TW202346297A - Compounds with activity of anti-kras-mutated tumors - Google Patents

Abstract

The present disclosure provides compounds of formula (A) that can be used as KRas inhibitors, pharmaceutical compositions containing the same, methods for preparing the same, and use of these compounds in the treatment of cancers.

Description

Compounds with activity against KRAS mutated tumors

The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with novel structures that can be used as KRAS inhibitors, pharmaceutical compositions containing such compounds, methods for preparing such compounds, and the use of these compounds in the treatment of cancer or tumors.

Ras, the rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, differentiation and other functions. These regulatory functions of Ras are performed by switching between the GDP-bound state and the GTP-bound state, a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13: 394-401). Ras bound to GDP is an inactive form and is in a dormant or off state. At this time, the signaling system is turned off. It will be activated when it is exposed to some growth-promoting stimuli. For example, it can be induced by guanine nucleotide exchange factor (GEF). GDP is released and combined with GTP. As a result, Ras is "turned on" and converted into the active form of Ras, which recruits and activates various downstream effectors for signal transmission and can transmit signals from the cell surface to the cytoplasm. , thus controlling many key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

Ras has GTPase activity, which can cleave the terminal phosphate of GTP and convert it into GDP, that is, convert itself into an inactive state. However, the endogenous GTPase activity of Ras is very low, and the exogenous protein GAP (GTPase activating protein) is required to convert GTP-Ras into GDP-Ras. GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation that affects the interaction between Ras and GAP or the conversion of GTP to GDP will cause Ras to remain active for a long time, thus continuously transmitting growth and division signals to cells, stimulating continuous cell proliferation, and ultimately leading to tumor formation. and development.

Among human tumor-related genes, there are three ubiquitously expressed Ras genes, H-RAS, K-RAS and N-RAS, which respectively encode highly homologous HRas, NRas and KRas proteins of approximately 21KDa. In 1982, researchers first discovered that Ras was mutated and activated in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large genome sequencing studies in different cancer types revealed that the Ras protein is mutated in more than 30% of cancer types, especially in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%) has the highest mutation rate. Transgenic and genetically engineered mouse models have also revealed that mutated Ras proteins are sufficient to drive and initiate many types of cancer, and that the Ras oncogene is also critical for the maintenance and progression of tumors in multiple cancer types, such as in Ras mutant cancer cells. In lines and cancer animal models, RNA intervention has been shown to slow tumor growth. These studies have made the Ras tumor protein a very attractive anti-cancer drug target that is widely accepted in the pharmaceutical field.

Research shows that Ras mutations are most common in KRas, and KRas mutations can be observed in about 85% of cancers driven by Ras mutations; the vast majority of Ras mutations occur in codons G12, G13, and Q61, and about 80% of KRas mutations are in Occurs at codon 12 of glycine, such as G12C mutation, G12D mutation, G12V mutation, G13D mutation, etc. KRas mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma, and are also found in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21(8 ),1797-1801,2015). Therefore, KRas mutant protein has become the most important branch of Ras drug target research, and the development of its inhibitors is also regarded as a very promising research direction in the development of anti-cancer/tumor drugs.

However, drug development for Ras in the past few decades has shown that due to the smooth surface of Ras protein, it lacks obvious grooves or pocket structures for binding small molecule inhibitors, and its affinity for guanine receptors is very high (Pi Molar level), causing the development of its small molecule inhibitors to fall into an insurmountable dilemma. As a result, Ras has long been considered an "undruggable" target in the industry. At the same time, there is still a great need for compounds with more structural types or patterns as KRas inhibitors to provide more treatment options, or to provide further improved inhibitory activity relative to existing Kras inhibitors, thereby providing more potent clinical applications. of therapeutic drugs.

The present invention addresses these and other needs. The present invention provides novel structural inhibitor compounds with KRas mutein inhibitory activity. Because these compounds of the present invention have improved structural patterns, compared with existing KRas mutant protein inhibitors in the prior art, they have enhanced activity in inhibiting KRas mutant proteins and related tumor inhibitory activities, and have good pharmacokinetic properties, thereby Have good drug-forming properties, such as being easier to administer after administration It is absorbed in the body with reduced toxic and side effects, improved drug resistance and safety, and reduced risk of drug interactions.

The present invention provides a compound of formula (A) as defined herein below, or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient or carrier.

The invention also provides a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.

The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use as an inhibitor of Ras mutein, especially KRas mutein, preferably KRas G12D.

The invention also provides compounds of the invention or pharmaceutically acceptable salts or solvates thereof for the treatment and/or prevention of diseases mediated by Ras mutein, especially KRas mutein, preferably KRas G12D mutein, or Pharmaceutical compositions containing the same.

The invention also provides compounds of the invention or pharmaceutically acceptable salts or solvates thereof or pharmaceutical compositions containing the same for the treatment and/or prevention of Ras mutant proteins, especially KRas mutant proteins, preferably KRas G12D mutations. Use in protein-mediated diseases.

The present invention also provides the compounds of the present invention or their pharmaceutically acceptable salts or solvates or pharmaceutical compositions containing them for use in the treatment and/or prevention of diseases caused by Ras mutant proteins, especially It is a use in drugs for diseases mediated by KRas mutant protein, preferably KRas G12D mutant protein.

The present invention also provides a method for treating and/or preventing diseases mediated by Ras mutein, especially KRas mutein, preferably KRas G12D mutein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or its Pharmaceutically acceptable salts or solvates or pharmaceutical compositions containing the same.

The present invention also provides a method of treating tumors or cancer, which includes administering a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the same, to a patient in need thereof.

The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D.

The invention also provides pharmaceutical combinations comprising a compound of the invention and one or more other pharmaceutically active agents.

The invention also provides methods for preparing the compounds of the invention.

Detailed description of the invention

definition

Unless otherwise indicated, each term used in the specification and claims has the meaning indicated below. Where a particular term or phrase is not specifically defined, it should be understood according to its ordinary meaning in the art. In case of conflict, the present specification, including definitions, will control.

In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

The term "Ras mutation" or "Ras mutant protein" as used herein refers to the protein encoded and expressed by the Ras gene in which one or more codons are mutated, typically including but not limited to glycine at codon 12 of Ras Ras proteins with mutations in acid, glycine at codon 13 or glutamine at codon 61, such as mutated HRas, NRas or KRas. These residues are located in the active site of Ras, and their mutations can impair the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the persistence of GTP-bound Ras.

For the purposes of the present invention, "Ras mutant" or "Ras mutein" and "Ras" with respect to which inhibitory activity is described are used interchangeably and generally refer to a mutated HRas, NRas or KRas, such as, but not limited to, KRas -G12C (mutation from glycine to cysteine at codon G12), KRas-G12D (mutation from glycine to aspartate at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of glycine to valine at codon G12), KRas-G13D (mutation of glycine to aspartate at codon G13); specifically KRas mutant protein, more specifically KRas - G12C mutein, KRas-G12D mutein, KRas-G12V mutein, KRas-G13D mutein, most particularly KRas-G12D mutein.

The term "treatment" as used herein refers to the administration of one or more compounds of the invention described herein or a pharmaceutically acceptable compound thereof to a subject, such as a mammal, such as a human, suffering from the disease, or having symptoms of the disease. Salts or solvates intended to cure, alleviate, reduce or affect the disease or the symptoms of the disease. Preferably, treatment is curative or ameliorative.

The term "prevention" as used herein is well known in the art and refers to a subject, such as a mammal, suspected of suffering from or susceptible to a Ras mutation-mediated disease, in particular a cancer or tumor, as defined herein. For example, administration of one or more compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, to a human results in a reduced risk of developing a defined disease, or prevents the onset of a disease. The term "prophylaxis" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological symptoms.

As used herein, the terms "inhibit" and "reduce" or any variations of these terms, refer to the ability of a biologically active agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target and is Refers to any measurable reduction or complete inhibition of the activity of a target of interest. For example, the activity (e.g., KRas activity) may be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% compared to normal conditions. %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range that may be derived therefrom.

As used herein, the term "selective inhibition" refers to the ability of a bioactive agent to preferentially reduce the signaling activity of a target of interest over off-target signaling activity by interacting directly or indirectly with the target. As for the compound of the present invention, it has the ability to selectively inhibit the G12 or G13 mutation of KRas, HRas or NRas protein relative to various mutations in one or more codons of Ras protein, such as G12C mutation, G12D mutation, G12V mutation and G13D mutation have better ability to selectively inhibit the G12D mutation of KRas protein. For example, the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof that may be derived therefrom A specific Ras mutation (e.g., KRas-G12D) that has at least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250- or 500-fold better activity.

The term "Ras mutation-mediated disease" as used herein refers to a disease in which Ras mutations promote the occurrence and development of the disease, or in which inhibition of Ras mutations will reduce the incidence of the disease, reduce or eliminate disease symptoms. For the purposes of the present invention, "Ras mutation-mediated disease" preferably refers to a KRas mutation-mediated disease, preferably a KRas-G12D-mediated disease, more preferably a cancer or tumor.

The term "cancer" or "tumor" as used herein refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. For various aspects of the invention, the cancer or tumor includes, but is not limited to, lung adenocarcinoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer , anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, thyroid cancer Parathyroid carcinoma, adrenal carcinoma, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors (CNS), primary CNS lymphoma, spinal tumors, brainstem glioma, or pituitary adenoma.

For various aspects of the invention, preferably, the cancer or tumor is associated with Ras mutation, especially KRas mutation, preferably KRas G12D mutation, including but not limited to the above tumor types and their preferred ranges. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, cholangiocarcinoma, leukemia and ovarian cancer.

As used herein, the terms "subject," "individual," or "patient" refer to a vertebrate animal. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cattle), sporting animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, the mammal is a human.

The term "therapeutically effective amount" as used herein refers to an amount or dosage generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment of said "Ras mutation-mediated disease" such as cancer or tumors. Those with ordinary skill in the art can determine the effective amount or dosage of the active ingredients in the present invention through conventional methods and combined with conventional influencing factors.

The term "pharmaceutical combination" as used herein means that the compounds of the invention may be combined with other active agents for carrying out the purposes of the invention. The other active agent may be one or more additional compounds of the invention, or may be a second or additional (eg, third) compound that is compatible with the compound of the invention, i.e. does not adversely affect each other, or has complementary activity, For example, these active agents are known to modulate other biologically active pathways, or to modulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention. Such active agents are suitably present in combination in an amount effective to achieve the intended purpose. The other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered separately from the compound of the present invention in separate discrete units, and when administered separately may occur simultaneously or sequentially. The successive administrations may be close or distant in time.

The term "pharmaceutically acceptable" as used herein means molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered in appropriate amounts to animals, such as humans.

The term "pharmaceutically acceptable salts" as used herein refers to those salts which retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable, including Including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" can be formed from compounds with basic groups and inorganic acids or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids can be selected from Aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, Maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid , phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, as well as those derived from pharmaceutically acceptable base addition salts. Accepts salts of organic non-toxic bases including, but not limited to, primary, secondary and tertiary amines, substituted ammoniums including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as amines, isopropylamine, trimethylamine , diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine acid, arginine , histamine, caffeine, procaine, hypamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine , N-ethylpiperidine, polyamine resin, etc.

The term "isomer" as used herein refers to any stereoisomer or enantiomeric mixture that may exist in the structure of a compound, including racemates, diastereomeric mixtures, geometric isomers, and antirotation Isomers and/or tautomers. Methods for determining the stereochemistry and separation of such isomers are well known to those of ordinary skill in the art (S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994).

Certain compounds of the present invention contain at least one asymmetric center and thus produce stereoisomers. Therefore, the present invention encompasses all possible isomeric forms of the compounds defined herein, as well as pharmaceutically acceptable salts or solvates thereof. , unless otherwise instructed.

”或“

”表示立體中心即手性中心的絕對構型，相應地在本發明所提供的化合物或中間體的命名中以R或S表示關於該手性中心的絕對構型；在有些本發明化合物定義中也可以使用軸手性表示化合物構型，這些構型的確定使用所屬技術領域具有通常知識者所熟知的Cahn-Ingold-Prelog規則，如下圖兩個示例結構中軸手性絕對構型描述如下： "

"or"

” represents the absolute configuration of the stereocenter, that is, the chiral center. Correspondingly, in the naming of the compounds or intermediates provided by the present invention, R or S represents the absolute configuration of the chiral center; in some definitions of the compounds of the present invention Axial chirality can also be used to represent the configuration of a compound. These configurations are determined using the Cahn-Ingold-Prelog rules that are well known to those with ordinary knowledge in the art. The absolute configurations of the axial chirality in the two example structures shown below are described as follows:

”指示與其交叉的鍵是結構片段連接於分子其餘部分的鍵。 The "

” indicates that the bond that crosses it is the bond that connects the structural fragment to the rest of the molecule.

Compounds of the invention include unlabeled forms of compounds of the invention and isotopically labeled forms thereof. Isotopically labeled forms of compounds are compounds that differ only in the replacement of one or more atoms by the corresponding isotopically enriched atom. Examples of isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁷ Cl and ¹²⁵ I. Such isotopically labeled compounds may be used, for example, as probes in biological assays, analytical tools, or as therapeutic agents. In certain embodiments, the compounds of the invention are provided in unlabeled form.

The term "solvate" as used herein refers to solvent addition forms of compounds containing stoichiometric or non-stoichiometric solvents, including any solvated form of the compounds of the present invention, including, for example, solvates with water, such as hydrates or as a solvate with an organic solvent such as methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrile respectively; or in the form of any polymorphic form. It is to be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.

The term "metabolite" as used herein means the product of a compound metabolized in the body. Such products may, for example, result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Identification and analysis of metabolite products is performed in a manner well known to those of ordinary skill in the art.

The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid filler or gel materials suitable for human use and of sufficient purity and sufficiently low toxicity, examples of which include but are not limited to cellulose and its derivatives (such as sodium carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate , vegetable oil, polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, Antioxidants, preservatives, etc.

The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-substituted" group as used herein in defining a group is intended to include mono- or polyhalogen groups in which one or more of the same or different halogens replaces one or more hydrogens in the corresponding group. .

The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1 to 10, for example 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C _{1 -6} alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include methyl, ethyl, propyl (including n- Propyl and isopropyl), butyl (including n-butyl, isobutyl, secondary butyl or tertiary butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl , 2-methylpentyl, etc.

The term "C _1-6 alkyl optionally substituted with halogen" as used herein refers to the C _1-6 alkyl groups described above, one or more of which (e.g. 1, 2, 3, 4 _or 5 ) hydrogen atoms are replaced by halogens as necessary. One of ordinary skill in the art will understand that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms. Examples of "halogen-substituted C ₁ - ₆ alkyl" include -CH ₂ F, -CHF ₂ , -CF ₃ , -CCl ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ CF ₃ or -CF (CF ₃ ) ₂ , etc.

The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond. Specifically, the alkenyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term " _C2-6 alkenyl" refers to _a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, Pentenyl, etc., the carbon atom in the alkenyl group connected to the rest of the molecule can be saturated or it can be an olefinic carbon atom.

The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Specifically, the alkynyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term " _C2-6 alkynyl" refers to a straight or branched chain alkynyl group having 2 _to 6 carbon atoms, such as ethynyl, propynyl, propargyl, butynyl Etc., the carbon atom in the alkynyl group attached to the rest of the molecule can be saturated or it can be an alkyne bonded carbon atom.

The term "cycloalkyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring carbon atoms. Cycloalkyl groups can have 3 to 12 carbon atoms (i.e., C _3-12 cycloalkyl), such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or polycyclic (eg bicyclic) structures including spiro Ring, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1]heptyl or bicyclo[3.2.1]octyl, etc. For example, the term "C _3-6 cycloalkyl" as used herein refers to monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "heterocycloalkyl" means a monocyclic, fused ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and the specified number of ring atoms. Combined polycyclic, spirocyclic or bridged polycyclic non-aromatic saturated ring structures, or their N-oxides, or their S-oxides or S-dioxides. Heterocycloalkyl groups may have 3 to 12 ring members (can be referred to as 3-12 membered heterocycloalkyl groups), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 6 ring members. Heterocycloalkyl groups generally contain up to 4 (eg 1, 2, 3 or 4) heteroatoms, such as 4-7 membered heterocycloalkanes containing 1 to 3 heteroatoms selected from N, O, S base. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl). -pyrrolidinyl), tetrahydrofuryl (such as 1-tetrahydrofuryl, 2-tetrahydrofuryl and 3-tetrahydrofuryl), tetrahydrothienyl (such as 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrofuryl) thienyl), pipera Aldyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl (e.g. N-morpholinyl), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepane Examples of radicals include 1,4-diazacycloheptyl, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl. The atom in the heterocycloalkyl group attached to the remainder of the compound may be a carbon atom or a heteroatom, as long as this is chemically feasible.

、

、

、

、 Preferred heterocycloalkyl groups include

,

,

,

,

、

、

；應當理解具有不對稱中心的結構涵蓋其外消旋的和/或單一的對映異構形式，例如

可代表

和/或

,

,

; It is understood that structures with asymmetric centers encompass their racemic and/or single enantiomeric forms, e.g.

representative

and / or

As used herein, the term "heteroaryl" means a monocyclic or fused ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and the specified number of ring atoms. Polycyclic aromatic ring structure, or its N-oxide, or its S-oxide or S-dioxide. Specifically, the aromatic ring structure may have 5 to 10 ring members. The heteroaryl group can be, for example, a 5-6 membered monocyclic ring, or composed of two fused 6-membered rings, two fused 5-membered rings, a fused 6-membered ring and a 5-membered ring, or a fused 5-membered ring. A fused bicyclic structure formed by a ring and a 4-membered ring. Heteroaryl rings will typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2 heteroatoms, for example individually selected from the group consisting of O, N and S, where N and S may be in the oxidized state Such as N oxide, S=O or S(O) ₂ . In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one ring oxygen atom. For example, the heteroaryl group may be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O, or S. Examples of suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl; examples of suitable 6-membered monocyclic heteroaryl include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazine base. For example, a heteroaryl group can also be a fused ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, such as benzofuran, benzothiophene, indole, benzimidazole, Indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b] Pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazole Para[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, purine, indol, imidazo[1,2-a]pyridine, imidazo[1,5- a]pyridine, pyrazolo[1,5-a]pyridazine, pyrro[1,2-b]pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-b] Pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline Phenoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,6-naphthyridine , 2,7-naphthyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d] Pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and Pyrimido[4,5-d]pyrimidine. The atom in the heteroaryl group attached to the remainder of the compound may be a carbon atom or a heteroatom, as long as this is chemically feasible.

The term "hydroxy" as used herein refers to the -OH group.

The term "cyano" as used herein refers to the -CN group.

As used herein, the term "optionally substituted", unless otherwise indicated, means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5 or more, or any derivative thereof range) is substituted with the substituents listed for this group, where the substituents may be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents that may be the same or different. In another embodiment, an optionally substituted group has 3 substituents that may be the same or different. In another embodiment, an optionally substituted group has 4 substituents that may be the same or different. In another embodiment, an optionally substituted group has 5 substituents that may be the same or different.

Many of the groups defined herein are optionally substituted, and the list of substituents given in this definitions section is exemplary only and is not intended to limit the substituents defined elsewhere in this specification and the claims.

Unless otherwise specified, C _n-n+m or C _n -C _m in the definition of the compound of the present invention includes various situations of n to n+m carbons, for example, C _1-6 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ also include any range from n to n+m. For example, C _0-6 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _0-1 , C _0-2 , C _0-3 , C _0-4 , C _0-5 , C _1-2 , C _1-3 , C _1-4 , C _2-3, etc., C _1-6 includes C _{1- 2} , C _1-3 , C _1-4 , C _2-6 , C _3-6 , etc. Similarly, n to n+m members in the definition of the compound of the present invention means that the number of ring atoms is n to n+m. For example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring. , 12-member ring, etc., also includes any range from n to n+m members. For example, 3-12-member ring includes 3-6-member ring, 3-8-member ring, 3-9-member ring, 4-10-member ring, 4-7 ring, 4-5 ring, 5-6 ring, 5-7 ring, 5-8 ring, 5-9 ring, 6-7 ring, 6-8 ring and 6- 10-member ring and so on.

Anyone with ordinary knowledge in the field of organic synthesis technology will understand that each group carried on the structure of the compound of the present invention, whether unsubstituted or substituted by various defined substituents, All are based on the premise of making the compound molecule chemically feasible and stable, in which the type and number of substituents are determined by the number and chemical valence of the atoms in the group.

As used in this specification and the claims that follow, the word "comprises" and variations of this word such as "includes" and "contains" mean "including but not limited to" and are not intended to exclude, for example, other additives , ingredient, integer or step. When an element is described as including a plurality of ingredients, steps or conditions, it will be understood that the element may also be described as including any combination of such multiple ingredients, steps or conditions, or as "consisting of a plurality or combination of ingredients, "consisting essentially of a plurality or combination of ingredients, steps or conditions".

It is to be understood that when the compounds of the present invention, pharmaceutical compositions, pharmaceutical compositions, kits and related uses and methods are described herein, the dosages referred to are based on the weight of the free form, excluding any salts, hydrates or salts thereof. Solvates, unless the instructions state that the dosage is based on the weight of the salt, hydrate, or solvate.

Problems solved by the invention

As mentioned above, compounds capable of inhibiting Ras muteins, particularly KRas muteins, and more particularly KRas-G12D muteins, can be used to treat or prevent diseases (eg, cancer or tumors) mediated by the muteins. Therefore, in this field, various structural types of Ras inhibitors have been developed (Duan Ni et al., Pharmacology & Therapeutics, Volume 202, October 2019, p1-17; US2019/0144444A1, WO2019/110751A1, WO2017/172979A1, WO2021/ 041671A1, WO2021/107160A1 and WO2021/081212A1).

However, on the one hand, existing KRas inhibitors still have problems that need to be solved, including, for example, many inhibitors have unsatisfactory anti-tumor activity or have toxic side effects. Poor drug resistance, or pharmacokinetic properties that do not allow for convenient administration, that is, poor "drugability", etc. Furthermore, even for inhibitors with good anti-tumor activity, people still hope to further improve their inhibitory activity against target proteins in vivo and further improve their drug resistance (fewer toxic side effects or better safety). ) and further improve its pharmacokinetic properties to provide more and better treatment options for clinical use.

problem solving methods

Through extensive and in-depth research, the present inventors have developed a group of compounds with significant inhibitory activity against Ras mutant proteins, especially KRas mutant proteins, and more particularly KRas-G12D mutant proteins. Through structural modification and activity verification, the inventors found that by modifying specific stereochemical substituents at specific positions of the pyrimidine ring of the KRas inhibitor structure, we obtained a product that was more effective than the corresponding racemic compound or enantiomer. It is said that the inhibitory activity against KRas-G12D mutant protein is further improved, and the compound obtained by such modification has good safety, has reduced risk of drug interaction, and also has good or even further improved pharmacokinetic properties. Enables administration in a convenient manner.

Therefore, the present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors, and more specifically KRas-G12D inhibitor compounds; pharmaceutical compositions containing such compounds as active ingredients; as medicines, for the treatment or prevention of diseases caused by The compound is a tumor or cancer that is mediated by or benefits from inhibition by Ras, specifically KRas, more specifically KRas-G12D; use of the compound is for the treatment or prevention of tumors or cancers caused by Ras, specifically KRas, more specifically KRas-G12D; Methods for diseases such as tumors or cancers that are mediated or benefited from inhibition by Ras, specifically KRas, more specifically KRas-G12D; and the compounds are prepared for use in the treatment or prevention of diseases caused by Ras , specifically KRas, more specifically KRas-G12D mediates or obtains Use in drugs that benefit diseases such as tumors or cancers that are inhibited by Ras, specifically KRas, more specifically KRas-G12D.

The present invention therefore provides the following technical solutions.

Compounds of the present invention

The terms "compounds of the invention" and "compounds of the invention" and the like used throughout this application, unless otherwise limited, encompass the compounds defined in each embodiment and its preferred embodiments herein or each specific embodiment thereof, including variants thereof. Conformers, including atropisomers, enantiomeric mixtures, especially racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopes Variations and salts (e.g., pharmaceutically acceptable salts).

Therefore, the above-mentioned various isomers and derivatives of the compounds of the present invention are therefore encompassed within the scope of the present invention, and their respective meanings, preparations and specific examples are as defined in the "Definitions" section above, or are well known to those skilled in the art. . However, preferred are compounds of the invention and/or pharmaceutically acceptable salts or solvates thereof.

The invention also encompasses N-oxides of the compounds of the invention, provided these compounds contain basic nitrogen atoms such as those present in nitrogen-containing heterocycles and are chemically and biologically feasible. Certain compounds of the invention may exist in polymorphic or amorphous forms and thus fall within the scope of the invention.

The present invention provides the following compound embodiments:

1. Embodiment 1: Compounds of formula (A) or their pharmaceutically acceptable salts or solvates,

in,

X is selected from N, CH, CF, C-Cl and C-CF ₃ ;

Y is selected from O, S and NR ^b ;

R ^a is selected from halogen, C _1-6 alkyl or -OC _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted by halogen;

R ^b at each occurrence is independently selected from H and C _1-6 alkyl optionally substituted by halogen;

R ₁ is selected from H, CN, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -(CH ₂ ) _p -C _3-6 cycloalkyl and -(CH ₂ ) _p -4-7 membered heterocycloalkyl, in which -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and 4- Each 7-membered heterocycloalkyl group is independently optionally substituted by halogen, CN, -C _1-6 alkyl, -OR ^b or -N(R ^b ) ₂ ; or

R ₁ and R ₃ connected to the ortho-position ring carbon atoms together with the ring carbon atoms to which they are connected form a fused C _3-6 cycloalkyl group;

R ₂ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally replaced by halogen, -C _{1 -6} alkyl, -OR ^b or -N(R ^b ) ₂ substitution; or when n is 2, two R ₂ together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group;

R ₃ is selected from H, halogen, -CN, -OH, -OC _1-6 alkyl, -O-(CH ₂ ) _p -C _3-6 cycloalkyl, -O-(CH ₂ ) _p -4- 7-membered heterocycloalkyl, -O-(CH ₂ ) _p -5-10-membered heteroaryl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -( CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl, -(CH ₂ ) _p -5- 10 membered heteroaryl, -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ and -OC(O)-N(R ^b ) ₂ , among which -C _1-6 alkyl, C _{3- 6-} cycloalkyl, 4-7-membered heterocycloalkyl and 5-10-membered heteroaryl are each independently optionally replaced by halogen, -CN, side oxygen, -C _1-6 alkyl, -OR ^b , -N( R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ , -OC(O)-N(R ^b ) ₂ substituted; or

Two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , spiro C _3-6 cycloalkyl or spiro 4-7 membered heterocycloalkyl, wherein R ^c is each independently selected from halogen and -C _1-6 alkyl optionally substituted by halogen; or

Two R ₃ connected to adjacent ring carbon atoms together with the ring carbon atoms to which they are connected form a fused C _3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group;

R ₄ is selected from H, -C _1-6 alkyl, -C _{2-6 alkenyl, -C 2-6 alkynyl} , -(CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl, -(CH ₂ ) _p -5-10 membered heteroaryl, -C(O)-OR ^b and -C(O)-N(R ^b ) ₂ , where Each of -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl Independently as appropriate, halogen, -CN, -C _1-6 alkyl, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution;

或

，其中 Z is selected from

or

,in

R ₅ and R ₇ are each independently selected from H or halogen;

R ₆ and R ₈ are each independently selected from H, halogen, -C _1-6 alkyl and -C _2-6 alkynyl;

m and p are each independently selected from an integer from 0 to 3;

n is an integer selected from 0-2.

1-1 . The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from N, CH, CF and C-Cl.

1-2 . The compound of embodiment 1-1 or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is selected from H, halogen, -CN, -OH, -OC _1-6 alkyl, -O- (CH ₂ ) _p -C _3-6 cycloalkyl, -O-(CH ₂ ) _p -4-7 membered heterocycloalkyl, -O-(CH ₂ ) _p -5-10 membered heteroaryl, - C _1-6 alkyl, -C _2-6 alkenyl, -(CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl, -(CH ₂ ) _p -5-10 membered heteroaryl, -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ and -OC(O)-N(R ^b ) ₂ , in which -C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are independently optionally flanked by halogen, -CN, Oxygen, -C _1-6 alkyl, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ , -OC(O)- N(R ^b ) ₂ substitution; or

Two R ₃ attached to the same carbon atom form a spiro C _3-6 cycloalkyl group or a spiro 4-7 membered heterocycloalkyl group; or

Two R ₃ connected to adjacent ring carbon atoms together with the ring carbon atoms to which they are connected form a fused C _3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group.

1-3 . The compound of embodiments 1 to 1-2 or a pharmaceutically acceptable salt or solvate thereof, which is a compound of formula (A-1),

in,

X is selected from N, CH, C-F and C-Cl;

Y is selected from O, S and NR ^b ;

R ^a is selected from F and Cl;

R ^b at each occurrence is independently selected from H and C _1-6 alkyl optionally substituted by halogen;

R ₁ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, wherein -C _1-6 alkyl and -C _3-6 cycloalkyl are each independently optionally replaced by halogen, - OR ^b or -N(R ^b ) ₂ substitution;

R ₂ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally replaced by halogen, -OR ^b or -N(R ^b ) ₂ substitution;

R ₃ is selected from H, halogen, -CN, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ , -OC(O) -N(R ^b ) ₂ and -C _1-6 alkyl, in which -C _1-6 alkyl is optionally replaced by halogen, -CN, -OR ^b , -N(R ^b ) ₂ , -C(O) -OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution;

R ₄ is selected from H, -C _1-6 alkyl, -C ^2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl, -C(O)-OR _b and -C (O)-N(R ^b ) ₂ , in which -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl are each independently optional By halogen, -CN, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution;

或

，其中 Z is selected from

or

,in

R ₅ and R ₇ are each independently selected from H or halogen;

R ₆ is selected from H, halogen, -C _1-6 alkyl and -C _2-6 alkynyl;

R ₈ is selected from H, halogen, -C _1-6 alkyl and -C _2-6 alkynyl.

2. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

3. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH.

4. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF.

5. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-Cl.

5-1. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-CF ₃ .

6. The compound of any one of embodiments 1 to 5-1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

7. The compound of any one of embodiments 1 to 5.1, wherein Y is S, or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of any one of embodiments 1 to 5.1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is NR ^b , such as but not limited to -NH-, -N(CH ₃ )-, -N( CH ₂ CH ₃ )-.

9. The compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein ^Ra is halogen, such as F or Cl.

10. The compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein ^Ra is C _1-6 alkyl or -OC _1-6 alkyl, optionally substituted by halogen, For example, but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ Cl, -O-CH ₂ CH ₃ , -O -CH ₂ CH ₂ CH ₃ , -O-CH ₂ - O-CH ₃ , -O-CH ₂ CH ₂ -O-CH ₃ , -O-CH ₂ F , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CH ₂ F, -O-CH ₂ CHF ₂ , -O-CH ₂ CF ₃ , -O-CH ₂ CH ₂ CF ₃ .

11. The compound of any one of embodiments 1 to 10, wherein _R1 is H, or a pharmaceutically acceptable salt or solvate thereof.

11-1. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is CN.

11-2 . The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -C _2-6 alkenyl or -C _2-6 alkynyl, such as but not Limited to vinyl and ethynyl groups.

12. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is selected from -C _1-6 alkyl, -(CH ₂ ) _p -C _3-6 ring Alkyl and -(CH ₂ ) _p -4-7 membered heterocycloalkyl, in which -C _1-6 alkyl, -C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently regarded as Need to be substituted by halogen, CN, -C _1-6 alkyl, -OR ^b or -N(R ^b ) ₂ .

12-1. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ and R ₃ connected to the ortho-position ring carbon atoms and the ring carbon atoms to which they are connected Together they form a fused C _3-6 cycloalkyl group such as, but not limited to, fused cyclopropyl or fused cyclobutyl.

12-2. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is selected from -C _1-6 alkyl and -C _3-6 cycloalkyl, each Independently optionally substituted by halogen, CN or -OR ^b .

13. The compound of embodiment 12-2, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is -C _1-6 alkyl, optionally substituted by halogen or -OR ^b , such as but not limited to -CH _3. -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C (CH ₃ ) ₃ , -CH ₂ -OH, -CH ₂ -CN, -CH ₂ CH ₂ -OH, -CH ₂ -O- _CH 2 CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ Cl, -CF(CF ₃ ) ₂ .

、

、

、

、 14. The compound of embodiment 12-2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -C _3-6 cycloalkyl, optionally substituted by halogen or -OR ^b , such as but not limited to cycloalkyl. Propyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

,

,

15. The compound of embodiment 12-2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is selected from -C _1-6 alkyl and -C _3-6 cycloalkyl, such as but not limited to -CH _3. -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

16. The compound of any one of embodiments 1 to 15, wherein _R2 is H, or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is selected from -C _1-6 alkyl and -C _3-6 cycloalkyl, each independently Optionally substituted by halogen or -OR ^b .

18. The compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is -C _1-6 alkyl, optionally substituted by halogen or -OR ^b , such as but not Limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ Cl, -CF(CF ₃ ) ₂ .

18-1 . The compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein when n is 2, the two R ₂ together with the carbon atom to which they are attached form C _{3- 6} cycloalkyl, such as cyclopropyl, cyclobutyl.

、

、

、 19. The compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is -C _3-6 cycloalkyl, optionally substituted by halogen or -OR ^b , such as but Not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

,

20. The compound of any one of embodiments 1 to 19, wherein _R3 is H, or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein _R3 is halogen, such as F, Cl, Br or I.

22. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein _R3 is -CN.

23. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH or -OC _1-6 alkyl, wherein C _1-6 alkyl is optional Substituted by -OH, halogen or -OC _1-6 alkyl, such as but not limited to -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O- CH ₂ CH ₂ CH ₃ , -O-CH ₂ -O-CH ₃ , -O-CH ₂ CH ₂ -O-CH ₃ , -O-CH ₂ F , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CH ₂ F, -O -CH ₂ CHF ₂ , -O-CH ₂ CF ₃ , -O-CH ₂ CH ₂ CF ₃ .

23-1. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is selected from -O-(CH ₂ ) _p -C _3-6 cycloalkyl, - O-(CH ₂ ) _p -4-7 membered heterocycloalkyl and -O-(CH ₂ ) _p -5-10 membered heteroaryl, where p is selected from 0, 1 or 2, such as but not limited to -O -oxa or azetidine, -O-CH ₂ -oxa or azetidine, -O-oxa or azetidine, -O-CH ₂ -oxa or azetidine Alkane, in which -C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, side oxygen, -C _1-6 alkyl , -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ , -OC(O)-N(R ^b ) ₂ substitution.

23-2 . The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is selected from -(CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl and -(CH ₂ ) _p -5-10 membered heteroaryl, where p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, Cyclopentyl, _{-CH 2} -cyclopropyl, -CH 2 -cyclobutyl, -CH ₂ -cyclopentyl, oxa or azetidinyl, oxa or azetidine, oxazacycle Pentyl, -CH ₂ -oxa or azetidine, -CH ₂ -oxa or azetidine, in which -C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5 -10-membered heteroaryl groups are each independently optionally replaced by halogen, -CN, side oxygen, -C _1-6 alkyl, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , - C(O)-N(R ^b ) ₂ , -OC(O)-N(R ^b ) ₂ substitution.

24. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ^b ) ₂ , such as but not limited to -NH ₂ , -NH-CH ₃ , -NH-CH ₂ CH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -NH-CH ₂ F , -NH-CHF ₂ , -N(CH ₃ )-CF ₃ , -NH-CH ₂ CH ₂ F, -NH-CH ₂ CHF ₂ , -NH-CH ₂ CF ₃ , -NH-CH ₂ CH ₂ CF ₃ .

25. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ , such as but not limited to -C(O)-OH, -C(O)-NH ₂ or -OC(O)-NH ₂ , -C(O)- OCH ₃ , -C(O)-N(CH ₃ ) ₂ , -OC(O)-N(CH ₃ ) ₂ .

26. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -C _1-6 alkyl, optionally replaced by halogen, -CN, -OR ^b , - N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ , preferably replaced by -OR as needed ^b or -OC(O)-N(R ^b ) ₂ substitution, such as but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ )(CH ₃ ), -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CHFCH _3. -CH ₂ CHF ₂ , -CH(CH ₃ )(CH ₂ F) , -CH ₂ CHFCH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CHF ₂ , - CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -CH ₂ CN, -CH ₂ CH ₂ CN, -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -C(CH ₃ ) ₂ ( OH), -CH ₂ -CH(CH ₃ )(OH), -CH(CH ₃ )CH ₂ OH, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH (CH ₃ )CH ₂ OCH ₃ , -CH ₂ -CH(CH ₃ )(OCH ₃ ), -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -NH ₂ , -CH ₂ -NH(CH ₃ ), -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH(CH ₃ ), -CH ₂ CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH ₂ CH ₂ -NH-CH ₃ , -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ - OC(O)-N(CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)- N(CH ₂ CH ₃ )(CH ₃ ).

26-1. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein two R ₃ attached to the same carbon atom form a spiro C _3-6 cycloalkyl group, For example, but not limited to spirocyclopropyl, spirocyclobutyl; or

Two R ₃ attached to the same carbon atom form a spiro 4-7 membered heterocycloalkyl group, such as but not limited to aza or oxetanyl, aza or oxetanyl; or

Two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , where R ^c is each independently selected from F, Cl, Br, I, -C _1-6 alkyl optionally substituted by halogen ;For example but not limited to =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ .

26-2. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein two R ₃ attached to adjacent ring carbon atoms are together with the ring carbon atoms to which they are attached. Forming a fused C _3-6 cycloalkyl group such as, but not limited to, fused cyclopropyl; or

Two R ₃ connected to adjacent ring carbon atoms together with the ring carbon atoms to which they are connected form a fused 4-7 membered heterocycloalkyl group, such as but not limited to fused aza or oxetane, Aza or oxolane.

26-3 . The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ -C _2-6 alkenyl or -C _2-6 alkynyl, such as but not limited to Vinyl, ethynyl.

27. The compound of embodiment 26, or a pharmaceutically acceptable salt or solvate thereof, wherein _R3 is _-C1-6 alkyl, substituted by -OC(O)-N( ^Rb ) ₂ , such as but not Limited to -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ CH ₂ -OC (O)-N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , - CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ).

28. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is selected from H, halogen, -OR ^b or -OC(O)-N(R ^b ) _2- substituted -C _1-6 alkyl, such as but not limited to H, F, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH ₂ CH ₂ CH ₃ , -O-CH (CH ₃ )(CH ₃ ), -O-CH ₂ F, -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CH ₂ F, -O-CH ₂ CHF ₂ , -O-CH ₂ CF ₃ , -O-CH ₂ CH ₂ CF ₃ , -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-N( CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O )-N(CH ₂ CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ ) (CH ₃ ).

29. The compound of any one of embodiments 1 to 28, wherein _R4 is H, or a pharmaceutically acceptable salt or solvate thereof.

30. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _1-6 alkyl, optionally replaced by halogen, -CN, -OR ^b , - N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution, such as but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH(CH ₃ )CH ₃ , -C( CH ₃ ) ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F , -CHFCH ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )(CH ₂ F) , -CH ₂ CHFCH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -CH ₂ CN, -CH ₂ CH ₂ CN, -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -C(CH ₃ ) ₂ (OH), -CH ₂ -CH(CH ₃ )(OH), -CH(CH ₃ )CH ₂ OH, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH(CH ₃ )CH ₂ OCH ₃ , -CH ₂ -CH(CH ₃ )(OCH ₃ ), -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -NH ₂ , -CH ₂ -NH(CH ₃ ), -CH ₂ - N(CH ₃ ) ₂ , -CH ₂ CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH(CH ₃ ), -CH ₂ CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH ₂ CH ₂ -NH-CH ₃ , -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)- N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ -OC (O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ).

31. The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is -C _1-6 alkyl, optionally replaced by halogen, ^-OR or -OC(O)-N(R ^b ) ₂ substitution, such as but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ F , -CHF ₂ , -CH ₂ CH ₂ F , -CHFCH ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )( CH ₂ F), -CH ₂ CHFCH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -C(CH ₃ ) ₂ (OH), -CH ₂ -CH(CH ₃ )(OH), -CH(CH ₃ )CH ₂ OH, - CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH(CH ₃ )CH ₂ OCH ₃ , -CH ₂ -CH(CH ₃ )(OCH ₃ ), -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N( CH ₂ CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ) .

、

、 32. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _2-6 alkenyl or -C _2-6 alkynyl, such as but not limited to

,

,

33. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C(O)-OR ^b and -C(O)-N(R ^b ) ₂ , such as but not limited to -C(O)-OCH ₃ , -C(O)-OCH ₂ CH ₃ , -C(O)-NH ₂ , -C(O)-NH-CH ₃ , -C(O) -N(CH ₃ ) ₂ , -C(O)-N(CH ₂ CH ₃ ) ₂ , -C(O)-N(CH ₂ CH ₃ )(CH ₃ ).

34. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is selected from -(CH ₂ ) _p -C3 _-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl and -(CH ₂ ) _p -5-10 membered heteroaryl, where p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl , -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, oxa or azetidinyl, oxa or azetidinyl, oxazacyclopentyl, Oxa or azetidine, -CH ₂ -oxa or azetidine, -CH ₂ -oxa or azetidine, pyrazolyl, -CH ₂ -pyrazolyl, where - C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, side oxygen, -C _1-6 alkyl, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ .

34-1 . The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _3-6 cycloalkyl, optionally replaced by halogen, -CN, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution, such as but not limited to Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl each independently substituted with a substituent selected from the following: F, Cl, Br, I , -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH ₂ CH ₂ CH ₃ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ).

35. The compound of embodiment 34-1, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _3-6 cycloalkyl, optionally substituted by halogen or -OR ^b , such as but not limited to cycloalkyl. Propyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclobutyl or cyclopentyl substituted by F, cyclopropyl, cyclobutyl or cyclopentyl substituted by -O- _CH3 .

、

、

、

、

-C(O)-NH₂、-C(O)-NH-CH₃、-C(O)-N(CH₃)₂、-C(O)-N(CH₂CH₃)₂、-C(O)-N(CH₂CH₃)(CH₃)、環丙基、環丁基、環戊基、環己基，或各自獨立地被選自以下的取代基取代的環丙基、環丁基、環戊基或環己基：F、Cl、Br、I、-CN、-OH、-O-CH₃、-O-CH₂CH₃和-O-CH₂CH₂CH₃。 36. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _{2- 6} alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , of which -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkyne The base and -C _3-6 cycloalkyl are each independently optionally substituted by halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ , such as but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ F, -CHF ₂ , -CH ₂ CH ₂ F, -CHFCH ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )(CH ₂ F), -CH ₂ CHFCH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -C(CH ₃ ) ₂ (OH), -CH ₂ -CH(CH ₃ )(OH), -CH(CH ₃ )CH ₂ OH, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH _3. -CH(CH ₃ )CH ₂ OCH ₃ , -CH ₂ -CH(CH ₃ )(OCH ₃ ), -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -OC(O)-NH ₂ , -CH ₂ CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ ) ₂ , -CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ), -CH ₂ CH ₂ -OC(O)-N(CH ₂ CH ₃ )(CH ₃ ),

,

,

,

,

-C(O)-NH ₂ , -C(O)-NH-CH ₃ , -C(O)-N(CH ₃ ) ₂ , -C(O)-N(CH ₂ CH ₃ ) ₂ , -C (O)-N(CH ₂ CH ₃ )(CH ₃ ), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropyl, cyclobutyl each independently substituted by a substituent selected from the following group, cyclopentyl or cyclohexyl: F, Cl, Br, I, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ and -O-CH ₂ CH ₂ CH ₃ .

37. The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _1-6 alkyl, optionally substituted by halogen or -OR ^b , preferably optionally F.

，R^a為F，由此式A具有式I：

，例如

，其中X、Y、R₁、R₂、R₃、R₄、R₅、R₆、n和m如以上實施方案1至37相應所定義。 38. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

, R ^a is F, so formula A has formula I:

,For example

, wherein X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n and m are as defined correspondingly in Embodiments 1 to 37 above.

39. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, which is formula I-1:

，例如

。

,For example

.

40. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, of formula I-2:

，例如

。

,For example

.

41. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, of formula I-3:

，例如

。

,For example

.

42. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, of formula I-4:

，例如

。

,For example

.

42-1. The compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, which is formula I-5:

，例如

。

,For example

.

43. The compound of any one of embodiments 38 to 42-1, or a pharmaceutically acceptable salt or solvate thereof, wherein

Y is O;

R ₁ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, as exemplified in Embodiments 11 and 15;

R ₂ is H;

R ₃ is selected from H, halogen, -OR ^b or -C _1-6 alkyl substituted by -OC(O)-N(R ^b ) ₂ , as exemplified in embodiments 21, 23 and 27;

R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , Among them, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl are each independently replaced by halogen, -OR ^b or -OC(O )-N(R ^b ) ₂ substituted, preferably -C _1-6 alkyl optionally substituted by halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ , as exemplified in Embodiment 36.

44. The compound of any one of embodiments 38 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein _R5 is selected from H or halogen, preferably F.

45. The compound of embodiments 38 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein _R6 is halogen, such as F, Cl, Br, I.

46. The compound of embodiments 38 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is -C _1-6 alkyl, such as but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ .

、

，較佳

。 47. The compound of embodiments 38 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein _R is -C _2-6 alkynyl, such as but not limited to

,

, better

.

，R^a為F，由此式A具有式II：

，例如

，其中X、Y、R₁、R₂、R₃、R₄、R₇、R₈、n和m各自如以上實施方案1至37相應所定義。 48. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

, R ^a is F, so formula A has formula II:

,For example

, wherein X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₈ , n and m are each as defined correspondingly in Embodiments 1 to 37 above.

49. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, of formula II-1:

，例如

。

,For example

.

50. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, of formula II-2:

，例如

。

,For example

.

51. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, of formula II-3:

，例如

。

,For example

.

52. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, of formula II-4:

，例如

。

,For example

.

52-1. The compound of embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, which is formula II-5:

，例如

。

,For example

.

53. The compound of any one of embodiments 48 to 52-1, or a pharmaceutically acceptable salt or solvate thereof, wherein

Y is O;

R ₁ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, as exemplified in Embodiment 15;

R ₂ is H;

R ₃ is selected from H, halogen, -OR ^b or -C _1-6 alkyl substituted by -OC(O)-N(R ^b ) ₂ , as exemplified in embodiments 21, 23 and 27;

R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , Among them, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl are each independently replaced by halogen, -OR ^b or -OC(O )-N(R ^b ) ₂ substituted, preferably -C _1-6 alkyl optionally substituted by halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ , as exemplified in Embodiment 36.

54. The compound of any one of embodiments 48 to 53, wherein _R7 is H, or a pharmaceutically acceptable salt or solvate thereof.

55. The compound of any one of embodiments 48 to 53, or a pharmaceutically acceptable salt or solvate thereof, wherein _R7 is halogen, preferably F.

56. The compound of any one of embodiments 48 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein _R8 is halogen, such as F, Cl, Br and I.

57. A compound selected from the group consisting of Examples 1 to 232 below, or a pharmaceutically acceptable salt or solvate thereof.

It should be noted that the compounds of the present invention cover each of the above independent embodiments or each specific embodiment, and also cover any combination or sub-combination of the above each embodiment or specific embodiment, and also cover any of the above preferred or specific embodiments. Any combination of the exemplified embodiments constitutes an embodiment.

Beneficial effects of the invention

As mentioned above, Ras mutant proteins, especially KRas mutant proteins, are known to play a role in tumorigenesis and various other diseases. We have surprisingly found that with the above The compounds of the present invention with structural characteristics can potently inhibit cell proliferation in cell lines carrying KRas mutant proteins, especially KRas-G12D mutant proteins, and thus have potential as an anti-tumor agent in the prevention, containment and/or treatment of related tumor diseases. Value of proliferative, pro-apoptotic and/or anti-invasive drugs. In particular, the compounds of the invention are expected to be useful in the prevention or treatment of those diseases or conditions mediated by or benefiting from inhibition by a Ras mutation, in particular a KRas-G12D mutein, such as as defined herein Cancer or tumor.

Specifically, it has been found through research that the compounds of the present invention can achieve one or more of the following technical effects:

˙High mutant protein inhibitory activity: The compounds of the present invention, especially the compounds specifically exemplified in this context, have been shown to have proliferation inhibitory activity against Ras mutations, especially KRas G12D mutant cells, in the KRAS G12D mutant cell AGS cell proliferation inhibition assay. The IC50 value is lower than 10μM, such as lower than 5μM, such as 0.001~5μM, 0.01~5μM; preferably lower than 1μM, such as 0.001~1μM, 0.01~1μM; more preferably lower than 0.5μM, such as 0.001~0.5μM, 0.01~ 0.5μM, 0.01~0.2μM, 0.01~0.1μM, 0.01~0.05μM, for example, measured according to the method described in Activity Example 1; and

In the KRASG12D mutated AGS (3D) cell proliferation inhibition assay, it is shown that it has proliferation inhibitory activity against Ras mutations, especially KRas G12D mutant cells, with an IC50 value of 0.001~5μM, such as 0.01~5μM, such as 0.001~0.5μM, preferably 0.01~0.2μM, preferably 0.01~0.1μM, optimally 0.01~0.05μM, as exemplified in Active Example 4;

˙Obviously satisfactory safety, reduced risk of drug interactions, and significantly reduced toxicity and/or side effects, as verified by Active Example 3;

˙Have good pharmacokinetic properties, such as having a longer t _1/2 , which can, for example, increase the dosing interval and longer half-life, allowing patients to have better compliance, as verified in Active Example 2 ;and / or

˙It has the best AUC _0-t data of safety/activity comprehensive effect, better druggability and higher bioavailability, as verified by Activity Example 2 below.

Based on the above beneficial effects of the compounds of the present invention, the present invention also provides technical solutions in the following aspects.

Compounds of the invention for use in therapy or as medicaments

In one aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a KRas mutein inhibitor, more specifically a KRAS G12D inhibitor.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the treatment and/or prevention of Ras mutein, specifically KRas mutein, more specifically KRAS G12D mutein mediated or a disease or condition that benefits from inhibition of a Ras mutation, specifically a KRas mutein, and more specifically a KRAS G12D mutein.

In specific embodiments, the present invention provides methods for treating and/or preventing Ras mutant proteins, specifically KRas mutant proteins, and more specifically KRAS G12D mutant proteins, which promote or inhibit the occurrence and development of the disease. Compounds of the invention, specifically KRas muteins, more specifically KRAS G12D muteins, will reduce the incidence of, reduce or eliminate disease symptoms, such as tumors or cancers, including but not limited to: Lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, uterus Endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, Prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors (CNS), primary CNS lymphoma, spinal tumors, brainstem nerves Glioma or pituitary adenoma.

In particular, the present invention provides a method for treating patients with pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, Compounds of formula (I) or isomers thereof, their pharmaceutically acceptable salts or solvates for patients with lung adenocarcinoma and cholangiocarcinoma.

Pharmaceutical compositions and their administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (A) as defined above or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V or KRas G13D mutations, especially KRas G12D mutations, such as tumors or cancers. .

The above-mentioned pharmaceutical composition of the present invention can be formulated by techniques known to those of ordinary skill in the art, such as the techniques disclosed in Remington’s Pharmaceutical Sciences, 20th edition. For example, it can be formulated into tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The composition may contain conventional components in pharmaceutical preparations, such as diluents (such as glucose, lactose or mannitol), carriers, pH adjuster, buffer, sweetener, filler, stabilizer, surfactant, wetting agent, lubricant, emulsifier, suspending agent, preservative, antioxidant, opacifier, glidant, processing aid , colorants, flavoring agents, flavoring agents, other known additives and other active agents. Suitable carriers and excipients are well known to those of ordinary skill in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004.

The administration and administration of the pharmaceutical compositions of the present invention are in accordance with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of agent delivery, the method of administration, the schedule of administration, and other factors well known to the medical practitioner. The optimal dosage level and administration frequency of the compounds or pharmaceutical compositions of the present invention can be determined by those with ordinary skill in the art through standard experiments in the field of pharmaceutical research.

The compositions of the invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhaled and Epidural and intranasal, and if local treatment is required, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, pharmaceutical compositions of the invention are administered orally.

For a human subject of 70 kg, a suitable dosage range of the compound of the invention can be routinely determined by one of ordinary skill in the art and may, for example, be 1-1000 mg/day.

When dosages of a drug or a pharmaceutically acceptable salt thereof are described herein, it is to be understood that the dosage is based on the weight of the free base, excluding any hydrates or solvates thereof, unless the instructions indicate that the dosage is based on the weight of a salt, hydrate, or solvent The weight of the compound.

Treatment methods and uses

As mentioned above, the compounds of the present invention and the compounds of its various embodiments, especially the compounds specifically prepared and characterized in the examples, show resistance to Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V or Inhibitory effects of KRas G13D mutations, especially KRas G12D.

Therefore, in another aspect, the invention provides a method for inhibiting Ras mutation, especially KRas mutation, preferably KRas G12D mutation, in a cell, comprising contacting the cell with a compound of the invention or a pharmaceutically acceptable salt or solvate thereof Contact to inhibit the activity of Ras mutations in cells, especially KRas mutations, preferably KRas G12D mutations.

Based on the same properties, the present invention also correspondingly provides a method for inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or Pharmaceutical compositions containing compounds of the present invention or pharmaceutically acceptable salts or solvates thereof.

On the other hand, the present invention provides a method for treating and/or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations, comprising administering to a subject in need thereof a therapeutically effective amount of the formula of the present invention. (A) compound or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the compound of formula (A) of the present invention or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, For inhibiting Ras mutations in cells, especially KRas mutations, preferably KRas G12D mutations, or for inhibiting abnormal cell growth in mammals, or for treatment and/or prevent diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, preferably KRas G12D mutations.

On the other hand, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the preparation of Use in a medicament for the treatment and/or prevention of diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations.

For each method and use technical solution provided by the above-mentioned invention, the abnormal cell growth may be mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, optimal KRas G12D mutation Disease refers in particular to cancer or tumors. Exemplary such cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, gastric cancer , colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland Carcinoma, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumors, brainstem glioma, or pituitary adenoma.

For each method and use technical solution provided by the above-mentioned invention, the abnormal cell growth or the disease mediated by Ras mutation, especially KRas mutation, preferably KRas G12D, is preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, lung cancer, and pancreatic cancer. Adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and cholangiocarcinoma.

Therefore, in a preferred embodiment of this aspect, the present invention provides the above-mentioned methods and uses for treating or preventing cancer or tumors by inhibiting KRas-G12D mutation. In a further preferred embodiment, the present invention provides the above-mentioned methods and application technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and cholangiocarcinoma by inhibiting KRas-G12D mutation.

The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D. Therefore, the present invention relates to the in vitro use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor, in particular a KRas G12D inhibitor, and in particular to a compound of the invention or a pharmaceutically acceptable salt thereof or In vitro use of solvates as study tool compounds for the efficacy of KRas inhibitors, particularly KRas G12D inhibitors. The invention also relates to a method of inhibiting KRas, in particular KRas G12D, in particular an in vitro method, which method comprises administering a compound of the invention or a pharmaceutically acceptable salt or solvate thereof to a sample (eg a biological sample). It is understood that the term "in vitro" is used in this particular context in the sense of "in vitro in living humans or animals", which specifically includes experiments with cells, cellular or subcellular extracts and/or biomolecules in artificial environments, For example, an aqueous solution or culture medium may be provided in a flask, test tube, petri dish, microtiter plate, etc.

drug combination

The compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies.

Accordingly, in another aspect, the present invention provides pharmaceutical combinations comprising, or consisting of, a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and other active agents. The pharmaceutical combination is used to inhibit abnormal cell growth in mammals or to treat and/or prevent diseases mediated by Ras mutations, preferably KRas mutations, or optimal KRas-G12D mutations.

The other active agent may be one or more additional compounds of the invention, or may be a second or additional (eg, third) compound that is compatible with the compound of the invention, i.e. does not adversely affect each other, or has complementary activity, For example, these active agents may be compounds known to modulate other biologically active pathways, or may be compounds that modulate different components of the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention. compound.

In a specific embodiment, other active agents that may be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiotherapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, Topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents.

Other active agents used in combination with the invention may be administered simultaneously, separately or sequentially with the compounds of the invention by the same or different routes of administration. The other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered separately from the compound of the present invention in different discrete units, such as a combination product, preferably in the form of a kit. When administered separately, they may be administered simultaneously or Performed sequentially, the successive administrations may be close or distant in time. They may be prepared and/or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other active agents may be administered (i) before the combination product is sent to the physician (for example, in the case of a kit containing a compound of the present invention and an additional drug); (ii) immediately before administration. The physician himself (or under the direction of the physician); (iii) the patient himself, for example, during the sequential administration of a compound of the invention and other active agents together in the combination therapy.

The compounds of the present invention can also be combined with anti-tumor therapies, including but not limited to surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.

Therefore, in another aspect, the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and each containing A device for the composition, such as a container, a dispenser bottle or a separate foil package, such as a blister pack for packaging tablets, capsules, etc., also includes instructions for use. The kit of the invention is particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, or for administering different compositions at different dosage intervals.

For the above-mentioned technical solutions of the pharmaceutical composition, pharmaceutical combination or kit of the present invention, the abnormal cell growth involved may be caused by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, Optimal KRas G12D mutation-mediated diseases are as defined above for the methods and uses of the invention.

For the above-mentioned compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits of the present invention, the compounds of the embodiments herein are preferred.

Preparation methods of compounds of the present invention

On the other hand, the present invention also provides methods for preparing the compounds defined in the present invention.

The compounds of the present invention or their pharmaceutically acceptable salts or solvates can be prepared by a variety of methods, including the general methods given below, the methods disclosed in the examples, or methods similar thereto.

Standard synthetic methods and procedures for the preparation of organic compounds and functional group transformations and manipulations are known in the art and can be found in standard textbooks, such as Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," pp. 7 Edition, Wiley, 2013). For each reaction step of each general synthetic scheme, appropriate reaction conditions are known or can be routinely determined by those skilled in the art. The process steps for the synthesis of the compounds of the invention may be carried out under reaction conditions known per se, including those specifically mentioned, in the absence or usually in the presence of solvents or diluents, including e.g. inert to the reagents used. and can dissolve the reagents used), in the absence or presence of catalysts, condensing agents or neutralizing agents (such as ion exchangers, such as cation exchangers, such as H ⁺ form), according to the reaction and/or the properties of the reactants at reduced, normal or elevated temperatures (e.g., from about -100°C to about 190°C, including, for example, from about -78°C to about 150°C, such as from about 0°C to about 125°C, chamber temperature, -20 to 40°C or reflux temperature), under atmospheric pressure or in a closed container, under pressure when appropriate, and/or under an inert atmosphere such as argon or nitrogen.

If not specifically stated, the raw materials and reagents used in the preparation of the compounds are commercially available, or compounds known in the literature, or can be prepared by the methods below, methods similar to the methods given below, or known in the art. Known standard methods are prepared by those with ordinary knowledge in the relevant technical field. Unless otherwise stated in the process description, suitable solvents are those conventional solvents known to those of ordinary skill in the art to be suitable for the specific reaction type involved, for example water, esters, ethers, liquid aromatic hydrocarbons , alcohols, nitriles, halogenated hydrocarbons, amides, alkalis, carboxylic acid anhydrides, cyclic, linear or branched chain hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for work-up, for example by chromatography or partitioning.

If necessary, the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, which include but are not limited to filtration, distillation, crystallization, chromatography, etc. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging. The material can be characterized using conventional methods including physical constants and spectral data. The reaction mixture is worked up in a customary manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography.

One of ordinary skill in the art will be able to recognize the presence or absence of stereocenters in the compounds of the present invention. At all stages of the reaction, the mixture of isomers formed can be separated into the individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, e.g. Racemates or mixtures of diastereomers, see for example "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).

In the case where a mixture of stereoisomers is produced during the preparation of a compound of the invention, the individual stereoisomers of the compound of the invention may be obtained by resolution, for example, by obtaining a compound of the invention as a mixture of stereoisomers Initially, well-known methods are used, such as formation of diastereomeric pairs by salt formation with optically active acids followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography; alternatively, one can use Starting materials or intermediates, or any known chiral resolution method can be used to obtain optically pure or enantiomerically enriched synthetic intermediates, which can then be used as such in subsequent steps at various stages of the above synthetic process.

In some specific cases, it may be necessary to protect specific reactive groups with appropriate protecting groups to avoid interfering with the reactions of other reactive groups. Suitable protecting groups and methods for protecting and deprotecting using such suitable protecting groups are common knowledge in the art. are well known; examples may be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).

The following merely illustrates a general synthetic scheme for the synthesis of the compounds of the present invention. Other routes as well as other reactants and intermediates known to those of ordinary skill in the art may also be used to obtain the compounds of the invention.

For the sake of clarity, in the exemplary synthesis schemes described below, unless otherwise specified, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ appearing in the structural formula of each intermediate compound , R ₈ ,

Synthesis Plan A

The synthesis of the compounds of general formula I and II of the present invention can be prepared according to the following scheme or its appropriate variation.

In step A, compound 1 is commercially available or can be obtained according to the method used in the examples herein or a method similar thereto. Compound 1 was introduced into compound 1 with Boc-protected 3,8-diazabicyclo[3.2.1]octane through aromatic nucleophilic substitution reaction to obtain compound 2. Typical aromatic nucleophilic substitution conditions are well known in the art, such as DIEA/THF, etc.

In step B, compound 2 is reacted with corresponding alcohols, amines or thiol compounds in, for example, DIEA/dioxane, NaH/THF and other conditions to obtain compound 3. The corresponding alcohols, amines or thiol compounds are commercially available, or can be obtained according to the methods used in the examples of this article or similar methods, or can be obtained according to the methods of relevant literature in the field of organic chemistry. The latter introduces phenolic compounds via Suzuki-Miyaura coupling reaction in step C to obtain compounds 4 or 5. In step D, the protective group carried by compound 4 or 5 is removed to obtain a compound of general formula I or II.

Typical Suzuki palladium coupling conditions are well known in the art, and those of ordinary skill in the art will recognize a variety of conditions for promoting such cross-coupling reactions, such as Pd(dtbpf)Cl ₂ /K ₃ PO ₄ /dioxin. alkane/water, or Pd(OAc) ₂ /rac-BIDIME/K ₂ CO ₃ /toluene; suitable palladium catalysts also include XantPhos Pd G2, cataCXium® A Pd G3, bis(triphenylphosphine) palladium(II) chloride , Pd(dppf)Cl ₂ , Pd ₂ dba ₃ , palladium tetraphenylphosphine and palladium (II) acetate, etc.; if necessary, suitable ligands may include tricyclohexylphosphine, triphenylphosphine, etc.; suitable bases also include fluorine Potassium chloride, cesium carbonate, sodium carbonate, tertiary potassium butoxide and potassium phosphate monohydrate, etc.

It should be noted that the removal of the protecting group in step D can be adjusted according to the protecting group carried by the molecule, and can be a one-step reaction or a multi-step reaction. For example, when the compound carries a protective group PG that is an acid-sensitive protective group such as MOM, PG and Boc can be removed simultaneously under conditions such as trifluoroacetic acid or hydrochloric acid to obtain the final compound; when the compound carries a protective group PG that is non-toxic such as TIPS. When using an acid-sensitive protecting group, compounds 4 or 5 need to remove the protecting group through a multi-step reaction, such as removing TIPS protection using reagents such as CsF, and then removing Boc using conditions such as trifluoroacetic acid or hydrochloric acid to obtain the final compound.

Synthesis Plan B

The synthesis of the compounds of general formula I and II of the present invention can also be prepared according to the following scheme or its appropriate variation.

In step A, compound 2 is commercially available or can be obtained according to standard methods well known in the field of organic chemistry, or the method steps described in synthetic scheme A. Compound 2 is fluorinated through a halogen exchange reaction under conditions such as KF/DMSO to obtain compound 6. Compound 6 then undergoes the Suzuki-Miyaura coupling reaction in step B, the aromatic nucleophilic substitution reaction in step C, and the protecting group removal reaction in step D to obtain the final compound I or II. The typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protecting group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.

Synthesis Scheme C

The synthesis of the compounds of general formula I and II of the present invention can also be prepared according to the following scheme or its appropriate variation.

The synthesis in this scheme starts from compound 6, and proceeds through aromatic nucleophilic substitution in step A, Suzuki-Miyaura coupling reaction in step B, and protecting group removal reaction in step C to obtain compounds of general formula I or II. The typical conditions involving coupling reaction, nucleophilic substitution reaction and protecting group removal reaction in this scheme are similar to the relevant reaction conditions described in Synthesis Scheme A, and can be implemented as a reference.

The typical reaction conditions and reagents used in the Suzuki-Miyaura coupling, aromatic nucleophilic substitution, and protective agent removal reactions involved in the above synthetic scheme are all well known in the art and fall within the scope of routine experience of those with ordinary knowledge in the technical field. , or can be determined by a person with ordinary skill in the art by making appropriate changes based on the typical conditions of such reactions in the art and based on the characteristics of the raw materials used and the target product.

Synthesis scheme D

The synthesis of compounds of general formula I and II involving axial chirality in the present invention can also be prepared according to the following scheme or its appropriate variation.

The synthesis of compound 7 in this scheme is as described in scheme B. In step C, compound 7 is resolved by SFC to obtain axially pure intermediate compounds 9 and 10. Intermediate 9 was used in the subsequent synthesis to prepare the final compound via steps D and E. The nucleophilic substitution reaction and protecting group removal reaction involved in steps D and E are carried out according to the method in synthesis scheme A.

Synthesis Example

The present invention will be further described below in conjunction with the examples. It should be noted that the following examples are exemplary and should not be regarded as limiting the scope of the present invention.

In the description of the embodiments and the specific examples that follow, the following abbreviations are used herein:

ACN (acetonitrile); Boc (tertiary butoxycarbonyl); CDCl ₃ (deuterated chloroform); DCM (dichloromethane); DIEA or DIPEA ( N , N -diisopropylethylamine); DMF ( N , N -dimethylformamide); DMSO (dimethyl sulfoxide); DMSO- d ₆ (hexadeuterated dimethyl sulfoxide); EA (ethyl acetate); EDTA-K2 (dipotassium ethylenediaminetetraacetate) salt); EtOH (ethanol); FCC (fast column chromatography); g (gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl/MeOH (hydrogen chloride in methanol solution); HLM (human liver microparticles body); H ₂ O (water); H ₂ SO ₄ (sulfuric acid); IV (intravenous administration); K ₂ CO ₃ (potassium carbonate); LCMS (liquid-mass spectrometry); LC-MS/MS (liquid spectrometry -Mass Spectrometer-Mass Spectrometer Connection); MeOH (methanol); Methanol- d ₄ (tetradeuterated methanol); mg (milligram); MHz (megahertz); min (minutes); mL (ml); mmol (millimol) ); MOM (methoxymethyl ether); MTBE (methyl tertiary butyl ether); m/z (mass-to-charge ratio); N ₂ (nitrogen); NaCl (sodium chloride); NaH (sodium hydride) ;NaHCO ₃ (sodium bicarbonate); Na ₂ SO ₃ (sodium sulfite); Na ₂ SO ₄ (sodium sulfate); NCS (chlorobutadiimide); NH ₄ Cl (ammonium chloride); NMR (nuclear magnetic resonance) ; PdCl ₂ (dtbpf) or Pd(dtbpf)Cl ₂ (1,1'-bis(di-tertiary butylphosphine) ferrocene palladium dichloride); PdCl ₂ (dppf) or Pd(dppf)Cl ₂ ( 1,1'-bisdiphenylphosphine ferrocene palladium dichloride); Pd(OAc) (palladium acetate); Pd(PPh ₃ ) ₄ (tetrakis triphenylphosphine palladium); PE (petroleum ether); PO (oral administration); POCl ₃ (phosphorus oxychloride); rt (room temperature); SiO ₂ (silica gel); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIPS (triethylamine) Propylsilyl); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); TsOH. H ₂ O (p-toluenesulfonic acid monohydrate); μL (microliter); μM (micromolar concentration); μmol (micromolar).

In the following examples, the name of the synthesized target compound and its structure are given. Any deviations in names or structures are not intended and in such cases the structure of the compound is reasonably determined in light of the context.

Experimental methods without specifying specific conditions in the following examples usually follow the conventional conditions for this type of reaction, or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless stated otherwise, ratios of liquids are by volume.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.

In the following examples, ¹ H-NMR spectra were recorded with a Bruker (400 MHz), and chemical shifts were expressed relative to the deuterated solvent peak (CDCl ₃ : δ = 7.26 ppm; CD ₃ OD : δ = 3.31 ppm; DMSO- d ₆ : δ=2.50ppm) expressed in δ (ppm); the liquid mass spectrometry was recorded using Aglient 1260 liquid chromatography + Aglient G6125B mass spectrometry LCMS liquid mass spectrometry instrument. The gas chromatography mass spectrometer used Shimadzu GCMS-QP2010SE for detection.

Chiral analysis method:

SFC-1: Waters UPCC, analytical column: Daicel Chiralpak®AD, 100*3mm 3μm; mobile phase A: CO ₂ , mobile phase B: EtOH (0.1%DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-0.5min A/B=95/5, 0.5-5.5min A/B=95/5-60/40, 5.5-8.0min A/B=60/40.

SFC-2: Waters UPCC, analytical column: Daicel Chiralpak®AD, 100*3mm 3μm; mobile phase A: CO ₂ , mobile phase B: IPA (0.1%DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-8.0min A/B=60/40.

SFC-3: Waters UPCC, analytical column: Daicel Chiralpak®AD, 100*3mm 3μm; mobile phase A: CO ₂ , mobile phase B: EtOH (0.1%DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-8.0min A/B=60/40.

SFC-4: Waters UPCC, analytical column: Daicel Chiralpak®IG, 100*3mm 3μm; mobile phase A: CO ₂ , mobile phase B: MeOH (0.1%DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-0.5min A/B=95/5, 0.5-5.0min A/B=95/5-60/40, 5.0-8.0min A/B=60/40.

SFC-5: Waters UPCC, analytical column: Daicel Chiralpak®IG, 100*4.6mm 5μm; mobile phase A: CO ₂ , mobile phase B: MeOH (0.1%DEA); flow rate: 2.0mL/min; column temperature :35℃; Back pressure: 1800psi; Gradient: 0-8.0min A/B=90/10.

SFC-6: Waters UPCC, analytical column: Daicel Chiralpak®IG, 100*4.6mm 5μm; mobile phase A: CO ₂ , mobile phase B: MeOH; flow rate: 1.5mL/min; column temperature: 40°C; reverse Pressure: 1800psi; Gradient: 0-8.0min A/B=95/5.

Intermediate A-I

(1 R ,5 S )-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Tertiary butyl acid

Step A: 7-Bromo-8-fluoroquinazoline-2,4( 1H , 3H )-dione

At room temperature, 2-amino-4-bromo-3-fluorobenzoic acid (10.0g, 42.7mmol) and urea (25.7g, 427.3mmol) were mixed together, heated to 200°C, and stirred for 2 hours. The reaction gradually changed from solid state to liquid state, and then continued to change to solid state. After the reaction was monitored by LCMS, it was washed with hot water (250 mL), and the solid was collected by filtration to obtain 7-bromo-8-fluoroquinazoline-2,4(1 H , 3H )-diketone (12g, crude product). LCMS (ESI, m/z): 258.9 (M+H).

Step B: 7-Bromo-2,4-dichloro-8-fluoroquinazoline

DIPEA (13.5 mL, 77.2 mmol) was added to 7-bromo-8-fluoroquinazoline-2,4( 1H , 3H )-dione (4.0g, 15.4mmol) and POCl at room temperature. ₃ (35.9 mL, 386.0 mmol) mixture, raise the temperature to 100°C and stir for 5 hours. After monitoring the reaction, concentrate to remove most of the solvent and alkali, and add ACN (10 mL) to dilute. With stirring at room temperature, the obtained dilution was slowly added dropwise to the water to precipitate the solid, filtered, and dried to obtain a yellow solid 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.8g, collected rate 83%). LCMS (ESI, m/z): 296.8 (M+H).

Step C: (1 R ,5 S )-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylic acid tertiary butyl ester

At room temperature, (1 R ,5 S )-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (5.2g, 24.7mmol) was added to 7- into a mixture of bromo-2,4-dichloro-8-fluoroquinazoline (7.3g, 24.7mmol), DIPEA (9.6g, 74.0mmol) and THF (30mL), and stirred at room temperature for 30min. After monitoring the reaction, add EA (100 mL) to dilute, add water (50 mL), and then extract with EA (100 mL × 3). Collect the extract, wash with brine (30 mL), and dry over anhydrous Na ₂ SO ₄ . Filter and concentrate under reduced pressure to obtain a yellow solid (1 R ,5 S )-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylic acid tertiary butyl ester (11.1g, yield 95%). LCMS (ESI, m/z): 473.0 (M+H).

Intermediate B-I

(1 R ,5 S )-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylic acid tertiary butyl ester

Step A: Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroethyl)ureido)benzoate

At room temperature, 2-amino-4-bromo-3,5-difluorobenzoic acid methyl ester (10 g, 37.6 mmol) and THF (100 mL) were added to a round-bottomed flask equipped with a stirrer. 2,2,2-trichloroacetyl isocyanate (8.5g, 45.1mmol) was added dropwise to the system with stirring at room temperature. The resulting mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure to obtain methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroethyl)ureido)benzoate as a brown solid. (crude product), used directly in the next step. LCMS (ESI, m/z): 452.8 (M+H).

Step B: 7-Bromo-6,8-difluoroquinazoline-2,4-diol

At room temperature, add 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroethyl)ureido)benzoic acid methyl ester with a stirrer. Add to the round bottom flask, then add NH ₃ (100 mL, 7M MeOH solution). The resulting mixture was stirred at room temperature for 2 h, and LCMS monitored the reaction to be complete. Concentrate under reduced pressure, beat the obtained solid with methyl tertiary butyl ether, and filter to obtain light yellow solid 7-bromo-6,8-difluoroquinazoline-2,4-diol (14g, crude product), no need Further purified and used directly in the next step. LCMS (ESI, m/z): 277.0 (M+H).

Step C: 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

Add 7-bromo-6,8-difluoroquinazoline-2,4-diol (14g, crude product) and POCl ₃ (112mL) into a round-bottomed flask equipped with a stirrer. While stirring at room temperature, DIEA (28 mL) was added dropwise to the system. After the dropwise addition was completed, the system was heated to 110°C and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure to about 30 mL, poured into water (600 mL), and the precipitated precipitate was filtered and collected. After drying, a yellow solid 7-bromo-2,4-dichloro-6,8-difluoroquinazoline ( 11g, crude product), used directly for subsequent reactions. LCMS (ESI, m/z): 312.9 (M+H).

Step D: (1 R ,5 S )-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo [3.2.1] Octane-8-carboxylic acid tertiary butyl ester

Add 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (11g, crude product), DIEA (10mL), and THF (100mL) into a round-bottomed flask equipped with a stirrer. While stirring at room temperature, (1 R ,5 S )-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (7.4g, 35mmol) was slowly added, and the resulting mixture was stirred and reacted. After 1 hour, the reaction solution was concentrated, poured into water, filtered, and dried to obtain the product yellow solid (1 R , 5 S )-3-(7-bromo-2-chloro-6,8-difluoroquinazoline-4). -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (15g, total yield in four steps: 65%). LCMS (ESI, m/z): 499.0 (M+H).

Intermediate B-II

(1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Tertiary butyl ester

Step A: (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -Tertiary butyl carboxylate

(1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - Tertiary butyl carboxylate (18g, 36.75mmol), KF (42.7g, 735mmol) and DMSO (200mL) were stirred at 100°C overnight. After the detection reaction is completed, return the reaction solution to room temperature, and then slowly pour it into H ₂ O (2L) water under stirring. A yellow solid will precipitate, filter it, and wash the filter cake with water (200 mL). Collect the filter cake. , after drying, the yellow product (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylic acid tertiary butyl ester (15.3g, yield 88%). LCMS (m/z): 473.4 (M+H).

Intermediate B-III

(1 R ,5 S )-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl) )oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

Step A: (1 R ,5 S )-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropyl) silyl)oxy)naphth-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

At room temperature, (1 R ,5 S )-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabibicyclo [3.2. 1] Octane-8-carboxylic acid tertiary butyl ester (5g, 10.56mmol), (7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy Naphthalene-1-yl)boronic acid (6.88g, 12.68mmol), Pd(OAc) ₂ (237mg, 1.06mmol), BIDIME (698mg, 2.11mmol), K ₃ PO ₄ (6.73g, 31.69mmol) were dissolved in Tertiary pentanol (60 mL), replaced with _N2 three times, heated to 110°C and stirred overnight. After the detection reaction is completed, pass through diatomaceous earth and wash with EA (50 mL). The obtained organic phase is concentrated and purified by FCC (SiO ₂ , EA/PE=0~50%) to obtain a yellow solid (1 R , 5 S )-3. -(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1-yl )quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (4.3g, yield 46%). ¹ H NMR(400MHz, CDCl ₃ )δ 7.74(dd, J =9.1,5.6Hz,1H),7.39(dd, J =9.8,1.7Hz,1H),7.34(d, J =2.6Hz,1H), 7.29(d, J =8.7Hz,1H),7.10(d, J =2.6Hz,1H),4.72(s,1H),4.40(s,2H),4.25-4.01(m,1H),3.77(d , J =16.4Hz,1H),3.43(s,1H),2.04(d, J =7.2Hz,3H),1.68(s,1H),1.57(s,4H),1.29(ddt, J =14.1, 9.8,7.3Hz,4H),1.11(dd, J =7.5,1.3Hz,19H),1.05(s,2H),0.89(d, J =7.4Hz,10H),0.84(d, J =7.5Hz, 9H), 0.54 (s, J =7.4Hz, 3H). LCMS (m/z): 891.4 (M+H).

Intermediate B-III-1 and Intermediate B-III-2

Compound (1 R ,5 S )-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilica) base)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (intermediate B-III , 40g) was separated by SFC (SFC350, Waters) (separation column: DAICEL CHIRALPAK®IC, 250*50mm, 10μm; mobile phase: CO ₂ /MeOH=75/25; flow rate: 140mL/min), and the first flushed The proposed isomer 1 is intermediate B-III-1 (24g, relatively short retention time). Chiral analysis method SFC-4, Rt=3.768min. LCMS (m/z): 891.4 (M+H). The isomer 2 that was subsequently washed out was intermediate B-III-2 (17 g, relatively long retention time). Chiral analysis method SFC-4, Rt=4.115min. ¹ H NMR(400MHz,Chloroform- d )δ 7.74(dd, J =9.1,5.7 Hz,1H),7.40(dd, J =9.7,1.7Hz,1H),7.34(d, J =2.5Hz,1H) ,7.29(d, J =8.7Hz,1H),7.10(d, J =2.6Hz,1H),4.81-4.64(m,1H),4.51-4.32(m,2H),4.18-4.03(m,1H ),3.91-3.69(m,1H),3.52-3.32(m,1H),2.30-1.93(m,3H),1.53(s,9H),1.37-1.21(m,4H),1.16-1.05(m ,18H),0.94-0.80(m,18H),0.62-0.47(m,3H). ¹⁹ F NMR(376MHz,Chloroform- d )δ -47.14,-105.65,-112.24,-120.80.LCMS(m/z ): 891.4(M+H).

Intermediate C-I

(1 R ,5 S )-3-(7-bromo-2-chloro-8-fluoropyridin[4,3- d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylic acid tertiary butyl ester

Intermediate C-I was prepared and characterized with reference to the document WO2021041671A1.

Intermediate a

( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol

Step A: 2-Fluoroethyl 4-toluenesulfonate

Under ice bath conditions, 4-toluenesulfonyl chloride (6.1g, 32mmol) was added to 2-fluoroethane-1-ol (2.0g, 31mmol), triethylamine (6.5mL, 47mmol) and DCM (20mL ) into the mixed solution, return to room temperature and stir overnight after the addition is completed. TLC monitored the completion of the reaction, added water (50 mL), and extracted with DCM (150 mL × 2). The organic phases were combined, washed with saturated brine, concentrated under reduced pressure and purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a colorless oily substance 2-fluoroethyl 4-toluenesulfonate (6.2g, collected rate 91%). GC-MS (EI, m/z): 218.

Step B: 1-(tertiary butyl)-2-methyl( R )-2-methylpyrrolidine-1,2-dicarboxylate

Under ice bath and nitrogen protection, a solution of CH ₃ I (6.4 g, 45.4 mmol) in DMF (10 mL) was slowly dropped into ( R )-1-(tertiary butoxycarbonyl)-2-methylpyrrolidine-2- Carboxylic acid (CAS: 166170-15-6, purchased from Bid Pharmaceuticals, product number: BD246964) (8.0g, 34.9mmol), K ₂ CO ₃ (14.5g, 104.7mmol) and DMF (40mL) mixture. After the dropwise addition was completed, the reaction solution was returned to room temperature and stirred overnight. TLC monitored the end of the reaction, added the reaction solution to water (300 mL), and extracted with EA (200 mL × 3). The combined organic phases were washed with saturated brine, concentrated under reduced pressure and purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a colorless oily substance 1-(tertiary butyl)-2-methyl ( R )-2-methylpyrrolidine-1,2-dicarboxylate (8.2g, yield 98%). LCMS (ESI, m/z): 266.30 (M+Na).

Step C: ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester‧hydrochloride

At room temperature, 4M HCl-dioxane (30 mL) was added to 1-(tertiary butyl)-2-methyl( R )-2-methylpyrrolidine-1,2-dicarboxylate (7.2g ,29.6mmol) and stirred at room temperature for 1h. After the reaction was monitored by LCMS, the reaction solution was directly concentrated to obtain a white solid ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (5.1 g, yield 96%). LCMS (ESI, m/z): 144.1 (M+H).

Step D: ( R )-1-(2-fluoroethyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester

At room temperature, combine ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol) and 2-fluoroethyl 4-toluenesulfonate (1.5g, 6.68mmol) and K ₂ CO ₃ (3.1g, 22.3mmol) were added to anhydrous acetonitrile (10mL) in sequence. The resulting mixture was heated to 90°C and stirred overnight, filtered through diatomaceous earth, and the filtrate was collected. Concentrate under reduced pressure to obtain a crude product, which is purified by FCC (SiO ₂ , EA/PE=0-15%) to obtain a colorless liquid ( R )-1-(2-fluoroethyl)-2-methylpyrrolidine-2-carboxylic Acid methyl ester (860 mg, yield 82%). LCMS (ESI, m/z): 190.1 (M+H).

Step E: ( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol

Under ice bath conditions, LiAlH ₄ (4.2 mL, 4.2 mmol, 1 M THF solution) was dropped into ( R )-1-(2-fluoroethyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (800 mg ,4.2mmol) in a solution of THF (20mL). The resulting mixture was stirred for 20 minutes at 0°C, and Na ₂ SO ₄ ‧10H ₂ O was slowly added until no gas was produced to quench the reaction. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product ( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (780 mg, crude), which was directly used Subsequent reactions. LCMS (ESI, m/z): 162.1 (M+H).

The following intermediates are prepared according to the synthesis method of intermediate a:

Intermediate b

( R )-(1-(2,2-difluoroethyl)-2-methylpyrrolidin-2-yl)methanol

The synthesis of intermediate b is carried out according to the synthesis scheme of intermediate a. In step A, 2,2-difluoroethane-1-ol is used instead of 2-fluoroethane-1-ol, and in step D, 2,2-difluoroethane-1-ol is used. Difluoroethyl 4-toluenesulfonate was used instead of 2-fluoroethyl 4-toluenesulfonate. LC-MS (ESI, m/z): 180.1 (M+H).

Intermediate c

( R )-(1,2-dimethylpyrrolidin-2-yl)methanol

Step A: ( R )-(1,2-dimethylpyrrolidin-2-yl)methanol

Under ice bath conditions, LiAlH ₄ (21.8 mL, 21.8 mmol, 1 M THF solution) was added dropwise to (R)-1-(tertiary butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.4 mmol) in THF (15 mL) solution, after the addition was completed, the temperature was raised to 70°C and stirred overnight. TLC monitors the end of the reaction, and slowly adds Na ₂ SO ₄ ‧10H ₂ O until no gas is produced to quench the reaction. The reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure to obtain the product ( R )-(1,2-dimethylpyrrolidin-2-yl)methanol (700 mg, crude), which was directly used in subsequent reactions.

Intermediate d

( R )-(1-ethyl-2-methylpyrrolidin-2-yl)methanol

Step A: ( R )-1-ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester

At room temperature, ethyl iodide (1.74g, 11.1mmol) was added to ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), potassium carbonate (3.07 g, 22.2 mmol) and CAN (20 mL), after the addition was completed, the temperature was raised to 90°C and stirred overnight. After the reaction is monitored by TLC (EA: PE=1:5, iodine is the chromogen), diatomaceous earth is filtered, the filtrate is collected and concentrated, and the crude product is passed through FCC (EA/PE=0-15%) to obtain colorless Liquid ( R )-1-ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester (600 mg, yield 63%). LCMS (ESI, m/z): 172.2 (M+H).

Step B: ( R )-1-Ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester

The synthesis method of step B is carried out as described in step E of intermediate a, using ( R )-1-ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester instead of ( R )-1-(2-fluoroethyl) base)-2-methylpyrrolidine-2-carboxylic acid methyl ester. LCMS (ESI, m/z): 143.2 (M+H).

The following intermediates are prepared according to the synthesis method of intermediate d:

Intermediate e

( R )-(1-cyclobutyl-2-methylpyrrolidin-2-yl)methanol

Step A: ( R )-1-Cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester

At room temperature, add bromocyclobutane (1.13g, 8.3mmol) to ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), potassium carbonate (2.30 g, 16.7mmol), copper iodide (311mg, 1.1mmol), N ¹ -benzyl- N ² -(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide ( 574 mg, 1.7 mmol) and DMSO (20 mL) in a mixed solution, replace with nitrogen for one minute, then raise the temperature to 100°C and stir overnight. After the TLC (EA:PE=1:5, iodine is the chromogen) detection reaction, add water (100mL) and extract with EA (50mL×3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure and pass through FCC (EA/PE=0-15%) to obtain colorless liquid ( R )-1-cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester (900 mg, yield 82%). LCMS (ESI, m/z): 198.1 (M+H).

Step B: ( R )-(1-cyclobutyl-2-methylpyrrolidin-2-yl)methanol

Under ice bath conditions, LiAlH ₄ (4.56mmol, 4.56mL, 1M THF solution) was dropped into ( R )-1-cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester (900mg, 4.56mmol) and THF (20mL), and react at 0°C for 20 minutes. After the reaction is detected by TLC (EA:PE=1:5, iodine is the chromogen), use Na ₂ SO ₄ ‧10H ₂ O The reaction was quenched until no gas was produced. The reaction solution was filtered through diatomaceous earth to yield the filtrate, which was concentrated under reduced pressure and purified by FCC (EA/PE= 0-15%, MeOH/DCM=0-10%) to obtain Colorless liquid ( R )-(1-cyclobutyl-2-methylpyrrolidin-2-yl)methanol (300 mg, yield 39%). LCMS (ESI, m/z): 170.1 (M+H).

Intermediate g

( S )-(2-Cyclopropyl-1-methylpyrrolidin-2-yl)methanol

Step A: ( 3S , 7aR )-3-(tertiary butyl)tetrahydro- 1H , 3Hpyrrolo [1,2- c ]oxazol-1-one

With stirring at room temperature, trifluoroacetic acid (891 mg, 7.82 mmol) was added dropwise to the solution of D-proline (10 g, 86.9 mmol), silica powder (10 g) and THF (150 mL). Then pivaldehyde (33.6g, 391mmol) and trimethoxymethane (11.1g, 104mmol) were added dropwise to the above reaction solution in sequence. After the dropwise addition was completed, stirring was continued at room temperature overnight. The silica powder was removed by filtration, and the mother liquor was collected and concentrated to obtain a yellow oily liquid (3 S ,7a R )-3-(tertiary butyl)tetrahydro- 1H , 3Hpyrrolo [1,2- c ]oxazole- 1-one (12.5g, yield 78.5%). ¹ H NMR (400MHz, CDCl ₃ ) δ 4.53 (s, 1H), 3.80 (dd, J =8.9, 4.4Hz, 1H), 3.21 (dt, J = 10.5, 6.5Hz, 1H), 2.83 (dt, J =10.5,6.3Hz,1H),2.25-2.10(m,1H),2.10-1.96(m,1H),1.88-1.76(m,1H),1.75-1.62(m,1H),0.93(s,9H ).

Step B: ( 3S , 7aS )-3-(tertiary butyl)-7a-cyclopropyltetrahydro- 1H , 3H -pyrrolo[1,2- c ]oxazol-1-one

Under nitrogen protection, in a dry ice-ethanol bath, LDA (20.46mL, 2.0M in THF) was added dropwise to ( 3S , 7aR )-3-(tertiary butyl)tetrahydro- 1H , 3Hpyrrole A solution of [1,2- c ]oxazol-1-one (5.0 g, 27.28 mmol) in anhydrous THF (50 mL). After stirring for 0.5 h while maintaining the cold bath temperature, bromocyclopropane (9.9g, 81.85 mmol) was dropwise added to the above reaction solution and continued to be stirred for 1 h. Pour the reaction solution into a saturated NH4Cl aqueous solution (100 mL), add EA (100 mL × 3), and extract. The organic phases were combined, washed with saturated NaCl (50 mL), concentrated and purified by FCC (SiO ₂ , EA/PE=0~15%) to obtain a yellow oily liquid (3 S , 7a S )-3-(tertiary butyl). ( 450 mg , yield 7.4%). LCMS (m/z): 224.1 (M+H).

Step C: ( S )-2-cyclopropylpyrrolidine-2-carboxylic acid hydrochloride

4M HCl-dioxane (10 mL) was mixed with ( 3S , 7aS )-3-(tertiary butyl)-7a-cyclopropyltetrahydro- 1H , 3H -pyrrolo[1,2- c A mixture of ]oxazol-1-one (400 mg, 1.79 mmol) was heated to 80°C and stirred overnight. The system was concentrated under reduced pressure to obtain ( S )-2-cyclopropylpyrrolidine-2-carboxylic acid hydrochloride (350 mg, yield 88%) as a brown solid. LCMS (m/z): 156.1 (M+H).

Step D: ( S )-2-Cyclopropyl-1-methylpyrrolidine-2-carboxylic acid

NaBH ₃ CN (185 mg, 2.90 mmol) was added to ( S )-2-cyclopropylpyrrolidine-2-carboxylic acid hydrochloride (300 mg, 1.93 mmol), formaldehyde (1.57 g, 19.3 mmol, 33% in water ) and MeOH (10 mL), the resulting system was stirred at room temperature for 1 h. Concentrate under reduced pressure to remove a large amount of methanol, add EA (30 mL) to dilute, and filter through diatomaceous earth. The organic phase was collected, concentrated under reduced pressure and purified by FCC (SiO ₂ , MeOH/DCM=0~30%) to obtain colorless liquid ( S )-2-cyclopropyl-1-methylpyrrolidine-2-carboxylic acid ( 280mg, yield 86%). LCMS (m/z): 170.1 (M+H).

Step E: ( S )-(2-cyclopropyl-1-methylpyrrolidin-2-yl)methanol

Borane (1 M in THF, 17.73 mL) was added to ( S )-2-cyclopropyl-1-methylpyrrolidine-2-carboxylic acid (300 mg, 1.77 mmol) in anhydrous THF (5 mL) at room temperature. ) solution. The system was heated to 65°C and stirred overnight. After the detection reaction is completed, cool it in an ice bath, and slowly add methanol dropwise with stirring until no gas is released. The system was filtered through diatomaceous earth, and the filter cake was washed with EA (50 mL). After the combined filtrate was concentrated under reduced pressure, it was purified by FCC (SiO ₂ , MeOH/DCM=0~30%) to obtain colorless oily liquid ( S )-(2-cyclopropyl-1-methylpyrrolidin-2-yl). )Methanol (200mg, yield 73%). LCMS (m/z): 156.1 (M+H).

Intermediate g1

( R )-(2-ethyl-1-methylpyrrolidin-2-yl)methanol

The synthesis of intermediate g1 is carried out according to the synthesis method of intermediate g, except that ethyl iodide is used instead of bromocyclopropane in step B. LCMS (m/z): 144.1 (M+H).

Intermediate h

((2 R )-1-(1-methoxyprop-2-yl)-2-methylpyrrolidin-2-yl)methanol

Step A: Methyl (2 R )-1-(1-methoxypropan-2-yl)-2-methylpyrrolidine-2-carboxylate

At room temperature, combine ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.57mmol) and 1-methoxypropan-2-one (980mg, 11.13mmol) , NaOH (222.6mg, 5.57mmol), HCO ₂ H (512mg, 11.13mmol) were added to the methanol (15mL) solution and stirred for 30 minutes, then NaBH ₃ CN (525mg, 8.35mmol) was added to the above reaction solution. Stir overnight at room temperature. After the detection reaction is completed, add EA (50mL) to dilute, H ₂ O (20 mL), EA (50 mL × 2) for extraction, collect the organic phase and concentrate it through FCC (SiO ₂ , EA/PE=0~20%) to obtain (2 R )-1-(1-methoxypropan-2-yl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (300 mg, yield 25%) is a colorless liquid. LCMS (m/z): 216.1 (M+H).

Step B: ((2 R )-1-(1-methoxyprop-2-yl)-2-methylpyrrolidin-2-yl)methanol

Under ice bath conditions, LiAH ₄ (1.86 mL, 1.86 mmol, 1 M in THF) was added dropwise to (2 R )-1-(1-methoxypropan-2-yl)-2-methylpyrrolidine-2 -a solution of methyl carboxylate (400 mg, 1.86 mmol) and THF (8 mL) and stirred for 10 minutes. After TLC monitoring of the reaction, slowly add Na ₂ SO ₄ ‧10H ₂ O into the reaction solution under ice bath conditions until no more gas is generated. Add anhydrous sodium sulfate dry solution, filter, collect the mother liquor and concentrate to obtain colorless liquid ((2 R )-1-(1-methoxypropan-2-yl)-2-methylpyrrolidin-2-yl)methanol ( 300 mg, yield 86%), which was directly used in subsequent reactions without further purification.

Intermediate h1

( R )-(2-methyl-1-(oxetan-3-yl)pyrrolidin-2-yl)methanol

The synthesis of intermediate h1 is carried out according to the synthesis method of intermediate h. In step A, oxetanone is used instead of 1-methoxypropan-2-one. LCMS (m/z): 172.1 (M+H).

Intermediate k

( R )-2-Methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

Step A: 2-Methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl)ester 2-ethyl ester

Under ice bath conditions, CH ₃ I (81.4g, 573mmol) was added dropwise to 3-oxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (59.0g, 229mmol) , K ₂ CO ₃ (79.2g, 573mmol) and anhydrous acetonitrile (600mL), after the dropwise addition was completed, the reaction solution was heated to 45°C and stirred overnight. After the reaction was detected by TLC, the solvent was concentrated to remove, and saturated NH ₄ Cl aqueous solution (500 mL) was added to quench. The obtained system was extracted with EA (600mL×2), and the combined organic phases were washed with saturated NaCl aqueous solution (500mL). The organic phases were collected, concentrated and purified by FCC (SiO ₂ , EA/PE=0-15%) to obtain colorless oil. Liquid 2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (42.0g, yield 68%). LCMS (m/z): 294.0 (M+Na). ¹ H NMR(400MHz,Chloroform- d )δ 4.21-4.10(m,2H),3.91-3.81(m,1H),3.75-3.68(m,1H),2.80-2.72(m,1H),2.69-2.60 (m,1H),1.63-1.58(m,3H),1.49-1.44(m,9H),1.27-1.24(m,3H).

Step B: ( R )-2-Methyl-3-pentoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

2-Methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (31g) was separated by SFC (SFC150, Waters) (separation column : DAICEL CHIRALPAK® IC, 250*25mm, 10μm; mobile phase: CO ₂ /MeOH=85/15; flow rate: 70mL/min), and the isomer 1 that was washed out first was obtained as intermediate k (11.8g, (relative retention time is short), chiral analysis method SFC-5, Rt=1.135min. LCMS (m/z): 891.4 (M+H). The isomer 2 that was subsequently washed out was compound ka (8.7g, relatively longer retention time), chiral analysis method SFC-5, Rt=1.502min.

Intermediate k1a and intermediate k1b

((2 S ,3 R )-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol ( k1a ) and ((2 S ,3 S )-3-methoxy-1 ,2-dimethylpyrrolidin-2-yl)methanol ( k1b )

Step A: (2 R )-3-Hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

Under ice bath conditions, add ( R )-2-methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (300 mg, 1.11 mmol) Sodium borohydride (62 mg, 1.66 mmol) was added to a solution of methanol (5 mL). The obtained reaction solution was reacted at 0°C for 20 minutes. After TLC detection of the completion of the reaction, 10 mL of saturated ammonium chloride solution and 30 mL of water were added to the reaction solution. The mixed reaction solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, Concentrate to obtain a colorless transparent oily crude product (2 R )-3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (300 mg, collected rate 99%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 5.61-5.47 (m, 1H), 4.17-3.90 (m, 3H), 3.62-3.45 (m, 1H), 3.26-3.14 (m, 1H), 1.97- 1.75(m,2H),1.47(s,3H),1.39-1.30(m,9H),1.21-1.10(m,3H).

Step B: (2 R ,3 R )-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester ( k1-2a ) And (2 R ,3 S )-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester ( k1-2b )

To (2 R )-3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (300 mg, 1.1 mmol) under ice bath conditions Sodium hydride (88 mg, 2.2 mmol) was added to the DMF (5 mL) solution, and the reaction solution was reacted at 0°C for 20 min. Then, methyl iodide (311 mg, 2.2 mmol) was added, and the reaction solution was continued to react at room temperature for 12 h. After TLC monitoring of the completion of the reaction, water (30 mL) was added to the reaction solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by FCC (SiO ₂ , EA/PE=5%-10 %) was purified to obtain yellow oily product k1-2a (90mg, yield 18%), ¹ H NMR (400MHz, DMSO- d ₆ ) δ 4.21-3.98 (m, 2H), 3.95-3.82 (m, 1H) ,3.42-3.34(m,1H),3.28-3.14(m,4H),2.21-2.08(m,1H),1.85-1.65(m,1H),1.38-1.36(m,3H),1.34-1.26( m, 9H), 1.23-1.15 (m, 3H); and yellow oily product k1-2b (285mg, yield 54%), ¹ H NMR (400MHz, DMSO- d ₆ ) δ 4.14-3.93 (m, 2H ),3.84-3.69(m,1H),3.60-3.47(m,1H),3.30-3.19(m,4H),2.11-1.99(m,1H),1.89-1.76(m,1H),1.53(s ,3H),1.40-1.29(m,9H),1.21-1.08(m,3H).

Step C: ((2 S ,3 R )-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol ( k1a ) and ((2 S ,3 S )-3-methoxy (1,2-dimethylpyrrolidin-2-yl)methanol ( k1b )

Under ice-water bath conditions, to (2 R , 3 R )-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester ( k1-2a ) (90 mg, 0.31 mmol), 1N lithium aluminum tetrahydride THF solution (1.3 mL, 1.3 mmol) was added. The resulting solution was stirred and reacted at 70°C for 12 h. After the LCMS detection reaction was completed, water (1 mL) and EtOAc (30 mL) were added to the reaction solution in sequence. The obtained reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a colorless and transparent oily crude product k1a (50 mg, yield 99%), which was directly used in subsequent steps. LCMS (m/z): 160.1 (M+H).

k1-2b (285mg, 0.99mmol) was prepared by the same method from (2 R ,3 S )-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) The ester 2-ethyl ester ( k1-2b ) was subjected to the above steps to obtain a colorless and transparent oily crude product k1b (130 mg, yield 88%).

Intermediate k2a

((2 R ,3 S )-1,2,3-trimethylpyrrolidin-2-yl)methanol

Step A: ( R )-2-Methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

While stirring in an ice bath, a tertiary potassium butoxide solution in THF (22.1 mL, 1 M, 22.1 mmol) was added dropwise to a solution of methyl triphenylphosphine bromide (7.94 g, 22.1 mmol) in toluene (50 mL). The resulting mixture was reacted in an ice bath for 0.5h. Dissolve ( R )-2-methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (4.0 g, 14.7 mmol) in toluene (10 mL) The solution was added dropwise to the above reaction system, the temperature was naturally raised to room temperature, and the reaction was stirred for 1 hour, and then the temperature was raised to 110°C and the reaction was stirred overnight. TLC monitors the completion of the reaction, cools to room temperature, and concentrates to dryness to obtain a crude product, which is purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product ( R )-2-methyl-3. -Methylenepyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (2.8 g, yield 71%). LCMS (m/z): 170.1 (M-Boc+H).

Step B: (2 R ,3 S )-2,3-dimethylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

Dissolve ( R )-2-methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (590 mg, 2.19 mmol) at room temperature. into ethanol (20 mL). Subsequently, under nitrogen protection, dry palladium on carbon (500 mg, 10% wt, 0.47 mmol) was added. The system was replaced three times with a hydrogen balloon, and then the reaction was stirred overnight under a hydrogen atmosphere. After the reaction was monitored by TLC, it was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain the colorless oily product (2 R , 3 S )-2,3-dimethylpyrrolidine-1,2-dicarboxylic acid 1-( Tertiary butyl ester 2-ethyl ester (450 mg, yield 76%). LCMS (m/z): 172.1 (M-Boc+H). ¹ H NMR (400MHz, CDCl ₃ ) δ 4.27-4.03(m,2H),3.84-3.64(m,1H),3.37-3.24(m,1H),2.21-2.02(m,1H),1.88-1.78( m,1H),1.78-1.67(m,1H),1.60-1.50(m,3H),1.49-1.37(m,9H),1.32-1.21(m,3H),0.95(d, J =7.0Hz, 3H).

Step C: ((2 R ,3 S )-1,2,3-trimethylpyrrolidin-2-yl)methanol

With stirring at room temperature, LiAlH ₄ (2.21 mL, 1 M THF solution, 2.21 mmol) was slowly added dropwise to (2 R , 3 S )-2,3-dimethylpyrrolidine-1,2-dicarboxylic acid 1 -(tertiary butyl) ester 2-ethyl ester (200 mg, 0.74 mmol) was dissolved in anhydrous THF (2 mL), and the resulting mixture was heated to 70°C and stirred for 3 hours. After TLC monitoring of the reaction, the system was cooled in an ice bath, and sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated. An appropriate amount of ethyl acetate was added, and the resulting system was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a colorless oily crude product ((2 R , 3 S )-1,2,3-trimethylpyrrolidin-2-yl) Methanol (100 mg, yield 95%) was directly used in subsequent reactions. LCMS (m/z): 144.1 (M+H).

Intermediate k2b

((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol

Step A: (2 R ,3 S )-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester

Dissolve (2 R , 3 S )-1-tertiary butoxycarbonyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (400 mg, 1.47 mmol) in dichloromethane (2 mL), and then add Trifluoroacetic acid (2 mL). The resulting solution was reacted at room temperature for 1 h. After TLC detection of the completion of the reaction, the reaction solution was concentrated to obtain a yellow oily crude product (2 R , 3 S )-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (250 mg, yield 99%). ¹ H NMR(400MHz,Chloroform- d )δ 4.36-4.18(m,2H),3.61-3.32(m,2H),2.43-2.16(m,2H),1.77-1.64(m,1H),1.64(s ,3H),1.31(t, J =7.1Hz,3H),1.04(d, J =6.9Hz,3H).

Step B: (2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester

Dissolve (2 R ,3 S )-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (250 mg, 1.46 mmol) in acetonitrile (5 mL), and then add potassium carbonate (1.01 g, 7.30 mmol) and ethyl iodide (455 mg, 2.92 mmol). The resulting solution was reacted at 80°C for 12 h. After the TLC detection reaction is completed, the reaction solution is filtered through diatomaceous earth, and the filtrate is concentrated. The crude product obtained is purified by FCC (SiO ₂ , EA/PE=50%~100%) to obtain a colorless oily product (2 R , 3 S )-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (190 mg, yield 65%). ¹ H NMR(400MHz,Chloroform- d )δ 4.13(q, J =7.1Hz,2H),3.27-3.16(m,1H),2.80-2.61(m,2H),2.36-2.18(m,1H), 2.12-1.94(m,2H),1.72-1.58(m,1H),1.31-1.22(m,6H),1.07(t, J =7.2Hz,3H),0.92(d, J =6.7Hz,3H) .

Step C: ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol

Dissolve (2 R , 3 S )-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (190 mg, 0.95 mmol) in THF (2 mL), slowly in an ice bath LiAlH ₄ -THF solution (1.9 mL, 1 M, 1.9 mmol) was added. The resulting solution was stirred and reacted at 0°C for 20 min. After the TLC detection reaction was completed, water (1 mL) and EA (30 mL) were added to the reaction solution in sequence. The obtained reaction liquid was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the colorless and transparent needle-like solid product ((2 R , 3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (110 mg , yield 73%). ¹ H NMR (400MHz, Chloroform- d )δ 3.33 (d, J =10.6Hz, 1H), 3.16 (dd, J =8.7, 6.7Hz, 1H), 3.10 (d, J =10.6Hz, 1H), 2.69 -2.56(m,1H),2.46-2.31(m,2H),1.88-1.74(m,2H),1.48-1.30(m,1H),1.11(t, J =7.2Hz,3H),1.07(d , J =6.6Hz,3H),0.87(s,3H).

Intermediate k2c

((2 R ,3 S )-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol

Step A: (2 R ,3 S )-1-allyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester

Dissolve (2 R ,3 S )-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (250 mg, 1.46 mmol) in acetonitrile (5 mL), and then add potassium carbonate (1.01 g, 7.30 mmol) and allyl bromide (353 mg, 2.92 mmol). The resulting solution was reacted at 80°C for 6 hours. After the TLC detection reaction is completed, the reaction solution is filtered through diatomaceous earth, and the filtrate is concentrated. The obtained crude product is purified by FCC (SiO ₂ , EA/PE=20%~50%) to obtain a colorless oily product (2 R , 3 S )-1-allyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (160 mg, yield 52%). ¹ H NMR(400MHz, DMSO- d ₆ )δ 5.85-5.67(m,1H),5.21-4.92(m,2H),4.08(q, J =7.1Hz,2H),3.31-3.23(m,1H) ,3.06-2.96(m,1H),2.87-2.76(m,1H),2.73-2.60(m,1H),2.02-1.85(m,2H),1.60-1.46(m,1H),1.25-1.14( m,6H),0.86(d, J =6.6Hz,3H).

Step B: ((2 R ,3 S )-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol

Dissolve (2 R ,3 S )-1-allyl-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (160 mg, 0.75 mmol) in THF (2 mL) under ice-water bath conditions Slowly add 1N lithium tetrahydroaluminum THF solution (1.5 mL, 1.5 mmol). The resulting solution was reacted at 0°C for 20 min. After the TLC detection reaction was completed, water (1 mL) and EA (30 mL) were added to the reaction solution in sequence. The obtained reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a colorless and transparent oily product ((2 R , 3 S )-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol (90 mg , yield 70%). ¹ H NMR(400MHz, DMSO- d ₆ )δ 5.87-5.69(m,1H),5.22-4.90(m,2H),3.50-3.25(m,2H),3.23-3.04(m,2H),2.85- 2.74(m,1H),2.64-2.52(m,1H),1.85-1.68(m,2H),1.47-1.33(m,1H),0.98(d, J =6.7Hz,3H),0.86(s, 3H).

Intermediates k3a and k3b

((2 S ,3 R )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (intermediate k3a ) and ((2 S ,3 S )-3-fluoro-1,2 -Dimethylpyrrolidin-2-yl)methanol (intermediate k3b )

Step A: ( S )-3-Fluoro-2-methyl-2,5-dihydro- 1H -pyrrole-1,2-dicarboxylate 1-(tertiary butyl)ester 2-ethyl ester

At room temperature, DAST (8.0 mL, 9.8 g, 60.8 mmol) was added to ( R )-2-methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) into a mixed solution of 2-ethyl ester (1.0g, 3.69mmol) and DCM (10mL), and the temperature was raised to 50°C and the reaction was stirred for 48h. LCMS monitored the end of the reaction. Return the reaction solution to room temperature, slowly add it to a semisaturated NaHCO ₃ aqueous solution (30 mL), and extract with DCM (50 mL × 3). The combined organic phases were washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by FCC (SiO ₂ , EA/PE=0~10%) to obtain a colorless oily liquid ( S )-3-fluoro-2-methyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester (350 mg, yield 35 %). ¹ H NMR(400MHz,Chloroform- d )δ 5.34-5.12(m,1H),4.22-4.15(m,2H),3.85-3.45(m,1H),2.57-2.19(m,1H),1.48-1.45 (m,3H),1.45-1.41(m,9H),1.31-1.27(m,3H).LCMS(m/z): 218.1(M+H-56).

Step B: ( 2S )-3-Fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl)ester 2-ethyl ester

At room temperature, Pd/C (5%wt, 1.09g, 0.51mmol) was added to ( S )-3-fluoro-2-methyl-2,5-dihydro- 1H -pyrrole-1,2 - In a mixed solution of 1-(tertiary butyl) 2-ethyl dicarboxylate (350 mg, 1.28 mmol), EA (10 mL) and CH ₃ COOH (10 mL), the resulting mixture was heated under 60 psi H ₂ pressure Reaction was carried out at room temperature overnight. LCMS monitored the end of the reaction, filtered through diatomaceous earth, washed with EA (50 ml), and concentrated the filtrate to obtain the colorless oily liquid product (2S)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-( Tertiary butyl ester 2-ethyl ester (350 mg, yield 99%). ¹ H NMR(400MHz,Chloroform- d )δ 5.04-4.78(m,1H),4.37-4.07(m,2H),3.79-3.58(m,2H),2.22-2.05(m,2H),1.67-1.54 (m,3H),1.51-1.39(m,9H),1.34-1.23(m,3H).LCMS(m/z): 220.0(M+H-56).

Step C: (2 S ,3 R )-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylate and 1-(tertiary butyl)2-ethyl (2 S ,3 S ) -3-Fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

(2 S )-3-Fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (350 mg, 1.27 mmol) was analyzed by SFC (SFC-150 , Waters) separation (separation column: DAICEL CHIRALPAK®IG 250*25mm, 10um; mobile phase: CO ₂ /MeOH=98/2; flow rate: 60mL/min), and the isomer 1 that was washed out first was obtained. Compound (2 S , 3 R )-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester ( k3-2a , 10 mg, retention time Relatively short), chiral analysis method SFC-6, Rt=1.192. LCMS (m/z): 220.0 (M+H-56). The isomer 2 extracted after the back flush is compound (2 S , 3 S )-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl Esters ( k3-2b , 180mg, relatively long retention time), chiral analysis method SFC-6, Rt=1.377. ¹ H NMR(400MHz,Chloroform- d ₃ )δ 5.03-4.79(m,1H),4.35-4.07(m,2H),3.80-3.59(m,2H),2.24-1.98(m,1H), 1.65- 1.56 (m, 3H), 1.49-1.39 (m, 9H), 1.32-1.22 (m, 3H). ¹⁹ F NMR (376MHz, Chloroform- d ₃ ) δ -180.50.

Step D: ((2 S ,3 S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol ( k3b )

At room temperature, LiAH ₄ (3.27 mL, 3.27 mmol, 1 M THF solution) was added to (2 S , 3 S )-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-( Tertiary butyl) ester 2-ethyl ester ( k3-2b , 180 mg, 0.65 mmol) was heated to 70°C and stirred for 3 hours. After the reaction is monitored by LCMS, Na ₂ SO ₄ ‧10H ₂ O is slowly added to the reaction solution under ice bath conditions until gas is no longer generated. An appropriate amount of EA is added, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain Colorless liquid (4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (95 mg, yield 99%). LCMS (m/z): 148.1 (M+H).

((2 S ,3 R )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol ( k3a ) was prepared from (2 S ,3 R )-3-fluoro-2- Methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester ( k3-2a ) is obtained through the above steps.

Intermediates k4a and k4b

(2 R ,3 S )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-nitrile and (2 R ,3 R )-2-(hydroxymethyl)-1,2- Dimethylpyrrolidine-3-nitrile

Step A: (2 R ,3 R )-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester

Under ice bath conditions, 1M BH ₃ /THF (11.4 mL, 11.4 mmol) was slowly added dropwise to ( R )-2-methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-( A solution of tertiary butyl ester 2-ethyl ester (2.80 g, 10.4 mmol) in anhydrous THF (60 mL). The resulting mixture was raised to room temperature and stirred for 3 hours, then cooled in an ice bath. 3N sodium hydroxide aqueous solution (3.8 mL, 11.4 mmol) and 30% hydrogen peroxide (9.0 mL, 88.1 mmol) were added dropwise to the reaction system in sequence. After the dropwise addition was completed, the system was returned to room temperature and the reaction was stirred overnight. After TLC monitoring of the reaction, the reaction solution was poured into ice water (100 mL) to quench, and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was purified by FCC (SiO ₂ , EA/PE=0-25%) to obtain colorless oil (2 R , 3 R )-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (1.2 g, yield 30%). LCMS (m/z): 187.9 (M-Boc+H). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.86 (brs, 1H), 4.29-4.12 (m, 1H), 4.12-4.00 (m, 1H), 3.80-3.62 (m, 1H), 3.61-3.44 (m, 2H),3.42-3.25(m,1H),2.64-2.21(m,1H),2.01-1.88(m,1H),1.88-1.47(m,4H),1.46-1.30(m,9H),1.27- 1.14(m,3H).

Step B: (2 R ,3 R )-3-formyl-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester

At room temperature, Desmartin oxidant (7.40g, 17.4mmol) was added to (2 R , 3 R )-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid in batches. A solution of acid 1-(tertiary butyl) ester 2-ethyl ester (1.00g, 3.48mmol) in dichloromethane (200mL) was stirred at room temperature overnight. A large amount of white solid was produced, and LCMS monitored the end of the reaction. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain the colorless oily product (2 R , 3 R )-3-formyl-2-methane. Pyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (660 mg, yield 66%). LCMS (m/z): 186.1 (M-Boc+H).

Step C: (2 R )-3-cyano-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester

At room temperature, (2 R , 3 R )-3-formyl-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (400 mg, 1.40 mmol) and diphenylphosphine hydroxylamine (DPPH, 392 mg, 1.68 mmol) were dissolved in toluene (10 mL) solution, the resulting mixture was heated to 85°C, and the reaction was stirred overnight. LCMS detects the end of the reaction, cools to room temperature, and concentrates to dryness to obtain a crude product, which is purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain a colorless oily product (2 R )-3-cyano. -2-Methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (240 mg, yield 61%). LCMS (m/z): 183.1 (M-Boc+H). ¹ H NMR (400MHz, CDCl ₃ ) δ 4.30-4.08 (m, 2H), 3.91-3.70 (m, 0.5 H), 3.68-3.54 (m, 0.5 H), 3.54-3.42 (m, 0.5 H), 3.41 -3.32(m,0.5 H),3.31-3.20(m,0.5 H),3.03-2.87(m,0.5 H), 2.35-2.22(m,1H),2.21-2.04(m,1H),1.71-1.57 (m,3H),1.43-1.32(m,9H),1.29-1.13(m,3H).

Step D: (2 R )-3-cyano-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride

At room temperature, 4M hydrochloric acid-dioxane (5 mL, 20 mmol) was added dropwise to (2 R )-3-cyano-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl ) ester 2-ethyl ester (220 mg, 0.78 mmol) in EA (5 mL). The resulting mixture was stirred for 1 h at room temperature. LCMS monitored the completion of the reaction and concentrated under reduced pressure to obtain (2 R )-3-cyano-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride (170 mg, yield 100%) as a white solid. LCMS (m/z): 183.1 (M+H). ¹ H NMR(400MHz,D ₂ O)δ 4.41-4.24(m,2H),3.93(t,J=7.9Hz,0.5H),3.71(t,J=7.9,6.4Hz,0.5H),3.67- 3.41(m,2H),2.70-2.35(m,2H),1.79(s,1.5H),1.71(s,1.5H),1.31-1.17(m,3H).

Step E: (2 R ,3 S )-3-cyano-1,2-dimethylpyrrolidine-2-carboxylic acid ethyl ester and (2 R ,3 S )-3-cyano-1,2- Dimethylpyrrolidine-2-carboxylic acid ethyl ester

At room temperature, add formaldehyde aqueous solution (5mL, 35~40%wt, ~60mmol) to ( 2R )-3-cyano-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride (170mg, 0.78 mmol) in methanol (10 mL), and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (244 mg, 3.89 mmol) was added in batches, and the resulting system continued to stir and react at room temperature for 1 h. LCMS monitored reaction completion. The reaction solution was concentrated to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product (2 R , 3 S )-3-cyano-1,2-dimethyl. Ethylpyrrolidine-2-carboxylate (59 mg, yield 39%), LCMS (m/z): 197.1 (M+H). ¹ H NMR (400MHz, CDCl ₃ ) δ 4.20 (q, J =7.2Hz, 2H), 3.51 (dd, J =9.4, 5.9Hz, 1H), 3.04-2.95 (m, 1H), 2.85-2.76 (m ,1H),2.38(s,3H),2.36-2.27(m,1H),2.18-2.08 (m,1H),1.49(s,3H),1.30(t, J =7.2Hz,3H); and colorless Oily product (2 R , 3 R )-3-cyano-1,2-dimethylpyrrolidine-2-carboxylic acid ethyl ester (50 mg, yield 33%), LCMS (m/z): 197.1 ( M+H). ¹ H NMR (400MHz, CDCl3) δ 4.28 (q, J =7.1Hz, 2H), 3.19-3.11 (m, 1H), 2.96-2.86 (m, 2H), 2.35-2.25 (m, 5H), 1.47 ( s,3H),1.35(t, J =7.1Hz,3H).

Step F: (2 R ,3 S )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-nitrile and (2 R ,3 R )-2-(hydroxymethyl)-1 ,2-dimethylpyrrolidine-3-nitrile

At room temperature, LiAlH ₄ -THF (0.4 mL, 0.4 mmol, 1 M THF solution) was slowly added dropwise to (2 R , 3 S )-3-cyano-1,2-dimethylpyrrolidine-2 -In a solution of ethyl carboxylate (50 mg, 0.25 mmol) in anhydrous THF (1 mL), the resulting mixture was stirred and reacted at room temperature for 0.5 h. TLC monitored the completion of the reaction, cooled it in an ice bath, and slowly added sodium sulfate decahydrate to quench the reaction until no bubbles were generated. Add an appropriate amount of ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain a colorless oily crude product (2 R , 3 S )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3. -Nitrile (intermediate k4a , 30 mg, yield 76%). LCMS (m/z): 155.1 (M+H).

(2 R ,3 R )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4b ) was prepared from (2 R ,3 R )-3-cyanohydrin by the same method. Ethyl-1,2-dimethylpyrrolidine-2-carboxylate (compound k4-6b ) was followed by the above steps to obtain intermediate k4b (30 mg, yield 76%). LCMS (m/z): 155.1 (M+H).

Intermediate k5a

((2 R ,3 R )-3-(difluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

Step A: (2 R ,3 R )-3-(difluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester

At room temperature, DAST (440 mg, 2.7 mmol) was added dropwise to (2 R , 3 R )-3-formyl-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butanol). 2-ethyl ester (260 mg, 0.91 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred at room temperature overnight. LCMS monitored the completion of the reaction. Add saturated NaHCO ₃ aqueous solution (10 mL), stir for 5 minutes, separate the liquids, and extract the aqueous layer twice with dichloromethane. The organic phases were combined and concentrated to dryness to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain a colorless oily product (2 R , 3 R )-3-(difluoromethyl). )-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (130 mg, yield 46%). LCMS (m/z): 208.0 (M-Boc+H). ¹ H NMR (400MHz, CDCl ₃ )δ 5.97-5.61(m,1H),4.33-4.10(m,2H),3.73-3.55(m,1H),3.54-3.40(m,1H),2.95-2.74( m,1H),2.13-2.03(m,1H),2.03-1.85(m,1H),1.54-1.45(m,3H),1.45-1.37(m,9H),1.33-1.21(m,3H).

Step B: ((2 R ,3 R )-3-(difluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

(2 R ,3 R )-3-(difluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl at room temperature The ester (130 mg, 0.423 mmol) was dissolved in anhydrous THF (1.5 mL), 1 M LiAlH ₄ -THF (1.27 mL, 1.27 mmol) was slowly added dropwise to the system, and the resulting mixture was heated to 70°C and stirred for 3 hours. TLC monitored the completion of the reaction, cooled it in an ice bath, and slowly added sodium sulfate decahydrate to quench the reaction until no bubbles were generated. Add an appropriate amount of ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain a colorless oily crude product ((2 R , 3 R )-3-(difluoromethyl)-1,2-dimethylpyrrolidine -2-yl)methanol (60 mg, yield 79%). LCMS (m/z): 180.0 (M+H).

Intermediate k6a

((2 R ,3 R )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

Step A: (2 R ,3 R )-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester

Under ice bath, DAST (247mg, 1.53mmol) was added to ( 2R , 3R )-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butanol) 2-ethyl ester (220 mg, 0.76 mmol) and DCM (5 mL), the resulting mixture was warmed to room temperature and stirred for 2 h. After the reaction was monitored by LCMS, saturated sodium bicarbonate (30 mL) was added and extracted with DCM (30 mL × 2). The organic phase was washed with saturated brine (70 mL), collected, concentrated and further purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain a colorless liquid (2 R , 3 R )-3-(fluoromethyl). (90 mg, yield 41%). LC-MS (m/z): 234.0 (M-56+H).

Step B: ((2 R ,3 R )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

At room temperature, LiAlH ₄ -THF (1M, 1.24mmol, 1.24mL) was added dropwise to (2 R , 3 R )-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid. In a solution of 1-(tertiary butyl) ester 2-ethyl ester (90 mg, 0.31 mmol) in THF (3 mL), the resulting system was heated to 70°C and stirred for 3 h. After monitoring the reaction with LCMS, add Na ₂ SO ₄ ‧10H ₂ O to quench the reaction until no gas is generated. The reaction solution is filtered through diatomaceous earth, and the filtrate obtained is concentrated at low temperature (35°C) to obtain a colorless liquid ((2 R ,3 R )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol (50 mg, yield 99%). LC-MS (m/z): 162.1 (M+H).

Intermediate k6b

((2 R ,3 S )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

Step A: ( R )-3-(Fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl)ester 2-ethyl ester

Under ice bath conditions, a THF solution of tertiary potassium butoxide (7.74mL, 1M, 7.74mmol) was added dropwise to (fluoromethyl)tetrafluoroborate triphenylphosphonate (2.96g, 7.74mmol) in toluene (30mL ) solution, the resulting system was stirred in an ice bath for 1 h. Dissolve ( R )-2-methyl-3-pentanoxypyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (1.40 g, 5.16 mmol) in toluene (5 mL) The solution was added dropwise to the above system, the temperature was maintained for 0.5h, the temperature was naturally raised to room temperature, and the reaction was stirred for 0.5h, and then the temperature was raised to 110°C and the reaction was stirred overnight. TLC monitors the completion of the reaction, cools to room temperature, and concentrates to dryness under reduced pressure to obtain a crude product, which is purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product (R)-3-( Fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tertiary butyl) ester 2-ethyl ester (700 mg, yield 47%). LCMS (m/z): 188.0 (M-Boc+H).

Step B: (2 R ,3 S )-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tertiary butyl) ester 2-ethyl ester

Under nitrogen protection at room temperature, add Pd/C (500mg, 10%w/w, 0.470mmol) to ( R )-3-(fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylic A solution of acid 1-(tertiary butyl)ester 2-ethyl ester (700 mg, 2.44 mmol) in methanol (25 mL). The system was replaced with a hydrogen balloon, and the reaction was stirred overnight in a hydrogen atmosphere. After the reaction was monitored by TLC, it was filtered with diatomaceous earth, and the filtrate was concentrated to dryness to obtain the colorless oily product (2 R , 3 S )-3-(fluoromethyl)-2-methylpyrrolidine-1,2-bis. 1-(tertiary butyl)carboxylate 2-ethyl ester (400 mg, yield 57%). LCMS (m/z): 190.0 (M-Boc+H). ¹ H NMR (400MHz, CDCl ₃ ) δ 4.55-4.46 (m, 0.5 H), 4.46-4.34 (m, 1H), 4.34-4.26 (m, 0.5H), 4.24-4.06 (m, 2H), 3.87- 3.69(m,1H),3.46-3.34(m,1H),2.52-2.33(m,1H),1.98-1.85(m,2H),1.70-1.59(m,3H),1.49-1.39(m,9H ),1.33-1.20(m,3H).

Step C: (2 R ,3 S )-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride

At room temperature, 4M hydrochloric acid-dioxane (10 mL, 20 mmol) was added dropwise to (2 R , 3 S )-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1 -(tertiary butyl) ester 2-ethyl ester (200 mg, 0.69 mmol) was dissolved in ethyl acetate (10 mL), and the resulting mixture was stirred and reacted at room temperature for 1 h. LCMS monitored the completion of the reaction, and concentrated under reduced pressure to obtain a white solid (2 R , 3 S )-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride (200 mg, crude product). LCMS (m/z): 190.2 (M+H).

Step D: (2 R ,3 S )-3-(fluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylic acid ethyl ester

Dissolve (2 R , 3 S )-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride (200 mg, crude product from the previous step) in methanol (5 mL) at room temperature. , add formaldehyde aqueous solution (2mL, 35~40%w/w, ~24mmol), and stir at room temperature for 0.5h. Sodium cyanoborohydride (244 mg, 3.89 mmol) was added in batches, and the resulting mixture was stirred and reacted at room temperature for 0.5 h. LCMS monitored the end of the reaction, concentrated it to obtain a crude product, and purified it by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product (2 R , 3 S )-3-(fluoromethyl)-1. , 2-dimethylpyrrolidine-2-carboxylic acid ethyl ester (100 mg). LCMS(m/z): 204.1(M+H).

Step E: ((2 R ,3 S )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol

At room temperature, LiAlH ₄ -THF (0.59mL, 1M, 0.59mmol) was slowly added dropwise to ( 2R , 3S )-3-(fluoromethyl)-1,2-dimethylpyrrolidine -2-Carboxylic acid ethyl ester (100 mg, 0.49 mmol) was dissolved in anhydrous THF (1 mL), and the resulting mixture was stirred and reacted at room temperature for 1 hour. TLC monitored the reaction to completion, cooled it in an ice bath, and added sodium sulfate decahydrate to quench the reaction until no bubbles were generated. Add an appropriate amount of ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain a colorless oily crude product ((2 R , 3 S )-3-(fluoromethyl)-1,2-dimethylpyrrolidine -2-yl)methanol (50.0 mg, yield 63%). LCMS (m/z): 162.1 (M+H).

According to the above synthetic scheme or appropriate variation, the following intermediates are prepared:

Example 1

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(( R )-1-(2 -Fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step A: (1 R ,5 S )-3-(7-bromo-8-fluoro-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl) Methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

At room temperature, NaH (176 mg, 4.4 mmol, 60%-mineral oil) was added to ( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (425 mg ,2.6 mmol) in THF (15 mL), stir at room temperature for 20 minutes, and then (1 R ,5 S )-3-(7-bromo-2,8-difluoroquinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (400 mg, 0.88 mmol) was added to the above mixed solution and continued to stir for 0.5 h. LCMS monitored the reaction completion, added water (50 mL), and extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , EA/PE=0-40%) to obtain a yellow solid (1 R , 5 S )-3-(7-bromo- 8-Fluoro-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (480 mg, yield 92%). LCMS (ESI, m/z): 618.3 (M+Na).

Step B: (1 R ,5 S )-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

Under nitrogen protection, (1 R ,5 S )-3-(7-bromo-8-fluoro-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidine-2- (yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (200 mg, 0.33 mmol), triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1- (206mg, 0.40mmol), Pd(dtbpf)Cl ₂ (22mg, 0.033mmol), K ₃ PO ₄ (285mg, 1.3mmol) and dioxane/H ₂ O (V/V=4 : 1,8 mL) mixed solution was heated to 100°C and stirred for 2 hours. After the reaction was monitored by LCMS, the system was cooled to room temperature, water (30 mL) was added, and extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine and concentrated under reduced pressure. The obtained crude product was purified by FCC (SiO ₂ , EA/PE=0-60%) to obtain a yellow oily substance (1 R ,5 S )-3-(8 -Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(( R )-1 -(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -Tertiary butyl carboxylate (140 mg, yield 46%). LCMS (ESI, m/z): 902.3 (M+H).

Step C: 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(( R )-1 -(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl )Naphthalen-2-ol

At room temperature, TFA (10 mL) was added to (1 R ,5 S )-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(tri Isopropylsilyl)ethynyl)naphth-1-yl)-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazole (140 mg, 0.16 mmol), the resulting system was stirred and reacted for 1 hour. LCMS monitored the end of the reaction, added EA (30 mL) to dilute, adjusted the pH to 8 with saturated NaHCO ₃ aqueous solution, and extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to obtain a yellow solid 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)- 8-Fluoro-2-(( R )-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol (100 mg, yield 85%). LCMS (ESI, m/z): 758.3 (M+H).

Step D: 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(( R )-1 -(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(( R )-1-( 2-Fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -A mixed solution of 2-ol (100 mg, 0.13 mmol), CsF (100 mg, 0.66 mmol) and DMF (3 mL) was heated to 50°C and stirred for 1 hour. LCMS monitors the end of the reaction. The system is lowered to room temperature and filtered. The obtained filtrate is purified by Pre-HPLC (C18E, ACN/(0.1%NH ₄ CO ₃ /H ₂ O)=50-70%) to obtain a white solid 4- (4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(( R )-1-(2-fluoro Ethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (40 mg, yield 51%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.96 (dd, J =9.2, 6.0Hz, 1H), 7.72 (d, J = 8.6Hz, 1H), 7.50-7.42 (m, 1H), 7.36 (d , J =2.5Hz,1H),7.17(dd, J =8.6,6.8Hz,1H),7.07(d, J =2.5Hz,1H),4.52-4.42(m,1H),4.41-4.26(m, 2H),4.24-4.11(m,3H),3.84(s,1H),3.51(s,2H),3.49-3.40(m,3H),3.08-2.90(m,2H),2.82-2.63(m, 2H),1.96-1.85(m,1H),1.79-1.63(m,6H),1.61-1.51(m,1H),1.06(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ - 110.55,-128.39,-217.69.LCMS(ESI,m/z): 602.2(M+H).

Example 2

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-(( R )-1-(2,2-di Fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The synthesis of Example 2 was carried out with reference to the synthesis scheme of Example 1, using ( R )-(1-(2,2-difluoroethyl)-2-methylpyrrolidin-2-yl)methanol (middle Substitute b) in place of ( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a). ¹ H NMR(400MHz, DMSO- d ₆ )δ 7.96(dd, J =9.2,6.0Hz,1H),7.73(d, J =8.7Hz,1H),7.49-7.42(m,1H),7.36(d , J =2.6Hz,1H),7.18(dd, J =8.6,6.8Hz,1H),7.07(d, J =2.5Hz,1H),6.12-5.75(m,1H),4.38-4.10(m, 5H),3.88-3.82(m,1H),3.58(s,2H),3.52-3.43(m,2H),3.19-2.98(m,2H),2.93-2.71(m,2H),1.95-1.85( m,1H),1.83-1.66(m,6H),1.64-1.53(m,1H),1.08(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.54,-118.71,-128.35 .LCMS(ESI,m/z): 620.3(M+H).

Example 3

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1,2-dimethylpyrrole Alk-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The synthesis of Example 3 was carried out with reference to the synthesis scheme of Example 1. In step A, ( R )-(1,2-dimethylpyrrolidin-2-yl)methanol (intermediate c) was used instead of ( R )-(1 -(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.96 (dd, J =9.2, 6.0Hz, 1H), 7.81-7.68 (m, 1H), 7.51-7.40 (m, 1H), 7.36 (d, J = 2.6Hz,1H),7.25-7.15(m,1H),7.13-7.02(m,1H),4.43-4.11(m,4H),3.91-3.82(m,1H),3.72(s,1H),3.52 (dd, J =12.2,5.5Hz,2H),2.96-2.84(m,1H),2.68-2.55(m,1H),2.30(s,3H),2.07-1.53(m,9H),1.06(s , 3H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -110.54, -128.30. LCMS (ESI, m/z): 570.3 (M+H).

Based on the general synthesis scheme and with reference to the synthesis methods of the above examples, the present invention also prepared and characterized the following compounds:

Example 36

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl-2- Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol

Step A: (1 R ,5 S )-3-(2-((( R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoro -7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazoline-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

NaH (215 mg, 5.38 mmol) was added to ( R )-(1-allyl-2-methylpyrrolidin-2-yl)methanol (intermediate d4, 418 mg, 2.69 mmol) and The mixture of THF (30 mL) was stirred at room temperature for 0.5 h. (1 R ,5 S )-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilica (yl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (1.20g, 1.34mmol ) into the mixed solution. Stir at room temperature for 1 hour. After the reaction was detected by LCMS, the reaction solution was added to saturated aqueous ammonium chloride solution (50mL), extracted with EA (50mL×2), washed with saturated brine (70mL), the organic phase was collected, concentrated and further FCC (SiO ₂ , EA/PE =0~40%) and purified to obtain brown solid (1 R ,5 S )-3-(2-((( R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy )-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (1.1 g, yield 80%). LCMS(m/z): 1026.5(M+H).

Step B: 4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl-2- Methylpyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylmethylsilyl)ethynyl)-3-((triisopropylsilyl)ethynyl) Propylsilyl)oxy)naphth-1-yl)quinazoline

At room temperature, (1 R ,5 S )-3-(2-((( R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6, 8-Difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)quino Zozolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (1.10g, 1.07mmol) and DCM/TFA (V/V=1: 1, 10 mL) mixture was stirred at room temperature for 1 h. After the reaction is detected by LCMS, add saturated sodium bicarbonate aqueous solution (70 mL) after concentration, and then extract with EA (70 mL × 2). Collect the extract, wash with brine (70 mL), dry over anhydrous Na ₂ SO ₄ , and concentrate to obtain a brown color. Solid 4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-cyclopropyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl) Silyl)oxy)naphth-1-yl)quinazoline (1.0 g, yield 99%). LCMS (m/z): 926.5 (M+H).

Step C: 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl -2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol

CsF (821 mg, 5.40 mmol) was added to 4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-( (( R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylmethyl) Silyl)ethynyl)-3-((triisopropylmethylsilyl)oxy)naphth-1-yl)quinazoline (1.00g, 1.08mmol) and DMF (10mL) in a mixture. Heat to 50°C and stir for 1 hour. Cool to room temperature and then filter. The crude filtrate obtained is purified by Pre-HPLC to obtain a white solid 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octane- 3-yl)-2-((( R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)- 5-Ethynyl-6-fluoronaphthalene-2-phenol (480 mg, yield 72%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.22 (s, 2H), 8.03-7.95 (m, 1H), 7.55 (s, 1H), 7.52-7.45 (m, 1H), 7.41 (d, J = 2.5Hz,1H),7.17-7.10(m,1H),5.84-5.67(m,1H),5.13(d, J =17.1Hz,1H),5.05-4.91(m,1H),4.36-4.11(m ,4H),3.97(d, J =3.5Hz,1H),3.77(s,2H),3.69-3.48(m,2H),3.43-3.28(m,1H),3.11-2.98(m,1H), 2.94-2.80(m,1H),2.59-2.51(m,1H),2.03-1.89(m,1H),1.89-1.65(m,6H),1.66-1.50(m,1H),1.08(s,3H ). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -110.24, -118.69, -124.53. LCMS (m/z): 614.3 (M+H).

Examples 36-1 and 36-2

( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl ( Sa ) -4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol

Compound 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1-allyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol via SFC (SFC-150, Waters) separation (separation column: AD 250*25mm, 10um (Daicel); mobile phase: CO ₂ /EtOH (0.1% 7M NH ₃ in MeOH) = 45/55; flow rate: 70mL/min), to obtain the first flush The proposed isomer 1 is Example 36-1 (relatively short retention time). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 8.02-7.94 (m, 1H), 7.58-7.46 (m, 2H), 7.41 (d, J =2.5Hz, 1H), 7.16 -7.11(m,1H),5.90-5.64(m,1H),5.22-5.07(m,1H),5.02-4.94(m,1H),4.32-4.11(m,4H),3.98(s,1H) ,3.57-3.36(m,4H),3.28-3.15(m,1H),3.11-2.97(m,1H),2.91-2.80(m,1H),2.60-2.52(m,1H),2.07-1.81( m,1H),1.78-1.56(m,7H),1.07(s,3H). ¹⁹ F NMR(376MHz, DMSO- d ₆ )δ -110.19,-119.24,-124.74.LCMS(m/z): 614.3 (M+H). Chiral analysis method SFC-1, Rt=4.496. The isomer 2 that was subsequently washed out was Example 36-2 (relatively longer retention time). ¹ H NMR(400MHz, DMSO- d ₆ )δ 8.05-7.93(m,1H),7.53(d, J =10.1Hz,1H),7.51-7.44(m,1H),7.41(d, J =2.2Hz ,1H),7.14(d, J =2.1Hz,1H),5.83-5.65(m,1H),5.21-5.07(m,1H),4.97(d, J =9.8Hz,1H),4.39-4.09( m,4H),3.96(s,1H),3.54-3.49(m,4H),3.35-3.31(m,1H),3.07-3.00(m,1H),2.90-2.80(m,1H),2.59- 2.52(m,1H),2.00-1.90(m,1H),1.77-1.56(m,7H),1.07(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.16,-119.28, -124.82.LCMS(m/z): 614.3(M+H). Chiral analysis method SFC-1, Rt=5.715.

Example 37

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methylpyrrole Alk-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol

The synthesis of Example 37 was carried out with reference to the synthesis method of Example 36. In step A, (R)-(1-ethyl-2-methylpyrrolidin-2-yl)methanol was used instead of (R)-(1-cyclopropyl). methyl-2-methylpyrrolidin-2-yl)methanol. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 8.08-7.87 (m, 1H), 7.54 (dd, J =10.3, 1.6Hz, 1H), 7.48 (t, J =9.0Hz ,1H),7.41(d, J =2.5Hz,1H),7.15(t, J =2.7Hz,1H),4.28-4.19(m,2H),4.18-4.11(m,2H),3.99-3.95( m,1H),3.58-3.51(m,2H),3.51-3.45(m,1H),3.45-3.36(m,1H),2.97-2.90(m,1H),2.73-2.63(m,1H), 2.60-2.52(m,1H),2.48-2.38(m,1H),1.97-1.87(m,1H),1.81-1.61(m,6H),1.61-1.51(m,1H),1.04(s,3H ), 1.01-0.92 (m, 3H). ¹⁹ F NMR (377MHz, DMSO- d ₆ ) δ -110.20, -119.26, -124.81. LCMS (m/z): 602.3 (M+H).

Examples 37-1 and 37-2

( Ra )-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol or ( Sa )-4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methylpyrrolidine- 2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol

Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol was resolved by SFC (SFC-150, Waters) (Separation column: AD 250*25mm, 10um (Daicel); mobile phase: CO ₂ /IPA (0.1% 7M NH ₃ in MeOH) = 45/55; flow rate: 70mL/min), and obtain the first flushed Isomer 1 is Example 37-1 (retention time is relatively small). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 7.99 (dd, J =9.2, 5.8Hz, 1H), 7.59-7.44 (m, 2H), 7.44-7.35 (m, 1H) ,7.15(s,1H),4.33-4.19(m,2H),4.19-4.10(m,2H),3.97(s,1H),3.60-3.47(m,4H),3.01-2.87(m,1H) ,2.77-2.63(m,1H),2.63-2.55(m,1H),2.49-2.38(m,1H),2.01-1.86(m,1H),1.85-1.61(m,6H),1.60-1.49( m,1H),1.04(s,3H),0.97(t, J =7.1Hz,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.19,-119.22,-124.79.LCMS(m/z ): 602.3(M+H). Chiral analysis method SFC-2, Rt=0.978. The isomer 2 that is subsequently washed out is Example 37-2 (relative retention time is larger). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 8.04 (dd, J =9.2 , 5.9Hz, 1H), 7.65-7.50 (m, 2H), 7.47 (d, J = 2.4Hz ,1H),7.20(d, J =2.5Hz,1H),4.34-4.26(m,2H),4.26-4.14(m,2H),4.02(s,1H),3.61-3.48(m,4H), 3.04-2.92(m,1H),2.82-2.67(m,1H),2.65-2.58(m,1H),2.53-2.43(m,1H),2.04-1.92(m,1H),1.84-1.66(m ,6H),1.66-1.55(m,1H),1.09(s,3H),1.01(t, J =7.0Hz,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.19,-119.28, -124.81.LCMS(m/z): 602.3(M+H). Chiral analysis method SFC-2, Rt=3.292.

Example 61

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((( R )-1,2-dimethylpyrrole Alk-2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The synthesis of Example 61 was carried out with reference to the synthesis scheme of Example 1. In step A, (1 R ,5 S )-3-(7-bromo-2-chloro-8-fluoropyridine[4,3- d ]pyrimidine- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (intermediate CI) instead of (1 R ,5 S )-3-(7-bromo- 2-Chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (intermediate AI), and use ( R )-(1,2-dimethylpyrrolidin-2-yl)methanol (intermediate c) instead of ( R )-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl) Methanol (intermediate a). LCMS (ESI, m/z): 571.3 (M+H).

Example 89

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( R )-1 -(2-Hydroxy-2-methylpropyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- alcohol

Step A: ( R )-1-(2-Hydroxy-2-methylpropyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester

At room temperature, add triethylamine (3.90g, 39.0mmol) to ( R )-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), 2,2-di into a mixed solution of methyl ethylene oxide (2.00g, 27.8mmol) and MeOH (20mL), the temperature was raised to 75°C, and the reaction was stirred overnight. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a colorless liquid ( R )-1-(2-hydroxy-2-methyl). Propyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (600 mg, yield 50%). LC-MS (m/z): 216.1 (M+H).

Step B: ( R )-1-(2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-2-methylpropan-2-ol

Under ice bath conditions, LiAlH ₄ (2.79mL, 1M THF solution, 2.79mmol) was dropped into ( R )-1-(2-hydroxy-2-methylpropyl)-2-methylpyrrolidine-2-carboxylic into a mixed solution of acid methyl ester (600 mg, 2.79 mmol) and THF (20 mL), and reacted at 0°C for 20 minutes. After TLC monitoring of the reaction, the reaction was quenched with Na ₂ SO ₄ ‧10H ₂ O until no gas was generated. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated at low temperature (35°C) to obtain a colorless liquid ( R )- 1-(2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-2-methylpropan-2-ol (300 mg, yield 57%). LC-MS (m/z): 188.1 (M+H).

Step C~Step E: 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-( (( R )-1-(2-hydroxy-2-methylpropyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6 -Fluoronaphen-2-phenol

The subsequent synthesis steps C to E of Example 89 are carried out with reference to the synthesis method of Example 36. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.30 (s, 2H), 7.99 (dd, J =9.2, 5.9Hz, 1H), 7.57 (d, J = 10.0Hz, 1H), 7.51-7.45 (m ,1H),7.42(d, J =2.5Hz,1H),7.17(d, J =2.5Hz,1H),4.31(d, J =12.6Hz,2H),4.25-4.06(m,2H),3.97 (d, J =2.6Hz,1H),3.88(s,2H),3.64(dd, J =25.4,12.9Hz,2H),3.23-3.09(m,1H),2.76(q, J =8.0Hz, 1H),2.56(dd, J =13.3,5.3Hz,1H),2.35(dd, J =13.2,2.8Hz,1H),2.00-1.80(m,6H),1.74(p, J =7.3Hz,2H ),1.65-1.46(m,1H),1.14-0.98(m,9H). ¹⁹ F NMR(376MHz, DMSO- d ₆ )δ -110.28,-118.39,-124.43.LC-MS(m/z): 646.2(M+H).

Example 154-1

( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( 2 S ,3 S )-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-Alcohol·dicarboxylate

The synthesis of Example 154-1 was carried out with reference to the synthesis method of Example 36. In step A, intermediate B-III-2 was used instead of intermediate B-III((1 R ,5 S )-3-(2,6,8 -Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinazoline-4- base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester); and use the intermediate k1b (((2 S ,3 S )-3-methoxy- 1,2-dimethylpyrrolidin-2-yl)methanol) instead of intermediate d4 (( R )-(1-allyl-2-methylpyrrolidin-2-yl)methanol). LCMS (m/z): 618.1 (M+H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.21 (s, 2H), 8.02-7.96 (m, 1H), 7.54 (d, J =10.4Hz ,1H),7.51-7.44(m,1H),7.41(d, J =2.5Hz,1H),7.15(d, J =2.4Hz,1H),4.32-4.25(m,1H),4.28-4.20( m,3H),3.98(s,1H),3.57-3.51(m,5H),3.25(s,3H),2.95-2.84(m,1H),2.63-2.57(m,1H),2.27(s, 3H), 2.13-2.06 (m, 1H), 1.83-1.65 (m, 5H), 1.07 (s, 3H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -110.20, -119.05, -124.64.

Example 154-2

( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( 2 S ,3 R )-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene- The synthesis of 2-alcohol‧dicarboxylate Example 154-1 was carried out with reference to the synthesis method of Example 36. In step A, intermediate B-III-2 was used instead of intermediate B-III ((1 R ,5 S )- 3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1- base)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester); and use the intermediate k1a(((2 S ,3 R )-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol) instead of intermediate d4(( R )-(1-allyl-2-methylpyrrolidin-2-yl) ) methanol). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.30 (s, 2H), 8.02-7.93 (m, 1H), 7.55 (d, J = 10.3, 1H), 7.50-7.44 (m, 1H), 7.41 ( d, J =2.6Hz,1H),7.15(d, J =2.5Hz,1H),4.31-4.25(m,3H),4.16-4.14(m,1H),3.97(s,1H),3.74-3.71 (m,2H),3.61-3.51(m,3H),3.23(s,3H),2.85-2.77(m,1H),2.58-2.51(m,1H),2.23(s,3H),2.12-2.02 (m,1H),1.85-1.70(m,4H),1.63-1.53(m,1H),0.88(s,3H).

Example 156-1

( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( 2 S,3S )-3-Fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step A: ( Ra )-(1 R ,5 S )-3-(6,8-difluoro-2-(((2 S ,3 S ))-3-fluoro-1,2-dimethylpyrrolidine -2-yl)methoxy)-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

At room temperature, NaH (17.5 mg, 0.44 mmol, 60%) was added to (((2 S ,3 S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (32 mg ,0.22mmol) and THF (3mL), and stirred at room temperature for 0.5h, then added ( Ra )-( 1R , 5S )-3-(2,6,8-trifluoro- 7-(7-fluoro-8-((triisopropylmethylsilyl)ethynyl)-3-(triisopropylethylsilyl)oxy)naphthyl-1-yl)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (intermediate B-III-2, 130 mg, 0.15 mmol), and the resulting mixture was stirred at room temperature overnight. After the reaction was detected by LCMS, the reaction solution was poured into saturated NH ₄ Cl aqueous solution (20 mL), extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated, a yellow solid ( Ra )-(1 R ,5 S )-3-(6,8-difluoro-2-((2 S ,3 S )-3-fluoro-1,2-di Methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazoline- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (110 mg, yield 87%). LCMS (m/z): 431.8 (M/2+H).

Step B: ( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2- (((2 S ,3 S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((tri Isopropylsilyl)ethynyl)naphthalen-2-ol

At room temperature, add CF ₃ COOH (10 mL) to ( Ra )-(1 R ,5 S )-3-(6,8-difluoro-2-(((2 S ,3 S ))-3- Fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-hydroxy-8-((triisopropylmethylsilyl)ethynyl)naphthalene-1 -quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (110 mg, 0.13 mmol) and stirred for 1 h, concentrated to remove the acid solution, add EA (30 mL) to dilute, adjust the pH to about 8 with saturated NaHCO ₃ solution (20 mL), add water (30 mL), separate the liquids, and extract the aqueous phase with EA (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid ( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo) [3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 S ,3 S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methyl Oxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (90 mg, yield 92%).

Step C: ( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2- (((2 S,3S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-alcohol

( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(( (2 S ,3 S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropyl) A mixture of methylsilyl)ethynyl)naphthalene-2-ol (90 mg, 0.12 mmol), CsF (179 mg, 1.2 mmol) and DMF (2 mL) was heated to 50°C and stirred for 1 h. LCMS monitors the end of the reaction, cools to room temperature, and removes insoluble matter by filtration to obtain a DMF solution of the crude product, which is prepared by Pre-HPLC (C18, CAN/(0.1%NH ₄ CO ₃ /H ₂ O)=35-45%) Obtained yellow solid ( Ra )-4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2- (((2 S,3S )-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-alcohol (20 mg, yield 35%). LCMS(m/z): 606.3(M+H). ¹ H NMR (400MHz, Methanol- d ₄ ) δ 7.87 (dd, J =9.1, 5.8Hz, 1H), 7.52 (dd, J = 10.0, 1.8Hz, 1H), 7.39-7.29 (m, 2H), 7.14 (d, J =2.6Hz,1H),4.74-4.56(m,2H),4.54-4.41(m,3H),3.76-3.56(m,4H),3.35(d, J =1.0Hz,1H), ¹⁹ F NMR (376MHz, Methanol- d ₄ ) δ -111.57, -119.31, -125.29, -180.42.

Example 165

4-(4-(1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2 R ,3 S )- 1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. diformate

Step A: (1 R ,5 S )-3-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylmethylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester

Compound ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b, 42 mg, 0.27 mmol) was dissolved in 5 mL of anhydrous THF, and incubated on ice. Under bath conditions, NaH (11 mg, 0.27 mmol) was added. After reacting at 0°C for 20 minutes, add (1 R ,5 S )-3-(2,6,8-trifluoro-7-((R)-7-fluoro-8-((triisopropylmethylsilyl) )Ethynyl)-3-(triisopropylmethylsiloxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tertiary butyl carboxylate (B-III-2, 120 mg, 0.13 mmol), the resulting reaction solution was continued to stir at room temperature for 2 h. After monitoring the reaction with LCMS, 20 mL of water was added to the reaction solution and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily crude product (1 R ,5 S )-3-( 6,8-Difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylic acid tertiary butyl ester (100 mg, yield 85%). LCMS(m/z): 1029.6(M+H).

Step B: 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropyl Silyl)ethynyl)naphthalen-2-ol

(1 R ,5 S )-3-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylmethylsilyl)ethynyl)naphthalene-1-yl )-2-(((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (100 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. The resulting reaction solution was at room temperature. Stir under conditions for 1 hour. After the reaction was monitored by LCMS, saturated sodium bicarbonate solution (20 mL) was added. The resulting reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid crude product 4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 R ,3 S )-1-ethyl- 2,3-Dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylmethylsilyl)ethynyl)naphthalene-2- Alcohol (80 mg, yield 90%). LCMS(m/z): 928.5(M+H).

Step C: 4-(4-(1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. diformate

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 R , 3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylmethylsilane Ethynyl)naphthalene-2-ol (80 mg, 0.1 mmol) and cesium fluoride (157 mg, 1 mmol) were dissolved in DMF (2 mL) and stirred at 50°C for 30 minutes. After the reaction was monitored by LCMS, the reaction solution was separated by pre-HPLC (C18, CAN/(0.1%FA/H ₂ O) = 15-95%) to obtain 4-(4-(1 R ,5 S )-3, 8-Diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidine- 2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol. Dicarboxylate (20 mg, yield 31%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.28 (s, 2H), 7.99 (dd, J =9.2, 6.0Hz, 1H), 7.54 (d, J = 10.0Hz, 1H), 7.51-7.45 (m ,1H),7.41(d, J =2.5Hz,1H),7.15(d, J =2.5Hz,1H),4.29-4.21(m,3H),4.15-4.08(m,1H),3.97(s, 1H),3.70-3.64(m,2H),3.59-3.49(m,2H),2.91-2.82(m,1H),2.80-2.71(m,1H),2.69-2.51(m,2H),1.97- 1.66(m,6H),1.62-1.49(m,1H),1.09-0.92(m,9H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -73.44,-110.26,-118.89,-124.61.LCMS (m/z): 616.3(M+H).

Example 166

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 R ,3 R )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- alcohol

The synthesis of Example 166 was carried out with reference to Example 165, using ((2 R ,3 R )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol (middle Intermediate k6a) instead of ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS(m/z): 620.3(M+H).

Example 167

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2 R ,3 S )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- alcohol. Formate

The synthesis of Example 167 was carried out with reference to Example 165, using (( 2R , 3S )-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol (middle Intermediate k6b) instead of ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 620.3 (M+H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.20 (s, 1H), 7.99 (dd, J =9.2, 5.9Hz, 1H), 7.55 (dd , J =10.3,1.6Hz,1H),7.52-7.44(m,1H), 7.41(d, J =2.6Hz,1H),7.15(d, J =2.5Hz,1H),4.74-4.67(m, 0.5 H),4.62-4.50(m,1H),4.45-4.39(m,0.5 H),4.34-4.22(m,3H),4.19-4.14(m,1H),3.99-3.94(m,1H), 3.71-3.64(m,2H),3.60-3.50(m,2H),2.93-2.86(m,1H),2.74-2.65(m,1H),2.35-2.18(m,4H),1.97-1.60(m ,6H),1.11(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.18,-118.75,-124.54,-218.24.

Example 168

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2 R ,3 S )-1-allyl (2,3-dimethylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The synthesis of Example 168 was carried out with reference to Example 165, using ((2 R ,3 S )-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2c) in step A ) instead of ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 314.7 (M/2+H). ¹ H NMR (400MHz, Chloroform-d) δ 7.67 (dd, J =9.2, 5.8Hz, 1H), 7.30-7.27 (m, 2H), 7.22-7.12(m,2H),5.97-5.70(m,1H),5.07(d, J =17.1Hz,1H),4.93(d, J =10.1Hz,1H),4.51(d, J =12.7Hz ,1H),4.32-4.15(m,3H),3.72-3.56(m,3H),3.44(d, J =12.4Hz,1H),3.39-3.26(m,2H),3.06-2.90(m,1H ),2.88-2.66(m,2H),2.16-1.96(m,1H),1.94-1.74(m,4H),1.74-1.48(m,2H),1.19(s,3H), 1.02(d, J =7.0Hz, 3H). ¹⁹ F NMR (376MHz, Chloroform-d) δ -110.05, -116.37, -121.85.

Example 169

4-(4-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2 R ,3 S )-1-cyclopropane (2,3-dimethylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The synthesis of Example 169 was carried out with reference to Example 165, using ((2 R ,3 S )-1-cyclopropyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2d) in step A ) instead of ((2 R ,3 S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 628.3 (M+H).

Example 170

4-(4-(1 R ,5 S )-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2 R ,3 S )- 1,2,3-Trimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. diformate

The synthesis of Example 170 was carried out with reference to Example 165. In step A, ((2 R ,3 S )-1,2,3-trimethylpyrrolidin-2-yl)methanol (intermediate k2a) was used instead of (( 2R , 3S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 602.3 (M+H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.31 (s, 2H), 7.98 (dd, J =9.2, 5.9Hz, 1H), 7.54 (dd , J =10.3,1.6Hz,1H),7.51-7.44(m,1H),7.41(d,J=2.6Hz,1H),7.16(d, J =2.5Hz,1H),4.30-4.20(m, 3H),4.15-4.10(m,1H),3.99-3.96(m,1H),3.55-3.46(m,4H),2.89-2.81(m,1H),2.73-2.66(m,1H),2.30( s,3H),1.97-1.87(m,2H),1.84-1.63(m,4H),1.58-1.42(m,1H),1.09-0.93(m,6H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ -110.29,-118.95,-124.65.

Example 171

(2 R ,3 S )-2-(((4-((1 R ,5 S ))-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyne ((7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-1,2-dimethylpyrrolidine-3-carbonitrile ‧Triformate

The synthesis of Example 171 was carried out with reference to Example 165, using (2 R , 3 S )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4a) in step A. Instead of (( 2R , 3S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 613.3 (M+H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.39 (brs, 3H), 7.98 (dd, J =9.2, 6.0Hz, 1H), 7.56 (d , J =10.2Hz,1H),7.51-7.44(m,1H),7.41(d, J =2.6Hz,1H),7.15(d, J =2.5Hz,1H),4.39-4.32(m,1H) ,4.30-4.18(m, 3H),3.97(s,1H),3.62-3.51(m,4H),2.95-2.88(m,1H),2.75-2.68(m,1H),2.31-2.21(m, 4H),2.02-1.93(m,1H),1.78-1.61(m,4H),1.44-1.42(m,1H),1.16(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ - 110.25,-118.94,-124.68.

Example 172

(2 R ,3 R )-2-(((4-((1 R ,5 S ))-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyne ((7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-1,2-dimethylpyrrolidine-3-carbonitrile

The synthesis of Example 172 was carried out with reference to Example 165, using (2 R , 3 R )-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4b) in step A. Instead of (( 2R , 3S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 613.3 (M+H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 7.99 (dd, J =9.2, 5.9Hz, 1H), 7.56 (d , J =10.4Hz,1H),7.52-7.45(m,1H),7.41(d, J =2.6Hz,1H),7.14(d, J =2.6Hz,1H),4.39-4.32(m,1H) ,4.31-4.16(m,3H),3.97(s,1H),3.55-3.44(m,5H),2.96-2.88(m,1H),2.75-2.69(m,1H),2.31-2.20(m, 4H),2.02-1.92(m,1H),1.78-1.58(m,4H),1.46-1.37(m,1H),1.16(s,3H). ¹⁹ F NMR(376MHz,DMSO- d ₆ )δ - 110.16,-118.99,-124.70.

According to the above synthesis scheme and appropriate condition changes, the present invention synthesizes the following compounds:

Active examples

Example 1: Proliferation inhibitory effect of compounds of the present invention on KRAS G12D mutated AGS cells

This experiment evaluates and verifies the proliferation inhibitory activity of representative compounds of the present invention on KRAS G12D mutant AGS cells.

The following cell lines were used in this experiment:

It was cultured at 37°C, 5% CO2, and 95% humidity.

The following materials, instruments and reagents were used in this experiment: fetal bovine serum FBS (GIBCO, Cat#10099-141); CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Cat#G7572); 96-well transparent flat bottom black wall plate (Corning ®, Cat# 3603); Envision multifunctional microplate reader, PE, 2104; CO ₂ incubator, Thermo Scientific, Model 3100 Series; Biological safety cabinet, Sujing Antai, Model 1300 Series A2; Inverted microscope, Chongqing Optoelectronics, XDS-1B. The AGS cell line was purchased from ATCC with the catalog number CRL-1739.

The experiment proceeds as follows:

Cell culture and seeding: Harvest cells in logarithmic growth phase and count using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 μL of cell suspension to the 96-well plate; culture the cells in the 96-well plate at 37°C and 5% _CO2 .

Carry out drug dilution and dosing as follows: Single-point inhibition rate determination Drug preparation: Prepare 10 times the drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is 1 μM, and set three times for each drug concentration. A compound hole. IC50 determination drug preparation: Prepare 10 times drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 μM, 3.16× dilution, 9 concentrations, and set three replicates for each drug concentration. hole. The cells in the drug-added 96-well plate were cultured at 37°C and 5% _CO2 for 3 days, and then CTG detection was performed.

Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal and read the luminescence value.

Data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC50 value was calculated.

Cell survival rate (%) = (Lum _{test drug} -Lum _{culture medium control} )/(Lum _{cell control} -Lum _{culture medium control} ) × 100%.

Representative compounds of the present invention show satisfactory anti-proliferative activity against KRAS G12D mutated AGS human gastric adenocarcinoma cells. Partial activity data are shown in the table below.

Example 2: Cassette pharmacokinetic properties of the compound of the present invention in rats

The pharmacokinetic characteristics of some compounds of the present invention were evaluated by rat Cassette pharmacokinetic experiment (Nagilla R. et al., J. Pharm. Sci. 2011 , 100 , 3862-3874.).

This study used male SD rats, age: 6-8 weeks, weight 220-250g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and the following reagents were used: Tolbutamide (Aladdin, Catalog No. H1401054); Sulfobutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biotechnology, Catalog No. 20191013); Propylene glycol (15) stearate (Solutol, Meilun Biotechnology, Catalog No. S0206A); DMSO (Vetec Company, Catalog No. WXBD0293V ); acetonitrile (Sigma-Aldrich, product number WXBD1744V); methanol (Sigma-Aldrich, product number WXBD2831V).

The compound combination was formulated into a solvent of 5% DMSO/10% Solutol/85% (20% Captisol). The final concentration of each compound was 1 mg/mL. The pharmaceutical preparation was injected into the SD through the tail vein with an injection volume of 1 mL/kg. Rats were punctured and collected blood from the external jugular vein at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h respectively, centrifuged at low temperature for 20 minutes, collected plasma, and stored it at -20°C for testing.

The compound LC-MS/MS analysis method is established as follows:

Standard curve preparation: Take 20 μL of 1 mg/mL DMSO stock solution for each compound, transfer it to 900 μL of 50% methanol working solution, and dilute it step by step to obtain a curve with concentrations of 20000, 10000, 5000, 1000, 500, 100, 50, and 20 , 10ng/mL standard curve working solution, then take 5μL standard curve working solution and mix with 45μL rat blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL. Curve for quantifying unknown samples.

Sample pretreatment: 50 μL of unknown plasma samples and standard curve samples, add 250 μL of acetonitrile containing tolbutamide as the internal standard as a precipitating agent, precipitate plasma proteins, extract the compounds to be tested in the plasma, centrifuge at low temperature for 20 minutes, and take the supernatant. The supernatant was mixed with 0.1% formic acid aqueous solution, 5 μL was injected, and LC-MS was used to analyze the drug plasma concentration.

The mass spectrometry software Analyst 1.6.1 was used to draw a standard curve and the unknown samples were quantified. The pharmacokinetic parameters were calculated using Winnonlin 8.2 based on the drug concentration of the unknown samples at each time point.

Experimental results show that in the pharmacokinetic evaluation of cassette administration, the compound of the present invention shows good pharmacokinetic properties.

Example 3: Inhibition test of cytochrome P450 by the compounds of the present invention

This experiment evaluates the inhibitory effect of the inventive compounds on cytochrome P450.

This experiment was performed using the following reagents: human liver microsomes (Corning Company, Cat. No. 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE Company, Cat. No. HY-F0003/CS-4998); phenacetin Acetaminophen, diclofenac, α-naphthoflavone, omeprazole and ketoconazole were purchased from TCI; S-mephenytoin and testosterone were purchased from CAYMAN; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from Damas-beta; sulfapyrazole was purchased from MCE; buturol was purchased from TRC.

Prepare 0.1M potassium phosphate buffer (K-buffer): Prepare 100mM potassium phosphate buffer (K-buffer) using potassium dihydrogen phosphate and dipotassium hydrogen phosphate, and adjust the pH to 7.4.

Prepare 400× test compound and positive control inhibitor:

Prepare test compound solution: Dissolve 8μL of 10mM test compound stock solution in 12μL acetonitrile; Prepare mixed solution of CYP1A2, CYP2C9 and CYP2D6 inhibitors: Dissolve 12μL of 1mM α-naphthoflavone, 10μL of 40mM sulfapyrazole, 10μL of 10mM Mix quinidine and 8μL DMSO solution; prepare CYP3A4 inhibitor solution: dissolve 8μL 2.5mM ketoconazole DMSO solution in 12μL acetonitrile; prepare CYP2C19 inhibitor solution: dissolve 8μL 100mM omeprazole DMSO solution in 12 μL acetonitrile.

Prepare 4×NADPH potassium phosphate solution: add 66.7mg NADPH to 10mL 0.1M K-buffer, pH7.4. Prepare 4× substrate potassium phosphate solution: Prepare each substrate according to the concentration requirements with 10mL 0.1M K-buffer to prepare a solution required for 4 times the concentration measurement.

Preparation of 0.2 mg/mL human liver microsomes (HLM) solution: Add 10 μL of 20 mg/mL human liver microsomes to 990 μL K-buffer and store on ice for later use.

Add 600 μL of 0.2 mg/mL HLM to the 96-well plate, and add 3 μL of the 400-fold test compound solution; add 200 μL of 0.2 mg/mL HLM to the 96-well plate, and add 1 μL of the diluted positive control inhibitor solution. Dispense 30 μL of the mixed solution of compound and human liver microsomes into a 96-well plate, and then add 15 μL of substrate solution. Preheat the solution obtained above and the prepared NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated NADPH solution to the reaction plate, mix well, and start the reaction. Incubate reaction plate at 37°C. 3A4 reacts for 5 minutes; 1A2, 2C9, 2D6 react for 10 minutes; 2C19 react for 45 minutes. At the end of the reaction, 120 μL of acetonitrile containing internal standard was added to terminate the reaction. The sample was vortexed for 10 minutes, centrifuged at 5594g for 15 minutes, and the sample was prepared and sent to LC-MS/MS analysis.

Experimental results show that at the test concentration, the compound of the present invention has no significant inhibitory effect on the key CYP subtypes of drug metabolism, and exhibits better drug-drug interaction safety.

Example 4: The inhibitory effect of the compound of the present invention on the proliferation of KRAS G12D mutated AGS (3D) cells

The inhibitory effect of representative compounds on the 3D proliferation of AGS cell lines was evaluated by non-adhesion and spherical growth in methylcellulose 3D culture medium.

The following materials, instruments and reagents were used in this experiment: culture medium RPMI1640 (HyClone, Cat#SH30809.01); fetal bovine serum FBS (GBICO, Cat#10099-141); CellTiter-Glo® Luminescent Cell Viability Assay (Nanjing Novozan , Cat#DD1101-04); 96-well polystyrene microplate (black wall) (Greiner Bio one, Cat.# 655096); methylcellulose (SIGMA, CAS: 9004-67-5); AGS cells ( KC-0405, Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.); multifunctional microplate reader (BMG LABTECH, CLARIOstar® Plus); CO ₂ incubator (Thermo Scientific, Model 3100 Series).

Cell culture and seeding: Harvest cells in logarithmic growth phase and count using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentration. After there is no visible air in the cell suspension, add 180 μL of cell suspension to the 96-well plate so that the final concentration of methylcellulose is 0.65% and the number of cells is 2400/well. The cells in the 96-well plate were cultured overnight at 37°C, 5% CO ₂ and 95% humidity.

Carry out drug dilution and dosing as follows: Use culture medium to prepare a 10-fold concentration drug solution, add 20 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 μM, 3.16× dilution, a total of 9 concentrations, each Three duplicate wells were set for each drug concentration, and the DMSO content was 0.1%; the cells in the 96-well plate with the drug added were placed in 37°C, 5% CO ₂ , and 95% humidity conditions for 120 h, and then CTG analysis was performed.

Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal, and then read the luminescence value.

Data were analyzed using GraphPad Prism 7.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC50 value was calculated.

Cell survival rate (%) = (Lum _{test drug} -Lum _{culture medium control} )/(Lum _{cell control} -Lum _{culture medium control} ) × 100%.

The compound of the present invention shows satisfactory inhibitory activity on the proliferation of KRas G12D mutant cells in 3D cultured AGS cell lines, with an IC50 value of 0.01~0.5 μM, such as 0.01~0.1 μM, 0.01~0.05 μM.

Detailed data for representative compounds are shown in the table below.

Example 5: Cassette pharmacokinetic properties of the compound of the present invention in mice

The pharmacokinetic characteristics of the representative compounds of the present invention were evaluated by mouse Cassette pharmacokinetic experiment (Nagilla R. et al., J. Pharm. Sci. 2011 , 100 , 3862-3874.).

This study used male CD-1 mice, age: 6-8 weeks, weight 18-22g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and the following reagents were used: Tolbutamide (Tolbutamide) Latin, Cat. No. H1401054); MC (Methylcellulose, Aladdin, Cat. No. M112866); DMSO (Sigma-Aldrich, Cat. No. 186403); Acetonitrile (Sigma-Aldrich, Cat. No. WXBD547V); Methanol (Sigma-Aldrich, Cat. No. F22M67201).

The compound combination was prepared into a solvent of 5% DMSO + 95% (0.5% MC). The final concentration of each compound was 1 mg/mL. The drug preparation was orally administered to CD-1 mice at a volume of 10 mL/kg. Blood was collected from the saphenous vein of the hind limbs at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h respectively, centrifuged at low temperature for 20 minutes, plasma was collected, and stored at -20°C for testing.

Establish a compound LC-MS/MS analysis method as follows

Standard curve preparation: Take 20 μL of 1 mg/mL DMSO stock solution for each compound, transfer it to 900 μL of 50% methanol working solution, and dilute it step by step to obtain a curve with concentrations of 20000, 10000, 5000, 1000, 500, 100, 50, and 20 , 10ng/mL standard curve working solution, then take 2μL standard curve working solution and mix with 18μL mouse blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL. Curve for quantifying unknown samples.

Sample pretreatment: 20 μL of unknown plasma samples and standard curve samples, add 250 μL of acetonitrile containing tolbutamide as the internal standard as a precipitating agent, precipitate plasma proteins, extract the compounds to be tested in the plasma, centrifuge at low temperature for 20 minutes, and take the supernatant. Mix the supernatant with 0.1% formic acid aqueous solution at a ratio of 1:1, draw 10 μL of the sample, and use LC-MS to analyze the drug plasma concentration.

The mass spectrometry software Analyst 1.6.1 was used to draw a standard curve and the unknown samples were quantified. The pharmacokinetic parameters were calculated using Winnonlin 8.2 based on the drug concentration of the unknown samples at each time point.

The experimental results show that in the pharmacokinetic evaluation of box-type administration, the compound of the present invention shows good pharmacokinetic properties.

Claims (23)

A compound of formula (A) or a pharmaceutically acceptable salt or solvate thereof,

in, X is selected from N, CH, CF, C-Cl and C-CF ₃ ; Y is selected from O, S and NR ^b ; R ^a is selected from halogen, C _1-6 alkyl or -OC _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted by halogen; R ^b at each occurrence is independently selected from H and C _1-6 alkyl optionally substituted by halogen; R ₁ is selected from H, CN, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -(CH ₂ ) _p -C _3-6 cycloalkyl and -(CH ₂ ) _p -4-7 membered heterocycloalkyl, in which -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and 4- Each 7-membered heterocycloalkyl group is independently optionally substituted by halogen, CN, -C _1-6 alkyl, -OR ^b or -N(R ^b ) ₂ ; or R ₁ and R ₃ connected to the ortho-position ring carbon atoms together with the ring carbon atoms to which they are connected form a fused C _3-6 cycloalkyl group; R ₂ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally replaced by halogen, -C _{1 -6} alkyl, -OR ^b or -N(R ^b ) ₂ substitution; or when n is 2, two R ₂ together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group; R ₃ is selected from H, halogen, -CN, -OH, -OC _1-6 alkyl, -O-(CH ₂ ) _p -C _3-6 cycloalkyl, -O-(CH ₂ ) _p -4- 7-membered heterocycloalkyl, -O-(CH ₂ ) _p -5-10-membered heteroaryl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -( CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl, -(CH ₂ ) _p -5- 10 membered heteroaryl, -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ and -OC(O)-N(R ^b ) ₂ , among which -C _1-6 alkyl, C _{3- 6-} cycloalkyl, 4-7-membered heterocycloalkyl and 5-10-membered heteroaryl are each independently optionally replaced by halogen, -CN, side oxygen, -C _1-6 alkyl, -OR ^b , -N( R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ , -OC(O)-N(R ^b ) ₂ substituted; or Two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , spiro C _3-6 cycloalkyl or spiro 4-7 membered heterocycloalkyl, wherein R ^c is each independently selected from halogen and -C _1-6 alkyl optionally substituted by halogen; or Two R ₃ connected to adjacent ring carbon atoms together with the ring carbon atoms to which they are connected form a fused C _3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group; R ₄ is selected from H, -C _1-6 alkyl, -C _{2-6 alkenyl, -C 2-6 alkynyl} , -(CH ₂ ) _p -C _3-6 cycloalkyl, -(CH ₂ ) _p -4-7 membered heterocycloalkyl, -(CH ₂ ) _p -5-10 membered heteroaryl, -C(O)-OR ^b and -C(O)-N(R ^b ) ₂ , where Each of -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl Independently as appropriate, halogen, -CN, -C _1-6 alkyl, -OR ^b , -N(R ^b ) ₂ , -C(O)-OR ^b , -C(O)-N(R ^b ) ₂ or -OC(O)-N(R ^b ) ₂ substitution; Z is selected from

or

,in R ₅ and R ₇ are each independently selected from H or halogen; R ₆ and R ₈ are each independently selected from H, halogen, -C _1-6 alkyl and -C _2-6 alkynyl; m and p are each independently selected from an integer from 0 to 3; n is an integer selected from 0-2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^a is F. The compound as described in claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is selected from -C _1-6 alkyl and -C _3-6 cycloalkyl. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is H. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is H. The compound as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -C _1-6 alkyl, optionally replaced by halogen, -OR ^b or -OC (O)-N(R ^b ) ₂ substituted, or R ₃ is halogen. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , among which -C _1-6 alkyl, -C _2-6 alkenyl, -C _{2- 6Alkynyl} and -C _3-6 cycloalkyl are each independently optionally substituted with halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ . The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C _1-6 alkyl, optionally substituted by halogen or -OR ^b . The compound of claim 1 or its pharmaceutically acceptable salt or solvate, which has formula I:

_{, wherein _ _ _ _}

The compound of claim 10 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O; R ₁ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl; R ₂ is H; R ₃ is selected from H, halogen, -OR ^b or -C _1-6 alkyl substituted by -OC(O)-N(R ^b ) ₂ ; R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , Among them, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl are each independently replaced by halogen, -OR ^b or -OC(O )-N(R ^b ) ₂ substituted, preferably -C _1-6 alkyl optionally substituted by halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ . The compound of claim 10 or 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is F, and R ₆ is

. The compound of claim 1 or its pharmaceutically acceptable salt or solvate, which has formula II:

_{, wherein _ _ _ _}

The compound or pharmaceutically acceptable salt or solvate thereof as described in claim 13, wherein Y is O; R ₁ is selected from H, -C _1-6 alkyl and -C _3-6 cycloalkyl; R ₂ is H; R ₃ is selected from H, halogen, -OR ^b or -C _1-6 alkyl substituted by -OC(O)-N(R ^b ) ₂ ; R ₄ is selected from -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl and -C(O)-N(R ^b ) ₂ , Among them, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl are each independently replaced by halogen, -OR ^b or -OC(O )-N(R ^b ) ₂ substituted, preferably -C _1-6 alkyl optionally substituted by halogen, -OR ^b or -OC(O)-N(R ^b ) ₂ . The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is H, and R ₈ is halogen. A compound, or a pharmaceutically acceptable salt or solvate thereof, which is a compound of Examples 1 to 232. The compound as described in any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament for the treatment and/or prevention of disease mediated by KRas mutations, preferably KRas G12D mutations disease. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A compound as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition as described in claim 18 or 19 for use in the prevention or treatment of KRas mutations , preferably for use in drugs for diseases mediated by KRas G12D mutations. Such as the use of claim 19, wherein the disease mediated by KRas mutation, preferably KRas G12D mutation is selected from: pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, Uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, Endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic Lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma. Such as the use of claim 20, wherein the disease mediated by KRas mutation, preferably KRas G12D mutation is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia ;Best selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer. A method of treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins, preferably KRas G12D mutant proteins, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1 to 16 The compound described in claim 18 or 19, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 22, wherein the disease mediated by the KRas mutation, preferably the KRas G12D mutation, is selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, and leukemia ;Best selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.