extracted with ethyl acetate (50mL × 2). The organic phase was washed with saturated brine (50mL × 3), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column separation (EA/PE ═ 1/1) to give compound 12-d (101mg, 99% yield) as a white solid. LC-MS (ESI) 600.2[ M +1 ]]⁺.

Synthesis of Compound 12-c

Compound 12-d (101mg, 0.168mmol) was dissolved in ethyl acetate (10mL) at room temperature, and MCPBA (85%, 88.4mg, 0.437mmol) was added at room temperature. After addition was complete, the mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (25mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (EA/PE ═ 1/4) to give compound 12-c (88mg, 82% yield) as a white solid. LC-MS (ESI) M/z 632.1[ M +1 ] ]⁺.

Synthesis of Compound 12-b

Compound 12-c (88mg, 0.139mmol) was dissolved in toluene (10mL) at room temperature, the reaction was cooled to 0 deg.C, and N-methyl prolinol (29. mu.L, 0.243mmol), t-BuONa (27mg, 0.278mmol) were added. After the addition was complete, the reaction mixture was stirred under nitrogen in an ice-water bath for 0.5 h, quenched with water (20mL) and extracted with ethyl acetate (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 12-b (78mg, 84% yield) as a white solid. LC-MS (ESI) M/z 667.3[ M +1 ]]⁺；

Synthesis of Compound 12-a

Compound 12-b (72mg, 0.108mmol) was dissolved in methanol (50mL) at room temperature, the reaction was cooled to-78 deg.C and purged with nitrogen 2 times, then Pd/C (150mg), ZnBr was added₂(24.3mg, 0.108mmol), hydrogen substitution 3 times, the reaction solution warmed to room temperature, and stirred under hydrogen for 5 hours. The reaction was filtered and concentrated to give the crude product which was purified by flash column separation (MeOH/DCM ═ 1:4) to give compound 12-a (20mg, 35% yield) as a white solid. LC-MS (ESI) 533.0[ M +1 ]]⁺.

Synthesis of Compound 12

Compound 2-fluoroacrylic acid (5.1mg, 0.0563mmol) was dissolved in DMF (2mL) at room temperature, followed by the addition of HATU (25.6mg, 0.0675mmol), DIPEA (18.6. mu.L, 0.113mmol) in that order at 0 ℃ and after completion of the addition, the reaction mixture was stirred at 0 ℃ under nitrogen for 20 minutes, then a solution of compound 12-a (20mg, 0.0375mmol) in DMF (3mL) was added to the reaction mixture, allowed to warm to room temperature and stirred for an additional 5 hours. Quench with brine (20mL), extract with ethyl acetate (25mL × 2), wash the organic phase with brine (50mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate to give the crude product, which is purified by PREP-TLC separation (MeOH/DCM ═ 1/10) to give compound 12(6mg, 26% yield) as a white solid. LC-MS (ESI) with M/z 605.2[ M +1 ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.99-7.93(m,1H),7.83(t,2H,J＝8.8Hz),7.62-7.49(m,2H),7.36(t,1H,J＝7.6Hz),6.55-6.44(m,1H),5.51-5.31(m,1H),5.25(d,1H,J＝16.8Hz),5.02-4.93(m,1H),4.82(dd,1H,J₁＝2.4Hz,J₂＝13.6Hz),4.48-4.38(m,1H),4.32-4.19(m,1H),4.17-4.04(m,1H),4.00(d,1H,J＝14Hz),3.87-3.70(m,1H),3.66-3.36(m,2H),3.31-3.16(m,2H),3.14-2.98(m,1H),2.96-2.69(m,4H),2.59(d,3H,J＝18Hz),2.52-2.34(m,1H),2.15-2.06(m,1H),1.87-1.74(m,2H),0.93-0.76(m,2H).

Synthesis of Compounds 12-1 and 12-2

Compound 12(260mg, 0.43mmol) was prepared by chiral resolution. Compound 12-1(76mg, 29% yield) was obtained as a white solid; compound 12-2(67mg, 26% yield) was obtained as a white solid.

12-1：LC-MS(ESI):m/z＝605.3[M+1]⁺；¹HNMR(400MHz,CDCl₃)δ7.96(d,1H,J＝7.2Hz),7.83(t,2H,J＝8.4Hz),7.65-7.50(m,2H),7.36(t,1H,J＝8.0Hz),6.47(dd,1H,J₁＝10.8Hz,J₂＝3.2Hz),5.42(d,1H,J＝49.2Hz),5.26(dd,1H,J₁＝3.6Hz,J₂＝16.8Hz),5.05-4.76(m,1H),4.97(d,1H,J＝13.6Hz),4.84(d,1H,J＝13.6Hz),4.36(dd,1H,J₁＝4.8Hz,J₂＝10.4Hz),4.17(dd,1H,J₁＝6.8Hz,J₂＝10.8Hz),4.06-3.87(m,1H),3.77(d,1H,J＝10Hz),3.59(dd,1H,J₁＝2.4Hz,J₂＝17.6Hz),3.50-3.15(m,3H),3.14-2.99(m,2H),2.96-2.82(m,2H),2.72-2.59(m,1H),2.47(s,3H),2.32-2.21(m,1H),2.10-1.98(m,1H),1.89-1.67(m,4H).

12-2：LC-MS(ESI):m/z＝605.2[M+1]⁺；¹HNMR(400MHz,CDCl₃)δ7.97(d,1H,J＝7.2Hz),7.83(t,2H,J＝9.2Hz),7.63-7.51(m,2H),7.36(t,1H,J＝7.6Hz),6.52(dd,1H,J₁＝3.2Hz,J₂＝10.8Hz),5.42(d,1H,J＝47.2Hz),5.25(dd,1H,J₁＝3.6Hz,J₂＝16.4Hz),4.99(d,1H,J＝14.0Hz),4.82(d,1H,J＝13.6Hz),5.05-4.72(m,1H),4.38(dd,1H,J₁＝4.8Hz,J₂＝10.4Hz),4.15(dd,1H,J₁＝6.8Hz,J₂＝10.8Hz),3.98(d,1H,J＝14Hz),3.87-3.73(m,1H),3.60(dd,1H,J₁＝2.4Hz,J₂＝18.4Hz),3.66-3.54(m,1H),3.54-3.41(m,1H),3.16-2.98(m,2H),2.95-2.71(m,3H),2.71-2.61(m,1H),2.46(s,3H),2.33-2.19(m,1H),2.10-1.98(m,1H),1.90-1.66(m,4H).

EXAMPLE 13 synthetic route to Compound 13

Synthesis of Compound 13

To a solution of 4-a (240mg, 0.47mmol) in DMF (5mL) was added HATU (356mg, 0.94mmol), N, N-diisopropylethylamine (0.23mL, 1.40mmol) and 2-fluoroacrylic acid (63.2mg, 0.70mmol), respectively, at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, water was added to precipitate a solid, which was filtered, the filter cake washed with water and dried to give the crude product, which was purified by silica gel column chromatography (DCM/MeOH 10/1) to give product 13(220mg, 80%) as a foamy white solid. LC-MS (ESI) M/z 585.0[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.78-7.83(m,2H),7.71-7.77(m,1H),7.45-7.50(m,1H),7.33-7.38(m,2H),6.00-6.07(m,1H),5.19-5.25(m,1H),4.89-4.97(m,1H),4.66-4.72(m,2H),4.54-4.60(m,2H),3.98-4.08(m,1H),3.90-3.98(m,1H),3.75-3.89(m,1H),3.58-3.75(m,2H),3.44-3.58(m,1H),3.04(d,3H,J＝4.4Hz),2.96-3.37(m,6H),2.93(s,3H),2.65-2.86(m,2H),2.26-2.42(m,2H),2.07-2.24(m,2H)。

Synthesis of Compounds 13-1 and 13-2

Purification of compound 13(200mg, 0.34mmol) by manual resolution gave compound 13-1(70mg, 35%) as a white solid and compound 13-2(71mg, 36%) as a white solid.

13-1：LC-MS(ESI):m/z＝585.0[M+1]⁺；¹H NMR(400MHz,CDCl₃):δ7.83(d,1H,J＝8.4Hz),7.74-7.77(m,2H),7.46(t,1H,J＝8.0Hz),7.34-7.39(m,2H),6.00(dd,1H,J＝9.6,4.0Hz),5.41(d,1H,J＝46.8Hz),5.25(dd,1H,J＝16.8,3.6Hz),4.84(d,1H,J＝14.0Hz),4.69(d,1H,J＝14.0Hz),4.51-5.08(m,1H),4.38(dd,1H,J＝10.4,5.2Hz),4.19(dd,1H,J＝10.4,6.4Hz),3.81-4.15(m,2H),3.69(d,1H,J＝11.2Hz),2.97-3.31(m,6H),2.94(s,3H),2.77-2.89(m,1H),2.64-2.74(m,1H),2.49(s,3H),2.25-2.34(m,1H),2.01-2.11(m,1H),1.68-1.89(m,4H).

13-2：LC-MS(ESI):m/z＝585.0[M+1]⁺；¹H NMR(400MHz,CDCl₃):δ7.82-7.84(m,2H),7.75(dd,1H,J＝7.2,2.0Hz),7.50(t,1H,J＝7.6Hz),7.33-7.38(m,2H),6.00(dd,1H,J＝10.4,3.2Hz),5.48(d,1H,J＝47.2Hz),5.25(dd,1H,J＝16.8,3.6Hz),4.97(d,1H,J＝13.6Hz),4.76(d,1H,J＝13.6Hz),4.52-5.05(m,1H),4.41(dd,1H,J＝10.8,4.8Hz),4.21(dd,1H,J＝10.8,6.0Hz),3.98(d,1H,J＝14.8Hz),3.91(d,1H,J＝12.8Hz),3.37-3.78(m,2H),2.97-3.31(m,4H),2.91(s,3H),2.69-2.84(m,3H),2.54(s,3H),2.33-2.40(m,1H),2.03-2.14(m,1H),1.76-1.93(m,4H).

EXAMPLE 14 synthetic route to Compound 14

Synthesis of Compound 14-b

Compound 4-c (100mg, 0.164mmol) was dissolved in toluene (10mL), N-dimethylisopropanolamine (33.7mg, 0.327mmol) and sodium tert-butoxide (31.4mg, 0.327mmol) were added under ice bath, stirred at this temperature under nitrogen for 30 minutes, with tlc monitoring that the reaction was not complete, supplemented with N, N-dimethylisopropanolamine (33.7mg, 0.327mmol) and sodium tert-butoxide (31.4mg, 0.327mmol), stirred for 30 minutes, with tlc monitoring that the reaction was complete, concentrated, and passed through a column (biotage,12g, sillica gel, UV254, MeOH: DCM ═ 0-8%) to give 14-b (82mg, 79%) as a white solid. LC-MS (ESI) M/z 635.3[ M + H ]]⁺.

Synthesis of Compound 14-a

14-b (82mg, 0.129mmol) was dissolved in methanol (10mL) and ethyl acetate (10mL), 10% palladium on carbon (80mg) was added, hydrogen was substituted three times, the mixture was stirred at room temperature for 2 hours, TLC monitored for completion of the reaction, and the reaction mixture was filteredConcentration gave 14-a (53mg, 82%) as a white solid. LC-MS (ESI) 501.3[ M + H ]]⁺.

Synthesis of Compound 14

14-a (53mg, 0.106mmol) was dissolved in dichloromethane (20mL), acryloyl chloride (14.3mg, 0.159mmol) and DIPEA (41mg, 0.318mmol) were added sequentially, stirred under nitrogen at room temperature for 1 hour, LCMS monitored for reaction completion, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30mL X3), dried, concentrated, and passed through a column (biotage,25g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 14(44mg, 75%) as a white solid. LC-MS (ESI) M/z 555.3[ M + H ]]⁺；¹H NMR(400MHz,CDCL₃):δ7.74-7.84(m,3H),7.44-7.52(m,1H),7.32-7.39(m,2H),6.51-6.63(m,1H),6.35-6.42(m,1H),5.96-6.02(m,1H),5.79-5.85(m,1H),5.41-5.52(m,1H),4.94-5.03(m,1H),4.68-4.90(m,1H),3.84-4.02(m,1H),3.48-3.75(m,1H),3.19-3.30(m,1H),2.97-3.17(m,2H),2.93(d,3H,J＝12.4Hz),2.68-2.87(m,2H),2.56-2.65(m,1H),2.42(s,6H),1.96-2.33(m,5H),1.33-1.38(m,3H).

EXAMPLE 15 synthetic route to Compound 15

Synthesis of Compound 15-b

4-c (100mg, 0.164mmol) was dissolved in toluene (10mL), S-4, 4-difluoro-1-methylpyrrolidine-2-methanol (49.4mg, 0.327mmol) and sodium tert-butoxide (31.4mg, 0.327mmol) were added under ice bath, stirred at this temperature under nitrogen for 30 minutes, LCMS monitored for reaction completion, quenched with water, extracted with ethyl acetate (50mL X2), dried, concentrated, and passed through a column (biotage,40g, Sillica gel, UV254, EA: PE ═ 0-100%) to give 15-b (97mg, 87%) as a colorless gum. LC-MS (ESI) M/z 683.3[ M + H ]]⁺.

Synthesis of Compound 15-a

15-b (97mg, 0.142mmol) was dissolved in ethyl acetate (10mL) and methanol (10mL), 10% palladium on carbon (97mg) was added, replaced three times with hydrogen, stirred at room temperature for 2 hours, TLC monitored completion of the reaction, filtered through celite, and spin dried to give 15-a (70mg, 90%) as a solid, was used directly in the next reaction. LC-MS (ESI) M/z 549.0[ M + H ]]⁺.

Synthesis of Compound 15

15-a (70mg, 0.128mmol) was dissolved in dichloromethane (15mL), acryloyl chloride (17.2mg, 0.192mmol) and DIPEA (82.4mg, 0.639mmol) were added sequentially, stirred at room temperature under nitrogen for 1 hour, LCMS monitored for reaction completion, quenched with saturated sodium bicarbonate solution, dichloromethane extracted (30mL X3), dried, concentrated, and passed through a column (biotage,12g, sillica gel, UV254, EA: PE ═ 0-100%) to afford 15(51mg, 66%) as a white solid. LC-MS (ESI) M/z 603.3[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.73-7.86(m,3H),7.44-7.52(m,1H),7.32-7.40(m,2H),6.51-6.62(m,1H),6.36-6.43(m,1H),5.96-6.03(m,1H),5.83(d,1H),4.92-5.07(m,1H),4.67-4.89(m,2H),4.41-4.48(m,1H),4.22-4.32(m,1H),3.85-4.03(m,2H),3.64-3.75(m,1H),3.36-3.57(m,2H),2.89-3.18(m,8H),2.61-2.85(m,3H),2.43-2.59(m,4H),2.18-2.39(m,1H).

EXAMPLE 16 synthetic route to Compound 16

Synthesis of Compound 16-b

4-c (100mg, 0.164mmol) was dissolved in toluene (10mL), N-methyl-D-prolinol (37.6mg, 0.327mmol) and sodium tert-butoxide (31.4mg, 0.327mmol) were added under ice bath, stirred at this temperature under nitrogen for 30 min, TLC monitored for completion, quenched with water, extracted with ethyl acetate (50mL X2), dried, concentrated, and passed through a column (ISCO,12g, sillica gel, UV254, MeOH: DCM ═ 0-7%) to give 16-b (92mg, 87%) as a white solid. LC-MS (ESI) M/z 647.3[ M + H ]]⁺.

Synthesis of Compound 16-a

16-b (92mg, 0.142mmol) was dissolved in ethyl acetate (10mL) and methanol (10mL), 10% palladium on carbon (90mg) was added, displaced three times with hydrogen, stirred at room temperature for 2 hours, LCMS monitored for reaction completion, filtered through celite, and spun dry to give 16-a (62mg, 85%) as a white solid, which was used directly in the next reaction. LC-MS(ESI):m/z＝513.3[M+H]⁺.

Synthesis of Compound 16

16-a (62mg, 0.121mmol) was dissolved in dichloromethane (20mL), acryloyl chloride (16.3mg, 0.182mmol) and DIPEA (46.9mg, 0.363mmol) were added sequentially, stirred at room temperature under nitrogen for 1 hour, LCMS monitored for reaction completion, quenched with saturated sodium bicarbonate solution, dichloromethane extracted (40mL X4), dried, concentrated, and passed through a column (biotage,25g, sillica gel, UV254, MeOH: DCM ═ 0-15%) to give 16(60mg, 87%) as a light brown solid. LC-MS (ESI) with M/z 567.3[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.84(m,3H),7.44-7.52(m,1H),7.32-7.39(m,2H),6.51-6.53(m,1H),6.24-6.41(m,1H),5.97-6.16(m,1H),5.68-5.84(m,1H),4.95-5.12(m,1H),4.68-4.88(m,3H),4.30-4.39(m,1H),3.36-3.75(m,3H),3.01-3.31(m,5H),2.93(d,3H,J＝15.6Hz),2.61-2.83(m,4H),2.51-2.61(m,1H),1.84-2.31(m,7H).

EXAMPLE 17 Synthesis of Compound 17

Add DIPEA (0.05mL, 0.3mmol) and (2E) -4- (dimethylamino) -2-butenoic acid (18.9mg, 0.015mmol), respectively, to a solution of 4-a (50mg, 0.1mmol) and HATU (74.2mg, 0.2mmol) in DMF (5 mL). The reaction solution was heated to 60 ℃ and stirred overnight. After the reaction, water was slowly added to precipitate a solid, which was collected by filtration and washed with water. After air drying, the crude product was obtained and purified by silica gel column chromatography (DCM/MeOH 4/1) to give product 17(17mg, 28%) as a light brown solid. LC-MS (ESI) M/z 624.3[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.84(m,3H),7.46-7.52(m,1H),7.34-7.37(m,2H),6.89-7.00(m,1H),6.38-6.63(m,1H),5.96-6.00(m,1H),4.89-5.12(m,1H),4.48-4.89(m,3H),4.21-4.35(m,1H),3.86-4.08(m,1H),3.56-3.78(m,1H),3.30-3.55(m,2H),2.85-3.29(m,8H),2.92(d,3H,J＝9.6Hz),2.66(d,3H,J＝8.8Hz),2.41-2.57(m,1H),2.32(s,6H),2.04-2.22(m,2H),1.76-2.03(m,4H).

EXAMPLE 18 Synthesis of Compound 18

Synthesis of Compound 18

Compound 2-a (0.3g, 0.58mmol) was dissolved in DMF (10mL) at room temperature, and DIPEA (0.15g, 1.16mmol), 2-fluoroacrylic acid (0.105g, 1.16mmol), and HATU (0.44g, 1.16mmol) were added in that order. After the mixture was stirred at room temperature under nitrogen for 20 hours, water (100mL) was added to precipitate a solid, which was filtered and dried under vacuum to give compound 18(300mg, 88%) as a white solid. LC-MS (ESI) M/z 589.2[ M +1 ] ]⁺；¹H NMR(500MHz,CD₃OD):δ7.82-7-87(m,1H),7.66-7.78(m,2H),7.54(t,1H,J＝9.5Hz),5.33-5.41(m,1H),5.27-5.32(m,1H),5.18-5.23(m,1H),5.03(d,1H,J＝20.0Hz),4.92-4.98(m,1H),4.75-4.88(m,2H),4.52(t,1H,J＝8.5Hz),4.20(d,1H,J＝9.5Hz),3.80-4.05(m,2H),3.60-3.77(m,1H),3.35-3.59(m,2H),3.05-3.32(m,3H),3.07(d,3H,J＝9.0Hz),2.83-3.03(m,3H),2.30-2.43(m,1H),2.15-2.26(m,1H),1.98-2.15(m,2H),1.28-1.41(m,1H).

Synthesis of Compounds 18-1 and 18-2

Compound 18(280mg, 0.48mmol) was purified by manual resolution to give compound 18-1(96mg, 34%), compound 18-2(68mg, 24%).

18-1：LC-MS(ESI):m/z＝589.2[M+1]⁺；¹H NMR(500MHz,CD₃OD):δ7.84(d,1H,J＝10.0Hz),7.68-7.78(m,2H),7.54(t,1H,J＝10.0Hz),5.34(d,1H,J＝55.5Hz),5.33(dd,1H,J₁＝4.5Hz,J₂＝21.0Hz),5.20(dd,1H,J₁＝4.5Hz,J₂＝13.5Hz),5.03(d,1H,J＝17.5Hz),4.85(d,1H,J＝17.0Hz),4.73(dd,1H,J₁＝4.5Hz,J₂＝16.0Hz),4.51(dd,1H,J₁＝8.5Hz,J₂＝15.5Hz),4.47(d,1H,J＝15.0Hz),3.91(d,1H,J＝12.5Hz),3.70-3.86(m,1H),3.60-3.70(m,1H),3.30-3.42(m,2H),3.10-3.28(m,3H),3.01(s,3H),2.96-3.07(m,1H),2.80-2.94(m,1H),2.30-2.43(m,1H),1.97-2.21(m,3H).

18-2：LC-MS(ESI):m/z＝589.2[M+1]⁺；¹H NMR(500MHz,CDCl₃):δ7.75(d,1H,J＝10.0Hz),7.60-7.70(m,2H),7.45(t,1H,J＝9.5Hz),5.42(d,1H,J＝59.5Hz),5.25(dd,1H,J₁＝4.0Hz,J₂＝21.0Hz),5.17(dd,1H,J₁＝4.0Hz,J₂＝14.0Hz),4.88(d,1H,J＝17.0Hz),4.77(d,1H,J＝16.5Hz),4.39(dd,1H,J₁＝6.5Hz,J₂＝13.0Hz),4.16(dd,1H,J₁＝9.0Hz,J₂＝13.0Hz),3.96(d,1H,J＝17.5Hz),3.74(d,1H,J＝16.5Hz),3.48(d,1H,J＝14.0Hz),2.97-3.13(m,3H),2.60-2.96(m,4H),2.49(s,3H),2.26-2.34(m,1H),1.97-2.10(m,1H),1.60-1.88(m,6H).

EXAMPLE 19 Synthesis of Compound 19-1, 19-2

Synthesis of Compound 19-c

2-d (500mg, 0.858mmol) was dissolved in ethyl acetate (25mL), MCPBA (434mg, 2.145mmol) was added, stirred at room temperature for 2 hours, LCMS monitored reaction complete, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL X3), dried, and concentrated to give 19-c (527mg, 100%) as a pale yellow solid which was used in the next reaction without purification. LC-MS (ESI) M/z 616.2[ M + H ]]⁺.

Synthesis of Compound 19-b

19-c (527mg, 0.857mmol) was dissolved in toluene (25mL), N-methyl-D-prolinol (197mg, 1.71mmol) and sodium tert-butoxide (165mg, 1.72mmol) were added under ice bath, stirred at this temperature for 30 minutes under nitrogen, TLC monitored for reaction completion, quenched with water, extracted with ethyl acetate (50mL X2), dried, concentrated, and passed through a column (biotage,40g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 19-b (452mg, 81%) as whiteAnd (3) a solid. LC-MS (ESI) M/z 651.2[ M + H ]]⁺.

Synthesis of Compound 19-a

19-b (452mg, 0.695mmol) was dissolved in 7N ammonia methanol solution (50mL), dried ice in acetone bath, 10% palladium on carbon (250mg) was added, replaced three times with hydrogen, stirred at room temperature for 1 hour, TLC monitored for reaction completion, filtered through celite, and spun to give 19-a (359mg, 100%) as a white solid, which was used directly in the next reaction. LC-MS (ESI) M/z 517.2[ M + H [ ] ]⁺.

Synthesis of Compound 19

19-a (359mg, 0.696mmol) was dissolved in DMF (15mL), 2-fluoroacrylic acid (125mg, 1.39mmol), HATU (529mg, 1.39mmol) and DIPEA (449mg, 3.48mmol) were added sequentially, stirred under nitrogen at room temperature for 1.5 hours, LCMS monitored for reaction completion, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (40mL X3), the organic phase washed with saturated brine (50mL X3), dried, concentrated, and column-packed (biotage,40g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 19(346mg, 85%) as a light brown solid. LC-MS (ESI) M/z 589.0[ M + H ]]⁺.

Synthesis of Compounds 19-1 and 19-2

19(346mg, 0.588mmol) was resolved by chiral preparation and separately spun dry and lyophilized to give 19-1(136mg, 39%) and 19-2(98mg, 28%) as white solids.

19-1：LC-MS(ESI):m/z＝589.0[M+H]⁺；¹H NMR(400MHz,CDCl₃):δ7.74(d,1H,J＝8.0Hz),7.67(d,1H,J＝8.0Hz),7.63(t,1H,J＝7.6Hz),7.44(t,1H,J＝7.6Hz),5.38(d,1H,J＝48.0Hz),5.24(dd,1H,J＝3.6,16.8Hz),5.19(dd,1H,J＝4.0,11.2Hz),4.89(d,1H,J＝13.6Hz),4.72(d,1H,J＝13.6Hz),4.51-4.65(m,3H),3.74-3.82(m,1H),3.65-3.72(m,1H),3.56-3.64(m,1H),3.26-3.43(m,2H),2.99-3.17(m,5H),2.83-2.95(m,2H),2.68-2.79(m,2H),2.08-2.37(m,4H).

19-2：LC-MS(ESI):m/z＝589.0[M+H]⁺；¹H NMR(400MHz,CDCl₃):δ7.76(d,1H,J＝7.6Hz),7.67(d,1H,J＝8.0Hz),7.63(t,1H,J＝7.6Hz),7.44(t,1H,J＝8.0Hz),5.41(d,1H,J＝47.6Hz),5.25(dd,1H,J＝3.6,16.8Hz),5.17(dd,1H,J＝3.2,11.2Hz),4.88(d,1H,J＝14.0Hz),4.77(d,1H,J＝13.6Hz),4.41(dd,1H,J＝5.2,10.8Hz),4.18(dd,1H,J＝6.4,10.4Hz),3.98(d,1H,J＝14.4Hz),3.70-3.78(m,1H),3.44-3.54(m,1H),2.99-3.17(m,3H),2.67-2.97(m,4H),2.50(s,3H),2.25-2.37(m,1H),2.02-2.12(m,1H),1.68-1.89(m,5H).

EXAMPLE 20 synthetic route to Compound 20

Synthesis of Compound 20-e

Compound 4-f (1.7g, 5.0mmol) was dissolved in DMF (20mL) and DCM (10mL), thionyl chloride (2.5mL, 34.4mmol) was added dropwise under nitrogen at 0 deg.C, and the mixture was stirred at 0 deg.C for 3 hours. The reaction was quenched by addition of ice water (80mL, 120mmol), extracted with dichloromethane (80mL x 2) and concentrated. The crude product was isolated and purified by flash column separation (petroleum ether/ethyl acetate 25/1) to give compound 20-e (1.1g, 62%) as a pale yellow solid. LC-MS (ESI) 357.1[ M +1 ] ]⁺.

Synthesis of Compound 20-d

Compound 20-e (0.25g, 0.70mmol) was dissolved in DMF (20mL) at room temperature, followed by the addition of DIPEA (0.135g, 1.05mmol), 2-tert-butoxycarbonyl-2, 7-diazaspiro [3.5 ]]Nonane (0.24g, 1.05 mmol). After the mixture was stirred at 100 ℃ for 2 hours, it was quenched by the addition of water (100mL), the solid precipitated, filtered and dried to give compound 20-d (0.29g, 76%) as a gray solid. LC-MS (ESI) M/z 547.3[ M +1 ]]⁺.

Synthesis of Compound 20-c

Compound 20-d (0.29g, 0.53mmol) was dissolved in ethyl acetate (20mL) and MCPBA (0) was added at room temperature28g, 1.36 mmol). After the mixture was stirred at room temperature for 1 hour, it was quenched by addition of saturated sodium bicarbonate solution (500mL), extracted with ethyl acetate (50mL × 2), the organic phase was concentrated and the crude product was purified by flash column separation (DCM/MeOH ═ 20/1) to give compound 20-c (0.31g, 98%) as a white solid. LC-MS (ESI) M/z 579.3[ M +1 ]]⁺.

Synthesis of Compound 20-b

To compound 20-c (0.31g, 0.536mmol) in toluene (15mL) was added sequentially N-methyl-L-prolinol (0.111g, 0.97mmol), t-BuONa (0.103g, 1.07mmol) with cooling in an ice-water bath. After stirring the mixture under nitrogen in an ice-water bath for 0.5 h, quench with water (10mL), extract with ethyl acetate (30mL × 2), concentrate the organic phase and purify the crude product by flash column separation (MeOH/DCM ═ 1/9) to give compound 20-b (0.28g, 85%) as a white solid. LC-MS (ESI) 614.4[ M +1 ] ]⁺.

Synthesis of Compound 20-a

Compound 20-b (0.28g, 0.46mmol) was added to a mixture of dichloromethane (15mL) and trifluoroacetic acid (15mL) and stirred under nitrogen for 2 hours. Concentration gave compound 20-a (0.26 g). LC-MS (ESI) 514.3[ M +1 ]]⁺.

Synthesis of Compound 20

Compound 20-a (0.26g, 0.51mmol) was dissolved in DCM (20mL) at room temperature, DIPEA (0.15g, 1.16mmol), acryloyl chloride (0.068g, 0.76mmol) were added sequentially, the mixture was stirred at room temperature under nitrogen for 2 hours, then water (10mL) and dichloromethane (30mL × 2) were added for extraction, the organic phase was concentrated, and the crude product was purified by flash column separation (MeOH/DCM ═ 1/20) to give compound 20(0.06g, two steps 23%) as a white solid. LC-MS (ESI) M/z 568.3[ M +1 ]]⁺；¹H NMR(500MHz,CD₃OD):δ7.85(d,1H,J＝10.0Hz),7.83(d,1H,J＝9.5Hz),7.60-7.80(m,1H),7.48(t,1H,J＝9.5Hz),7.33-7.41(m,2H),6.20-6.43(m,2H),6.06(dd,1H,J₁＝5.0Hz,J₂＝12.5Hz),5.76(dd,1H,J₁＝2.0Hz,J₂＝12.5Hz),5.01(d,1H,J＝17.5Hz),4.68(d,1H,J＝17.5Hz),4.41-4.59(m,2H),4.08(dd,2H,J₁＝10.5Hz,J₂＝16.0Hz),3.84(dd,2H,J₁＝13.0Hz,J₂＝16.0Hz),3.46-3.60(m,2H),3.34-3.45(m,4H),3.10-3.22(m,1H),2.94(s,3H),2.80-2.92(m,1H),2.82(s,3H),2.20-2.31(m,1H),1.79-2.10(m,8H).

EXAMPLE 21 Synthesis of Compound 32

Synthesis of Compound 32-b

12-c (527mg, 0.333mmol) was dissolved in toluene (15mL), N-methyl-D-prolinol (76.5mg, 0.666mmol) and sodium tert-butoxide (64mg, 0.667mmol) were added under ice bath, stirred at this temperature for 30 minutes under nitrogen, TLC monitored for completion, stirred directly with silica gel, and passed through a column (biotage,25g, Sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 32-b (202mg, 91%) as a white solid. LC-MS (ESI) M/z 667.3[ M + H ] ]⁺.

Synthesis of Compound 32-a

32-b (202mg, 0.303mmol) was dissolved in acetonitrile (20mL), iodotrimethylsilane (200uL, 1.4mmol) was added, stirring was carried out under nitrogen at 30 ℃ for 2 hours, LCMS monitored for incomplete reaction, iodotrimethylsilane (827mg, 4.13mmol) was added, stirring was continued for 2 hours, LCMS monitored for complete reaction, 1mL of triethylamine was added, and the mixture was spun dry to give 32-a (crude) as a dark solid which was used in the next reaction without purification. LC-MS (ESI) 533.0[ M + H ]]⁺.

Synthesis of Compound 32

Dissolve 32-a (crude) in DMF (10mL), add 2-fluoroacrylic acid (54.6mg, 0.607mmol), HATU (231mg, 0.608mmol) and DIPEA (196mg, 1.52mmol) in that order, stir under nitrogen at room temperature for 1.5 overnight, monitor reaction completion by LCMS, quench with saturated sodium bicarbonate solution, extract with ethyl acetate (30mL X3), wash the organic phase with saturated brine (50mL X3), dry, concentrate, column pass (biotage,40g, Sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 32(151mg, 82%). LC-MS (ESI) M/z 605.0[ M + H ]]⁺.

Synthesis of Compounds 32-1 and 32-2

32(151mg, 0.25mmol) was resolved using chiral preparation and spun dry, lyophilized, respectively, to give 32-1(46mg, 30%) and 32-2(51mg, 34%) as white solids.

32-1：LC-MS(ESI):m/z＝604.9[M+H]⁺；¹H NMR(400MHz,CDCl₃):δ7.96(d,1H,J＝7.2Hz),7.83(t,2H,J＝8.8Hz),7.60(d,1H,J＝7.2Hz),7.55(t,1H,J＝7.6Hz),7.37(t,1H,J＝7.6Hz),6.48(dd,1H,J＝2.8,10.8Hz),5.42(d,1H,J＝47.6Hz),5.26(dd,1H,J＝2.8,16.8Hz),4.97(d,1H,J＝13.6Hz),4.84(d,1H,J＝14.0Hz),4.38(dd,1H,J＝4.8,10.8Hz),4.18(dd,1H,J＝6.8,10.8Hz),3.98(d,1H,J＝10.0Hz),3.77(d,1H,J＝10.4Hz),3.58(d,1H,J＝16.8Hz),3.18-3.31(m,2H),3.02-3.13(m,2H),2.84-2.94(m,2H),2.63-2.72(m,1H),2.48(s,3H),2.23-2.33(m,1H),1.96-2.10(m,1H),1.69-1.90(m,6H).

32-2：LC-MS(ESI):m/z＝605.0[M+H]⁺；¹H NMR(400MHz,CDCl₃):δ7.97(d,1H,J＝6.8Hz),7.84(t,2H,J＝9.2Hz),7.49-7.67(m,2H),7.37(t,1H,J＝8.4Hz),6.51(d,1H,J＝10.8Hz),5.40(d,1H,J＝50.0Hz),5.25(d,1H,J＝15.6Hz),4.99(d,1H,J＝14.0Hz),4.83(d,1H,J＝13.6Hz),4.54-4.66(m,1H),4.42-4.54(m,1H),4.08-4.17(m,1H),3.76-3.91(m,1H),3.50-3.60(m,3H),3.33-3.47(m,1H),3.00-3.33(m,5H),2.80-2.92(m,3H),1.98-2.41(m,7H).

EXAMPLE 22 Synthesis of Compound 22

Synthesis of Compound 22-d

20-e (100mg, 0.281mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (104mg, 0.337mmol) were dissolved in 1, 4-dioxane (10mL), followed by addition of water (1mL),potassium carbonate (116mg, 0.84mmol), tetrakis (triphenylphosphine) palladium (32mg, 0.028mmol), displaced three times with nitrogen, stirred overnight at 100 ℃, LCMS monitored reaction completion, silica gel spin dried directly and column filtered (biotage,25g, sillica gel, UV254, EA: PE ═ 0-25%) to give 22-d (137mg, 97%) as a white solid. LC-MS (ESI) 504.3[ M + H ]]⁺.

Synthesis of Compound 22-c

22-d (137mg, 0.272mmol) was dissolved in ethyl acetate (20mL), MCPBA (138mg, 0.682mmol) was added and stirred at room temperature for 2 hours, LCMS monitored reaction complete, quenched with saturated sodium bicarbonate solution, ethyl acetate extracted (30mL X2), dried, concentrated, and column passed (biotage,25g, Sillica gel, UV254, EA: PE ═ 0-50%) to give 22-c (130mg, 89%) as a white solid. LC-MS (ESI) with M/z 558.2[ M + Na ]]⁺.

Synthesis of Compound 22-b

22-c (130mg, 0.243mmol) was dissolved in toluene (15mL), N-methyl-L-prolinol (55.9mg, 0.486mmol) and sodium tert-butoxide (47mg, 0.489mmol) were added under ice bath, stirred at this temperature for 30 minutes under nitrogen, LCMS monitored for completion, stirred directly on silica gel, and passed through a column (biotage,25g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 22-b (65mg, 47%) as a white solid. LC-MS (ESI) M/z 571.3[ M + H ] ]⁺.

Synthesis of Compound 22-a

22-b (65mg, 0.114mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (0.5mL) was added, stirring was performed at room temperature for 6 hours, LCMS monitored reaction completion, trifluoroacetic acid was removed, saturated sodium bicarbonate solution was added, dichloromethane extraction (20mL X2), drying, and filtration gave filtrate as 22-a (solution) which was used directly in the next reaction. LC-MS (ESI) M/z 471.3[ M + H ]]⁺.

Synthesis of Compound 22

To the 22-a solution was added acryloyl chloride (15.4mg, 0.171mmol) and DIPEA (73.6mg, 0.57mmol), stirred at room temperature under nitrogen for 2 hours, LCMS monitored completion of the reaction, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (40mL X2), dried, concentrated, and passed through a column (ISCO,25g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to afford 22(20mg, two 33% yield steps)) Is a solid. LC-MS (ESI) M/z 525.3[ M + H ]]⁺；¹H NMR(400MHz,CD₃OD):δ7.73-7.87(m,3H),7.48(t,1H,J＝7.2Hz),7.33-7.40(m,2H),6.52-6.69(m,1H),6.31-6.39(m,1H),5.87-6.01(m,2H),5.71-5.80(m,1H),4.85-4.97(m,2H),4.65-4.78(m,1H),4.23-4.48(m,2H),3.73-3.93(m,2H),3.39-3.52(m,1H),3.26-3.36(m,1H),3.10-3.21(m,1H),2.92(d,3H,J＝2.0Hz),2.75(s,3H),2.56-2.68(m,1H),2.43-2.55(m,1H),1.87-2.27(m,7H).

EXAMPLE 23 synthetic route to Compound 23

Synthesis of Compound 23-d

Dissolving 22-d (200mg, 0.398mmol) in methanol (100mL), adding palladium hydroxide (200mg), replacing with hydrogen for three times, stirring for 2 hours at 50 ℃, monitoring incomplete reaction by LCMS, supplementing palladium hydroxide (200mg), continuing to react for 2 hours, supplementing palladium hydroxide (200mg), reacting for 2 hours, monitoring complete reaction by LCMS, filtering, concentrating, passing through a column (biotage,25g, Sillica gel, UV254, EA: PE is 0-20%), and obtaining 23-d (80mg, 40%) as a white solid. LC-MS (ESI) 506.3[ M + H ] ]⁺.

Synthesis of Compound 23-c

23-d (80mg, 0.158mmol) was dissolved in ethyl acetate (30mL), MCPBA (80mg, 0.395mmol) was added and stirred at room temperature for 2 hours, LCMS monitored reaction completion, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL X2), dried, and concentrated to give 23-c (85mg, 100%) as a white solid which was used directly in the next reaction.

Synthesis of Compound 23-b

Dissolving 23-c (85mg, 0.158mmol) in toluene (20mL), adding N-methyl-L-prolinol (36.4mg, 0.316mmol) and sodium tert-butoxide (30mg, 0.313mmol) under ice bath, stirring for 30 min at this temperature under nitrogen, LCMS monitoring the completion of the reaction, quenching with water, extracting with ethyl acetate (30mL X2), drying, concentrating, passing through a column (biotage,12g, Sillica gel, UV254, MeOH: DCM ═ 0-10%) to give 23-b (52mg, 57%) as whiteA colored solid. LC-MS (ESI) with M/z 573.3[ M + H ]]⁺.

Synthesis of Compound 23-a

23-b (52mg, 0.091mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1mL) was added and stirred at room temperature for 2 h, LCMS monitored reaction completion, trifluoroacetic acid removed at room temperature, saturated sodium bicarbonate solution was added, dichloromethane extracted (30mL X3), dried, filtered, concentrated to give 23-a (43mg, 100%) as a solid which was used directly in the next reaction. LC-MS (ESI) M/z 473.3[ M + H ] ]⁺.

Synthesis of Compound 23

Dissolve 23-a (43mg, 0.091mmol) in dichloromethane (20mL), add acryloyl chloride (12.3mg, 0.137mmol) and DIPEA (58.8mg, 0.456mmol), stir at room temperature under nitrogen for 2 hours, LCMS monitor reaction completion, quench with saturated sodium bicarbonate solution, dichloromethane extract (30mL X3), dry, concentrate, column (ISCO,12g, sillica gel, UV214, MeOH: DCM ═ 0-10%) to give 23(26mg, 54%) as a light brown solid. LC-MS (ESI) M/z 527.3[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.87(m,3H),7.49(t,1H,J＝7.2Hz),7.32-7.39(m,2H),6.63(dd,1H,J＝16.8,10.4Hz),6.31(dd,1H,J＝16.8,1.60Hz),5.87-5.93(m,1H),5.72(dd,1H,J＝10.4,1.6Hz),4.91-5.02(m,2H),4.61-4.88(m,2H),4.36-4.48(m,1H),4.11-4.21(m,1H),3.40-3.58(m,1H),3.10-3.27(m,4H),2.89(d,3H,J＝3.2Hz),2.58-2.84(m,6H),1.75-2.26(m,8H)。

EXAMPLE 24 Synthesis of Compound 24

Synthesis of Compound 24

To a solution of 4-a (50mg, 0.1mmol) in DMF (5mL) under ice bath were added triethylamine (0.034mL, 0.24mmol) and 2-butynoic acid (12.3mg, 0.15mmol), followed by 1-propylphosphoric anhydride (46.5mg, 0.073 mmol). After the addition, the reaction solution was warmed to room temperature and stirred overnight. After the reaction is finished, slowly adding water to separate out solid, filtering and collecting the solid, washing the solid with water, drying the solid to obtain a crude product, and performing silica gel column chromatography on the crude productPurification (DCM/MeOH 10/1) afforded product 24(20mg, 35% yield) as a white solid. LC-MS (ESI) M/z 579.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.84(m,3H),7.44-7.52(m,1H),7.31-7.40(m,2H),5.98-6.01(m,1H),4.65-5.03(m,3H),4.44-4.56(m,1H),4.31-4.38(m,1H),4.10-4.30(m,1H),3.90-4.08(m,1H),3.61-3.84(m,1H),3.36-3.53(m,1H),2.96-3.32(m,5H),2.92(d,3H,J＝12.8Hz),2.67-2.88(m,2H),2.57(s,3H),2.28-2.65(m,2H),2.00-2.17(m,4H),1.69-1.99(m,3H).

EXAMPLE 25 Synthesis of Compound 25

Synthesis of Compound 25

Compound 12-a (55mg, 0.103mmol) was dissolved in DCM (10mL) at room temperature, followed by the addition of DIPEA (85uL, 0.515mmol) followed by acryloyl chloride (14mg, 0.155 mmol). After the addition was complete, the reaction mixture was stirred at room temperature under nitrogen for 3 hours, quenched with saturated sodium bicarbonate solution (50mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 25(30mg, 50% yield) as a white solid. LC-MS (ESI) M/z 587.3[ M +1 ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.96(d,1H,J＝7.2Hz),7.83(t,2H,J＝9.2Hz),7.64-7.49(m,2H),7.36(t,1H,J＝7.6Hz),6.68-6.64(m,2H),6.39(d,1H,J＝16.8Hz),6.31-6.04(m,1H),5.83(d,1H,J＝10.4Hz),5.73-4.90(m,2H),4.89-4.79(m,1H),4.79-4.68(m,1H),4.45-4.31(m,1H),4.16-3.64(m,3H),3.66-3.43(m,3H),3.30-3.16(m,2H),3.00-2.79(m,3H),2.74(d,3H,J＝8.4Hz),2.63(t,1H,J＝8.4Hz),2.26-2.13(m,1H),2.13-2.00(m,1H),2.00-1.84(m,2H).

EXAMPLE 26 Synthesis of Compound 30

Synthesis of Compound 30-i

NaH (60%, 4.26g, 106.54mmol) was added to 150mL of THF at room temperature, followed by methyl acetoacetate (11.49mL, 106.54mmol) under nitrogen. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 42.62mL, 106.54mmol) was added dropwise at-15 ℃ to-10 ℃ and the mixture was kept at this temperature for 30 minutes, followed by addition of a solution of the compound o-chlorobenzaldehyde (4.0mL, 35.51mmol) in THF (20 mL). After the mixture was stirred at low temperature (-10 ℃ C. to 0 ℃ C.) for 2 hours, the reaction was quenched with saturated ammonium chloride solution (100mL), followed by extraction with ethyl acetate (100 mL. times.3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column chromatography to give 30-i (7.9g, 87%) as a pale yellow oil.

Synthesis of Compound 30-h

Compound 30-i (7.9g, 30.78mmol) was dissolved in DCM (250mL), DMF-DMA (4.9mL, 36.93mmol) was added under nitrogen at room temperature, stirred at room temperature for 45 min, and BF was added₃.Et₂O (4.6mL, 36.93mmol), the mixture was stirred at room temperature for 1 hour, diluted with 200mL of dichloromethane and the organic phase was successively diluted with saturated NaHCO ₃The solution (400mL) was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Purification on flash column afforded 30-h (7.5g, 91%) as a yellow oil. LC-MS (ESI) M/z 267.0[ M +1 ]]⁺.

Synthesis of Compound 30-g

Compound 30-h (7.5g, 28.12mmol) was dissolved in THF (200mL) and then lithium tri-sec-butylborohydride tetrahydrofuran solution (1M, 30.94mL, 30.94mmol) was added dropwise under nitrogen at-78 ℃, the mixture was stirred at this temperature for 1 hour and quenched with saturated ammonium chloride (100mL), extracted with ethyl acetate (100mL x 3), the organic phase was concentrated to give the crude product which was purified on flash column to give 30-g (5g, 66%) as a yellow oil. LC-MS (ESI) where M/z is 269.0[ M +1 ]]⁺.

Synthesis of Compound 30-f

30-g (5g, 18.6mmol) of the compound was dissolved in methanol (30mL), and then at room temperature,sodium carbonate (13.8g, 111.7mmol) and the compound 2-methyl-2-mercaptourea sulfate (10.4g, 37.2mmol) were added successively. The mixture was stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to 5 with 1N diluted hydrochloric acid, and a white solid was precipitated, filtered, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 30-f (4g, 70%) as a white solid. LC-MS (ESI) M/z 309.1[ M +1 ] ]⁺.

Synthesis of Compound 30-e

To a solution of compound 30-f (4.0g, 12.9mmol) in DCM (100mL) was added DIPEA (4.28mL, 25.9mmol), and trifluoromethanesulfonic anhydride (3.3mL, 19.4mmol), respectively, under ice-bath conditions. After the addition, the reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude compound, which was purified by flash column to give 30-e (4g, 70%) as a white solid. LC-MS (ESI) M/z 441.0[ M +1 ]]⁺.

Synthesis of Compound 30-d

To a solution of 30-e (4.0g, 9.07mmol) in DMF (10mL) was added N, N-diisopropylethylamine (4.5mL, 27.2mmol) and (S) -benzyl 2-cyanomethylpiperazine-1-carboxylate hydrochloride (2.95g, 9.98mmol), respectively, at room temperature. After the addition, the reaction solution was heated to 100 ℃ and stirred for two hours. After the reaction is finished, ethyl acetate is added for dilution, and the mixture is washed by water, saturated salt water, dried by anhydrous sodium sulfate, filtered and dried by spinning. The crude product was isolated and purified by flash column chromatography to give 30-d (4g, 80%) as a white solid. LC-MS (ESI) M/z 550.2[ M + H ]]⁺.

Synthesis of Compound 30-c

Compound 30-d (0.4g, 0.73mmol) was dissolved in ethyl acetate (20mL) under ice-bath conditions, then m-chloroperoxybenzoic acid (369.1mg, 1.82mmol) was added and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to neutralize, extracted with dichloromethane (15mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column (DCM/MeOH ═ 10/1) to afford 30-c (0.35g, 83%) as a white solid. LC-MS (ESI) 582.2[ M +1 ] ]⁺.

Synthesis of Compound 30-b

To a solution of 30-c (350mg, 0.6mmol) and N-methyl-L-prolinol (138.5mg, 1.2mmol) in toluene (10mL) under ice-bath was added sodium tert-butoxide (115.6mg, 1.2 mmol). After the addition, the reaction solution was stirred for 10 minutes in an ice bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 30-b (300mg, 80%) as a brown oil. LC-MS (ESI) M/z 617.2[ M + H ]]⁺.

Synthesis of Compound 30-a

To a solution of 30-b (300mg, 0.49mmol) in acetonitrile (40mL) was added trimethyliodosilane (0.35mL, 2.43mmol) at room temperature. After the addition, the reaction mixture was heated to 30 ℃ and stirred for 5 hours. After the reaction was complete, the reaction was neutralized with triethylamine (10mL) and concentrated under reduced pressure to give 30-a (200mg, 85%) as a dark gray solid. LC-MS (ESI) M/z 483.1[ M + H ]]⁺.

Synthesis of Compound 30

Add N, N-diisopropylethylamine (0.21mL, 1.24mmol) and 30-a (200mg, 0.41mmol) to a solution of 2-fluoroacrylic acid (55.9mg, 0.62mmol) and HATU (314.9mg, 0.83mmol) in DMF (5mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, a solid was precipitated by addition of gentle water, collected by filtration and washed with water, air dried to give the crude product, which was purified by flash column separation (DCM/MeOH 10/1) to give product 30(100mg, 44%) as a white solid. LC-MS (ESI) M/z 555.0[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.55(d,1H,J＝7.2Hz),7.36-7.39(m,1H),7.30-7.35(m,1H),7.24-7.28(m,1H),5.36(d,1H,J＝49.6Hz),5.15-5.26(m,2H),4.40-4.92(m,5H),3.45-4.02(m,6H),3.08-3.38(m,5H),3.03(d,3H,J＝13.2Hz),2.27-2.86(m,2H),2.32-2.38(m,1H),2.03-2.20(m,3H).

EXAMPLE 27 Synthesis of Compound 31

Synthesis of Compound 31-b

To a solution of compound 4-bromocrotonate ethyl ester (0.5mL, 4.25mmol) in DCM (10mL) was added potassium carbonate (1.18g, 8.5mmol), potassium iodide (40mg, 0.21mmol), and morpholine (0.56mL, 6.38mmol), respectively, under ice-bath. After the addition, the reaction mixture was stirred at 0 ℃ for 30 minutes, and then slowly warmed to room temperature and stirred for 4 hours. After the reaction is finished, adding water for quenching, extracting by using ethyl acetate, washing an organic phase by using saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering, and carrying out spin-drying to obtain a crude compound, and purifying by using a rapid separation column to obtain 31-b (0.75g, 95%) which is a brown oily substance. LC-MS (ESI) with M/z of 200.0[ M +1 ]]⁺.

Synthesis of Compound 31-a

To a reaction flask were added compound 31-b (750mg, 3.76mmol), lithium hydroxide (632mg, 15.1mmol), tetrahydrofuran (12ml), methanol (6ml) and water (6 ml). The mixture was stirred at room temperature overnight. After the reaction is finished, the organic solvent is removed under reduced pressure, dilute hydrochloric acid is added into a water layer to adjust the pH value to 6-7, ethyl acetate is used for extraction, the organic phase is washed with water, saturated sodium chloride aqueous solution is washed, anhydrous sodium sulfate is used for drying, filtering and spin-drying are carried out, and the crude compound 31-a (500mg, 78%) is gray solid. LC-MS (ESI) M/z 172.0[ M + H ] ]⁺.

Synthesis of Compound 31

Add N, N-diisopropylethylamine (37.8mg, 0.3mmol) and 4-a (50mg, 0.1mmol) to a solution of 31-a (25mg, 0.15mmol) and HATU (74.2mg, 0.2mmol) in DMF (5mL) at room temperature. The reaction was stirred at room temperature overnight. And after the reaction is finished, adding slow water to separate out a solid, filtering and collecting the solid, washing the solid with water, and airing to obtain a crude product. The crude product was purified by flash column (DCM/MeOH 5/1) to give product 31(15mg, 23%) as a foamy white solid. LC-MS (ESI) M/z 666.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.84(m,3H),7.45-7.52(m,1H),7.32-7.39(m,2H),6.87-6.99(m,1H),6.36-6.52(m,1H),5.97-6.07(m,1H),4.93-5.11(m,1H),4.64-4.93(m,2H),4.32-4.60(m,2H),3.80-4.28(m,2H),3.32-3.81(m,6H),2.97-3.31(m,6H),2.93(d,3H,J＝8.4Hz),2.56-2.83(m,6H),2.48(s,3H),2.34-2.55(m,1H),2.14-2.76(m,1H),1.86-2.11(m,4H).

EXAMPLE 28 Synthesis of Compound 34

Synthesis of Compound 34-d

To a solution of 2-e (205mg, 0.43mmol) and (R) -1-BOC-3-hydroxymethylpiperazine (140mg, 0.65mmol) in DMF (8mL) at room temperature was added DIPEA (111mg, 0.86 mmol). After the addition was complete, the reaction temperature was slowly raised to 100 ℃, after stirring at this temperature for 1 hour, cooled to room temperature, water was added, extracted with ethyl acetate (50mL), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was purified by flash column separation (0-50%, EA/PE) to give compound 34-d (111mg, 47%) as a white solid. LC-MS (ESI) M/z 541.2[ M + H ]]⁺.

Synthesis of Compound 34-c

To a solution of 34-d (111mg, 0.21mmol) in ethyl acetate (8mL) was added 85% m-chloroperoxybenzoic acid (104mg, 0.51mmol) under ice-bath conditions. The reaction was slowly warmed to room temperature, stirred for 3 hours, added with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (30mL × 2), the combined organic phases dried over anhydrous sodium sulfate, filtered, and spin-dried to give crude compound 34-c (118mg, 100%) as a white solid. LC-MS (ESI) M/z 572.8[ M + H ] ]⁺.

Synthesis of Compound 34-b

To a solution of 34-c (118mg, 0.21mmol) in toluene (8mL) at room temperature was added N-methyl-L-prolinol (36mg, 0.31mmol) followed by sodium tert-butoxide (40mg, 0.41mmol), the mixture was stirred at room temperature for 3 hours, concentrated and the crude product was purified by Pre-TLC separation (DCM: MeOH ═ 10:1) to give compound 34-b (56mg, 45%) as a yellow solid. LC-MS (ESI) M/z 608.3[ M + H ]]⁺.

Synthesis of Compound 34-a

To a solution of 34-b (56mg, 0.09mmol) in dichloromethane (3mL) at room temperature was added TFA (1mL), the mixture was stirred at room temperature for 1 hour, concentrated, and then saturated aqueous sodium bicarbonate was added thereto, followed by addition of ethyl acetateEthyl acid (30mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun-dried to give crude compound 34-a (47mg, 100%) as a yellow solid. LC-MS (ESI) with M/z 508.3[ M + H ]]⁺.

Synthesis of Compound 34

To a solution of 34-a (47mg, 0.09mmol) and 2-fluoroacrylic acid (13mg, 0.14mmol) in DMF (5mL) at rt was added HATU (68mg, 0.18mmol) and DIPEA (35mg, 0.27mmol), the reaction temperature was raised to rt, the mixture was stirred at rt for 1 h, concentrated, water was added, extracted with ethyl acetate (30mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, spun dry and the crude product was isolated by Pre-HPLC to afford compound 34(12mg, 22%) as a white solid. LC-MS (ESI) M/z 580.2[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.75(d,J＝7.6Hz,1H),7.69–7.62(m,2H),7.45(t,J＝7.6Hz,1H),5.40(d,J＝46Hz,1H),5.28–5.14(m,2H),4.86(dd,J＝14,8Hz,1H),4.74(dd,J＝13.6,5.6Hz,1H),4.62–4.36(m,2H),4.23–4.13(m,2H),4.09–3.94(m,1H),3.84(dd,J＝11.6,7.2Hz,1H),3.72–3.22(m,4H),3.17–2.86(m,4H),2.77–2.66(m,1H),2.48(d,J＝4.8Hz,3H),2.31(dd,J＝16.4,9.2Hz,1H),2.15–1.98(m,2H),1.91–1.66(m,3H).

EXAMPLE 29 Synthesis of comparative Compound 1

Comparative compound 1' was synthesized with reference to the method of WO2017201161a 1.

EXAMPLE 30 Synthesis of comparative Compound 2

Compound 2' -a was synthesized by referring to the method of WO2017201161A 1.

2' -a (44mg, 0.085mmol) was dissolved in DMF (10mL) and 2-fluoroacrylic acid (15.4mg, 0.171mmol), HATU (65mg, 0.171mmol) and DIPEA (70.5. mu.L, 0.427mmol) were added in that order and stirred at room temperature under nitrogenOvernight. The reaction was monitored by LCMS for completion, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL X3), and the organic phase washed with saturated brine (30mL X3), dried, concentrated, and passed through a column (biotage,25g, sillica gel, UV254, MeOH: DCM ═ 0-10%) to give comparative compound 2' (49mg, 98%) as a pale yellow solid. LC-MS (ESI) M/z 587.9[ M + H ]]⁺；¹H NMR(400MHz,CDCL₃):δ7.67(d,1H,J＝8.4Hz),7.59(t,1H,J＝7.6Hz),7.44(d,1H,J＝8.0Hz),7.30(t,1H,J＝8.0Hz),5.38(d,1H,J＝47.2Hz),5.24(dd,1H,J＝4.0,16.8Hz),4.54-4.63(m,2H),4.24-4.34(m,1H),4.00-4.10(m,3H),3.71-3.79(m,1H),3.60-3.68(m,1H),3.33-3.43(m,1H),3.05-3.24(m,4H),3.01(s,3H),2.93-2.98(m,1H),2.72-2.86(m,4H),2.26-2.41(m,2H),2.03-2.21(m,4H).

EXAMPLE 31 Synthesis of Compound 35

Synthesis of Compound 35-i

NaH (60%, 0.97g, 24.17mmol) was suspended in 30mL of THF at room temperature, followed by the addition of methyl acetoacetate (2.61mL, 24.17mmol) under nitrogen. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 9.67mL, 24.17mmol) was added dropwise at-15 ℃ to-10 ℃, the mixture was kept at this temperature for 30 minutes, and then a solution of the compound o-fluorobenzaldehyde (1.0g, 8.06mmol) in THF (10mL) was added dropwise. After the mixture was stirred at low temperature (-10 ℃ C. to 0 ℃ C.) for 2 hours, the reaction was quenched with saturated ammonium chloride solution (20mL), followed by extraction with ethyl acetate (20 mL. times.3), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column to give 35-i (1.2g, 62%) as a pale yellow oil. LC-MS (ESI) M/z 263.1[ M + Na ]⁺.

Synthesis of Compound 35-h

Compound 35-i (1.2g, 5.0mmol) was dissolved in DCM (50mL), DMF-DMA (0.8mL, 6.0mmol) was added under nitrogen at room temperature, stirred at room temperature for 45 min, and BF was added₃·Et₂O (0.74mL, 6.0mmol), the mixture was stirred at room temperature for 1 hour, diluted with 20mL of dichloromethane and the organic phase was successively diluted with saturated NaHCO₃The solution (40mL) was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Purification on a flash column afforded 35-h (1g, 80%) as a tan oil. LC-MS (ESI) 251.1[ M +1 ]]⁺.

Synthesis of Compound 35-g

Compound 35-h (1.0g, 4.0mmol) was dissolved in THF (30mL) and then lithium tri-sec-butylborohydride (1M, 4.4mL, 4.4mmol) was added dropwise under nitrogen at-78 ℃, the mixture was stirred at this temperature for 1 hour, the reaction was quenched with saturated ammonium chloride (20mL), extracted with ethyl acetate (20mL x 3), the organic phase was concentrated to give the crude product, which was purified on flash column to give 35-g (0.6g, 60%) as a yellow oil. LC-MS (ESI) 253.2[ M +1 ]]⁺.

Synthesis of Compound 35-f

After 35-g (0.6g, 2.4mmol) of the compound was dissolved in methanol (15mL), sodium carbonate (1.77g, 14.3mmol) and the compound 2-methyl-2-mercaptourea sulfate (1.3g, 4.8mmol) were added in this order at room temperature. The mixture was stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to 5 with 1M dilute hydrochloric acid, and a white solid was precipitated, filtered, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 35-f (0.3g, 43%) as a white solid. LC-MS (ESI) M/z 293.1[ M +1 ] ]⁺.

Synthesis of Compound 35-e

To a solution of compound 35-f (0.3g, 1.0mmol) in DCM (20mL) was added DIPEA (265.3mg, 2.0mmol), and trifluoromethanesulfonic anhydride (434.3mg, 1.54mmol), respectively, under ice-bath conditions. After the addition, the reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude compound, which was purified by flash column to give 35-e (260mg, 60%) as a white solid. LC-MS (ESI) M/z 425.1[ M +1 ]]⁺.

Synthesis of Compound 35-d

At room temperature to 35-e (0.2)6g, 0.61mmol) in DMF (10mL) was added DIPEA (0.3mL, 1.84mmol) and (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (199.3mg, 0.67mmol), respectively. After the addition, the reaction solution was heated to 100 ℃ and stirred for two hours. After the reaction is finished, ethyl acetate is added for dilution, and the mixture is washed by water, saturated salt water, dried by anhydrous sodium sulfate, filtered and dried by spinning. The crude product was isolated and purified by flash column chromatography to give 35-d (0.28g, 86%) as a white solid. LC-MS (ESI) with M/z 534.2[ M + H ]]⁺.

Synthesis of Compound 35-c

Compound 35-d (0.28g, 0.52mmol) was dissolved in ethyl acetate (20mL) under ice-bath, MCPBA (266.2mg, 1.31mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to neutralize, extracted with dichloromethane (15mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column (DCM/MeOH ═ 10/1) to give 35-c (0.26g, 88%) as a white solid. LC-MS (ESI) M/z 566.3[ M +1 ] ]⁺.

Synthesis of Compound 35-b

To a solution of 35-c (260mg, 0.46mmol) and N-methyl-L-prolinol (105.6mg, 0.92mmol) in toluene (10mL) under ice-bath was added sodium tert-butoxide (88.4mg, 0.92 mmol). After the addition, the reaction solution was stirred for 10 minutes in an ice bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 35-b (80mg, 29%) as a brown oil. LC-MS (ESI) M/z 601.0[ M + H ]]⁺.

Synthesis of Compound 35-a

Trimethyliodosilane (0.1mL, 0.67mmol) was added to a solution of 35-b (80mg, 0.13mmol) in acetonitrile (20mL) at room temperature. After the addition, the reaction mixture was heated to 30 ℃ and stirred for 5 hours. After the reaction was complete, the reaction was neutralized with triethylamine (10mL) and concentrated under reduced pressure to give 35-a (20mg, 32%) as a dark gray solid. LC-MS (ESI) M/z 467.0[ M + H ]]⁺.

Synthesis of Compound 35

At room temperature, by chemical combinationTo a solution of substance 35-a (20mg, 0.043mmol) in dichloromethane (10ml) were added acryloyl chloride (7.8mg, 0.086mmol) and DIPEA (16.6mg, 0.13 mmol). The reaction was stirred at room temperature overnight. After the reaction, the crude product is obtained by concentration. The crude product was purified by flash column chromatography (DCM/MeOH 10/1) to give compound 35(5mg, 22%) as a tan oil. LC-MS (ESI) with M/z 521.2[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.48-7.52(m,1H),7.29-7.33(m,1H),7.20(t,1H,J＝7.6Hz),7.08(t,1H,J＝8.0Hz),6.49-6.78(m,1H),6.39(d,1H,J＝16.8Hz),5.82(d,1H,J＝10.4Hz),4.72-5.31(m,4H),4.49-4.61(m,1H),3.45-4.08(m,5H),2.66-3.44(m,10H),2.26-2.41(m,1H),2.05-2.21(m,1H),1.38-1.59(m,4H).

EXAMPLE 32 synthetic route to Compound 36

Synthesis of Compounds 36-i-1 and 36-i-2

Scale-up gave compound 12-i (8.5g, 27.8mmol) which was resolved by hand to give compound 36-i-1(2.5g, 29%) as a white solid and compound 36-i-2(2.6g, 31%) as a white solid.

36-i-1：LC-MS(ESI):m/z＝329.1[M+Na]⁺.

36-i-2：LC-MS(ESI):m/z＝329.1[M+Na]⁺.

Synthesis of Compound 36-h

Compound 36-i-1(2.3g, 7.5mmol) was dissolved in DCM (80mL) at room temperature, followed by the addition of DMF-DMA (1.2mL, 9.0mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 45 minutes, and BF was added thereto₃·Et₂O(1.2mL，9.0 mmol). After the addition was complete, the mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (100mL × 2), and the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound 36-h (2.0g, 84%) which was used directly in the next reaction. LC-MS (ESI) M/z 317.1[ M +1 ]]⁺.

Synthesis of Compound 36-g

Compound 36-h (2.0g, 6.31mmol) was dissolved in THF (60mL) at room temperature, then lithium tri-sec-butylborohydride (1M in THF, 6.95mL, 6.95mmol) was added dropwise at-78 deg.C under nitrogen. After the addition was completed, the mixture was stirred at-78 ℃ for 1 hour, quenched with 1M hydrochloric acid solution (20mL), extracted with ethyl acetate (100mL × 2), the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column (PE/EA ═ 0-15%) to give 36-g (1.8g, 89%) of compound as a yellow oil. LC-MS (ESI) M/z 319.0[ M +1 ] ]⁺.

Synthesis of Compound 36-f

Compound 36-g (1.5g, 4.71mmol) was dissolved in methanol (30mL) at room temperature, and then sodium methoxide (1.27g, 23.5mmol) and compound 2-methyl-2-mercaptourea sulfate (1.18g, 4.24mmol) were added in this order under nitrogen at 0 ℃. After the addition was complete, the mixture was warmed to room temperature and stirred for 20 hours. The reaction solution was adjusted to pH 5 with 1M dilute hydrochloric acid, a solid precipitated, filtered, and the filter cake was washed with a mixed solution of ethyl acetate (20mL) and petroleum ether (20mL), and the solid was collected and dried in vacuo to give crude 36-f (0.65g, 39%) as a white solid. LC-MS (ESI) 359.1[ M +1 ]]⁺.

Synthesis of Compound 36-e

Compound 36-f (0.6g, 1.67mmol) was dissolved in DCM (50mL) at room temperature, followed by the addition of DIPEA (0.83mL, 5.02mmol), triflic anhydride (0.51mL, 3.01mmol) in that order under nitrogen in an ice-water bath. After the addition was complete, the reaction mixture was stirred for 2 hours in an ice-water bath, quenched with saturated sodium bicarbonate solution (50mL), extracted with DCM (50mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product,the crude product was isolated and purified by flash column separation (EA/PE 0-5%) to give compound 36-e (380mg, 463%) as a white solid. LC-MS (ESI) M/z 491.1[ M +1 ] ]⁺；chiral-HPLC 100％(ee％).

Synthesis of Compound 36-d

Compound 36-e (360mg, 0.73mmol) was dissolved in DMF (15mL) at room temperature, followed by the addition of DIPEA (0.36mL, 2.2mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (238.6mg, 0.81mmol) in that order. After the addition was completed, the mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched with saturated brine (50mL), and extracted with ethyl acetate (50mL × 2). The organic phase was washed with saturated brine (50mL × 3), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column separation (EA/PE ═ 0-40%) to give compound 36-d (360mg, 80%) as a white solid. LC-MS (ESI) 600.2[ M +1 ]]⁺.

Synthesis of Compound 36-c

Compound 36-d (340mg, 0.57mmol) was dissolved in ethyl acetate (25mL) at room temperature, and MCPBA (85%, 287.5mg, 1.42mmol) was added at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (50mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified by flash column separation (EA/PE ═ 0-60%) to give compound 36-c (320mg, 89%) as a white solid. LC-MS (ESI) M/z 632.2[ M +1 ] ]⁺.

Synthesis of Compound 36-b

Compound 36-c (300mg, 0.47mmol) was dissolved in toluene (10mL) at room temperature, and the reaction was cooled to 0 ℃ and N-methyl-L-prolinol (109.3mg, 0.95mmol), t-BuONa (91.2mg, 0.95mmol) were added in that order. After the addition was complete, the reaction mixture was stirred under nitrogen in an ice-water bath for 0.5 h, quenched with water (20mL) and extracted with ethyl acetate (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column separation (MeOH/DCM ═ 0-7%) to give compound 36-b (290mg, 91%) as a white solid。LC-MS(ESI):m/z＝667.3[M+1]⁺.

Synthesis of Compound 36-a

Compound 36-b (200mg, 0.3mmol) was dissolved in acetonitrile (20mL) at room temperature, then iodotrimethylsilane (0.21mL, 1.5mmol) was added with stirring, stirred at 30 ℃ for 2 hours, quenched with triethylamine (1mL), and concentrated to give compound 36-a (crude) as a brown solid. LC-MS (ESI) 533.3[ M +1 ]]⁺.

Synthesis of Compound 36

Add DIPEA (60.6mg, 0.47mmol) and 4- (dimethylamino) -2-butenoic acid hydrochloride (23.3mg, 0.14mmol), respectively, to a solution of compound 36-a (50mg, 0.094mmol) and HATU (71.3mg, 0.19mmol) in DMF (5mL) under ice bath. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give a crude product which was purified by silica gel column chromatography (DCM/MeOH 5/1) to give 36(16mg, 26%) as a white solid. LC-MS (ESI) M/z 644.3[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.97(d,1H,J＝6.8Hz),7.83(t,2H,J＝8.4Hz),7.60(d,1H,J＝7.2Hz),7.56(t,1H,J＝7.6Hz),7.36(t,1H,J＝8.0Hz),6.91-6.97(m,1H),6.51(dd,1H,J＝11.2,3.2Hz),6.37-6.55(m,1H),5.00(d,1H,J＝13.6Hz),4.83(d,1H,J＝14.0Hz),4.55-5.10(m,1H),4.47(dd,1H,J＝10.8,5.2Hz),4.21(dd,1H,J＝10.8,6.4Hz),3.99(d,1H,J＝13.6Hz),3.78-3.96(m,1H),3.62-3.78(m,1H),3.59(dd,1H,J＝18.4,2.8Hz),3.39-3.54(m,1H),3.02-3.24(m,4H),2.62-2.95(m,5H),2.53(s,3H),2.32-2.39(m,1H),2.29(s,6H),2.04-2.10(m,1H),1.75-1.90(m,3H).

EXAMPLE 33 Synthesis of Compound 37

Synthesis of Compound 37-c

Referring to the synthesis of compound 36-c, 37-c was synthesized using (S) -tert-butyl 2-cyanomethylpiperazine-1-carboxylate instead of benzyl (S) -2-cyanomethylpiperazine-1-carboxylate hydrochloride.

Synthesis of Compound 37-b

To a solution of 37-c (200mg, 0.34mmol) and 1-dimethylamino-2-propanol (68.9mg, 0.67mmol) in toluene (10mL) under ice bath was added sodium tert-butoxide (64.3mg, 0.67 mmol). After the addition, the reaction solution was stirred for 10 minutes in an ice bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 37-b (150mg, 72%) as a white solid. LC-MS (ESI) M/z 621.3[ M + H ]]⁺.

Synthesis of Compound 37-a

To a solution of 37-b (150mg, 0.24mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated, carefully neutralized with a saturated solution of sodium hydrogencarbonate to a pH of more than 7 while cooling on ice, extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 37-a (100mg, 79%) as an amber oil. LC-MS (ESI) with M/z 521.3[ M +1 ] ]⁺.

Synthesis of Compound 37

Add DIPEA (74.4mg, 0.58mmol) and acrylic acid (20.7mg, 0.29mmol), respectively, to a solution of 37-a (100mg, 0.19mmol) and HATU (145.9mg, 0.38mmol) in DMF (5mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give the crude product which was purified by silica gel column chromatography (DCM/MeOH 10/1) to give 37(25mg, 23%) as a white solid. LC-MS (ESI) M/z 575.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.97(d,1H,J＝7.6Hz),7.81-7.86(m,2H),7.54-7.62(m,2H),7.37(t,1H,J＝8.0Hz),6.48-6.75(m,2H),6.38(d,1H,J＝16.8Hz),5.83(d,1H,J＝10.8Hz),5.39-5.53(m,1H),4.48-5.12(m,3H),3.46-4.22(m,5H),2.70-3.35(m,7H),2.55-2.67(m,6H),1.39(dd,3H,J＝6.0,1.6Hz).

EXAMPLE 34 Synthesis of Compound 38

Synthesis of Compound 38

Add 2-chloroethanesulfonyl chloride (47.7mg, 0.29mmol) and triethylamine (59.3mg, 0.59mmol) to a solution of Compound 4-a (100mg, 0.20mmol) in dichloromethane (10mL) at room temperature, respectively. The reaction was stirred at room temperature overnight. After the reaction was complete, the crude product was concentrated and purified by flash column chromatography to give compound 38(40mg, 34%) as a white solid. LC-MS (ESI) M/z 603.3[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.74-7.84(m,3H),7.45-7.49(m,1H),7.34-7.37(m,2H),6.55(dd,1H,J＝16.8,2.8Hz),6.34(dd,1H,J＝16.4,2.0Hz),6.05(dd,1H,J＝9.6,3.6Hz),5.97-6.00(m,1H),4.88(dd,1H,J＝54.8,13.6Hz),4.68(dd,1H,J＝35.2,13.2Hz),4.44-4.51(m,1H),4.34-4.38(m,1H),4.17-4.25(m,1H),3.42-3.98(m,4H),2.96-3.31(m,5H),2.92(d,3H,J＝12.8Hz),2.76-2.88(m,2H),2.55(s,3H),2.35-2.41(m,1H),2.02-2.13(m,1H),1.80-1.92(m,4H).

EXAMPLE 35 Synthesis of Compound 39

Synthesis of Compound 39

Compound 32-a (55mg, 0.103mmol) was dissolved in DCM (10mL) at room temperature, followed by the addition of DIPEA (85. mu.L, 0.515mmol), acryloyl chloride (14mg, 0.155mmol) in that order. After the addition was complete, the reaction mixture was stirred at room temperature under nitrogen for 3 hours, quenched with saturated sodium bicarbonate solution (50mL) and extracted with DCM (50mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column separation (MeOH/DCM ═ 1/10) to give compound 39(20mg, 33% yield). LC-MS (ESI) M/z 587.3[ M +1 ] ]⁺.

EXAMPLE 36 synthetic route to Compound 40

Synthesis of Compound 40-i

NaH (60%, 3.6g, 90.0mmol) was added to THF (150mL) at room temperature, and methyl acetoacetate (8mL, 77.0mmol) was added under nitrogen at room temperature. After the mixture was stirred at room temperature under nitrogen for 30 minutes, n-BuLi (2.5M, 36.0mL, 90.0mmol) was added dropwise at-15 ℃ to-10 ℃. After the addition was completed, the reaction mixture was stirred at this temperature for 30 minutes, and then a solution of compound 4-isoquinolinecarboxaldehyde (5.0g, 30.0mmol) in THF (150mL) was added dropwise. After the addition, the mixture was stirred at low temperature (-10 ℃ C. -0 ℃ C.) for 2 hours. The reaction was quenched by addition of saturated ammonium chloride solution (100mL), extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column separation (EA/PE ═ 1/3) to give compound 40-i (6.2g, 75.7%) as a pale yellow liquid. LC-MS (ESI) M/z 274.1[ M + H ]]⁺.

Synthesis of Compound 40-h

Compound 40-i (6.2g, 22.7mmol) was dissolved in DCM (100mL) and DMF-DMA (4.05g, 34.1mmol) was added under nitrogen at room temperature. After stirring the reaction solution at room temperature for 45 minutes, BF was added₃Et2O (4.84g, 34.1 mmol). The mixture was stirred at room temperature for 1 hour, diluted with dichloromethane (200mL) and the organic phase was successively diluted with saturated NaHCO ₃The solution (400mL) was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by flash column separation (EA/PE ═ 1/3) to give compound 40-h (5.3g, 83%) as a pale red liquid. LC-MS (ESI) M/z 283.9[ M + H ]]⁺.

Synthesis of Compound 40-g

To a solution of compound 40-h (5.3g, 18.7mmol) in THF (100mL) at-78 deg.C under nitrogen was added lithium tri-sec-butylborohydride tetrahydrofuran (1M, 28.1mL, 28.1mmol) dropwise. After the addition was complete, the mixture was stirred at this temperature for 1 hour, the reaction was quenched by addition of saturated ammonium chloride (20mL), extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated sodium chloride and concentrated to give the crude product which was purified by flash column separation (EA/PE ═ 1/4) to give compound 40-g (5.3g, 100%) as a yellow oil. LC-MS (ESI) M/z 286.2[ M + H ]]⁺.

Synthesis of Compound 40-f

To a solution of 40-g (5.3g, 18.6mmol) of the compound in methanol (150mL) was added sodium methoxide (10.0g, 18.6mmol) and urea 2-methyl-2-mercaptosulfate (10.6g, 37.2mmol) in this order in an ice-water bath. After the addition was completed, the reaction solution was warmed to room temperature and stirred overnight. The pH was adjusted to 5 with 1M hydrochloric acid solution and the solid precipitated, filtered, washed with water (50mL x 3) and dried to give crude 40-f (3.1g, 51%) as a pale yellow solid. LC-MS (ESI) M/z 326.1[ M + H ] ]⁺.

Synthesis of Compound 40-e

To a solution of compound 40-f (1.3g, 4.0mmol) in DCM (20mL) and DMF (10mL) under an ice-water bath was added thionyl chloride (2.5mL) at 0 ℃, the mixture was stirred under an ice-water bath for 3 hours, quenched by addition of ice-water solution (80mL), extracted with DCM (80mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by flash column separation (EA/PE ═ 1/25) to give compound 40-e (0.51g, 37%). LC-MS (ESI) M/z 344.1[ M + H ]]⁺.

Synthesis of Compound 40-d

Compound 40-e (0.51g, 1.49mmol) was dissolved in DMF (12mL) at room temperature, followed by the addition of DIPEA (0.39g, 3.0mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid benzyl ester hydrochloride (0.48g, 1.6 mmol). After the addition was complete, the mixture was stirred at 100 ℃ under nitrogen for 1 hour, cooled to room temperature, quenched by addition of water (100mL), extracted with ethyl acetate (80mL × 2), the organic phase washed with saturated brine (100mL × 3), concentrated, and the crude product was purified by flash column separation (EA/PE ═ 1/1) to afford compound 40-d (0.7g, 83%) as a white solid. LC-MS (ESI) M/z 567.2[ M + H ] +.

Synthesis of Compound 40-c

Compound 40-d (0.7g, 1.24mmol) was dissolved in ethyl acetate (20mL) and MCPBA (0.63g, 3.1mmol) was added at room temperature. After the mixture was stirred at room temperature for 1 hour, it was quenched by addition of saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50mL × 2), filtered, and concentrated to give crude compound 40-c which was directly charged to the next reaction.

Synthesis of Compound 40-b

To a solution of compound 40-c (0.66g, 1.1mmol) in toluene (10mL) under ice-water bath was added N-methyl-L-prolinol (0.254g, 2.2mmol), t-BuONa (0.21g, 2.2mmol) in that order. After the addition was complete, the mixture was stirred under nitrogen in an ice-water bath for 0.5 h, quenched by addition of water (10mL), extracted with ethyl acetate (30mL × 2), the organic phase was concentrated and the crude product was purified by flash column separation (MeOH/DCM ═ 1/9) to give compound 40-b (0.39g, 50% yield over two steps). LC-MS (ESI) M/z 634.0[ M + H ]]⁺.

Synthesis of Compound 40-a

A solution of compound 40-b (0.18g, 0.28mmol) in methanolic ammonia (7M, 50mL) was cooled to-78 ℃ and replaced with nitrogen 2 times, 10% Pd-C (55mg) was added and replaced with hydrogen 3 times. The reaction solution was warmed to room temperature and stirred under hydrogen for 2 hours. The reaction mixture was filtered and concentrated to obtain compound 40-a (0.093g, 66%). LC-MS (ESI) with M/z 500.2[ M + H ]]⁺.

Synthesis of Compound 40

Compound 40-a (0.09g, 0.18mmol) was dissolved in DCM (10mL) at room temperature, and DIPEA (0.046g, 0.36mmol) and acryloyl chloride (27uL, 0.27mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen overnight, quenched by addition of water (10mL), extracted with DCM (50mL × 3), the organic phase concentrated and the crude product purified by flash column separation (MeOH/DCM ═ 1/9) to give compound 40(13mg, 7%) as a white solid. LC-MS (ESI) M/z 554.3[ M + H ] ]⁺；¹H NMR(400MHz,CD₃OD):δ9.25(s,1H),8.59(d,1H,J＝6.8Hz),8.27(d,1H,J＝8.8Hz),8.20(d,1H,J＝7.6Hz),7.88(t,1H,J＝7.6Hz),7.61(t,1H,J＝7.6Hz),6.72-6.90(m,1H),6.31(d,1H,J＝15.6Hz),5.76-5.95(m,1H),5.56-5.65(m,1H),5.53(t,2H,J＝10.0Hz),4.43-4.47(m,3H),3.38-4.21(m,3H),3.43-3.52(m,2H),3.30-3.36(m,1H),2.93-3.20(m,4H),2.88-2.95(m,1H),2.80-2.83(m,1H),2.51-2.61(m,3H),2.30-2.44(m,1H),2.08-2.22(m,1H),1.81-1.93(m,2H),1.73-1.79(m,1H).

EXAMPLE 37 synthetic route to Compound 41

Synthesis of Compound 41

To a solution of compound 36-a (50mg, 0.094mmol) in DMF (2mL) under ice bath was added cesium carbonate (61.1mg, 0.19mmol) and cyanogen bromide (10.9mg, 0.1 mmol). After the addition, the reaction mixture was stirred at 0 ℃ for 2 hours. After the reaction was complete, the reaction was filtered and the filtrate was purified directly by Prep-HPLC to give compound 39(5mg, 9.6%) as a white solid. LC-MS (ESI) with M/z 558.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.95(d,1H,J＝7.2Hz),7.83(t,2H,J＝8.8Hz),7.60(dd,1H,J＝7.6,1.2Hz),7.56(t,1H,J＝8.0Hz),7.37(t,1H,J＝8.0Hz),6.44-6.54(m,1H),4.87-4.96(m,1H),4.72-4.80(m,1H),4.36-4.44(m,1H),4.13-4.21(m,1H),3.91-4.00(m,1H),3.75-3.88(m,1H),3.46-3.67(m,4H),3.25-3.44(m,2H),3.06-3.16(m,1H),2.81-2.95(m,3H),2.62-2.74(m,1H),2.48(s,3H),2.21-2.35(m,1H),1.96-2.11(m,1H),1.66-1.92(m,3H).

EXAMPLE 38 synthetic route to Compound 42

Synthesis of Compound 42-c

To a solution of 37-c (600mg, 1.0mmol) and N-methyl-L-prolinol (231mg, 2.0mmol) in toluene (10mL) under ice-bath was added sodium tert-butoxide (192.8mg, 2.0 mmol). After the addition, the reaction solution was stirred for 30 minutes in an ice bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 42-c (550mg, 87%) as a white solid. LC-MS (ESI) M/z 633.2[ M + H ]]⁺.

Synthesis of Compound 42-b

To a reaction flask, compound 42-c (150mg, 0.24mmol), potassium carbonate (4.91mg, 0.04mmol), and dimethyl sulfoxide (2mL) were added. Under ice bath, H is added dropwise₂O₂Aqueous solution (30%, 107.4mg, 0.95mmol), after addition, the mixture was warmed to room temperature and stirred overnight. The next day, adding water to the reaction solution to separate out solid, filtering, washing the filter cake with water, and drying to obtain white Solid 42-b (130mg, 84%), LC-MS (ESI) M/z 651.3[ M + H ═]⁺.

Synthesis of Compound 42-a

To a solution of 42-b (130mg, 0.20mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, concentration was performed, the pH was carefully neutralized with a saturated solution of sodium hydrogencarbonate to more than 7 under ice bath, extraction was performed with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product 42-a (100mg, 90%) as an amber oil. LC-MS (ESI) M/z 551.2[ M +1 ]]⁺.

Synthesis of Compound 42

Add N, N-diisopropylethylamine (70.4mg, 0.54mmol) and 2-fluoroacrylic acid (24.5mg, 0.27mmol) to a solution of 42-a (100mg, 0.18mmol) and HATU (138.0mg, 0.36mmol) in DMF (5mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water, dried to give crude product, which was purified by Prep-HPLC to give 42(60mg, 53%) as a white solid. LC-MS (ESI) M/z 623.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.95(d,1H,J＝6.8Hz),7.83(t,2H,J＝8.4Hz),7.60(dd,1H,J＝7.2,1.2Hz),7.55(t,1H,J＝7.6Hz),7.36(t,1H,J＝8.0Hz),6.46(dd,1H,J＝10.8,3.2Hz),6.05-6.21(m,1H),5.36(s,1H),5.32(dd,1H,J＝47.6,4.0Hz),5.20(dd,1H,J＝16.8,3.6Hz),4.73-4.96(m,3H),3.80-4.59(m,5H),2.97-3.82(m,5H),2.55(s,3H),2.44-2.95(m,4H),2.28-2.44(m,1H),1.86-2.16(m,4H).

EXAMPLE 39 synthetic route to Compound 43

Synthesis of Compound 43-e

Thionyl chloride (9.3g, 78.0mmol) was added dropwise to a solution of 36-f (4.0g, 11.1mmol) in DMF (40mL) and DCM (20mL) under an ice-water bath. After the addition, the reaction solution was stirred in an ice-water bath for 4 hours. Slowly dropping the reaction solution into 60mL of water, controlling the internal temperature to be 0-10 ℃, and extracting with DCM. And washing the organic phase with saturated sodium bicarbonate, washing with water, concentrating, adding n-heptane, pulping, cooling to 0-10 ℃, filtering and drying to obtain the compound 43-e (3.2g, 76%). LC-MS (ESI) M/z 377.0[ M + H ]]⁺The compound has a structure determined by single crystal analysis.

Synthesis of Compound 43-d

To a solution of 43-e (150mg, 0.40mmol) in DMF (10mL) at room temperature were added DIPEA (154.2mg, 1.19mmol) and (R) -benzyl 2-cyanomethylpiperazine-1-carboxylate hydrochloride (134mg, 0.52mmol), respectively. After the addition, the reaction solution was heated to 100 ℃ and stirred for two hours. After the reaction is finished, ethyl acetate is added for dilution, and the mixture is washed by water, saturated salt water, dried by anhydrous sodium sulfate, filtered and dried by spinning. The crude product was isolated and purified by flash column chromatography to give 43-d (0.2g, 84%) as a white solid. LC-MS (ESI) 600.0[ M + H ]]⁺.

Synthesis of Compound 43-c

Compound 43-d (0.2g, 0.33mmol) was dissolved in ethyl acetate (20mL) under ice-bath conditions, m-chloroperoxybenzoic acid (143.8mg, 0.83mmol) was added, and the mixture was allowed to warm to room temperature slowly and stirred for 2 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to neutralize, extracted with ethyl acetate (15mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column separation (PE/EA ═ 2/1) to afford 43-c (0.18g, 85%) as a white solid. LC-MS (ESI) M/z 632.0[ M +1 ] ]⁺.

Synthesis of Compound 43-b

To a solution of 43-c (180mg, 0.28mmol) and N-methyl-L-prolinol (65.6mg, 0.57mmol) in toluene (10mL) under ice-bath was added sodium tert-butoxide (54.7mg, 0.57 mmol). After the addition, the reaction solution was stirred for 10 minutes in an ice bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a brown oil, which was purified by flash column chromatography to obtain 43-b (150mg, 79%) as a white solid. LC-MS (ESI) M/z 667.2[ M + H ]]⁺.

Synthesis of Compound 43-a

To a solution of 43-b (150mg, 0.22mmol) in acetonitrile (20mL) at room temperatureTrimethyliodisilane (224.9mg, 1.12mmol) was added. After the addition, the reaction mixture was heated to 30 ℃ and stirred for 5 hours. After the reaction was complete, the reaction was neutralized with triethylamine (5mL) and concentrated under reduced pressure to give 43-a (80mg, 67%) as a dark gray solid. LC-MS (ESI) 533.2[ M + H ]]⁺.

Synthesis of Compound 43

To a solution of 43-a (80mg, 0.15mmol) and HATU (114.1mg, 0.30mmol) in DMF (5mL) at room temperature were added N, N-diisopropylethylamine (58.2mg, 0.45mmol) and acrylic acid (16.2mg, 0.23mmol), respectively. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give a crude product which was purified by silica gel column chromatography (DCM/MeOH 10/1) to give 43(40mg, 45%) as a white solid. LC-MS (ESI) M/z 587.3[ M + H ] ]⁺；¹H NMR(400MHz,CDCl₃):δ7.96(d,1H,J＝7.2Hz),7.84(t,2H,J＝9.2Hz),7.61(d,1H,J＝7.2Hz),7.56(t,1H,J＝8.0Hz),7.38(t,1H,J＝8.0Hz),6.53-6.75(m,1H),6.46-6.53(m,1H),6.36(d,1H,J＝16.4Hz),5.83(d,1H,J＝10.4Hz),4.82-5.03(m,3H),3.74-4.75(m,5H),3.23-3.71(m,6H),3.02-3.19(m,2H),2.95(s,3H),2.68-2.90(m,2H),2.01-2.30(m,4H).

EXAMPLE 40 synthetic route to Compound 44

Synthesis of Compound 44-a

To the compound glyoxylic acid (50% in H) at room temperature₂O, 2g, 13.5mmol) in acetone (20mL) was added morpholine hydrochloride (1.67g, 13.5 mmol). The reaction was stirred at room temperature for 1 hour and then heated under reflux overnight. After the reaction was completed, the mixture was concentrated to remove acetone. The crude product is diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 44-a (0.5g, 32%) as a white solid. LC-MS (ESI) 115.1[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆):δ13.12(bs,1H),6.80(d,1H,J＝16Hz),6.66(d,1H,J＝16Hz),2.34(s,3H).

Synthesis of Compound 44

Add N, N-diisopropylethylamine (36.4mg, 0.28mmol) and 44-a (10.1mg, 0.14mmol) respectively to a solution of 36-a (50mg, 0.094mmol) and HATU (71.3mg, 0.19mmol) in DMF (5 mL). The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give a crude product which was purified by silica gel column chromatography (DCM/MeOH 10/1) to afford compound 44(25mg, 42%) as a white solid. LC-MS (ESI) M/z 629.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.97(d,1H,J＝6.8Hz),7.83(t,2H,J＝8.8Hz),7.60(d,1H,J＝7.2Hz),7.56(t,1H,J＝4.0Hz),7.36(t,1H,J＝7.6Hz),7.07-7.17(m,1H),6.49-6.53(m,1H),4.51-5.14(m,3H),4.44(dd,1H,J＝10.4,5.2Hz),4.18(dd,1H,J＝10.8,2.4Hz),3.36-4.02(m,5H),2.64-3.30(m,7H),2.51(s,3H),2.38(s,3H),2.27-2.63(m,2H),2.00-2.13(m,1H),1.70-1.94(m,3H).

EXAMPLE 41 Synthesis of Compound 45

Synthesis of Compound 45-b

To a solution of 37-c (150mg, 0.25mmol) in dioxane (20mL) was added N, N-dimethylethylenediamine (110.5mg, 1.25mmol) at room temperature. The reaction was heated to reflux overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 45-b (130mg, 85%) as a white solid. LC-MS (ESI) M/z 606.2[ M + H ] ]⁺.

Synthesis of Compound 45-a

To a solution of 45-b (130mg, 0.21mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, concentration was performed, the pH was carefully neutralized with a saturated solution of sodium hydrogencarbonate in an ice bath to more than 7, extraction was performed with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 45-a (80mg, 74%) as an amber oil as a productAnd (4) forming a substance. LC-MS (ESI) 506.2[ M +1 ]]⁺.

Synthesis of Compound 45

To a solution of 45-a (80mg, 0.16mmol) and HATU (120.2mg, 0.32mmol) in DMF (5mL) at room temperature were added DIPEA (61.3mg, 0.48mmol) and acrylic acid (17.1mg, 0.24mmol), respectively. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give a crude product which was purified by silica gel column chromatography (DCM/MeOH 10/1) to give 45(15mg, 17%) as a white solid. LC-MS (ESI) 560.2[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃):δ7.98(d,1H,J＝7.6Hz),7.82(t,2H,J＝7.6Hz),7.52-7.61(m,2H),7.36(t,1H,J＝7.6Hz),6.52-6.66(m,1H),6.48(dd,1H,J＝10.8,3.2Hz),6.38(d,1H,J＝16.4Hz),5.77-5.86(m,1H),5.42-5.55(m,1H),4.47-5.15(m,3H),3.25-4.06(m,8H),2.89-3.09(m,1H),2.59-2.88(m,5H),2.41(s,6H).

EXAMPLE 42 Synthesis of Compound 46

Synthesis of Compound 46-b

To a solution of 37-c (200mg, 0.33mmol) in acetonitrile (20mL) was added 2-dimethylaminoethanethiol hydrochloride (236.8mg, 1.67mmol) and triethylamine (338.4mg, 3.34mmol) at room temperature. After the addition, the reaction solution was heated under reflux overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a brown oil, which was purified by flash column chromatography to give 46-b (100mg, 48%) as a white solid. LC-MS (ESI) M/z 623.2[ M + H ] ]⁺.

Synthesis of Compound 46-a

To a solution of 46-b (100mg, 0.16mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was concentrated, neutralized with a saturated solution of sodium hydrogencarbonate in ice bath to a pH of more than 7, extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfateDrying, filtration and concentration gave product 46-a (70mg, 83%) as an amber oil. LC-MS (ESI) 523.0[ M +1 ]]⁺.

Synthesis of Compound 46

Add DIPEA (51.9mg, 0.40mmol) and acrylic acid (14.5mg, 0.20mmol) to a solution of 46-a (70mg, 0.16mmol) and HATU (101.8mg, 0.27mmol) in DMF (5mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, solid was precipitated by addition of gentle water, collected by filtration and washed with water to give a crude product which was purified by silica gel column chromatography (DCM/MeOH 10/1) to give 46(15mg, 19%) as a white solid. LC-MS (ESI) M/z 577.2[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆):δ7.95-8.04(m,3H),7.65-7.74(m,2H),7.46-7.55(m,1H),6.78-6.98(m,1H),6.34-6.47(m,1H),5.76-6.21(m,1H),4.54-5.16(m,3H),3.78-4.49(m,3H),3.37-3.77(m,6H),3.02-3.28(m,6H),2.61-3.04(m,7H),2.26-2.43(m,1H).

EXAMPLE 43 Synthesis of comparative Compound 3

Comparative compound 3' was synthesized according to the method of WO2019155399A 1.

Effect example 1 detection of proliferation inhibition of Compounds on NCI-H358, A549 and A375 cell lines by CTG method

NCI-H358 was a human non-small cell lung cancer cell with KRAS G12C mutation, a549 was a human non-small cell lung cancer cell with KRAS G12V mutation, a375 was a wild-type malignant melanoma cell. The inhibition of different mutations by the compounds was evaluated by examining their proliferation inhibitory activity on three cell lines.

To 3 384-well plates (except for peripheral wells) was added 40. mu.L of each of the test cell suspensions (plate 1: NCI-H358 cell suspension, plate 2: A549 cell suspension, plate 3: A375 cell suspension). The plates were placed in a carbon dioxide incubator overnight. The prepared compound (10 concentration gradients of compound obtained by 3-fold dilution) was added to each well. Cell plate in carbon dioxide incubatorAnd (4) incubating for 120 hours. To a 384 well plate 25. mu.L of CellTiter Glo reagent was added, shaken for 10 minutes in the dark, and incubated for 10 minutes. Place the plate in an EnVision read plate, draw a pharmacodynamic inhibition curve using XLFit and calculate IC₅₀The value is obtained. The activity results for representative compounds are shown in table 1. Wherein, the "IC₅₀>1 μ M "by" "," IC₅₀≦ 1 μ M "indicated by". x ". "- - -" indicates not measured.

Table 1 proliferation inhibitory activity of representative compounds of the present invention on H358 cells, a549 cells and a375 cells

From the results of the above tests, it was confirmed that the compound of the present invention had a significant cell proliferation inhibitory effect on NCI-H358 cells, but had a weak cell proliferation inhibitory activity on a549 cells and a375 cells.

And activity comparison was carried out by pyranopyrimidine skeleton compounds 2-2 and 18-2 of the present invention with the corresponding piperidinopyrimidine skeleton compounds comparative compound 1 'and comparative compound 2'. From the results, the activity of compound 2-2 was significantly superior to that of the corresponding comparative compound 1 ', and the activity of compound 18-2 was significantly superior to that of the corresponding comparative compound 2'.

Effect example 2

Experiment for detecting proliferation inhibition of compound on NCI-H358 cell line by CTG method

Operation same as in example 1

Experiment for detecting compound proliferation inhibition on MIA PaCa-2 cell line by CTG method

Add 40. mu.L of MIA PaCa-2 fine to 384 well plates (except for peripheral wells)And (3) suspending the cells. The plates were placed in a carbon dioxide incubator overnight. The prepared compound (10 concentration gradients of compound obtained by 3-fold dilution) was added to each well. The cell plates were incubated in a carbon dioxide incubator for 120 hours. To a 384 well plate 25. mu.L of CellTiter Glo reagent was added, shaken for 10 minutes in the dark, and incubated for 10 minutes. Place the plate in an EnVision read plate, draw a pharmacodynamic inhibition curve using XLFit and calculate IC ₅₀The value is obtained. The activity results for representative compounds are shown in table 1. Wherein, the "IC₅₀>1 μ M "by" "," IC₅₀≦ 1 μ M "indicated by". x ". "- - -" indicates not measured.

MIA PaCa-2 is a human pancreatic cancer cell with KRAS G12C mutation, and the activity of a compound can be evaluated by detecting the proliferation-inhibiting activity of the compound on the cell line.

TABLE 2 proliferation inhibitory Activity of representative compounds of the invention on H358 and MIA PaCa-2 cells

From the results, the activity of compound 2-2 is significantly better than that of the corresponding comparative compounds 1 'and 3'. Compound 18-2 is significantly superior in activity to the corresponding comparative compound 2'.

Effect example 3 in vitro Metabolic enzyme inhibitory Activity

The purpose of the test is as follows: the test utilizes human liver microsomes and CYP enzyme specific substrates to detect the influence of the tested compound on the metabolism speed of the enzyme specific substrates under different concentrations, so as to determine the inhibition effect of the tested compound on the CYP enzyme in the human liver microsomes.

The operation process is as follows:

1. 100mM potassium phosphate buffer (pH7.4) was prepared.

2. Stock solutions of test compounds (10mM), NADPH solution (8mM, 4-fold final concentration), stock solutions of positive compounds, stock solutions of substrates, and human liver microsome solutions were prepared (see Table below).

3. Preparation of test compound solutions: mu.L of a 10mM stock of test compound was dissolved in 12. mu.L acetonitrile and then diluted with a gradient 1:3 mixture of 40% DMSO and 60% acetonitrile (concentration 400-fold of final concentration): 4mM, 1.333mM, 0.444mM, 0.148mM, 0.0494mM, 0.0165mM, 0.00549mM, 0 mM.

4. Preparing a positive control inhibitor solution: mu.L of the positive control inhibitor stock was dissolved in 12. mu.L acetonitrile and then diluted with a gradient of 40% DMSO to 60% acetonitrile 1:3 (concentration 400-fold the final concentration, see Table below).

5. Preparing a mixed solution of the test compound and human liver microsomes: mu.L of 0.2mg/mL human liver microsomes was added to a 96-well plate, and 2. mu.L of a 400-fold test compound solution was added.

6. Preparing a mixed solution of a positive control compound and human liver microsomes: 200. mu.L of 0.2mg/mL human liver microsomes were added to a 96-well plate, and 1. mu.L of the diluted positive control compound solution was added.

7. mu.L of the mixed solution of the compound and human liver microsomes was dispensed into a 96-well plate, and then 15. mu.L of the substrate solution was added. mu.L of the preheated NADPH solution was added to the preheated reaction plate, mixed well and the reaction was started.

The reaction plates were incubated at 8.37 ℃. 3A4 for 5 minutes; 1A2, 2C9, 2D6 for 10 min; 2C19 for 45 minutes.

9. At the end of the reaction, 120. mu.L of acetonitrile containing an internal standard was added to terminate the reaction. After termination of the reaction the sample was shaken for 10 minutes at 600 rpm on a shaker and centrifuged for 15 minutes at 3220 Xg. After centrifugation, 50. mu.L of the supernatant was removed, mixed with 50. mu.L of water and analyzed by LC-MS/MS.

Data processing:

data were generated using a dose-response model of GraphPad Prism software according to the equation belowFitting to the plot and calculating IC₅₀。

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)×HillSlope))

X represents the log concentration of inhibitor and Y is the relative activity of the enzyme at a certain inhibitor concentration (relative to the absence of inhibitor).

And (3) test results:

as a result, the IC for inhibiting each of the CYP isozymes (1A2,2C9,2C19,2D6,3A4) was determined to be 18-2₅₀Are respectively as>10、>10、>10、>10、>10, weak Inhibition (IC) against each metabolic enzyme₅₀>10 μmol/L) better than the compounds MRTX849 and AMG-510 currently in clinical use.

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims

1. An oxygen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, wherein:

m is 0, 1 or 2;

R⁵independently is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

G is N, C or CH;

n is 0, 1, 2 or 3;

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, orR is^10j、R^10kAnd N connected therewith to form a "4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms which are one or more of O and N".

2. The oxygen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof of claim 1, wherein R is¹Is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R ^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N; r^1-6And R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

and/or, m is 0;

and/or, R³is-OR³¹or-NR³³R³⁴；R³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r^31-1Independently by one or more R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR^e1R^e2；R^d15Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C_1-6Alkoxy, halogen, -NR^e5R^e6or-C (═ O) NR^e7R^e8；R^1-8-1Independently is halogen; r^e5、R^e6、R^e7And R^e8Independently is hydrogen or C_1-6An alkyl group; r^e1And R^e2Independently is C_1-6An alkyl group;

and/or ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic or spiro; g is N, C or CH;

and/or n is 0 or 1; r⁴Independently is C_1-6Alkyl, or substituted by one or more R^4-1Substituted C_1-6An alkyl group; r^4-1Independently is cyano;

And/or, R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O)₂-C(R^a)＝C(R^b)(R^f)；R^aIndependently hydrogen or halogen; r^bAnd R^fIndependently of one another is hydrogen, C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group; r^b-1Independently of one another is halogen, hydroxy, C_1-6Alkoxy, or, -NR^10jR^10k；R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N attached to it together form a "4-to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms, which is one or more of O and N".

3. The oxygen-containing heterocyclic compound of formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound of claim 2, wherein R is¹Is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group; r^1-6Independently of one another, halogen, C_1-6Alkyl, or substituted by one or more R^1-6-1Substituted C_1-6An alkyl group; r^1-6-1Independently is halogen;

and/or, R³is-OR³¹or-NR³³R³⁴；R³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r^31-1Independently by one or more R^d15SubstitutionA 5-to 7-membered heterocycloalkyl group containing 1 to 3 hetero atoms which are one or more of O and N, or-NR^e1R^e2；R^e1、R^e2And R^d15Independently is C_1-6An alkyl group;

and/or ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms; the heterocyclic ring is a saturated heterocyclic ring or a partially saturated heterocyclic ring; the heterocyclic ring is monocyclic; g is N;

and/or, R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；R^aIndependently hydrogen or halogen; r^bAnd R^fIndependently is hydrogen or C_1-6An alkyl group.

4. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 1,

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N; r^1-6And R^1-7Independently of one another, halogen, C_1-6Alkyl, or substituted by one or more R^1-6-1Substituted C_1-6An alkyl group; r^1-6-1Independently is halogen;

and/or, R³is-OR³¹、-SR³²or-NR³³R³⁴；R³¹、R³²And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl, or substituted by one or more R^31-1Substituted C_1-6An alkyl group; r^31-1Independently by one or more R^d15Substituted 5-to 7-membered heterocycloalkyl containing 1 to 3 hetero atoms which are one or more of O and N, or-NR ^e1R^e2；R^d15Independently is C_1-6Alkyl or halogen; r^e1And R^e2Independently is C_1-6An alkyl group;

and/or n is 0 or 1; r⁴Independently is C_1-6Alkyl, or substituted by one or more R^4-1Substituted C_1-6An alkyl group; r^4-1Independently is hydroxy, cyano, or, -C (═ O) NR^4eR^4f；R^4eAnd R^4fIndependently is hydrogen or C_1-6An alkyl group;

and/or, R²Is CN, -C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O)₂-C(R^a)＝C(R^b)(R^f)；R^aIndependently hydrogen or halogen; r^bAnd R^fIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, or, substituted with one or more R^b-1Substituted C_1-6An alkyl group; r^b-1Independently is-NR^10jR^10k；R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N attached to it together form a "4-to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms, which is one or more of O and N".

5. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 1,

R³is-OR³¹or-NR³³R³⁴；R³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r^31-1Independently by one or more R^d15Substituted "containing 1-3 heteroatoms, which are one of O and NOne or more kinds of 5-to 7-membered heterocycloalkyl groups, or-NR ^e1R^e2；R^d15Independently is C_1-6Alkyl or halogen; r^e1And R^e2Independently is C_1-6An alkyl group;

and/or n is 0 or 1; r⁴Independently is C_1-6Alkyl, or substituted by one or more R^4-1Substituted C_1-6An alkyl group; r^4-1Independently is hydroxy or cyano;

and/or, R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f) -C (═ O) -C.ident.C-Me or, -S (═ O)₂-C(R^a)＝C(R^b)(R^f)；R^aIndependently hydrogen or halogen; r^bAnd R^fIndependently of one another is hydrogen, C_1-6Alkyl, or substituted by one or more R^b-1Substituted C_1-6An alkyl group; r^b-1Independently is-NR^10jR^10k；R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N attached to it together form a "4-to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms, which is one or more of O and N".

6. The oxygen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof of claim 1, wherein the oxygen-containing heterocyclic compound of formula I is defined as scheme 1, scheme 2, scheme 3, scheme 4, scheme 5, scheme 6, or scheme 7:

scheme 1:

R¹is C_6-20Aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from one or more of O, S and N, and one or more R^1-6Substituted C_6-20Aryl, or, by one or more R ^1-7Substituted 5-12 membered heteroaryl containing 1-4 heteroatoms, wherein the heteroatoms are one or more of O, S and N;

R^1-6and R^1-7Independently halogen, hydroxy、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N, C or CH;

n is 0 or 1;

R^4-1independently is cyano;

R^aIndependently hydrogen or halogen;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N connected with the N to form a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms are one or more of O and N;

scheme 2:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^e1、R^e2And R^d15Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^bAnd R^fIndependently is hydrogen or C_1-6An alkyl group;

scheme 3:

R^1-6and R^1-7Independently of one another is halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-1Substituted C_1-6Alkyl, or substituted by one or more R^1-6-2Substituted C_1-6An alkoxy group; r^1-6-1And R^1-6-2Independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C_1-6Alkoxy radical,Halogen, -NR^e5R^e6or-C (═ O) NR^e7R^e8；

R^e1and R^e2Independently is C_1-6An alkyl group;

G is N, C or CH;

n is 0 or 1;

R^4-1independently cyano or hydroxy;

R^aIndependently hydrogen or halogen;

scheme 4:

R¹is C_6-20Aryl, or, by one or more R^1-6Substituted C_6-20An aryl group;

R^1-6independently of one another, halogen, C_1-6Alkyl, or, by oneOr a plurality of R^1-6-1Substituted C_1-6An alkyl group;

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹or-NR³³R³⁴；

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

G is N;

n is 0 or 1;

R^4-1independently is cyano;

R²is-C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

R^b-1independently is-NR^10jR^10k；

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R^10j、R^10kAnd N connected therewith to form a compound containing 1-3 hetero atoms of one or more of O and N4-to 10-membered heterocycloalkyl group of (a);

scheme 5:

R^1-6and R^1-7Independently halogen, hydroxy, -C (═ O) R⁶⁵、-NR⁶³R⁶⁴、-C(＝O)OR⁶⁶、-C(＝O)NR⁶⁹R⁶¹⁰、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl, 5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O and N, and C_6-20Aryl, 5-to 7-membered heteroaryl containing 1 or 2 heteroatoms, which is one or more of O and N, and one or more R^1-6-1Substituted C _1-6Alkyl, by one or more R^1-6-2Substituted C_1-6Alkoxy, by one or more R^1-6-3Substituted C_3-10Cycloalkyl radicals, substituted by one or more R^1-6-4Substituted '5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms which are one or more of O and N', substituted with one or more R^1-6-5Substituted C_6-20Aryl, or, by one or more R^1-6-6Substituted 5-7 membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are one or more of O and N;

m is 0, 1 or 2;

R⁵independently is C_1-6An alkyl group;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R^d15And R^d16Independently is C_1-6Alkyl, by one or more R^1-8-1Substituted C_1-6Alkyl, hydroxy, C _1-6Alkoxy, halogen, -NR^e5R^e6or-C (═ O) NR^e7R^e8；

g is N, C or CH;

n is 0, 1, 2 or 3;

R^4a、R^4band R^4cIndependently is hydrogen or C_1-6An alkyl group;

R^aIndependently hydrogen, deuterium, halogen or C_1-6An alkyl group;

R^10jAnd R^10kIndependently is hydrogen or C_1-6Alkyl, or, R ^10j、R^10kAnd withN connected with the above form a 4-to 10-membered heterocycloalkyl group containing 1 to 3 hetero atoms, the hetero atoms being one or more of O and N;

scheme 6:

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group;

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

G is N, C or CH;

n is 0 or 1;

R^aIndependently hydrogen or halogen;

scheme 7:

R^1-6-1independently is halogen;

m is 0;

R³is-OR³¹、-SR³²or-NR³³R³⁴；

R³¹、R³²And R³⁴Independently by one or more R ^31-1Substituted C_1-6An alkyl group; r³³Independently H, C_1-6Alkyl or by one or more R^31-1Substituted C_1-6An alkyl group;

R^d15Independently is C_1-6Alkyl or halogen;

R^e1and R^e2Independently is C_1-6An alkyl group;

g is N;

n is 0 or 1;

R⁴independently by one or more R^4-1Substituted C_1-6An alkyl group;

R²is CN, -C (═ O) -C (R)^a)＝C(R^b)(R^f)；

R^aIndependently hydrogen or halogen;

7. The oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotopic compound thereof according to any one of claims 1 to 6, wherein the structure of the oxygen-containing heterocyclic compound shown in the formula I is as follows:

in a molar ratio such as 1: 1 ";

and/or, when said R is¹Is C_6-20When aryl, said C _6-20Aryl is phenyl or naphthyl;

and/or, when said R is¹When the heteroaryl group is a 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N, the 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N is a 9-10 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N;

and/or, when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said C_6-20Aryl is phenyl or naphthyl;

and/or, when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said plurality is 2 or 3;

and/or, when said R is^1-6When independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or, when said R is^1-6Independently is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said plurality is 2 or 3;

and/or, when said R is^1-6-1When independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

And/or, when said R is³¹、R³³And R³⁴Independently by one or more R^31-1SubstitutionC of (A)_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said plurality is 2 or 3;

and/or, when said R is^31-1Independently by one or more R^d15When the substituted '4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N', the '4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N' is '5-to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N';

and/or, when said R is^31-1Independently by one or more R^d15When the substituted '4-10 membered heterocycloalkyl containing 1-3 heteroatoms which are one or more of O and N', the number of the heteroatoms is 2 or 3;

and/or, when said R is^d15Independently is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is^d15When independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or, when said R is^e1And R^e2Independently is C_1-6When alkyl, said C _1-6Alkyl is C_1-4An alkyl group;

and/or when the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms, the 4-12 membered heterocyclic ring containing 1-4N atoms is a 6-9 membered heterocyclic ring containing 1-2N atoms;

and/or, when said R is⁴Independently is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said plurality is 2 or 3;

and/or, when said R is^aWhen independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or, when said R is^bAnd R^fIndependently is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When alkyl, said plurality is 2 or 3;

and/or, when said R is^10jAnd R^10kIndependently is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

8. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 7, wherein when R is ¹When the aryl group is a 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N, the 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N is an isoquinolyl group;

and/or, when said R is¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said C_6-20Aryl is phenyl or 1-naphthyl;

and/or, when said R is^1-6When independently halogen, said halogen is fluorine or chlorine;

and/or, when said R is^1-6Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^1-6-1When independently halogen, said halogen is fluorine;

and/or, when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, when said R is^31-1Independently by one or more R^d15When the substituted '4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N', the '4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N' is '5-to 7-membered heterocycloalkyl containing 1 heteroatom and one or more of O and N';

and/or, when said R is^d15Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^d15When independently halogen, said halogen is fluorine;

and/or, when said R is^e1And R^e2Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when the ring Y is a 4-12 membered heterocyclic ring containing 1-4N atoms, the 4-12 membered heterocyclic ring containing 1-4N atoms is

Its upper end and R²Connecting;

and/or, when said R is⁴Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^aWhen independently halogen, said halogen is fluorine;

and/or, when said R is^bAnd R^fIndependently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or, when said R is^10jAnd R^10kIndependently is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

9. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof of claim 8, wherein when R is¹When the aryl group is a 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N, the aryl group is a 5-12 membered heteroaryl group containing 1-4 heteroatoms and one or more of O, S and N

And/or, when said R is^1-6Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is^1-6Independently by one or more R^1-6-1Substituted C_1-6When alkyl, said is substituted by one or more R^1-6-1Substituted C_1-6Alkyl is trifluoromethyl;

and/or, when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or, when said R is^31-1Independently by one or more R^d15When the substituted 4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N is used, the 4-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms and one or more of O and N is tetrahydropyrrole;

and/or, when said R is^d15Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is^e1And R^e2Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl or ethyl;

and/or the structure of the oxygen-containing heterocyclic compound shown in the formula I is as follows:

and/or, when said R is⁴Independently is C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is⁴Independently by one or more R ^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is^bAnd R^fIndependently is C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is^bAnd R^fIndependently by one or more R^b-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl;

and/or, when said R is^10jAnd R^10kIndependently is C_1-6When alkyl, said C_1-6The alkyl group is a methyl group.

10. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 9,

and/or, when said R is³³Independently is C_1-6When alkyl, said C_1-6The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and can also be methyl, ethyl, n-propyl or isopropyl;

and/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R^4-1Substituted C_1-6Alkyl is hydroxymethyl, cyanomethyl or

And/or, when said R is^bAnd R^fIndependently is C_1-6When alkyl-C (═ O) -, said C_1-6C in alkyl-C (═ O) -) _1-6The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and can also be methyl;

and/or, said R²Is CN,

11. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 9,

And/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R^4-1Substituted C_1-6Alkyl is hydroxymethyl or cyanomethyl;

and/or, when said R is^10jAnd R^10kAnd N connected with the N to form a 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms and one or more of O and N, the 4-to 10-membered heterocycloalkyl containing 1 to 3 hetero atoms and one or more of O and N is a 5-to 6-membered heterocycloalkyl containing 2 hetero atoms and one or more of O and N

And/or, said R²Is composed of

12. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof of claim 9, wherein when R is said ¹Is represented by one or more R^1-6Substituted C_6-20When aryl, said is substituted by one or more R^1-6Substituted C_6-20Aryl is

And/or, when said R is³¹、R³³And R³⁴Independently by one or more R^31-1Substituted C_1-6When alkyl, said is substituted by one or more R^31-1Substituted C_1-6Alkyl is

And/or, when said R is⁴Independently by one or more R^4-1Substituted C_1-6When alkyl, said is substituted by one or more R^4-1Substituted C_1-6Alkyl is cyanomethyl;

and/or, said R²Is composed of

13. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof of claim 1, wherein the oxygen-containing heterocyclic compound represented by the formula I has any one of the following structures:

14. the oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 1, wherein the oxygen-containing heterocyclic compound represented by the formula I is any one of the following compounds:

compounds with a retention time of 0.92min under the following conditions

SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO ₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.74min under the following conditions

compounds with a retention time of 0.97min under the following conditions

DeviceSFC Method Station (Thar, Waters); chromatographic column AD-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂ETOH (0.5% TEA) 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 2.40min under the following conditions

a compound having a retention time of 0.97min under the following conditions:

Compounds with a retention time of 1.94min under the following conditions

compounds with a retention time of 1.22min under the following conditions

compound with retention time of 2.67min under the following conditions

compound with retention time of 3.26min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column R, R-WHELK-O14.6 x 100mm,5 μm (REGIS); the column temperature is 40 ℃; mobile phase CO2/(MeOH/ACN ═ 3:2 (0.1% TEA)) ═ 55/45; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 4.16min under the following conditions

compounds with a retention time of 1.36min under the following conditions

compound with retention time of 2.77min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column OJ-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 60/40; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back of bodyThe pressure is 120 bar;

compounds with a retention time of 1.17min under the following conditions

compound with retention time of 2.76min under the following conditions

compounds with a retention time of 0.78min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatographic column AD-H4.6 × 100mm,5 μm (Daicel); the column temperature is 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compound with retention time of 2.42min under the following conditions

compounds with a retention time of 0.79min under the following conditions

Instrument SFC Method Station (Thar, Waters); chromatography column OD-H4.6 x 100mm,5 μm (Daicel); column temperatureAt the temperature of 40 ℃; mobile phase of CO₂MeOH (0.1% TEA) ═ 65/35; the flow rate is 4.0 ml/min; the wavelength is 254 nm; back pressure of 120 bar;

compounds with a retention time of 2.29min under the following conditions

Compounds with a retention time of 1.45min under the following conditions

compounds with a retention time of 2.81min under the following conditions

15. The oxygen-containing heterocyclic compound represented by the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 1, wherein the oxygen-containing heterocyclic compound represented by the formula I is any one of the following compounds:

16. a method for preparing the oxygen-containing heterocyclic compound shown in the formula I according to any one of claims 1 to 15, which is a route one or a route two:

route one

Wherein, X₁Is a leaving group, Alk is an alkyl group, PG is an amino protecting group;

on the second route, the first route is,

wherein, X₃PG is an amino protecting group for a leaving group.

17. A compound of formula a5, a6, a7, A8, a9, a10, C1, C2, C3, C4 or C5;

Wherein R is¹、R³、R⁴G, Y and n are as defined in any one of claims 1 to 15;

X¹and X³Independently is a leaving group, PG is an amino protecting group; for example, the compound represented by formula a5, a6, a7, A8, a9, a10, C1, C2, C3, C4 or C5 is any one of the following compounds:

18. a pharmaceutical composition comprising substance a and a pharmaceutical excipient; the substance A is the oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotope compound thereof according to any one of claims 1 to 15.

19. The application of a substance A in preparing a RAS inhibitor is the oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotopic compound thereof according to any one of claims 1-15.

20. Use of substance a in the manufacture of a medicament for the treatment or prevention of a RAS-mediated disease; alternatively, the medicament is for treating or preventing cancer;

the substance A is the oxygen-containing heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof or isotope compound thereof according to any one of claims 1 to 15.