WO2023280280A1 - Fused-ring compound that acts as kras g12d inhibitor - Google Patents

Abstract

A fused-ring compound that acts as a KRas G12D inhibitor, specifically, the present invention relates to a compound represented by general formula (1) and a preparation method therefor, as well as a use of the compound represented by general formula (1) and isomers, crystal forms, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as a KRas G12D inhibitor. The compound and the isomers, crystal forms, pharmaceutically acceptable salt, hydrate or solvate thereof can be used for preparing a drug for treating or preventing related diseases mediated by KRas G12D.

Description

Fused ring compounds as KRas G12D inhibitors

This application claims the priority of Chinese patent application 2021107672086 with a filing date of July 7, 2021. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The present invention relates to the field of medicinal chemistry, and more specifically, relates to a class of fused-ring compounds with KRas G12D protein inhibitory effect, a preparation method thereof, and the use of such compounds for preparing, treating, regulating or preventing related diseases mediated by KRas G12D. Application in the medicine of disease.

Background technique

KRas (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) is a class of GTPases and a member of the oncogene Ras family. In cells, Kras protein has a GDP-bound form (inactive form) and a GTP-bound form (activated form), and these two forms of KRas protein will be transformed into each other to transduce the activation signals of various upstream tyrosine kinases to downstream effector proteins to regulate a series of important physiological functions, such as cell proliferation.

Studies in the past three decades have shown that the activated form of KRas protein plays a key role in tumorigenesis. About 20% of all cancers are associated with abnormal expression of KRas protein. Oncogenic KRas mutations can stabilize the binding of GTP to KRas mutant proteins, resulting in the sustained activation of KRas proteins and downstream signaling pathways. Studies have reported that up to 25-30% of lung adenocarcinomas have such KRas mutations. The KRas G12D mutation is the most common KRas mutation. Studies have shown that 25% of pancreatic ductal carcinoma patients, 13.3% of colon adenocarcinoma patients, 10.1% of rectal adenocarcinoma patients, 4.1% of non-small cell lung cancer patients and 1.7% of small cell lung cancer patients have KRas G12D mutation.

The important role of KRas in carcinogenesis and the discovery of common KRas mutations in numerous tumors make KRas a very attractive target. Although a large number of studies have attempted to find KRas inhibitors in the past 30 years, except for KRas G12C irreversible inhibitors that have observed efficacy in clinical trials, so far no other KRas inhibitors have shown outstanding efficacy and safety in clinical trials.

Therefore, the development of specific and highly active KRas G12D small molecule inhibitors has important clinical value for the treatment of tumors with KRas G12D mutations.

Contents of the invention

The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

R ¹ is -H, -OH, halogen, (C1-C3) alkyl, (C1-C3) alkyl substituted by nitrile, (C1-C3) alkyl substituted by hydroxy, HC(=O)-, - CO ₂ R ⁵ , -CO ₂ N(R ⁵ ) ₂ or (5-6 member) heteroaryl;

Y is 0 or NR ⁵ ;

Ring A is phenyl, (5-7 membered) heteroaryl, (C5-C7) cycloalkyl or (5-7 membered) heterocycloalkyl;

Each R is independently -H, halogen, (C1 ^- C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member ) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member) heteroaryl can each independently be optionally substituted by 1, 2, 3 or 4 R ⁶ ;

Each ^R3 is independently -H, halogen, -OH, (C1-C3) alkyl, (C1-C3) alkyl substituted with hydroxy, (C1-C3) haloalkyl, (C1-C3) alkoxy , (5-7 membered) heteroaryl, -CN, -SO ₂ F,

NHC(O)R ⁸ , -N(R ⁵ ) ₂ ,

-CH ₂ OC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)OR ⁷ , -CH ₂ NHC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)R ⁷ , -CH ₂ NHS(O) ₂ R ⁷ , -CH ₂ OC(O)R ⁸ , -OC(O)N(R ⁵ ) ₂ , -OC(O)NH(CH ₂ ) _m OR ⁷ , -OC(O) NH(CH ₂ ) _m O(CH ₂ ) _n R ⁸ , -OC(O)R ⁸ , -CH ₂ R ⁸ , wherein the (C1-C3) alkyl, hydroxyl substituted (C1-C3) alkyl , (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-7) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen , R ⁷ and R ⁸ ; or when two R ³ are connected to the same atom, two R ³ can form an oxo group;

Q is a chemical bond or O;

Ring B is (C5-C7) cycloalkyl, phenyl, (5-7 member) heteroaryl or (5-7 member) heterocycloalkyl;

Each R ⁴ is independently -H, -D, halogen, R ⁹ , -OH, -(CH ₂ ) _n OR ⁹ , -(CH ₂ ) _n NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ R ¹⁰ , -CN, -C(O)NR ⁹ R ¹⁰ , -NR ¹⁰ C(O)R ⁹ , -NR ¹⁰ S(O) ₂ R ⁹ , -S(O) _p R ⁹ , -S(O) ₂ NR ⁹ R ¹⁰ , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein ( C1-C6) Alkyl, (C1-C6) Haloalkyl, (C2-C6) Alkenyl, (C2-C6) Alkynyl or (C3-C9) Cycloalkyl can be independently optionally replaced by 1,2,3 Or substituted by 4 of the following groups: -H, halogen, R ⁷ , -OH, -(CH ₂ ) _n OR ⁷ , -(CH ₂ ) _n N(R ⁷ ) ₂ , -OR ⁷ , -N(R ⁷ ) ₂ , -CN, -C(O)N(R ⁷ ) ₂ , -NR ⁷ C(O)R ⁷ , -NR ⁷ S(O) ₂ R ⁷ , -S(O) _p R ⁷ and -S (O) ₂ N(R ⁷ ) ₂ ; or when two R ⁴ are connected to the same atom, two R ⁴ can form an oxo group;

each R is independently -H or (C1 ^- C3) alkyl;

R ⁶ is -H, halogen, -OH, -CN, -OR ⁷ , -SR ⁷ , (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7 Yuan) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy, -CH ₂ C(=O)N(R ⁵ ) ₂ , -N(R ⁵ ) ₂ or (C3-C6 ) cycloalkyl, wherein said (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7) heteroaryl, (C1-C4) haloalkyl, (C1-C4)alkoxy or (C3-C6)cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, halogen, -OH, _-NH2 , -CN and R ⁷ ;

Each R is independently (C1 ^- C6) alkyl, (C1-C6) haloalkyl or (C1-C3) alkoxy;

Each R is independently ( ^5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl, wherein the (5-7 membered) heterocycloalkyl, (5-7 membered )heteroaryl or phenyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -CN, -C(O)H, -(CH ₂ ) _n OR ⁷ and -(CH ₂ ) _n N(R ⁷ ) ₂ ;

R ⁹ and R ¹⁰ are each independently -H, (C1-C6) alkyl or (C3-C7) cycloalkyl, or R ⁹ and R ¹⁰ on the same nitrogen atom and the N atom they are connected to can jointly Constitutes a (3-7 membered) heterocycloalkyl group, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C3) alkyl, (C3- C5) cycloalkyl or (C1-C3) alkoxy; and

p is an integer of 0, 1 or 2, r is an integer of 1, 2, 3 or 4, s is an integer of 0, 1, 2, 3 or 4, t is an integer of 0, 1, 2, 3 or 4, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

In another preferred example, wherein in the general formula (1), R ¹ is -H, -OH, -F,

HC(=O)-, -CO ₂ CH ₃ or -CO ₂ N(CH ₃ ) ₂ .

In another preferred example, in the general formula (1), Y is O, NH or NCH ₃ .

In another preferred example, in the general formula (1), ring A is phenyl, 6-membered heteroaryl, cyclohexyl or (5-6-membered) heterocycloalkyl.

In another preferred example, in the general formula (1), ring A is:

The end marked with * is connected to a nitrogen atom.

In another preferred example, in the general formula (1), each R ² is independently -H, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1- C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl , (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, - F, -Cl, -Br, -I, -OH, -CN, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ CF ₃ , - SCH ₃ , -SCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -NH ₂ , -NH(CH ₃ ),

-SCF ₃ ,

In another preferred example, in the general formula (1), the structural unit

for:

In another preferred example, in the general formula (1), each R ³ is independently -H, -OH, -F, -Cl, -Br, -I, (C1-C3) alkyl, Hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-6) heteroaryl, -CN,

NHC(O)R ⁸ , -N(R ⁵ ) ₂ , -CH ₂ OC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)OR ⁷ , -CH ₂ NHC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)R ⁷ , -CH ₂ NHS(O) ₂ R ⁷ , -CH ₂ OC(O)R ⁸ , -OC(O)N(R ⁵ ) ₂ , -OC(O )NH(CH ₂ ) _m OR ⁷ , -OC(O)NH(CH ₂ ) _m O(CH ₂ ) _n R ⁸ , -OC(O)R ⁸ , -CH ₂ R ⁸ , wherein the (C1- C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-6 member) heteroaryl can be independently optionally replaced by 1, 2, 3 or 4 of the following groups are substituted: -H, -F, -CH ₃ , -OCH ₃ or -CH ₂ CH ₃ ; or when two R ³ are connected to the same atom, two R ³ can form an oxo group.

In another preferred example, in the general formula (1), each R ³ is independently: -H, -OH, -F, -Cl, -Br, -I, -CN, -SO ₂ F , -OCH ₃ , -CF ₃ ,

In another preferred example, in the general formula (1), ring B is (C5-C6) cycloalkyl, phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocyclic alkyl.

In another preferred example, in the general formula (1), ring B is:

The end marked with * is connected to a nitrogen atom.

In another preferred example, in the general formula (1), each R ⁴ is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OR ⁹ , -CH ₂ NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ R ¹⁰ , -CN, -C(O)NR ⁹ R ¹⁰ , -NR ¹⁰ C(O)R ⁹ , -NR ¹⁰ S(O) ₂ R ⁹ , -SR ⁹ , -S(O) ₂ R ⁹ , -S(O) ₂ NR ⁹ R ¹⁰ , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) Alkynyl or (C3-C6)cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH _3. -N(CH ₃ ) ₂ and -CN; or when two R ⁴ are connected to the same atom, the two R ⁴ can form an oxo group.

In another preferred example, in the general formula (1), each R ⁴ is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OCH _3. -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ )-C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -NCH ₃ S(O) ₂ CH ₃ , -SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N(CH ₃ ) ₂ ,

Or when two R ⁴ are connected on the same atom, two R ⁴ can form an oxo group.

In another preferred example, in the general formula (1), the structural unit

for:

In another preferred example, wherein said general formula (1) has a structure as shown in general formula (1a) or general formula (1b):

Wherein R ¹ , R ² , R ³ , R ⁴ , Y, B, r, s and t are as defined above and exemplified in the examples.

In another preferred example, the general formula (1) has the structure shown in the general formula (2a)-general formula (2d):

Wherein R ¹ , R ² , R ³ , R ⁴ , Y, r, s and t are as defined above and exemplified in the examples.

In various embodiments, the compound of general formula (1) has one of the following structures:

Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.

Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Application in the preparation of medicines for treating, regulating or preventing diseases related to KRas G12D; said diseases are preferably cancers, and said cancers are hematological cancers and solid tumors.

Another object of the present invention is also to provide a method for treating, regulating or preventing related diseases mediated by KRas G12D, comprising administering to a subject a therapeutically effective amount of a compound represented by general formula (1) of the present invention, or its Each isomer, each crystal form, a pharmaceutically acceptable salt, hydrate or solvate or the above pharmaceutical composition; the disease is preferably cancer, and the cancer is blood cancer and solid tumor.

By synthesizing and carefully studying a variety of new compounds related to KRas G12D protein inhibition, the inventors found that among the compounds of general formula (1), the compound unexpectedly has strong KRas G12D inhibitory activity.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

compound synthesis

The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.

In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following general reaction scheme 1 or general reaction scheme 2:

General reaction scheme 1

Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R ¹ , R ² , R ³ , R ⁴ , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen, and X represents nitrogen or carbon. As shown in the general reaction scheme 1, compound 1-1 and 1-2 undergo a substitution reaction under basic conditions to generate compound 1-3, and compound 1-3 reacts with 1-4 or 1-5 to generate compound 1- 6. Compound 1-6 reacts under acidic conditions to generate 1-7, compound 1-7 reacts with compound 1-8 to generate compound 1-9, compound 1-9 reacts with POCl ₃ to generate compound 1-10, compound 1- Compound 1-12 is produced by substitution reaction between 10 and compound 1-11, compound 1-14 is produced by substitution reaction between compound 1-12 and compound 1-13, and compound 1-14 is deprotected under acidic conditions to produce 1-15.

General reaction scheme 2

Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R ¹ , R ² , R ³ , R ⁴ , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen. As shown in general reaction scheme 2, compounds 2-1 and 2-2 undergo a substitution reaction under basic conditions to generate compound 2-3, compound 2-3 and 2-4 undergo a substitution reaction to generate compound 2-5, compound 2- 5. Selective deprotection under acidic conditions to generate 2-6. Compound 2-6 reacts with compound 2-7 or 2-8 to generate compound 2-9. Compound 2-9 deprotects under acidic conditions. Generate 2-10.

Further forms of compounds

"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.

The term "pharmaceutically acceptable salt" refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound. In some specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.

References to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.

In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.

In another aspect, the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur. Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

the term

Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _CF3CH2 , _CF3 ( _{CH3 ) CH} , ^iPr , ^nPr , ^iBu , ^nBu or ^tBu .

Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.

Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. A lower alkynyl group having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.

Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.

Unless otherwise specified, "alkoxy" means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH ₃ , OCF ₃ , CHF ₂ O, CF ₃ CH ₂ O, ^i- PrO, ^n- PrO, ^i- BuO, ^n- BuO or ^t- BuO.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ether oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy.

Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic. For example a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,

Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

Unless otherwise specified, "heterocycloalkyl" means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine or Benzo derivatives such as thienyl. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butane Amide group, valerolactam group, imidazolinone group, hydantoin group, dioxolan group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

Unless otherwise specified, "oxo" means =O; for example, a group formed by replacing a carbon with an oxo group is "carbonyl

"; The group formed by the substitution of sulfur by an oxo group is "sulfinyl

", the group formed by the substitution of sulfur by two oxo groups is "sulfonyl

".

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substitution") appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.

Unless otherwise noted, keys with wedge-shaped solid lines

and dotted wedge keys

Indicates the absolute configuration of a stereocenter, with a straight solid-line bond

and straight dashed keys

Indicates the relative configuration of the stereocenter, with a wavy line

Indicates wedge-shaped solid-line bond

or dotted wedge key

or with tilde

Indicates a straight solid line key

or straight dotted key

Unless otherwise specified, use

Indicates a single or double bond.

Certain pharmaceutical and medical terms

The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom. As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers. The asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound Wait.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood to mean the number of significant digits indicated plus the usual rounding method.

Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.

therapeutic use

The compound of general formula (1) or the pharmaceutical composition provided by the present invention can generally be used to inhibit KRas G12D protein, and therefore can be used to treat one or more diseases related to the activity of KRas G12D protein. Therefore, in certain embodiments, the present invention provides a method for treating a KRas G12D protein-mediated disorder, the method comprising administering a compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof. step.

In some embodiments, there is provided a method for treating cancer, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof. In some embodiments, the cancer is mediated by the KRas G12D protein. In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts . Wherein, "safe and effective amount" means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.

"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

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

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

detailed description

In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions will be described in detail, so that the content of the present invention will become very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.

In all the examples, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.

The present invention adopts the following abbreviations: Ac ₂ O stands for acetic anhydride; (Boc) ₂ O stands for di-tert-butyl dicarbonate; CDCl ₃ stands for deuterated chloroform; CO stands for carbon monoxide; Cs ₂ CO ₃ stands for cesium carbonate; CsF stands for Cesium fluoride; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN or CH ₃ CN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1, 4-dioxane; DMF stands for N,N-dimethylformamide; DMAP stands for 4-(dimethylamino)pyridine; DMSO stands for dimethyl sulfoxide; Dichloro(p-cymene)ruthenium(II) dimer stands for di Chloro(p-cymene)ruthenium(II) dimer; DPPA stands for diphenylphosphoryl azide; _EtOH stands for ethanol; hr stands for hour _; K2CO3 stands for potassium carbonate; KOAc stands for potassium acetate _; K3 PO ₄ stands for potassium phosphate; LiAlH ₄ stands for lithium aluminum hydride; LiHMDS stands for lithium bis(trimethylsilyl)amide; min stands for minute; MeOH stands for methanol; MS stands for mass spectrum; MOMCl stands for chloromethyl methyl ether; MOM stands for formazan MTBE stands for tert-butyl methyl ether; _NaHCO3 stands for sodium bicarbonate; _Na2SO4 stands for sodium _sulfate ; n-BuLi stands for n-butyllithium; NMR stands for nuclear magnetic resonance; NIS stands for iodosuccinimide ; Pd/C stands for palladium on carbon; Pd(dppf)Cl ₂ stands for [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; Pd(PPh ₃ ) ₂ Cl ₂ stands for bis Triphenylphosphine palladium dichloride; PE represents petroleum ether; POCl ₃ represents phosphorus oxychloride; psi represents pounds force per square inch; SOCl ₂ represents thionyl chloride; t-BuOH represents tert-butanol; TEA represents triethyl Amine; TFA stands for trifluoroacetic acid; Tf ₂ O stands for trifluoromethanesulfonic anhydride; THF stands for tetrahydrofuran; TIPS stands for triisopropylsilyl; Toluene or Tol stands for toluene; XantPhos stands for 4,5-bisdiphenylphosphine-9 , 9-dimethylxanthene; TLC stands for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl.

Synthesis of Preparation Example 1 Intermediate Int_A-1

Step 1: Synthesis of compound int_A-1-2

Int_A-1-1 hydrochloride (31g, 178.13mmol) was dissolved in water (500mL), and NaHCO ₃ (37.41g, 445.34mmol) was added at room temperature, and after stirring for 30 minutes, acetic anhydride (20.00g , 195.95mmol, 18.35mL), the reaction solution was stirred at room temperature for another 4 hours, and a white solid precipitated out. LC-MS detection showed that the reaction was complete. Filtration gave a filter cake, which was washed with water (50 mL X 2) and dried to give the crude product. The crude product was slurried with MTBE (300ml) at room temperature for 30 minutes, filtered to obtain a filter cake and dried to obtain a white solid (18g, yield: 56.3%).

¹ H NMR: (400MHz,CHLOROFORM-d)δ=6.40(br s,1H),5.06-4.97(m,1H),4.05-3.98(m,1H),3.95-3.89(m,1H),3.87- 3.81(m,3H),2.15-2.06(m,3H)

Step 2: Synthesis of compound int_A-1-4

Int_A-1-2 (17.01g, 94.74mmol) and Int_A-1-3 (10g, 72.87mmol) were dissolved in acetonitrile (100mL), and DIPEA (9.42g, 72.87mmol, 12.69mL) was added dropwise at 0°C Acetonitrile (100 mL) solution, the mixture was raised to room temperature and stirred for 16 hours, LC-MS detection showed that the reaction was complete. 3 mL of water was added to the reaction solution and stirring was continued for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to obtain a yellow oil (10 g, yield: 60.4%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ = 6.80-6.33 (m, 1H), 4.74-4.57 (m, 1H), 3.76 (d, J = 2.0Hz, 3H), 2.48-2.08 (m, 5H ),2.07-1.99(m,4H),1.95-1.76(m,2H),1.63-1.54(m,1H)

Step 3: Synthesis of compound int_A-1-5

Int_A-1-4 (10g, 44.00mmol) was dissolved in 10% hydrochloric acid (320.88g, 880.06mmol, 314.59mL), and the mixture was heated to 80°C for 3 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 95.9%).

Step 4: Synthesis of compound int_A-1-6

Int_A-1-5 (8g, 52.23mmol) and Pd/C (3g, 5.22mmol, 10%purity) were dissolved in ethanol (200mL), and the mixture was hydrogenated at 15psi for 16 hours. LC-MS detection showed that the reaction completely. Filtrate was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 98.7%).

Step 5: Synthesis of compound int_A-1-7

Int_A-1-6 (7g, 45.10mmol) was dissolved in methanol (200mL), and SOCl ₂ (10.73g, 90.21mmol, 6.54mL) was slowly added dropwise at 20°C, and the reaction solution was stirred at room temperature for 16 hours, LC- MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 105%).

Step 6: Synthesis of compound int_A-1-8

Int_A-1-6 (8g, 47.3mmol) was dissolved in dichloromethane (200mL), and TEA (23.92g, 236mmol, 32.9mL) and Boc ₂ O (12.38g, 56.73mmol, 13.03mL) were added at room temperature, After the reaction solution was stirred at room temperature for 16 hours, LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=4/1) to obtain a colorless oil (10 g, yield: 78.5%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=4.46-4.12(m,2H),3.77-3.68(m,3H),2.75-2.63(m,1H),2.49-2.33(m,1H),2.04 -1.86(m,2H),1.84-1.73(m,2H),1.51-1.34(m,11H)

Step 7: Synthesis of compound int_A-1-10

Int_A-1-8 (9.1g, 33.79mmol) was dissolved in THF (160mL), LiHMDS (1M, 54.06mL) was slowly added dropwise at -60°C, and the reaction solution was stirred at -60°C for 1 hour, and then added to the reaction Int_A-1-9 (7.98g, 50.68mmol, 4.99mL) was added to the solution, and the reaction solution was stirred at -60°C for 1 hour, then raised to room temperature for 2 hours, and LC-MS detection showed that the reaction was complete. 10mL saturated ammonium chloride aqueous solution and 20mL water were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 15/1) to obtain a yellow gum (6 g, yield: 51.3%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=4.41-4.09(m,1H),3.76-3.69(m,3H),3.66-3.49(m,2H),2.85-2.65(m,1H),2.40 -2.24(m,1H),2.21-2.06(m,1H),2.05-1.63(m,8H),1.55-1.37(m,11H)

Step 8: Synthesis of compound int_A-1-11

Dissolve Int_A-1-10 (6g, 17.35mmol) in dichloromethane (10mL), control the temperature below 10°C and slowly add dioxane hydrochloride solution (4M, 43.37mL) dropwise, and the reaction solution continues to stir at room temperature After 3 hours, LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (5g, yield: 117%).

Step 9: Synthesis of compound int_A-1-12

Int_A-1-11 hydrochloride (5g, 17.72mmol) was dissolved in methanol (150mL), K ₂ CO ₃ (7.35g, 53.15mmol) was added at room temperature, the reaction solution was stirred at room temperature for 16 hours, LC-MS Assays showed the reaction was complete. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, DCM/MeOH=10/1) to obtain a yellow oil (2.5 g, yield: 67.4%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=3.76-3.69(m,3H),3.30-3.24(m,1H),3.14(td,J=6.9,11.1Hz,1H),2.88-2.80(m ,1H),2.70-2.58(m,1H),2.24-2.16(m,2H),2.14-2.05(m,1H),1.94-1.36(m,10H)

Step 10: Synthesis of compound int_A-1

Int_A-1-12 (2.3g, 10.99mmol) was dissolved in THF (50mL), LiAlH4 (834mg, 21.98mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. LC-MS detection showed that the reaction was complete . 10·H2O·Na2SO4 (20 g) was added to the reaction solution at 0° C. and the mixture was raised to room temperature and stirred for half an hour. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was suspended in dichloromethane (10 mL), filtered again to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (1.5 g, yield: 75.3%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=3.31-3.20(m,2H),3.18-3.11(m,1H),2.92-2.77(m,2H),2.69-2.57(m,1H),2.04 -1.91(m,2H),1.80(dd,J＝7.2,12.9Hz,1H),1.76-1.44(m,12H)

Synthesis of Preparation Example 2 Intermediate Int_A-2

Step 1: Synthesis of compound int_A-2-2

Int_A-2-1 hydrochloride (75g, 430.97mmol) was dissolved in water (1000mL), and NaHCO ₃ (90.51g, 1.08mol) was added at room temperature, and after stirring for 30 minutes, acetic anhydride (48.40g , 474.07mmol, 44.40mL), the reaction solution was stirred at room temperature for another 4 hours, and a white solid precipitated out. LC-MS detection showed that the reaction was complete. Filtration gave a filter cake, which was washed with water (50 mL X 2) and dried to give the crude product. The crude product was slurried with MTBE (500ml) at room temperature for 30 minutes, filtered to obtain a filter cake and dried to obtain a white solid (40g, yield: 51.7%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=6.41(br s,1H),5.08-4.99(m,1H),4.03-3.97(m,1H),3.96-3.89(m,1H),3.84( s,3H),2.10(s,3H)

Step 2: Synthesis of compound int_A-2-4

Int_A-2-2 (25g, 182.19mmol, 26.57mL) and Int_A-2-3 (39.27g, 218.62mmol) were dissolved in acetonitrile (300mL), and DIPEA (23.55g, 182.19mmol, 31.73 mL) in acetonitrile (300 mL), the mixture was raised to room temperature and stirred for 16 hours, and LC-MS detection showed that the reaction was complete. 3 mL of water was added to the reaction solution and stirring was continued for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to obtain a yellow oil (24 g, yield: 57.9%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ = 6.82-6.37(m, 1H), 4.74-4.55(m, 1H), 3.76(d, J = 2.0Hz, 3H), 2.49-2.32(m, 2H ),2.31-2.00(m,9H),1.94-1.78(m,2H),1.64-1.54(m,1H)

Step 3: Synthesis of compound int_A-2-5

Int_A-2-4 (25g, 110.01mmol) was dissolved in 10% hydrochloric acid (401.10g, 1.10mol, 393.23mL), and the mixture was heated to 80°C for 3 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (18g, crude product).

Step 4: Synthesis of compound int_A-2-6

Int_A-2-5 (15g, 97.93mmol) and Pd/C (1.5g, 10%purity) were dissolved in ethanol (40mL), and the mixture was hydrogenated under 15psi pressure for 16 hours. LC-MS detection showed that the reaction was complete. The filtrate was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (15g, crude product).

Step 5: Synthesis of compound int_A-2-7

Int_A-2-6 (15g, 96.65mmol) was dissolved in methanol (200mL), and SOCl ₂ (23.00g, 193.31mmol, 14.02mL) was slowly added dropwise at 20°C, and the reaction solution was stirred at room temperature for 16 hours, LC- MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (16g, crude product).

Step 6: Synthesis of compound int_A-2-8

Int_A-2-6 (16g, 94.55mmol) was dissolved in dichloromethane (200mL), and TEA (61.10g, 472.76mmol, 82.35mL) and Boc ₂ O (30.95g, 141.83mmol, 32.58mL) were added at room temperature After the reaction solution was stirred at room temperature for 16 hours, LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=4/1) to obtain a colorless oil (16 g, yield: 62.83%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=4.47-4.13(m,2H),3.82-3.71(m,3H),2.76-2.63(m,1H),2.49-2.34(m,1H),2.04 -1.87(m,2H),1.87-1.66(m,3H),1.61(s,4H),1.57-1.34(m,10H)

Step 7: Synthesis of compound int_A-2-10

Int_A-2-8 (16g, 59.41mmol) was dissolved in THF (300mL), and LiHMDS (1M, 89.11mL) was slowly added dropwise at -60°C, and the reaction solution was stirred at -60°C for 1 hour, and then added to the reaction solution Int_A-2-9 (14.03g, 89.11mmol, 8.77mL) was added, and the reaction solution was stirred at -60°C for 1 hour, then raised to room temperature for 2 hours, and LC-MS detection showed that the reaction was complete. 100mL saturated aqueous ammonium chloride solution and 100mL water were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (150mL×3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 15/1) to obtain a yellow gum (17 g, yield: 82.7%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=4.34-4.10(m,1H),3.78-3.70(m,3H),3.66-3.49(m,2H),2.82-2.70(m,1H),2.37 -2.24(m,1H),2.21-2.07(m,1H),2.04-1.56(m,10H),1.53-1.38(m,11H)

Step 8: Synthesis of compound int_A-2-11

Dissolve Int_A-2-10 (17g, 49.15mmol) in dichloromethane (50mL), and slowly add dioxane hydrochloride solution (4M, 122.88mL) dropwise while controlling the temperature below 10°C, and the reaction solution continues to stir at room temperature After 3 hours, LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (12g, yield: 99.35%).

Step 9: Synthesis of compound int_A-2-12

Int_A-2-11 (12g, 48.83mmol) was dissolved in methanol (200mL), K ₂ CO ₃ (20.25g, 146.49mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 16 hours. LC-MS detection showed that the reaction completely. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, DCM/MeOH=10/1) to obtain a yellow oil (7 g, yield: 68.50%).

¹ H NMR: (400MHz, CHLOROFORM-d) δ=3.76-3.69(m,3H),3.30-3.24(m,1H),3.14(td,J=6.9,11.1Hz,1H),2.88-2.80(m ,1H),2.70-2.58(m,1H),2.24-2.16(m,2H),2.14-2.05(m,1H),1.94-1.36(m,10H)

Step 10: Synthesis of compound int_A-2

Int_A-2-12 (7g, 33.45mmol) was dissolved in THF (150mL), LiAlH4 (2.54g, 66.89mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. LC-MS detection showed that the reaction was complete . 10·H2O·Na2SO4 (50 g) was added to the reaction solution at 0° C. and the mixture was raised to room temperature and stirred for half an hour. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was suspended in dichloromethane (10 mL), filtered again to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (5 g, yield: 82.5%).

Synthesis of Preparation Example 3 Intermediate Int_B-1

Step 1: Synthesis of compound int_B-1-3

Int_B-1-1 (25g, 156mmol), Int_B-1-2 (49g, 188mmol), Dichloro (p-cymene) ruthenium (II) dimer (9.5g, 15.6mmol) and potassium acetate (30.6g, 312mmol) Dissolved in dioxane (300 mL), the reaction solution was reacted at 110° C. for 12 hours, and LC-MS detection showed that the reaction was complete. 500 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (500 mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1) to obtain the product (46 g, yield: 86.7%).

ESI-MS m/z:341[M+H] ⁺ .

Step 2: Synthesis of compound int_B-1-4

Int_B-1-3 (90g, 264.5mmol) and DIPEA (103g, 0.8mol, 138mL) were dissolved in dichloromethane (800mL), and MOMCl (31.9g, 396.5mmol, 30.1mL) was added at 0°C, and the reaction solution React at 0°C for half an hour, and LC-MS detection shows that the reaction is complete. 600 mL of water was added to the reaction solution, the aqueous phase was extracted with dichloromethane (300 mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1) to obtain the product (51 g, yield: 50.5%).

¹ H NMR (400MHz, CHLOROFORM-d) δ=9.26(s, 1H), 7.70(dd, J=0.8, 8.0Hz, 1H), 7.50(dd, J=1.2, 7.2Hz, 1H), 7.32(dd ,J=7.2,8.4Hz,1H),6.99(d,J=2.4Hz,1H),6.78(d,J=2.4Hz,1H),5.28(s,2H),3.52(s,3H),1.20 -1.16(m,21H).

Step 3: Synthesis of compound int_B-1-5

Dissolve Int_B-1-4 (100g, 260mmol) and DIPEA (101g, 0.78mol, 136mL) in dichloromethane (1200mL), add Tf ₂ O (110g, 390mmol, 64.5mL) at -40°C, and the reaction solution React at -40°C for half an hour, and LC-MS detection shows that the reaction is complete. 800 mL of water was added to the reaction liquid to quench the reaction, the aqueous phase was extracted with dichloromethane (500 mL X 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1) to obtain the product (115 g, yield: 85.8%).

Step 4: Synthesis of compound int_B-1

Int_B-1-5 (115g, 222.5mmol), Int_B-1-6 (113g, 445mmol), Pd(dppf)Cl2 ( _16.3g , 23mmol) and potassium acetate (76g, 0.78mol) were dissolved in toluene ( 800 mL), the reaction solution was reacted at 110° C. for 3 hours under nitrogen protection, and LC-MS detection showed that the reaction was complete. 500 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (500 mL X 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1) to obtain the product (56 g, yield: 50.9%).

¹ H NMR (400MHz, CHLOROFORM-d) δ=7.71-7.66(m,2H),7.47(d,J=2.4Hz,1H),7.39-7.32(m,2H),5.28(s,2H),3.52 (s,3H),1.43(s,12H),1.19-1.15(m,21H).

The synthesis of embodiment 1 compound 2

Step 1: Synthesis of compound int_2-2

Int_2-1 (60g, 343mmol), TEA (103.5g, 1.03mol, 142.6mL), tert-butanol (336.7g, 4.53mol, 433mL) and DPPA (26g, 0.26mol) were dissolved in toluene (400mL), The reaction solution was reacted at 110° C. for 6 hours under nitrogen protection, and LC-MS detection showed that the reaction was complete. 600 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (500 mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 5/1) to obtain the product (59 g, yield: 69.7%).

¹ H NMR (400MHz, methanol-d4) δ=8.11(t, J=5.6Hz, 1H), 7.99(d, J=5.6Hz, 1H), 1.52(s, 9H).

Step 2: Synthesis of compound int_2-3

Int_2-2 (0.95g, 3.85mmol) was dissolved in dichloromethane (6mL), and TFA (3mL) was slowly added dropwise at a temperature lower than 10°C. The reaction solution was reacted at room temperature for 6 hours, and LC-MS detection showed that the reaction was complete . The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (564mg, yield: 100%).

¹ H NMR (400MHz, CHLOROFORM-d): δ=7.82(d, J=5.4Hz, 1H), 6.60(t, J=5.8Hz, 1H), 4.38(br s, 2H).

Step 3: Synthesis of compound int_2-4

Int_2-3 (10.7g, 73mmol) and NIS (19.7g, 87.6mmol) were dissolved in acetonitrile (50mL), p-toluenesulfonic acid (0.7g, 3.65mmol) was added at room temperature, and the reaction solution was stirred at 70°C for 16 Hours, LC-MS detection showed that the reaction was complete. 50 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction (18 g, yield: 90.9%).

Step 4: Synthesis of compound int_2-5

Int_2-4 (7.8g, 28.8mmol), Pd(PPh ₃ ) ₂ Cl ₂ (2g, 2.88mmol) and TEA (10.5g, 0.1mol, 14.5mL) were dissolved in ethanol (200mL), the reaction solution was in CO The reaction was carried out at 80° C. for 16 hours under atmosphere (15.0 psi), and LC-MS detection showed that the reaction was complete. 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL X 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography to obtain the product (5.3 g, yield: 84.1%).

¹ H NMR (400MHz, dmso-d6) δ=8.36(s,1H),7.49-7.42(m,2H),4.31(q,J=7.2Hz,2H), 1.31(t,J=7.2Hz,3H ).

Step 5: Synthesis of compound int_2-7

Dissolve Int_2-5 (10g, 36.5mmol) in THF (30mL), slowly add Int_2-6 (10g, 55mmol, 6.5mL) dropwise at a controlled temperature below 10°C, and react at room temperature for 1 hour, LC-MS Assays showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (13.7g, yield: 92.5%).

Step 6: Synthesis of compound int_2-8

Int_2-7 (10g, 21mmol) was dissolved in methanol (100mL), and ammonia in methanol solution (10mL, 20%purity) was slowly added dropwise to the solution, and the reaction solution was reacted at room temperature for 1 hour, and LC-MS detection showed that the reaction was complete . The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was slurried in MTBE to obtain the product (3.9 g, yield: 86.7%).

ESI-MS m/z:216[M+H] ⁺ .

Step 7: Synthesis of compound int_2-9

Int_2-8 (2g, 9.3mmol) was dissolved in toluene (10mL), and phosphorus oxychloride (4.3g, 27.8mmol, 2.6mL) and DIPEA (3.6g, 27.8mmol, 4.85 mL), the reaction solution was heated to 110° C. for 5 hours, and LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (2.1g, yield: 89.7%).

Step 8: Synthesis of compound int_2-11

Int_2-9 (1.0g, 3.961mmol) was dissolved in DCM (25mL), DIPEA (2.6g, 19.81mmol) was added, and DCM of Int_2-10 (841mg, 3.961mmol) was added dropwise at -40°C under nitrogen protection ( 10mL) solution, after dripping, the reaction solution was reacted at -40°C for 0.5 hours, LC-MS detection showed that the reaction was complete, 50mL water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50mL X 3), and the organic phase was extracted with saturated Washed with brine and dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction (1.65 g, 97.1%).

ESI-MS m/z:428[M+H] ⁺

Step 9: Synthesis of compound int_2-12

Dissolve Int_2-11 (500 mg, 1.167 mmol) in DMF (7 mL), add Int_A-1 (212 mg, 1.169 mmol) and cesium carbonate (760 mg, 2.338 mmol), and react at 80°C for 16 hours. LC-MS detection showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared by reverse-phase HPLC to obtain a yellow solid product (120 mg, yield: 17.1%).

ESI-MS m/z:573[M+H] ⁺

Step 10: Synthesis of compound int_2-13

Dissolve Int_2-12 (120mg, 0.209mmol) in a mixed solution of dioxane/water (5mL/1mL), add Int_B-1 (104mg, 0.209mmol), potassium carbonate (43mg, 0.314mmol) and Ruphos- Pd-G3 (52mg, 0.062mmol), the reaction solution was raised to 100°C for 16 hours under the protection of but, and the LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared by reverse-phase HPLC to obtain a yellow solid product (30 mg, yield: 15.8%).

ESI-MS m/z:453[M/2+H] ⁺

Step 11: Synthesis of compound int_2-14

Int_2-13 (30mg, 0.033mmol) was dissolved in DMF (2mL), cesium fluoride (50mg, 0.33mmol) was added, and the reaction solution was reacted at room temperature under nitrogen protection for 2 hours. LC-MS detection showed that the reaction was complete. 10mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was subjected to reverse phase HPLC A yellow solid product (20 mg, yield: 79.1%) was prepared.

ESI-MS m/z:375[M/2+H] ⁺

Step 12: Synthesis of compound 2

Int_2-14 (20mg, 0.026mmol) was dissolved in methanol (1mL), cooled to -5°C in an ice bath, and 4M dioxane hydrochloride solution (2mL) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was The reaction was kept at -5°C for 2 hours, and LC-MS detection showed that the reaction was complete. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain crude The product, the crude product was prepared by reverse phase HPLC to give the product as a yellow solid (5 mg, 31.6%).

¹ H NMR (400MHz, Methanol-d4) δ = 9.04 (d, J = 3.6Hz, 1H), 8.53 (s, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.51 (dd, J = 7.2 ,1.3Hz,1H),7.44-7.37(m,1H),7.33(d,J=2.6Hz,1H),7.16(dd,J=2.6,1.4Hz,1H),4.57(dd,J=17.7, 12.2Hz, 6H), 3.79-3.65(m, 3H), 3.48(dd, J＝3.3, 1.6Hz, 2H), 3.14(dt, J＝6.8, 3.4Hz, 2H), 3.04-2.90(m, 2H ),2.38-2.27(m,1H),2.17(dq,J=11.7,6.1,5.1Hz,2H),2.00(dd,J=13.5,6.7Hz,2H),1.93-1.72(m,5H). 1.70-1.50(m,2H)ESI-MS m/z:605[M+H] ⁺

The synthesis of embodiment 2 compound 3

Step 1: Synthesis of compound int_3-1

Dissolve Int_2-11 (500 mg, 1.167 mmol) in DMF (7 mL), add Int_A-2 (212 mg, 1.169 mmol) and cesium carbonate (760 mg, 2.338 mmol), and react at 80°C for 16 hours. LC-MS detection showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared by reverse-phase HPLC to obtain a yellow solid product (105 mg, yield: 15%).

ESI-MS m/z:573[M+H] ⁺

Step 2: Synthesis of compound int_3-2

Dissolve Int_3-1 (105mg, 0.183mmol) in a mixed solution of dioxane/water (5mL/1mL), add Int_B-1 (91mg, 0.183mmol), potassium carbonate (38mg, 0.275mmol) and Ruphos- Pd-G3 (52mg, 0.062mmol), the reaction solution was raised to 100°C for 16 hours under the protection of but, and the LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared by reverse-phase HPLC to obtain a yellow solid product (45 mg, yield: 27.1%).

ESI-MS m/z:453[M/2+H] ⁺

Step 3: Synthesis of compound int_3-3

Int_3-2 (45mg, 0.0497mmol) was dissolved in DMF (2mL), cesium fluoride (75mg, 0.497mmol) was added, and the reaction solution was reacted at room temperature under nitrogen protection for 2 hours. LC-MS detection showed that the reaction was complete. 10mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was subjected to reverse phase HPLC A yellow solid product (28 mg, yield: 75.3%) was prepared.

ESI-MS m/z:375[M/2+H] ⁺

Step 4: Synthesis of compound 3

Int_3-3 (28mg, 0.0366mmol) was dissolved in methanol (1.5mL), cooled to -5°C in an ice bath, and 4M dioxane hydrochloride solution (3mL) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction The solution was kept at -5°C for 2 hours, and LC-MS detection showed that the reaction was complete. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain crude The product, the crude product was prepared by reverse phase HPLC to give the product as a yellow solid (7 mg, 31.8%).

¹ H NMR (400MHz, Methanol-d4) δ = 9.08 (d, J = 4.3Hz, 1H), 8.47 (s, 1H), 7.83 (dd, J = 8.5, 1.3Hz, 1H), 7.51 (dd, J ＝7.1,1.3Hz,1H),7.43–7.32(m,2H),7.16(t,J＝2.2Hz,1H),4.75–4.58(m,4H),4.03–3.89(m,3H),3.83( d,J=13.3Hz,2H),3.78–3.64(m,2H),3.54–3.42(m,1H),3.18–3.07(m,1H),2.39(dd,J=13.9,8.7Hz,1H) ,2.34–1.79(m,11H),1.77–1.62(m,2H).

ESI-MS m/z:605[M+H] ⁺

The synthesis of embodiment 3-348 compound 1 and compound 4-348

The target compound 1 and compounds 4-348 in Table 1 can be obtained by using the above synthesis method and using different raw materials.

Table 1

Example 349 Compounds Determination of Anti-proliferation Activity on Aspc-1 Cells

The human pancreatic cancer cell line Aspc-1 carrying the KRAS-G12D mutation was suspended in RPMI1640 medium containing fetal bovine serum, planted in a 96-well ultra-low adsorption plate (Corning 7007), and the number of cells per well was 2500. Incubate for 1 day at 37°C in an incubator with 5% CO ₂ gas. On the second day, add the serially diluted compound, the final concentration of DMSO is 0.3%, and then incubate at 37°C in an incubator containing 5% CO ₂ for another 3 days, add Cell Titer-Glo and mix for 10 minutes, pass the enzyme label The instrument detects the luminescence, measures the content of ATP in the cells, evaluates the condition of the cell growth, and calculates the IC ₅₀ of the compounds inhibiting the cell growth. The results are shown in Table 2 below.

Table 2 Compounds of the present invention have antiproliferative activity on Aspc-1 cells (IC ₅₀ , nM)

compound	IC50	compound	IC50	compound	IC50	compound	IC50
1	++	2	++	3	+++	4	N.D.
5	N.D.	6	++	7	++	8	+++
9	N.D.	10	N.D.	11	++	12	++
13	++	14	N.D.	15	N.D.	16	N.D.
17	++	18	+++	19	N.D.	20	N.D.
twenty one	N.D.	twenty two	++	twenty three	++	twenty four	N.D.
25	N.D.	26	N.D.	27	++	28	++
29	N.D.	30	N.D.	31	N.D.	32	++
33	++	34	N.D.	35	N.D.	36	N.D.
37	++	38	++	43	+++	44	+++
45	++	46	++	47	N.D.	48	++
49	++	50	++	51	++	52	N.D.
53	+++	54	+++	55	+++	56	++
57	N.D.	58	+++	59	+++	60	++
61	++	62	N.D.	63	++	64	++
75	++	76	++	77	++	78	++
79	N.D.	80	+++	81	+++	82	++

83	++	84	N.D.	85	+++	86	+++
87	++	88	++	89	N.D.	90	++
91	++	92	++	93	++	94	N.D.
95	++	96	++	97	++	98	++
99	N.D.	100	++	101	++	102	++
103	++	104	N.D.	105	N.D.	106	+++
107	+++	108	+++	109	+++	110	N.D.
129	N.D.	130	++	131	++	132	N.D.

+++ means IC ₅₀ less than or equal to 500nM

++ means _IC50 from 500nM to 1000nM

+ indicates _IC50 greater than 1000nM

N.D means activity not determined

It can be seen from the data in Table 2 that the compounds of the present invention have strong anti-proliferation activity on Aspc-1 cells.

Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (18)

1. A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

   

   In general formula (1):

   R ¹ is -H, -OH, halogen, (C1-C3) alkyl, (C1-C3) alkyl substituted by nitrile, (C1-C3) alkyl substituted by hydroxy, HC(=O)-, - CO ₂ R ⁵ , -CO ₂ N(R ⁵ ) ₂ or (5-6 member) heteroaryl;

   Y is 0 or NR ⁵ ;

   Ring A is phenyl, (5-7 membered) heteroaryl, (C5-C7) cycloalkyl or (5-7 membered) heterocycloalkyl;

   Each R is independently -H, halogen, (C1 ^- C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member ) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member) heteroaryl can each independently be optionally substituted by 1, 2, 3 or 4 R ⁶ ;

   Each ^R3 is independently -H, halogen, -OH, (C1-C3) alkyl, (C1-C3) alkyl substituted with hydroxy, (C1-C3) haloalkyl, (C1-C3) alkoxy , (5-7 membered) heteroaryl, -CN, -SO ₂ F,

   

   

   NHC(O)R ⁸ , -N(R ⁵ ) ₂ ,

   

   -CH ₂ OC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)OR ⁷ , -CH ₂ NHC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)R ⁷ , -CH ₂ NHS(O) ₂ R ⁷ , -CH ₂ OC(O)R ⁸ , -OC(O)N(R ⁵ ) ₂ , -OC(O)NH(CH ₂ ) _m OR ⁷ , -OC(O) NH(CH ₂ ) _m O(CH ₂ ) _n R ⁸ , -OC(O)R ⁸ , -CH ₂ R ⁸ , wherein the (C1-C3) alkyl, hydroxyl substituted (C1-C3) alkyl , (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-7) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen , R ⁷ and R ⁸ ; or when two R ³ are connected to the same atom, two R ³ can form an oxo group;

   Q is a chemical bond or O;

   Ring B is (C5-C7) cycloalkyl, phenyl, (5-7 member) heteroaryl or (5-7 member) heterocycloalkyl;

   Each R ⁴ is independently -H, -D, halogen, R ⁹ , -OH, -(CH ₂ ) _n OR ⁹ , -(CH ₂ ) _n NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ R ¹⁰ , -CN, -C(O)NR ⁹ R ¹⁰ , -NR ¹⁰ C(O)R ⁹ , -NR ¹⁰ S(O) ₂ R ⁹ , -S(O) _p R ⁹ , -S(O) ₂ NR ⁹ R ¹⁰ , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein ( C1-C6) Alkyl, (C1-C6) Haloalkyl, (C2-C6) Alkenyl, (C2-C6) Alkynyl or (C3-C9) Cycloalkyl can be independently optionally replaced by 1,2,3 Or substituted by 4 of the following groups: -H, halogen, R ⁷ , -OH, -(CH ₂ ) _n OR ⁷ , -(CH ₂ ) _n N(R ⁷ ) ₂ , -OR ⁷ , -N(R ⁷ ) ₂ , -CN, -C(O)N(R ⁷ ) ₂ , -NR ⁷ C(O)R ⁷ , -NR ⁷ S(O) ₂ R ⁷ , -S(O) _p R ⁷ and -S (O) ₂ N(R ⁷ ) ₂ ; or when two R ⁴ are connected to the same atom, two R ⁴ can form an oxo group;

   each R is independently -H or (C1 ^- C3) alkyl;

   R ⁶ is -H, halogen, -OH, -CN, -OR ⁷ , -SR ⁷ , (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7 Yuan) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy, -CH ₂ C(=O)N(R ⁵ ) ₂ , -N(R ⁵ ) ₂ or (C3-C6 ) cycloalkyl, wherein said (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7) heteroaryl, (C1-C4) haloalkyl, (C1-C4)alkoxy and (C3-C6)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, halogen, -OH, _-NH2 , -CN and R ⁷ ;

   Each R is independently (C1 ^- C6) alkyl, (C1-C6) haloalkyl or (C1-C3) alkoxy;

   Each R is independently ( ^5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl, wherein the (5-7 membered) heterocycloalkyl, (5-7 membered )heteroaryl or phenyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -CN, -C(O)H, -(CH ₂ ) _n OR ⁷ and -(CH ₂ ) _n N(R ⁷ ) ₂ ;

   R ⁹ and R ¹⁰ are each independently -H, (C1-C6) alkyl or (C3-C7) cycloalkyl, or R ⁹ and R ¹⁰ on the same nitrogen atom and the N atom they are connected to can jointly Constitutes a (3-7 membered) heterocycloalkyl group, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C3) alkyl, (C3- C5) cycloalkyl or (C1-C3) alkoxy; and

   p is an integer of 0, 1 or 2, r is an integer of 1, 2, 3 or 4, s is an integer of 0, 1, 2, 3 or 4, t is an integer of 0, 1, 2, 3 or 4, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
2. The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ¹ is -H, - OH, -F,

   

   

   HC(=O)-, -CO ₂ CH ₃ or -CO ₂ N(CH ₃ ) ₂ .
3. The compound as claimed in claim 1 or 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Y is O, NH or _NCH3 .
4. The compound according to any one of claims 1-3 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is phenyl, 6-membered heteroaryl, cyclohexyl or (5-6 membered) heterocycloalkyl.
5. The compound according to any one of claims 1-4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is

   

   

   The end marked with * is connected to a nitrogen atom.
6. The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each Each R ² is independently -H, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14 ) aryl or (5-14 member) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or The (5-14 membered) heteroaryl groups can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CN, - OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ CF ₃ , -SCH ₃ , -SCH ₂ CH ₃ , -N(CH ₃ ) ₂ , - NH ₂ , -NH(CH ₃ ),

   

   
7. The compound according to any one of claims 1-6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structure unit

   

   for:

   

   

   

   

   

   

   

   
8. The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each Each ^R3 is independently -H, -OH, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1-C3) alkyl substituted by hydroxyl, (C1-C3) haloalkyl , (C1-C3) alkoxy, (5-6 member) heteroaryl, -CN,

   

   NHC(O)R ⁸ , -N(R ⁵ ) ₂ , -CH ₂ OC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)OR ⁷ , -CH ₂ NHC(O)N(R ⁵ ) ₂ , -CH ₂ NHC(O)R ⁷ , -CH ₂ NHS(O) ₂ R ⁷ , -CH ₂ OC(O)R ⁸ , -OC(O)N(R ⁵ ) ₂ , -OC(O )NH(CH ₂ ) _m OR ⁷ , -OC(O)NH(CH ₂ ) _m O(CH ₂ ) _n R ⁸ , -OC(O)R ⁸ , -CH ₂ R ⁸ , wherein the (C1- C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-6 member) heteroaryl can be independently optionally replaced by 1, 2, 3 or 4 of the following groups are substituted: -H, -F, -CH ₃ , -OCH ₃ or -CH ₂ CH ₃ ; or when two R ³ are connected to the same atom, two R ³ can form an oxo group.
9. The compound as claimed in claim 8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R ³ is independently : -H, -OH, -F, -Cl, -Br, -I, -CN, -OCH ₃ , -CF ₃ ,

   

   
10. The compound according to any one of claims 1-9 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring B is (C5-C6) cycloalkyl, phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocycloalkyl.
11. The compound according to claim 10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring B is:

    

    

    The end marked with * is connected to a nitrogen atom.
12. The compound according to any one of claims 1-11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each Each R ⁴ is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OR ⁹ , -CH ₂ NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ R ¹⁰ , -CN, -C(O)NR ⁹ R ¹⁰ , -NR ¹⁰ C(O)R ⁹ , -NR ¹⁰ S(O) ₂ R ⁹ , -SR ⁹ , -S(O) ₂ R ⁹ , -S (O) ₂ NR ⁹ R ¹⁰ , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, Wherein said (C1-C3) alkyl group, (C1-C3) haloalkyl group, (C2-C4) alkenyl group, (C2-C4) alkynyl group or (C3-C6) cycloalkyl group can each be independently optionally replaced by 1 , 2, 3 or 4 of the following groups are substituted: -H, -F, -Cl, -Br, -I, -OH, -OCH ₃ , -N(CH ₃ ) ₂ and -CN; or when two R When ⁴ is connected on the same atom, two R ⁴ can form an oxo group.
13. The compound as claimed in claim 12 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R ⁴ is independently : -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ ) -C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -NCH ₃ S(O) ₂ CH ₃ , -SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N(CH ₃ ) ₂ ,

    

    

    

    Or when two R ⁴ are connected on the same atom, two R ⁴ can form an oxo group.
14. The compound according to any one of claims 1-13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structure unit

    

    for:

    

    

    

    
15. The compound according to any one of claims 1-14 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:

    

    

    

    

    

    

    

    

    

    

    

    

    

    

    

    

    
16. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-15, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
17. A compound as described in any one of claims 1-15, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the drug as claimed in claim 16 Application of the composition in preparing medicines for treating, regulating or preventing KRas G12D-related diseases.
18. The use according to claim 17, wherein said disease is cancer, and said cancer is blood cancer and solid tumor.