CN117327102A - KRAS inhibitor, preparation method and application thereof - Google Patents

Abstract

The present invention provides a compound that has an inhibitory effect on KRAS mutation, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, as shown in formula (I), and the definition of each group in the formula See instructions for details. In addition, the present invention also discloses a pharmaceutical composition containing the compound and its use in preparing a kit for treating cancer, immune diseases or assessing the prognosis of cancer patients.

Description

KRAS inhibitor, preparation method and application thereof

Technical Field

The present disclosure relates to the field of medicine, and in particular to a compound having KRAS inhibitory effect, a pharmaceutical composition, and uses and preparation methods thereof.

Background Art

Kirsten rat sarcoma 2 viral oncogene homolog (KRas) is a small GTPase and a member of the Ras family. KRas protein is inactive when bound to GDP; when extracellular growth and differentiation factors transmit signals to KRAS protein, the protein binds to GTP and activates it, thereby activating KRAS and downstream signals (Nature Review cancer 3: 11-22, 2003). Signaling pathways such as RAS-RAF-MEK-ERK and RAS-PI3K-AKT regulate multiple cellular processes, including cell proliferation, differentiation and survival. KRAS mutations can continuously activate downstream cell signals, promote cell proliferation, migration and anti-apoptosis, and induce tumorigenesis.

KRAS mutations are closely related to tumor formation and development. The role of KRAS in malignant tumors was observed more than 30 years ago (for example, see Santos et al., (1984) Science 223: 661-664). About 20% of all human tumors have abnormal expression of KRAS, and KRAS mutations are detected in 25-30% of lung adenocarcinomas (for example, see Samatar and Poulikakos (2014) Nat Rev Dmg Disc 13 (12): 928-942 doi: 10.1038/nrd428). 80% of KRAS mutations occur at the 12th codon, causing a single amino acid substitution, the most important of which are G12C and G12D. KRASG12C mutation refers to the mutation of glycine at position 12 of the protein to cysteine. The frequency of occurrence in tumors is pancreatic cancer (57%), colorectal cancer (35%), bile duct cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer (15%) and ovarian cancer (14%) (Seminars in Cancer Biology. 2019Jun 27.pii: S1044-579X(18)30060-9). KRAS G12D mutation refers to the mutation of glycine at position 12 of the protein to aspartic acid. The frequency of occurrence in tumors is pancreatic cancer (25.0%), colon cancer (13.3%), rectal cancer (10.1%), non-small cell lung cancer (4.1%) and small cell lung cancer (1.7%) (for example, see The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8): 818-831. Dataset Version 4). In addition to G12C and G12D, KRAS has many other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. The frequency of occurrence of different KRAS mutations in different types of cancer cells is also different.

Since KRAS mutations are frequently found in various tumor types, it has become a popular anti-cancer target in the pharmaceutical industry (see MeCormick (2015) Clin Cancer Res. 21(8): 1797-1801). The development of KRAS small molecule inhibitors is generally divided into three approaches: (i) competitive ligands to prevent GTP binding; (ii) allosteric modulation to lock KRAS G12C in an inactive state; (iii) protein-protein interaction inhibitors to disrupt KRAS and its effector proteins and guanine nucleotide exchange factors (GEFs) (such as son of sevenless (SOS), RAF, and PI3K).

Over the past few decades, drug development targeting KRAS has mostly ended in failure, so KRAS was once considered undruggable. However, in recent years, with the breakthrough progress in biology and protein structure, including comparative studies of different structures of mutant and wild-type KRAS proteins, small molecule inhibitors targeting KRAS G12C have been successful in clinical practice. Amgen's First-in-Class KRAS G12C inhibitor AMG 510 has been approved for marketing by the US FDA on May 28, 2021 for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations. Mirati and many biopharmaceutical companies at home and abroad are also developing drugs targeting KRAS, but most of them are targeting KRAS G12C or KRAS G12D mutations. As mentioned above, in addition to KRAS G12C or KRASG12D mutations, KRAS has many other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. These KRAS mutations play an important role in the formation and development of many types of cancer. Therefore, it is urgent to develop drugs targeting these KRAS mutations. In addition, with the successful launch of drugs targeting KRAS G12C, we expect that cancer patients receiving treatment will develop drug resistance. Therefore, in response to these unmet clinical needs, it is of great significance to develop a new generation of broad-spectrum KRAS inhibitors that are innovative and target multiple KRAS mutations to counteract drug resistance mechanisms.

Summary of the invention

In one aspect of the present invention, a novel substituted fused-ring aromatic compound is provided, which is a selective and broad-spectrum inhibitor of KRAS mutation and has high inhibitory activity.

In one aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In formula (I), X and Y are selected from -CR ⁴ or N, and X and Y are not simultaneously -CR ⁴ or N, wherein R ⁴ is selected from -H, -D, halogen, -CF3, -OH, -CN, -NR ^a R ^b , -C(O)OR ^a , C _1-6 alkoxy, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl:

^R1 is

R ⁵ and R ⁶ are each independently -H, -D, halogen, -CF ₃ , -OH, ＝O, -CN, -NR ^a R ^b , -C(O)OR ^a or C _1-6 alkoxy, R ⁷ at each substitution position is each independently selected from -H, -D, halogen, -CF ₃ , -OH, -CN, -NR ^a R ^b , -C(O)OR ^a , C _1-6 alkoxy, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, and p is optionally 0, 1, 2, 3, 4, 5 or 6;

It represents the absence of chemical bonds or single or double bonds;

W is selected from N, C, O or S atoms;

n is optionally 0, 1 or 2;

m and q are each independently selected to be 0 or 1;

^R2 is selected from 5- to 6-membered monocyclic heteroaryl, _C6-10 aryl, 8- to 10-membered bicyclic heteroaryl;

^R3 is selected from H, D, _-C1-3alkoxy - _{C3-9cycloalkyl} , _-C1-3alkoxy -3 to 9-membered heterocycloalkyl, _-C1-3alkoxy -5 to 6-membered monocyclic heteroaryl, _-C1-3alkoxy - _C6-10aryl or _-C1-3alkoxy -8 to 10-membered bicyclic heteroaryl;

The _C1-6 alkoxy, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 to 6 membered monocyclic heteroaryl, _C6-10 aryl or 8 to 10 membered bicyclic heteroaryl is optionally substituted by 0, 1, 2 or 3 groups independently selected from halogen, methyl, ethyl, propyl, isopropyl, vinyl, 1-allyl, 2-allyl, ethynyl, propynyl, trifluoromethyl ^, amino, hydroxyl, carboxyl, -C(O) ^NRaRb

Substituent substitution;

Said R ^a and R ^b are each independently H, D, C _1-6 alkyl, -C _1-3 alkyl-C _3-9 cycloalkyl or -C _1-3 alkyl-3 to 9 membered heterocycloalkyl;

The heterocycloalkyl, monocyclic heteroaryl, bicyclic heteroaryl has at least one heteroatom selected from N, O and S as a ring atom;

The halogen is selected from F, Cl, Br or I.

In one embodiment, in formula (I), R ¹ is selected from wherein R ⁵ , R ⁶ , R ⁷ , ^Ra , n, p and W are as defined above.

In one embodiment, in formula (I), R ² is Wherein, R ⁸ and R ⁹ at each substitution position are independently selected from halogen, methyl, ethyl, propyl, isopropyl, vinyl, 1-allyl, 2-allyl, ethynyl, propynyl, trifluoromethyl, amino, hydroxyl, carboxyl, -C(O)NR ^a R ^b , the halogen is preferably fluorine, g and f are independently selected from 0, 1, 2 or 3, and g and f are independently preferably 0, 1 or 2.

In one embodiment, in formula (I), R ³ is wherein d is optionally 1, 2 or 3, and the A ring is selected from C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 to 6 membered monocyclic heteroaryl, C _6-10 aryl or 8 to 10 membered bicyclic heteroaryl.

In a preferred embodiment, in formula (I), R ¹ is selected from the following structures:

In a preferred embodiment, in formula (I), R ² is selected from the following structures:

In a preferred embodiment, in formula (I), R ³ is selected from the following structures:

In one embodiment, the compound described in formula (I) is as shown in formula (II-a), formula (II-b), formula (II-c) or formula (II-d),

In ^the formula, R ² , R ³ , R ⁴ , R 5 , R ⁶ , R ⁷ , Ra , R ^b , m, n, ^q and p have the same definitions as described above.

In a preferred embodiment, the compound described in formula (I) is as shown in formula (II-e), formula (II-f), formula (II-g), formula (II-h) or formula (II-i),

^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^Ra , ^Rb , m, n, q and p are as defined above.

In one embodiment, the compound described in formula (I) is as shown in formula (III-a) or formula (III-b),

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, q and p are as defined above, and d and ring A are as defined above.

In a preferred embodiment, the compound described in formula (I) is as shown in formula (III-c), formula (III-d), formula (III-e), formula (III-f), formula (III-g), formula (III-h), formula (III-i), formula (III-j), formula (III-k) or formula (III-l),

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, q and p are as defined above, and d and ring A are as defined above.

In a preferred embodiment, the compound is as shown in formula (III-m), formula (III-n), formula (III-o) or formula (III-p),

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, q and p are as defined above, and d and ring A are as defined above.

In one embodiment, the pharmaceutically acceptable salt includes but is not limited to any one or a combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, acetate, trifluoroacetate, propionate, methanesulfonate, lactate, benzenesulfonate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate or malate.

In one embodiment, the compound of formula (I) includes but is not limited to the following structures, or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof:

Another aspect of the present invention provides a method for preparing the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, comprising the following steps:

(1) Compound (I-1) and compound (R ^1' H) undergo a substitution reaction to generate compound (I-2), wherein R ^1' H is selected from R ¹ or R ¹ substituted with Boc;

(2) the compound (I-2) and the compound After Suzuki coupling reaction, compound (Ma) is generated, wherein R ² H is selected from R ² or R ² substituted with a protecting group;

(3) Compound (Ma) and compound (R ³ H) undergo coupling reaction to generate compound (Mb);

(4) removing the protecting group of the compound (M-b) under acidic conditions to generate compound (M);

The definitions of R ¹ , R ² and R ³ are as described above.

Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition further comprises another drug for treating cancer or immune disease.

Another aspect of the present invention provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method in the preparation of a kit for treating cancer, immune diseases or evaluating the prognosis of cancer patients.

Another aspect of the present invention provides a use of the above-mentioned pharmaceutical composition in preparing a kit for treating cancer, immune diseases or evaluating the prognosis of cancer patients.

In one embodiment, the use is use in a disease associated with a KRAS mutation.

In one embodiment, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer.

In a preferred embodiment, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, small intestine cancer, endometrial cancer and ovarian cancer.

In one embodiment, the immune disease is a KRAS-mediated immune disease.

Another aspect of the present invention provides use of the above compound, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the above method in the preparation of a KRAS inhibitor.

Another aspect of the present invention provides a use of the above pharmaceutical composition in the preparation of a KRAS inhibitor.

Preferably, the KRAS inhibitor is a KRAS G12D inhibitor.

Another aspect of the present invention provides a method for inhibiting KRAS mutation in a biological sample, comprising contacting the biological sample with the above compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above method, or the above pharmaceutical composition.

DETAILED DESCRIPTION

According to the contents of the present disclosure, in accordance with common technical knowledge and customary means in the art, without departing from the basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes may be made.

I. Definition

Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

The compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence of said event or circumstance and the non-occurrence of said event or circumstance.

Numeric ranges herein refer to each integer in the given range. For example, "C _1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C _3-6 " means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom or group are replaced by a substituent, as long as the valence state of the particular atom or group is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be any on the basis of chemically achievable.

In this disclosure, when any variable (e.g., ^Rn ) occurs more than once in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-5 R, the group may be optionally substituted with up to 5 R, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present disclosure.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

"Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, the cycloalkyl ring containing at least 3 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Non-limiting examples of heterocyclyl include pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazepanyl and piperazinyl.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising heteroatoms and carbon atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkylthio-alkyl" refers to an alkylthio group attached to an alkyl group, wherein alkyl and alkylthio are as defined above; "alkylaminocarbonyl" refers to (alkyl)-N-C(O)-, wherein alkyl is as defined above; "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above; "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above; "haloalkoxy" refers to an alkylthio group substituted by one or more halogens, wherein alkylthio is as defined above; "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

The hydrogen atoms described in the present disclosure may all be replaced by their isotope deuterium.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.

In this disclosure, Refers to the chemical bond connection.

Drug or drug composition

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.

The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oil esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing the compound of formula I as the active compound can also introduce beads, microspheres or microcapsules, such as those constructed from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, i.e., administered intravenously (i.v.), intracerebroventricularly (i.c.v.), subcutaneously (s.c.), intraperitoneally (i.p.), intramuscularly (i.m.), subcutaneously (s.d.) or intradermally (i.d.), by direct injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the form of an excipient, in the form of a suspension, solution or emulsion in an oil or aqueous carrier, and can include formulation agents such as anti-settling agents, stabilizers and/or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as a suppository or retention enema (eg, containing a conventional suppository base such as cocoa butter or other glycerides).

The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

The terms "reduce," "inhibit," "mitigate," or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, suppress or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and/or physiological effect. The exact dosage will vary according to a variety of factors, such as variables that the subject depends on (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective amount can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of a subject before or without administration of a drug or drug combination, or in the case of a drug combination, the combined effect can be compared to the effect of administering only one drug.

The term "excipient" is used herein to include any other compound that may be contained in or on the microparticles that is not a therapeutic or biologically active compound. Thus, an excipient should be pharmaceutically or biologically acceptable or relevant, e.g., an excipient is generally non-toxic to a subject. An "excipient" includes a single such compound, and is also intended to include a plurality of compounds.

The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

Uses and treatments

The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof amenable to the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject, or individual is a human.

According to the methods of the present disclosure, the compounds or compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease associated with KRAS.

The present disclosure relates to a method of inhibiting KRAS in a biological sample, comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioanalysis, gene expression studies, and identification of biological targets.

The method of inhibiting KRAS in a patient of the present disclosure comprises the step of administering a compound of the present disclosure or a composition comprising the compound to the patient.

The provided compounds are KRAS inhibitors and are therefore useful for treating one or more conditions associated with KRAS activity. Thus, in certain embodiments, the present disclosure provides a method for treating a KRAS-mediated condition comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

As used herein, the term "KRAS-mediated" disorder, disease and/or condition as used herein means any disease or other deleterious condition in which KRAS or a mutant thereof is known to play a role. Therefore, another embodiment of the present disclosure is directed to treating or lessening the severity of one or more diseases in which KRAS or a mutant thereof is known to play a role.

The present disclosure provides a method for treating one or more disorders, diseases, and/or conditions, wherein the disorder, disease, or condition is a proliferative disorder, such as cancer, an inflammatory disorder, or a viral infection.

In certain embodiments, the present disclosure provides a method of treating cancer or another proliferative disorder, comprising administering a compound or composition of the present disclosure to a patient suffering from cancer or another proliferative disorder. In certain embodiments, the method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present disclosure to a mammal. In certain embodiments, the mammal is a human.

As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or survival of cancer cells, and/or causing the death of cancer cells, either individually or collectively with other cancer cells, by cytotoxicity, nutrient depletion or induction of apoptosis.

Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and for which the methods described herein are applicable include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary glands, adrenal glands, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, and stomach.

Cancers treated by the compounds or compositions of the present disclosure include, but are not limited to, melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colorectal cancer, etc. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

The compounds of the present disclosure can be used to treat a proliferative disease selected from the group consisting of a benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma or a gastrointestinal cancer (particularly a colon cancer or a colorectal adenoma) or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, an undifferentiated tumor, papillary carcinoma, a seminoma, melanoma, a MYD88 driven disorder, DLBCL, ABC DLBCL, IL-1 driven disorders, rheumatic or indolent multiple myeloma or leukemia.

Cancers described in the present disclosure include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myelocytic leukemias, acute myeloblastic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumors, the ovarian, ovarian, prostate, squamous cell, basal cell, adenocarcinoma, sweat gland, sebaceous gland, papillary, papillary adenocarcinoma, cystadenocarcinoma, medullary, bronchogenic, renal cell, hepatoma, bile duct, choriocarcinoma, seminoma, embryonal, Wilms' tumor, cervical, uterine, testicular, lung, small cell lung cancer, bladder, epithelial, glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

In some embodiments, the cancer is a glioma, an astrocytoma, a glioblastoma multiforme (GBM, also known as a glioblastoma), a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, an hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a schwannoma, a neurofibrosarcoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

In some specific embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-multiforme astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or a pediatric patient.

In another specific embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal tract (stomach, colorectal and duodenum), uterine 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, parathyroid cancer, kidney cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the above cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct cancer or pancreatic cancer; gastrointestinal tract/gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

The term "primary tumor" is relative to secondary tumor. Primary tumor refers to a tumor that first appears in a certain part of the body such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

The term "inflammatory disease" includes such autoimmune, allergic and inflammatory disorders, for example selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, Sjogren's syndrome, and blistering disorders (e.g. pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (cancer or infection primary or secondary). The allergic disorder may be selected in particular from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollens and related allergens, berylliosis. The respiratory disorder may be selected from, inter alia, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension and emphysema, among others.

The term "viral infection" includes but is not limited to retroviral infection, hepatitis virus infection, COVID-19 novel coronavirus infection, Zika virus infection, dengue virus infection, etc.

Combination therapy approach

The present disclosure provides a combination therapy using compounds as described in the present disclosure and other therapeutic drugs. The term "combination therapy" used in the present disclosure includes the administration of these agents in a sequential manner, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents, or at least two agents, is substantially performed simultaneously. The order of each agent, or substantially simultaneous administration, can be affected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, subcutaneous routes, and direct absorption through mucosal tissue. The agents can be administered by the same route or different routes. For example, the first agent can be administered orally, and the second agent can be administered intravenously. In addition, the selected combination can be administered by intravenous injection, and the other agents of the combination can be administered orally. Alternatively, for example, two or more agents can be administered by intravenous or subcutaneous injection.

II. Embodiment

The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is clear that many changes and variations can be made according to the teachings of this application specification. The purpose of selecting and describing exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present disclosure and various different selections and changes.

Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

Instruments and reagents:

NMR: Agilent 400MRDD2 nuclear magnetic spectrometer, the solvents for determination are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard is tetramethylsilane (TMS). LC-MS: Agilent 1260 Infinity II-InfinityLab LC/MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C18 5um 150x 4.6mm column).

Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plate (Yucheng Chemical (Shanghai) Co., Ltd.), specification 0.2mm＝0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Aiger Fino Claricep Flash amorphous silica gel purification column).

Reagents: 5,6-amino-2,4(1H,3H)-dihydroxypyrimidine, ethyl glyoxylate, phosphorus oxychloride, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, (3-(ethoxymethoxy)-8-fluorothen-1-yl)boric acid, tetrakis(triphenylphosphine)palladium, palladium acetate, ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol, 1,1′-dimethoxy-2,2′-tetrahydro-1H-pyrrolizin-7a-yl)methanol, Diphenylphosphine, 1-tetraboric acid, (S)-(1-methylpyrrolidin-2-yl)methanol, 4,4-difluoropyridine, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II)methanesulfonate, potassium phosphate, (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)tetraboran-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, N-methyl-L -prolinol, (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane, 4-methylpiperidin-4-ol, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol, cesium fluoride, thiomorpholine 1,1-dioxide, (1R,5S)-8-oxo- 3-Azabicyclo[3.2.1]octane, 4-methylpiperidin-4-ol, dioxane hydrochloride, (R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, etc. The reagents and other reagents and starting materials were purchased from Shanghai Bidex, Leyan Reagent Company, Jiangsu Aikon Biopharmaceutical R&D Company, Anage Chemical Reagent Company, Shanghai McLean Reagent Company, Sane Chemical Reagent Company, etc., or synthesized using methods known in the art.

Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring, in dry nitrogen or argon, with dry solvents and reaction temperatures in degrees Celsius.

The following are the intermediate numbers:

(1) Synthesis of Intermediate I-1: 2,4,7-Trichloroteridine

Step 1: Synthesis of 2,4,7-trihydroxypterin (I-1a)

5,6-Amino-2,4(1H,3H)-dihydroxypyrimidine (5 g, 35.21 mmol) and potassium carbonate (5.3 g, 38.71 mmol) were dissolved in water (80 ml), heated to 100°C, stirred for 1 hour, cooled to 60°C, and ethyl glyoxylate (4.3 g, 42.21 mmol) was added. The reaction solution was stirred at 60°C for 16 hours, heated to 100°C, and stirred for 24 hours. The solution was filtered while hot, and the filtrate was collected. After cooling, the pH value was adjusted to 3 with dilute hydrochloric acid, filtered, the filter cake was collected, and dried to obtain 5.41 g of 2,4,7-trihydroxypterin (I-1a) with a yield of 85.7%.

Step 2: Synthesis of 2,4,7-trichloropterycine (I-1)

2,4,7-trihydroxypterin (I-1a, 5 g, 27.8 mmol) was dissolved in phosphorus oxychloride (250 ml), and then N,N-diisopropylethylamine (DIPEA) (5.39 mg, 1.5 eq.) was slowly added dropwise while stirring, and the mixture was reacted at 110°C for 16 hours under nitrogen protection. The phosphorus oxychloride was removed as much as possible by vacuum distillation, and the residue was diluted with dichloromethane and purified by column to obtain 3.59 g of the target product 2,4,7-trichloropteridine (I-1), with a yield of 54.81%, and ESI [M+H] ⁺ = 235.0, 237.0.

(2) Intermediate I-2: Synthesis of tert-butyl (1R, 5S)-3-(2,7-dichloropterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate

2,4,7-Trichloropteridin (I-1, 287 mg, 1.22 mmol) was dissolved in anhydrous dichloromethane (DCM) (15 ml), N,N-diisopropylethylamine (DIPEA) (47 mg, 0.366 mmol) was slowly added at -40°C, and then tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (388 mg, 1.83 mmol) (tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in 5 ml of dichloromethane and the addition was completed within 10 min) was added dropwise, and the reaction was carried out at -40°C for 5 hours. The organic solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain 421 mg of the target product tert-butyl (1R,5S)-3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-2) in a yield of 83.86%, ESI[M+H] ⁺ =411.2, 413.2.

Example 1: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol hydrochloride (1)

Step 1: Synthesis of tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluoronaphthalen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1-a)

Tert-butyl (1R, 5S)-3-(2,7-dichloropterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2, 20 mg, 0.05 mmol), (3-(ethoxymethoxy)-8-fluorothen-1-yl)boric acid (I-2, 16 mg, 0.06 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and cesium carbonate (33 mg, 0.10 mmol) were dissolved in toluene (2.0 ml), the reaction system was replaced with nitrogen and heated to 60° C. under nitrogen atmosphere for 4 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column gave 12 mg of tert-butyl (1R,5S)-3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1-a), with a yield of 40%. ESI [M+H] ⁺ = 595.3

Step 2: Synthesis of tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-b)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1-a, 10 mg, 0.017 mmol), ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (5 mg, 0.034 mmol), palladium acetate (4 mg, 0.018 mmol), cesium carbonate (27 mg, 0.083 mmol) and 1,1′-diamino-2,2′-bis(diphenylphosphine) (10 mg, 0.016 mmol) were dissolved in toluene (0.5 ml). The reaction system was heated to 110° C. under nitrogen atmosphere and reacted for 0.5 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=10/1) and preparative HPLC to give 10 mg of tert-butyl (1R,5S)-3-(7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-b) in a yield of 82%. ESI [M+H] ⁺ = 717.3

Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol hydrochloride (1)

Tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-b, 10 mg, 0.017 mmol) was dissolved in hydrochloric acid/ethyl acetate (1 ml, 4 M). The reaction mixture was reacted at 20°C for 1 hour. The reaction system was filtered, and the filter cake was washed with ethyl acetate and dried to obtain the target product 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-fluorothen-2-ol hydrochloride (1) 6 mg, yield 77%. ESI [M+H] ⁺ = 560.3. 1H NMR (600 MHz, CD ₃ OD) δ9.01-8.94 (m, 1H), 7.66 (d, J=8.3Hz, 1H), 7.50-7.44 (m, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.03 (dd, J=13.0, 7.7Hz, 1H), 5.61 (d, J=51.5Hz, 1H), 5.46 -5.32(m,1H),5.00-4 .89(m,2H),4.37(s,2H),4.15-3.93(m,3H),3.93-3.71(m,3H),3.52-3.44(m,1H),2.79-2.62(m,2H),2.55-2.48(m,1H),2.42-2.32(m,2H),2.30 -2.25(m,1H),2.15(s,4H).

Example 2: Synthesis of 4-(4-((1R,5S))-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol hydrochloride (2)

Step 1: Synthesis of tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy)naphthalen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-a)

Tert-butyl (1R, 5S)-3-(2,7-dichloropterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2, 89 mg, 0.22 mmol), (3-(ethoxymethoxy)then-1-yl)boric acid (64 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (51 mg, 0.044 mmol) and cesium carbonate (143 mg, 0.44 mmol) were dissolved in toluene (3.0 ml), the reaction system was replaced with nitrogen and heated to 60° C. under nitrogen atmosphere for 4 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column (petroleum ether/ethyl acetate = 2/1) gave 80 mg of tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy)then-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-a) in a yield of 63%. ESI[M+H] ⁺ =576-3, ¹ HNMR (600 MHz, CDCl ₃ )δ8.94 (s, 1H), 8.21 (d, J = 8.5Hz, 1H), 7.84 (d, J = 8.2Hz, 1H), 7.59 (s, 2H), 7.51 (t, J = 7.5Hz, 1H), 7.41 (t, J = 8.1, 7.2Hz, 1H), 6.02 (s, 1H), 5.39 (s, 2H), 4.99 (s, 1H), 4.41 (s, 2H), 3.84-3.76 (m, 2H), 3.71 (s, 1H), 3.32 (s, 1H), 2.02 (s, 2H), 1.84 (d, J=6.2Hz, 2H), 1.51 (s, 9H), 1.25 (t, J=7.0, 1.1Hz, 3H).

Step 2: Synthesis of tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)naphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-b)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy) thea-1-yl) pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-a, 17 mg, 0.03 mmol), ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (7 mg, 0.044 mmol), palladium acetate (1.3 mg, 0.006 mmol), cesium carbonate (19 mg, 0.06 mmol) and 1,1′-diamino-2,2′-bis(diphenylphosphine) (5 mg, 0.006 mmol) were dissolved in toluene (3.0 ml). The reaction system was heated to 110° C. under nitrogen atmosphere and reacted for 0.5 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column (dichloromethane/methanol=14/1) to obtain 20 mg of tert-butyl (1R,5S)-3-(7-(3-(ethoxymethoxy)then-1-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-b) in a yield of 95%. ESI [M+H] ⁺ 700.3

Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol hydrochloride (2)

Tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)then-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2-b, 20 mg, 0.029 mmol) was dissolved in hydrochloric acid/ethyl acetate (1 ml, 4 M). The reaction mixture was stirred for 20 min. ℃ for 1 hour. The reaction system was filtered, and the filter cake was washed with ethyl acetate and dried to obtain 15 mg of the target product 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pterin-7-yl)-5-fluorothen-2-ol hydrochloride (2), with a yield of 95%, ESI[M+H] ⁺ =542.3. ¹ HNMR (600 MHz, CD ₃ OD) δ9.14 (s, 1H), 8.21 (d, J = 7.7Hz, 1H), 7.80 (d, J = 8.1Hz, 1H), 7.547.46 (m, 2H), 7.41-7.31 (m, 2H), 5.63 (d, J = 51.5Hz, 1H), 5.51-5.34 (m, 1H), 5.07-4 .97(m, 1H), 4.39(s, 2H), 4.26-3.71(m, 6H), 3.53-3.44(m, 1H), 2.85-2.72(m, 1H), 2.72-2.63(m, 1H), 2.54(s, 1H), 2.45-2.33(m, 2H), 2.28(s, 1H), 2.26 -2.08(m,4H).

Example 3: Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)pteridine trifluoroacetate (3)

Step 1: Synthesis of tert-butyl (1R, 5S)-3-(2-chloro-7-(naphthalen-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-a)

Tert-butyl (1R, 5S)-3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-2, 100 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.048 mmol), potassium carbonate (66 mg, 0.48 mmol) and 1-boronic acid (62 mg, 0.36 mmol) were dissolved in toluene (15 ml) and reacted at 60° C. under nitrogen protection for 4 hours. The solvent was distilled off under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain 90 mg of the product tert-butyl (1R,5S)-3-(2-chloro-7-(thea-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-a) in a yield of 74.38%, ESI[M+H] ⁺ =503.3.

Step 2: Synthesis of tert-butyl (1R, 5S)-3-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (3-b)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(thea-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2-a, 90 mg, 0.18 mmol), palladium acetate (8 mg, 0.036 mmol), 1,1′-diaminothea-2,2′-bis(diphenylphosphine) (22 mg, 0.036 mmol), cesium carbonate (117 mg, 0.36 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (41 mg, 0.36 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=10/1) to give 41 mg of the product tert-butyl (1R,5S)-3-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thea-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (3-b), with a yield of 39.05%, ESI [M+H] ⁺ =582.4

Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)pteridine trifluoroacetate (3)

Tert-butyl (1R, 5S)-3-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thea-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (3-b, 41 mg, 0.07 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain 32 mg of the target product, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thea-1-yl)pteridine trifluoroacetate (3), in a yield of 76.19%. ESI[M+H] ⁺ =482.4, ¹ H NMR (600 MHz, CD ₃ OD-d ₄ )δ8.99 (d, J=15.7Hz, 1H), 8.29 (t, J=7.8Hz, 1H), 8.12 (t, J=7.6Hz, 1H), 8.04 (t, J=7.9Hz, 1H), 7.87 (d, J=7.0Hz, 1H), 7.70 (t, J=7.6Hz, 1H), 7.64-7.56 (m ,2H),4.93-4.88(m,2H),4. 72 (dd, J=12.7, 6.9Hz, 1H), 4.32 (s, 2H), 3.97-3.89 (m, 1H), 3.83-3.62 (m, 3H), 3.27 (d, J=17.0Hz, 1H), 3.12 (s, 3H), 2.44 (dt, J=13.1, 7.2Hz, 1H), 2.3 1-2.06(m,8H),2.051.89(m,1H)

Example 4: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol trifluoroacetate (4)

Step 1: Synthesis of tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (4-a)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1-a, 6 mg, 0.01 mmol), N-methyl-L-prolinol (2 mg, 0.016 mmol), palladium acetate (1 mg, 0.004 mmol), cesium carbonate (7 mg, 0.02 mmol) and 1,1′-diamino-2,2′-bis(diphenylphosphine) (3 mg, 0.005 mmol) were dissolved in toluene (1 ml). The reaction system was heated to 110° C. under nitrogen atmosphere and reacted for 0.5 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The product was purified by thin layer preparation on silica gel plate (dichloromethane/methanol=10/1) to obtain 6 mg of the product tert-butyl (1R,5S)-3-(7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (4-a), with a yield of 89%. ESI[M+H] ⁺ =674.3

Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-7-yl)-5-fluoronaphthalen-2-ol trifluoroacetate (4)

Tert-butyl (1R, 5S)-3-(7-(3-(ethoxymethoxy)-8-fluorothen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (4-a, 6 mg, 0.009 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml) was added. The reaction solution was reacted at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product which was purified by HPLC to obtain 3 mg of the target product, 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pterin-7-yl)-5-fluorothen-2-ol trifluoroacetate (4), with a yield of 32%. ESI[M+H] ⁺ =516.3, ¹ HNMR (400 MHz, CD ₃ OD) δ8.80 (d, J=3.0Hz, 1H), 7.64 (d, J=8.3Hz, 1H), 7.47-7.41 (m, 1H), 7.41-7.34 (m, 1H), 7.26 (d, J=2.2Hz, 1H), 6.99 (dd, J=13.1, 7.6Hz, 1H), 4.87-4.82 (m,2H),4.67 (dd, J=12.8, 6.9Hz, 1H), 4.28 (s, 2H), 3.97-3.87 (m, 1H), 3.82-3.54 (m, 4H), 3.27-3.21 (m, 1H), 3.09 (s, 3H), 2.45-2.37 (m, 1H), 2.27-2.14 (m, 5H), 2 .11-2.01(m,2H).

Example 5: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (5)

Step 1: Synthesis of 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a)

2,4,7-Trichloropteridine (I-1, 100 mg, 0.42 mmol) was dissolved in anhydrous dichloromethane (5 ml), N,N-diisopropylethylamine (54 mg, 0.42 mmol) was slowly added at -40°C, and then 4,4-difluoropyridine (61 mg, 0.54 mmol) was added dropwise (4,4-difluoropyridine was dissolved in 5 ml dichloromethane, and the addition was completed within 10 min). The mixture was reacted at -40°C for 1 hour. The organic solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparation silica gel plate (dichloromethane/methanol=50/1) to obtain 131 mg of the product 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a), with a yield of 97.76%, and ESI [M+H] ⁺ = 320.1, 322.0.

Step 2: Synthesis of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)pteridine (5-b)

2,7-Dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 60 mg, 0.19 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II)methanesulfonate (29 mg, 0.04 mmol), potassium phosphate (81 mg, 0.38 mmol) and (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane) were added. Cyclopentaborane (68 mg, 0.19 mmol) was dissolved in tetrahydrofuran (6 ml) and water (0.6 ml), and reacted at 60°C for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparation silica gel plate (dichloromethane/methanol=50/1) to obtain 7.1 mg of the product 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)pteridine (5-b), with a yield of 13.22%, and ESI [M+H] ⁺ =518.3.

Step 3: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pteridine (5-c)

2-Chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)pteridine (5-b, 42 mg, 0.08 mmol), palladium acetate (4 mg, 0.02 mmol), 1,1′-dichlorothen-2,2′-bisdiphenylphosphine (12 mg, 0.02 mmol), cesium carbonate (52 mg, 0.16 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (25 mg, 0.16 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=10/1) to obtain 11.5 mg of the product 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)tetramethyleneimine-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pteridine (5-c) with a yield of 22.42%, ESI[M+H] ⁺ =641.4.

Step 4: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (5)

4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pteridine (5-c, 11.5 mg, 0.018 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluorothen-2-ol (5) 7.45 mg, yield 67.73%. ESI[M+H] ⁺ =597.3, ¹ H NMR (600MHz, CD ₃ OD-d ₄ ) δ8.82 (s, 1H), 7.70 (dd, J=9.0, 5.7Hz, 1H), 7.34-7.27 (m, 2H), 7.12 (d, J=2.6Hz, 1H), 5.63-5.52 (m, 1H), 4.69 (d, J=12.2Hz, 2H), 4.63 (d, J=12.3Hz, 2H), 3.95-3.82 (m, 3H), 3.46 (td, J= 11.0, 6.0Hz, 1H), 2.73-2.56 (m, 2H), 2.43 (q, J=8.5, 7.2Hz, 2H), 2.34 (dq, J=11.8, 5.8, 4.8Hz, 3H), 2.24 (dq, J=12.7, 6.5, 5.6Hz, 5H), 2.17 (dd, J=9.6, 5.8Hz, 2H), 0.82 (t, J=7.4Hz, 3H).

Example 6: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol trifluoroacetate (6)

Step 1: Synthesis of tert-butyl (1R, 5S)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-a)

Tert-butyl (1R, 5S)-3-(2,7-dichloropterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2, 20 mg, 0.05 mmol), (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (20 mg, 0.055 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (7 mg, 0.01 mmol) and potassium phosphate (32 mg, 0.05 mmol) were added. 0.15mmol) was dissolved in tetrahydrofuran (1.0ml) and water (0.1ml), the reaction system was replaced with nitrogen and heated to 60°C for 4 hours under nitrogen atmosphere. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer preparation silica gel plate (petroleum ether/ethyl acetate=3/1) to obtain tert-butyl (1R,5S)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-a) 19mg, yield 62%, ESI[M+H] ⁺ =609.3.

Step 2: Synthesis of tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-b)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy) thea-1-yl) pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-a, 19 mg, 0.03 mmol), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (10 mg, 0.06 mmol), palladium acetate (2 mg, 0.009 mmol), cesium carbonate (29 mg, 0.09 mmol) and 1,1′-diamino-2,2′-bis(diphenylphosphine) (9 mg, 0.015 mmol) were dissolved in toluene (3 ml). The reaction system was heated to 110° C. under nitrogen atmosphere and reacted for 0.5 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. After purification by thin layer Prep-HPLC, 10 mg of tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-b) was obtained in a yield of 45%, ESI [M+H] ⁺ = 732.3.

Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol trifluoroacetate (6)

Tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (6-b, 10 mg, 0.014 mmol) was dissolved in dichloromethane (0.5 ml), and trifluoroacetic acid (0.5 ml) was added dropwise. The reaction solution was reacted at 20° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain 3 mg of the target product, 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluorothen-2-ol trifluoroacetate (6), in a yield of 31%. ESI[M+H] ⁺ =588.3. ¹ HNMR (400 MHz, CD ₃ OD) δ8.83 (s, 1H), 7.71 (dd, J=9.0, 5.8Hz, 1H), 7.37-7.23 (m, 2H), 7.12 (d, J=2.4Hz, 1H), 5.58 (d, J=51.9Hz, 1H), 4.67 (q, J=12.2Hz, 2H), 4.29 (s, 2H), 4.0 3-3.85 (m, 3H), 3.82-3.57 (m, 3H), 3.51-3.43 (m, 1H), 2.78-2.68 (m, 1H), 2.68-2.52 (m, 2H), 2.50-2.29 (m, 4H), 2.28-2.01 (m, 6H), 0.82 (t, J=7.3 Hz, 3H).

Example 7: Synthesis of 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridin-7-yl)naphthalen-2-ol (7)

Step 1: Synthesis of 2,7-dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a)

2,4,7-Trichloropterin (I-1, 140 mg, 0.59 mmol), 4-(trifluoromethyl)piperidine (91.1 mg, 1 eq.), N,N-diisopropylethylamine (103.6 uL, 1 eq.) were dissolved in dichloromethane (2 ml) and reacted at -40°C for 30 minutes. The organic solvent was removed by distillation under reduced pressure, and the residue was diluted with dichloromethane and purified by Flash column (petroleum ether/ethyl acetate = 3/1) to obtain 140 mg of the product 2,7-dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a), with a yield of 66.83%, ESI [M+H] ⁺ = 353.14.

Step 2: Synthesis of 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-b)

2,7-Dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a, 100 mg, 0.39 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (38.6 mg, 0.08 mmol), potassium phosphate (81 mg, 0.78 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (135 mg, 0.39 mmol) were dissolved in tetrahydrofuran (1 ml) and water (0.1 ml), and the reaction was carried out at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain 160 mg of the product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-b) in a yield of 57.24%.

Step 3: Synthesis of 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-c)

2-Chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-b, 160 mg, 0.23 mmol), palladium acetate (10 mg, 0.046 mmol), 1,1′-dichlorothen-2,2′-bis(diphenylphosphine) (28.4 mg, 0.046 mmol), cesium carbonate (111.4 mg, 0.345 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (25 mg, 0.16 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=10/1) to obtain 25.6 mg of the product 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)tetramethylene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-c), with a yield of 13.6%, ESI[M+H] ⁺ =825.01.

Step 4: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-d)

7-(7-Fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-c, 25 mg, 0.048 mmol) and cesium fluoride (44.5 mg, 0.288 mmol) were dissolved in N,N-dimethylformamide (2 ml) and reacted at room temperature for 3 hours. The crude product was added with 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)tetramethylene-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-d, 20 mg, crude product). ESI[M+H] ⁺ =669.67

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphthalen-2-ol trifluoroacetate (7)

7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-d, 15 mg, 0.022 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain 3.21 mg of the target product 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)then-2-ol (7), with a yield of 22.94%. ESI[M+H] ⁺ 625.62. ¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ8.68 (s, 1H), 8.46 (s, 1H), 7.86 (td, J=8.7, 8.2, 4.8Hz, 1H), 7.46-7.38 (m, 1H), 7.37-7.31 (m, 2H), 7.2 7(d, J=2.5Hz, 1H), 5.58-5.35(m, 2H), 3.82-3.54(m, 6H), 2.76-2.53 (m, 3H), 2.46 (dd, J=13.6, 8.9Hz, 2H), 2.32 (t, J=8.9Hz, 1H), 2.27-2.15 (m, 3H), 2.14-1.99 (m, 5H), 1.76 (q, J=13.7Hz, 3H), 1.33-1.21 (m,1H).

Example 8: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8)

Step 1: Synthesis of 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (8-a)

2,4,7-Trichloropteridin (I-1, 50 mg, 0.212 mmol) was dissolved in dichloromethane (0.5 ml), and the reaction system was stirred at -40°C for 3 minutes, and then N,N-diisopropylethylamine (27.4 mg, 0.212 mmol, dissolved in dichloromethane (0.25 ml)) was slowly added dropwise while stirring. After continuing to stir for 3 minutes, 4-methylpiperidin-4-ol (24.5 mg, 0.212 mmol) was dissolved in dichloromethane (0.25 ml) and slowly added dropwise to the reaction system. The reaction was carried out at -40°C for 1 hour. The solvent was removed as much as possible by vacuum distillation, and the residue was diluted with dichloromethane and purified by TLC plate (ethyl acetate/petroleum ether = 1/1) to obtain the target product 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (8-a, 56 mg, yield 84.24%). ESI [M+H] ⁺ = 314.09.

Step 2: Synthesis of 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (8-b)

1-(2,7-Dichloropteridin-4-yl)-4-methylpiperidin-4-ol (8-a, 30 mg, 0.0958 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (14.0 mg, 0.019 mmol), potassium phosphate (40.7 mg, 0.192 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.5 mg, 0.0958 mmol) were dissolved in tetrahydrofuran:water=10:1 (3.3 ml) and reacted at 60°C under nitrogen protection for 6 hours. The solvent was removed by distillation under reduced pressure, and water (5 ml) and ethyl acetate (5 ml * 3) were added for extraction. The organic phase was back-extracted with brine again, and finally the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude product was purified by TLC plate (dichloromethane/methanol = 20/1) to obtain the target product 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (8-b, 47 mg, yield 95.92%). ESI [M+H] ⁺ = 512.2.

Step 3: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8-c)

1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (8-b, 47 mg, 0.092 mmol), palladium acetate (4 mg, 0.018 mmol), 1,1′-dichlorothen-2,2′-bisdiphenylphosphine (11.5 mg, 0.018 mmol), cesium carbonate (45 mg, 0.138 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (22 mg, 0.138 mmol) were dissolved in toluene (3 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column (dichloromethane/methanol=10/1) to obtain the target product 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8-c, 22 mg, yield 37.74%). ESI[M+H] ⁺ =634.2

Step 4: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8)

1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8-c, 22 mg, 0.035 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (0.4 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (NH ₄ HCO ₃ :ACN) to give 1-(7-(8-ethyl-7-fluoro-3-hydroxythen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8, 5.01 mg, yield 24.39%). ESI[M+H] ⁺ ＝591.3. ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.70 (s, 1H), 7.70 (dd, J=9.0, 5.8Hz, 1H), 7.33-7.25 (m, 2H), 7.12 (d, J=2.6Hz, 1H), 5.33 (d, J=53.9Hz, 2H), 4.31-4.21 (m, 2H), 3.87 (d, J=25.2Hz, 2H) ,3.25(d,J=20.3Hz,3 H), 3.04 (tt, J=9.5, 4.3Hz, 1H), 2.38 (dd, J=15.0, 4.7Hz, 2H), 2.32-2.12 (m, 5H), 2.01 (dq, J=12.4, 6.1Hz, 3H), 1.82 (q, J=4.6, 4.2Hz, 4H), 1.33 (s, 5H), 0.85(t, J=7.4Hz, 4H).

Example 9: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (9)

Step 1: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pteridine (9-a)

2,7-Dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 150 mg, 0.47 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (68 mg, 0.094 mmol), potassium phosphate (200 mg, 0.94 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (241 mg, 0.47 mmol) were dissolved in 1,4-dioxane (7.5 ml) and water (0.75 ml), and the mixture was reacted at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pteridine (9-a, 230 mg, yield 74.92%).

Step 2: 4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (9-b)

2-Chloro-4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pteridine (9-a, 230 mg, 0.35 mmol), palladium acetate (16 mg, 0.07 mmol), 1,1′-dichlorothen-2,2′-bisdiphenylphosphine (44 mg, 0.07 mmol), cesium carbonate (228 mg, 0.7 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (167 mg, 1.05 mmol) were dissolved in toluene (10 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate preparation (dichloromethane/methanol=10/1) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (9-b, 136 mg, yield 48.92%). ESI[M+H] ⁺ =793.4

Step 3: 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (9-c)

4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (9-b, 136 mg, 0.17 mmol) and cesium fluoride (155 mg, 1.02 mmol) were dissolved in N,N-dimethylformamide (5 ml) and reacted at room temperature for 1 hour. The crude product was added with 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)tetramethylene-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (9-c, 143 mg, crude product). ESI[M+H] ⁺ =637.3

Step 4: 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (9)

4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (9-c, 143 mg, 0.22 mmol) was dissolved in dichloromethane (8 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative liquid chromatography (alkaline) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluorothen-2-ol (9, 2.15 mg, yield 1.6%). ESI[M+H] ⁺ =593.3. ¹ H NMR (600MHz, CD ₃ OD-d ₄ ) δ8.62 (d, J=6.7Hz, 1H), 7.88 (dd, J=9.2, 5.6Hz, 1H), 7.387.33 (m, 2H), 7.29 (d, J=2.5Hz, 1H), 5.36 (d, J=4. 5Hz, 1H), 5.27 (t, J=3.9Hz, 1H), 4.29 (d, J=10.9Hz, 1H), 4.254.21 (m, 1H), 3. 68 (s, 2H), 3.28-3.20 (m, 4H), 3.02 (p, J=5.9Hz, 1H), 2.372.32 (m, 1H), 2.30-2.24 (m, 1H), 2.21 (d, J=10.7Hz, 1H), 2.13 (d, J=9.6Hz, 1H), 2.01 (dq, J= 11.4, 5.3Hz, 3H), 1.93-1.84(m, 6H).

Example 10: Synthesis of 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (10)

Step 1: tert-butyl (1R, 5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a)

Tert-butyl (1R, 5S)-3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-2, 150 mg, 0.36 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (51 mg, 0.07 mmol), potassium phosphate (153 mg, 0.72 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (184 mg, 0.36 mmol) were dissolved in 1,4-dioxane (7.5 ml) and water (0.75 ml), and the reaction was carried out at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product, tert-butyl (1R, 5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a, 215 mg, yield 78.47%).

Step 2: tert-butyl (1R, 5S))-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-b)

Tert-butyl (1R, 5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a, 215 mg, 0.28 mmol), palladium acetate (13 mg, 0.056 mmol), 1,1′-diaminothen-2,2′-bis(diphenylphosphine) (35 mg, 0.056 mmol), cesium carbonate (182 mg, 0.56 mmol) and ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (134 mg, 0.84 mmol) were dissolved in toluene (10 ml) and reacted at 110° C. for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate preparation (dichloromethane/methanol=10/1) to obtain the target product tert-butyl (1R, 5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-b, 100 mg, yield 40.32%). ESI [M+H] ⁺ = 884.5

Step 3: tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-c)

Tert-butyl (1R, 5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-b, 100 mg, 0.11 mmol) and cesium fluoride (100 mg, 0.66 mmol) were dissolved in N,N-dimethylformamide (5 ml) and reacted at room temperature for 1 hour. The crude product was added with 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)tetra-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-c, 112 mg, crude product). ESI [M+H] ⁺ = 728.4

Step 4: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (10)

Tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-c, 112 mg, 0.15 mmol) was dissolved in dichloromethane (8 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (alkaline) to obtain the target product 4-(4-(1R, 5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluorothen-2-ol (10, 3.27 mg, yield 3.74%). ESI[M+H] ⁺ =584.4. ¹ H NMR (600 MHz, CD ₃ OD-d ₄ )δ8.62 (d, J=6.6Hz, 1H), 7.88 (dd, J=9.2, 5.6Hz, 1H), 7.387.33 (m, 2H), 7.29 (d, J=2.5Hz, 1H), 5.36 (d, J=4.3Hz, 1H), 5.27 (t, J=3.8Hz, 1H), 4.31-4.28 (m , 1H), 4.23 (dd, J=10.6, 3.1Hz, 1H), 3.68 (s, 2H), 3 .28-3.19 (m, 4H), 3.02 (dd, J=9.6, 5.6Hz, 1H), 2.34 (dd, J=15.0, 4.9Hz, 1H), 2.28-2.23 (m, 1H), 2.22-2.19 (m, 1H), 2.13 (d, J=9.6Hz, 1H), 2.01 (ddt, J=1 8.2, 12.2, 6.2Hz, 4H), 1.88 (dd, J=28.8, 9.4Hz, 6H).

Example 11: Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxytrifluoroacetate (11)

Step 1: 4-(2,7-dichloropteridin-4-yl)thiomorpholine 1,1-dioxide (11-a)

2,4,7-Trichloropteridine (I-1, 400 mg, 1.70 mmol) was dissolved in anhydrous dichloromethane (5 ml), N,N-diisopropylethylamine (220 mg, 1.70 mmol) was slowly added at -40°C, and then thiomorpholine 1,1-dioxide (thiomorpholine 1,1-dioxide was dissolved in 5 ml dichloromethane and added dropwise over 10 min. 276 mg, 2.04 mmol) was added dropwise. The mixture was reacted at -40°C for 1 hour. During the reaction, the product precipitated and the target product 4-(2,7-dichloropteridine-4-yl)thiomorpholine 1,1-dioxide (11-a, 380 mg, yield 66.90%) was obtained by filtration. ESI [M+H] ⁺ = 334.0, 336.0

Step 2: 4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin-4-yl)thiomorpholine 1,1-dioxide (11-b)

4-(2,7-Dichloropteridin-4-yl)thiomorpholine 1,1-dioxide (11-a, 60 mg, 0.18 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (26 mg, 0.036 mmol), potassium phosphate (76 mg, 0.36 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (92 mg, 0.18 mmol) were dissolved in 1,4-dioxane (3 ml) and water (0.3 ml), and the mixture was reacted at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product 4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)thiomorpholine 1,1-dioxide (11-b, 90 mg, yield 73.17%).

Step 3: 4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxide (11-c)

4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)thiomorpholine 1,1-dioxide (11-b, 90 mg, 0.13 mmol), palladium acetate (6 mg, 0.026 mmol), 1,1′-dichlorothen-2,2′-bis(diphenylphosphine) (16 mg, 0.026 mmol), cesium carbonate (85 mg, 0.26 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (84 mg, 0.65 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate preparation (dichloromethane/methanol=10/1) to obtain the target product 4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxide (11-c, 36 mg, yield 34.29%). ESI[M+H] ⁺ =807.7

Step 4: 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxy (11-d)

4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxide (11-c, 36 mg, 0.045 mmol) and cesium fluoride (41 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (3 ml) and reacted at room temperature for 1 hour. The crude product was added with 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)tetra-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxy (11-d, 35 mg, yield 121%). ESI[M+H] ⁺ =651.7

Step 5: 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxytrifluoroacetate (11)

4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxyl (11-d, 35 mg, 0.05 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-(7-(8-ethynyl-7-fluoro-3-hydroxythen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxy trifluoroacetate (11, 8.78 mg, yield 24.39%). ESI[M+H] ⁺ ＝607.3. ¹ H NMR (600MHz, CD ₃ OD-d ₄ )δ8.80 (s, 1H), 7.92 (dd, J=9.1, 5.6Hz, 1H), 7.42-7.36 (m, 2H), 7.31 (d, J=2.5Hz, 1H), 5.59 (dt, J=51.6, 3.7Hz, 1H), 4.99 (s, 3H), 4.73 (dd, J=12.5, 2.2Hz ,1H), 4.69-4.65 (m, 1H), 3.98-3.89 (m, 3H), 3.51-3.39 (m, 7H), 2.72-2.59 (m, 2H), 2.46 (dq, J=10.6, 6.7, 5.0Hz, 1H), 2.40-2.33 (m, 2H), 2.18 (dt, J=13. 7, 7.2Hz, 1H).

Example 12: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethylnaphthalen-2-ol trifluoroacetate (12)

Step 1: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pteridine (12-a)

2,7-Dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 30 mg, 0.09 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (15 mg, 0.018 mmol), potassium phosphate (38 mg, 0.18 mmol) and triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)silane (45 mg, 0.09 mmol) were dissolved in tetrahydrofuran (3.6 ml) and water (0.36 ml), and the reaction was carried out at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pteridine (12-a, 10 mg, yield 16.95%).

Step 2: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R ,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin (12-b)

2-Chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pteridine (12-a, 47 mg, 0.07 mmol), palladium acetate (3 mg, 0.014 mmol), 1,1′-dichlorothen-2,2′-bisdiphenylphosphine (9 mg, 0.014 mmol), cesium carbonate (46 mg, 0.14 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (56 mg, 0.35 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate (dichloromethane/methanol=10/1) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin (12-b, 15.5 mg, yield 28.70%). ESI[M+H] ⁺ =775.4

Step 3: 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (12-c)

4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin (12-b, 15.5 mg, 0.02 mmol) and cesium fluoride (18 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (2 ml) and reacted at room temperature for 1 hour. The crude product was added with 50 ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)tetramethylene-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (12-c, 4 mg, yield 33.33%). ESI[M+H] ⁺ =619.3

Step 4: 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethylnaphthalen-2-ol trifluoroacetate (12)

4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pteridine (12-c, 4 mg, 0.007 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethylthen-2-ol trifluoroacetate (12, 1.72 mg, yield 35.83%). ESI[M+H] ⁺ 575.30. ¹ H NMR (600MHz, CD ₃ OD-d ₄ ) δ8.75 (s, 1H), 7.85 (d, J=8.1Hz, 1H), 7.54 (d, J=7.0Hz, 1H), 7.46-7.42 (m, 1H), 7.36 (d, J=2.6Hz, 1H), 7. 24 (d, J=2.5Hz, 1H), 5.60 (t, J=3.8Hz, 1H), 5.52 (t, J=3.8Hz, 1H), 4.45 (d, J=7.0Hz, 2H), 4.09-4.06 (m, 2H), 3.91 (d, J=13.5Hz, 2H), 3.42 (d, J=1.9Hz, 1H), 3.26 (d, J=5.1Hz, 1H), 2.37-2.31 (m, 4H), 2.28-2.22 (m, 6H), 2.04-2.0 0(m,1H),1.33-1.31(m,2H).

Example 13: Synthesis of 4-(4-(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (13)

Step 1: Synthesis of (1R, 5S)-3-(2,7-dichloropteridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-a)

2,4,7-Trichloropteridine (I-1, 150 mg, 0.64 mmol) was dissolved in dichloromethane (5 ml) and cooled to -40°C. N,N-diisopropylethylamine (83 mg, 0.64 mmol) was added, followed by dropwise addition of (1R, 5S)-8-oxo-3-azabicyclo[3.2.1]octane (72 mg, 0.64 mmol) and the mixture was reacted at -40°C for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (1R, 5S)-3-(2,7-dichloropteridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-a, 93 mg, yield 46.5%). ESI[M+H] ⁺ ＝312.1

Step 2: Synthesis of (1R,5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-b)

(1R,5S)-3-(2,7-dichloropteridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (90 mg, 0.3 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (153 mg, 0.3 mmol), potassium phosphate (190 mg, 0.9 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol) were dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60° C. for reaction for 6 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 2%) to give the target product (1R, 5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-b, 88 mg, yield 46.3%).

Step 3: Synthesis of (1R, 5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (13-c)

(1R, 5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (88 mg, 0.13 mmol), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (42 mg, 0.26 mmol), cesium carbonate (64 mg, 0.2 mmol), palladium acetate (7 mg, 0.03 mmol), 1,1′-diamino-2,2′-bis(diphenylphosphine) (18 mg, 0.03 mmol) were added to toluene. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 110° C. for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product (1R, 5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)tea-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (13-c, 24 mg, yield 23%). ESI [M+H] ⁺ = 785.4

Step 4: Synthesis of (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (13-d)

(1R, 5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxyl-3-azabicyclo[3.2.1]octane (24 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (46 mg, 0.3 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated and purified on a preparative plate to obtain the target product (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (13-d, 15 mg, yield 78.1%). ESI [M+H] ⁺ = 629.1

Step 5: Synthesis of 4-(4-(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (13)

Dissolve (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (15 mg, 0.02 mmol) in 1,4-dioxane (2 ml), add hydrochloric acid 1,4-dioxane solution (0.2 ml) in an ice bath, slowly return to room temperature, and react for 1 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluorotearin-2-ol (13.6 mg, yield 42.8%). ESI[M+H] ⁺ =585.3, ¹ H NMR (400MHz, DMSO-d6) δ10.78 (s, 1H), 10.32 (s, 1H), 8.73 (s, 1H), 8.05-7.99 (m, 1H), 7.55-7.41 (m, 2H), 7.25 (d, J = 2.4Hz, 1H), 5. 65 (s, 1H), 5.52 (s, 1H), 4.85-4.30 (m, 6H), 3.95-3.66 (m, 4H), 2.35-2.05 (m, 5H), 1.99-1.71 (m, 5H), 1.51 (d, J=7.0Hz, 2H).

Example 14: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14)

Step 1: Synthesis of 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (14-a)

2,4,7-Trichloropteridin (I-1, 200 mg, 0.849 mmol) was dissolved in dichloromethane (2 ml), and the reaction system was stirred at -40°C for 3 minutes, and then N,N-diisopropylethylamine (109.6 mg, 0.849 mmol, dissolved in dichloromethane (0.5 ml)) was slowly added dropwise while stirring. After continuing to stir for 3 minutes, 4-methylpiperidin-4-ol (98 mg, 0.849 mmol) was dissolved in dichloromethane (0.5 ml) and slowly added dropwise to the reaction system. The reaction was carried out at -40°C for 1 hour. The solvent was removed as much as possible by distillation under reduced pressure, and the residue was diluted with dichloromethane and purified by TLC plate (ethyl acetate/petroleum ether = 1/1) to obtain the target product 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (14-a, 203.6 mg, yield 76.54%). ESI[M+H] ⁺ ＝314.09

Step 2: Synthesis of 1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (14-b)

1-(2,7-Dichloropteridin-4-yl)-4-methylpiperidin-4-ol (14-a, 75 mg, 0.2396 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (35 mg, 0.0479 mmol), potassium phosphate (101.7 mg, 0.479 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (122.7 mg, 0.2396 mmol) were dissolved in tetrahydrofuran:water=10:1 (1.5 ml) and reacted at 60°C under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, water (5 ml) and ethyl acetate (5 ml * 3) were added for extraction, the organic phase was back-extracted with brine again, and finally the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by TLC plate (dichloromethane/methanol = 20/1) to obtain the target product 1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (14-b, 125 mg, yield 78.62%). ESI [M+H] ⁺ = 664.2

Step 3: Synthesis of 1-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-c)

1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (14-b, 125 mg, 0.188 mmol), palladium acetate (8.4 mg, 0.0377 mmol), 1,1′-diaminothen-2,2′-bis(diphenylphosphine) (23 mg, 0.0377 mmol), cesium carbonate (92 mg, 0.283 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (45 mg, 0.283 mmol) were dissolved in toluene (2 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, water (5 ml) and ethyl acetate (5 ml * 3) were added for extraction, the organic phase was back-extracted with brine again, and finally the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was purified by Prep-HPLC (formic acid/acetonitrile) to obtain the target product 1-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)tetra-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-c, 30 mg, yield 20.27%). ESI [M+H] ⁺ = 787.2

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-d)

1-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-c, 30 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (2.5 ml) and cesium fluoride (35 mg, 0.229 mmol) and reacted at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-d, 45 mg). ESI) [M+H] = 631.2

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14)

1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-d, 43 mg, 0.052 mmol) was dissolved in dioxane (1.9 ml) and hydrochloric acid-dioxane (0.38 ml) and reacted at room temperature for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (NH ₄ HCO ₃ :ACN) to give 1-(7-(8-ethynyl-7-fluoro-3-hydroxythen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14, 7.89 mg, yield 19.73%). ESI[M+H] ⁺ =587.3. ¹ H NMR (400MHz, DMSO-d6) δ10.24 (s, 1H), 8.60 (s, 1H), 7.99 (dd, J=9.2, 6.0Hz, 1H), 7.50-7.44 (m, 1H), 7.40 (d, J=2.6Hz, 1H), 7.22 (d, J=2.5Hz, 1H), 5.27 (d, J=5 4.5Hz, 2H), 4.53(d . 69-1.60 (m, 5H), 1.17 (s, 3H).

Example 15: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol trifluoroacetate (15)

Step 1: 2,7-dichloro-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-a)

2,4,7-Trichloropteridine (I-1, 100 mg, 0.425 mmol) was dissolved in dichloromethane (1 ml), and the reaction system was stirred at -40°C for 3 minutes, and then N,N-diisopropylethylamine (54.8 mg, 0.425 mmol, dissolved in dichloromethane (0.5 ml)) was slowly added dropwise while stirring. After continuing to stir for 3 minutes, 4-methylpiperidin-4-ol (43 mg, 0.425 mmol) was dissolved in dichloromethane (0.5 ml) and slowly added dropwise to the reaction system. The reaction was carried out at -40°C for 1 hour. The solvent was removed as much as possible by distillation under reduced pressure, and the residue was diluted with dichloromethane and purified by TLC plate (ethyl acetate/petroleum ether = 1/1) to obtain the target product 2,7-dichloro-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-a, 118 mg, yield 92.91%). ESI[M+H] ⁺ ＝300.3

Step 2: 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-b)

2,7-Dichloro-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-a, 65 mg, 0.217 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (31.6 mg, 0.0435 mmol), potassium phosphate (92.3 mg, 0.435 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (111.4 mg, 0.217 mmol) were dissolved in tetrahydrofuran:water=10:1 (2 ml), and the mixture was reacted at 60°C under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, water (5 ml) and ethyl acetate (5 ml * 3) were added for extraction, the organic phase was back-extracted with brine again, and finally the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by TLC plate (dichloromethane/methanol = 20/1) to obtain the target product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-b, 90 mg, yield 63.83%). ESI [M+H] ⁺ = 649.4

Step 3: 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (15-c)

2-Chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-b, 90 mg, 0.1386 mmol), palladium acetate (6 mg, 0.0277 mmol), 1,1′-diaminothen-2,2′-bis(diphenylphosphine) (17 mg, 0.0277 mmol), cesium carbonate (68 mg, 0.208 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (33 mg, 0.208 mmol) were dissolved in toluene (2 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, water (5 ml) and ethyl acetate (5 ml * 3) were added for extraction, the organic phase was back-extracted with brine again, and finally the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (formic acid/acetonitrile) to obtain the target product 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)tetra-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (15-c, 15 mg, yield 14.02%). ESI[M+H] ⁺ =773.5

Step 4: 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-d)

7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin (15-c, 15 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (2.5 ml) and cesium fluoride (17.7 mg, 0.1165 mmol) and reacted at room temperature for 4 hours. The solvent was distilled off under reduced pressure to obtain the product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-d, 30 mg). ESI[M+H] ⁺ ＝617.3

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-((tetrahydrofuran-2-yl)methyl)amino)pterin-7-yl)naphthalen-2-ol trifluoroacetate (15)

7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-d, 30 mg, 0.0487 mmol) was dissolved in dioxane (2 ml) and hydrochloric acid-dioxane (0.4 ml), and reacted at room temperature for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (TFA:ACN) to give 5-ethynyl-6-fluoro-4-(2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-((tetrahydrofuran-2-yl)methyl)amino)pterin-7-yl)then-2-ol trifluoroacetate (15, 8.29 mg, yield 29.76%). ESI[M+H] ⁺ =573.4. ¹ H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 10.30 (s, 1H), 8.94 (q, J=6.4Hz, 1H), 8.74 (d, J=7.7Hz, 1H), 8.01 (dd, J=9.2, 5.9Hz, 1H), 7.49 (t, J=9.0Hz, 1H), 7.42 (d, J=2.6Hz, 1H), 7.22 (d, J=2.5Hz, 1H), 5.765.40 (m, 1H), 4.59 (s, 2 H), 4.23-4.05 (m, 2H), 3.88-3.70 (m, 4H), 3.64 (q, J=7.3Hz, 2H), 3.34-3.24 (m, 2H), 2.60-2.52 (m, 1H), 2.41-2.24 (m, 2H), 2.16 (q, J=5.8Hz, 2H), 2.0 6(d, J=4.1Hz, 1H), 1.89 (ddt, J=33.8, 12.9, 6.6Hz, 3H), 1.74-1.62 (m, 1H).

Example 16: Synthesis of 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridin-7-yl)naphthalen-2-ol (16)

Step 1: 2,7-dichloro-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-a)

2,4,7-Trichloropterin (I-1, 200 mg, 0.85 mmol), 3-(trifluoromethyl)piperidine (130.2 mg, 1 eq.), N,N-diisopropylethylamine (148 uL, 1 eq.) were dissolved in dichloromethane (2 ml) and reacted at -40°C for 2 hours. The organic solvent was removed by distillation under reduced pressure, and the residue was diluted with dichloromethane and purified by Flash column (petroleum ether/ethyl acetate = 3/1) to obtain the target product 2,7-dichloro-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-a, 210 mg, yield 70.16%). ESI [M+H] ⁺ 353.14.

Step 2: 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-b)

2,7-Dichloro-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-a, 80 mg, 0.212 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (30.8 mg, 0.04 mmol), potassium phosphate (90 mg, 0.78 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (108.6 mg, 0.212 mmol) were dissolved in tetrahydrofuran (1 ml) and water (0.1 ml), and the mixture was reacted at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-b, 140 mg, yield 94.08%).

Step 3: 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-c)

2-Chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-b, 140 mg, 0.199 mmol), palladium acetate (8.9 mg, 0.04 mmol), 1,1′-dichlorothen-2,2′-bis(diphenylphosphine) (24.7 mg, 0.04 mmol), cesium carbonate (97.25 mg, 0.298 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (95 mg, 0.597 mmol) were dissolved in toluene (5 ml) and reacted at 110° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate preparation (dichloromethane/methanol=10/1) to obtain the target product 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)tetra-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-c, 47 mg, yield 28.67%). ESI[M+H] ⁺ =825.01

Step 4: 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-d)

7-(7-Fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-c, 47 mg, 0.057 mmol) and cesium fluoride (51.9 mg, 0.342 mmol) were dissolved in N,N-dimethylformamide (2 ml) and reacted at room temperature for 3 hours. The crude product was added with 50 ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)tetramethylene-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-d, 60 mg). ESI[M+H] ⁺ =669.67

Step 5: 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphthalen-2-ol (16)

7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-d, 50 mg, 0.075 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative liquid chromatography (FA) to obtain the target product 5-ethynyl-6-fluoro-4-(2-(2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)then-2-ol (16, 3 mg, yield 6.41%). ESI[M+H] ⁺ =625.62. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 8.56 (d, J = 25.7Hz, 1H), 8.05-7.96 (m, 1H), 7.51 (ddd, J = 26.6, 16.9, 8.5Hz, 2H), 7.31-7.22 (m, 1H), 7.09 (d, J = 51.0Hz, 1H), 5.60 (dd, J = 52.7, 12.2Hz , 2H), 4.68-4.31 (m, 4H), 4.11 (d, J=23.6Hz, 1H), 3.83 (ddd, J=33.4, 25.2, 11.2Hz, 3H), 2.37-1.87 (m, 8H), 1.74 (d, J=5.2Hz, 2H), 1.52 (d, J=7.0Hz, 2H) ,1.23(s,2H).

Example 17: Synthesis of 5-ethynyl-6-fluoro-4-(2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((R)-pyrrolidin-2-yl)methyl)amino)pterin-7-yl)naphthalen-2-ol trifluoroacetate (17)

Step 1: tert-Butyl (R)-2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-a)

2,4,7-Trichloropteridine (I-1, 150 mg, 0.64 mmol) was dissolved in anhydrous dichloromethane (5 ml), N,N-diisopropylethylamine (83 mg, 0.64 mmol) was slowly added at -40°C, and then (R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester ((R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (128 mg, 0.64 mmol) was dissolved in 5 ml dichloromethane, and the addition was completed in 10 minutes). The mixture was reacted at -40°C for 1 hour, and the organic solvent was removed by distillation under reduced pressure. The crude product was purified by thin layer preparation silica gel plate (dichloromethane/methanol=50/1) to obtain the target product tert-butyl (R)-2-((2,7-dichloropteridine-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-a, 197 mg, yield 76.95%).

Step 2: tert-butyl (R)-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-b)

Tert-butyl (R)-2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-a, 100 mg, 0.25 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (38 mg, 0.05 mmol), potassium phosphate (110 mg, 0.5 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)then-1-yl)ethynyl)triisopropylsilane (266 mg, 0.3 mmol) were dissolved in 1,4-dioxane (5 ml) and water (0.5 ml), and the mixture was reacted at 60° C. under nitrogen protection for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer preparative silica gel plate (dichloromethane/methanol=50/1) to obtain the target product, tert-butyl (R)-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-b, 135 mg, yield 69.23%).

Step 3: tert-butyl (R)-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-c)

Tert-butyl (R)-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-b, 130 mg, 0.17 mmol), palladium acetate (8 mg, 0.034 mmol), 1,1′-diaminothen-2,2′-bisdiphenylphosphine (21 mg, 0.034 mmol), cesium carbonate (111 mg, 0.34 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (135 mg, 0.85 mmol) were dissolved in toluene (10 ml) and reacted at 110° C. for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the crude product was purified by thin layer silica gel plate (dichloromethane/methanol=10/1) to obtain the target product tert-butyl (R)-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-c, 48 mg, yield 32.43%). ESI [M+H] ⁺ 872.8

Step 4: tert-Butyl (R)-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-d)

Tert-butyl (R)-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)then-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-c, 48 mg, 0.055 mmol) and cesium fluoride (50 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (3 ml) and reacted at room temperature for 1 hour. The crude product was added with 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, tert-butyl (R)-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-d, 46 mg, yield 120%). ESI) [M+H] ⁺ = 716.8

Step 5: 5-ethynyl-6-fluoro-4-(2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((R)-pyrrolidin-2-yl)methyl)amino)pterin-7-yl)naphthalen-2-ol trifluoroacetate (17)

Tert-butyl (R)-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)then-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-d, 46 mg, 0.06 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the target product, 5-ethynyl-6-fluoro-4-(2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((R)-pyrrolidin-2-yl)methyl)amino)pterin-7-yl)then-2-ol trifluoroacetate (17, 7.04 mg, yield 17.17%). ESI[M+H] ⁺ =572.3. ¹ H NMR (600 MHz, CD ₃ OD-d ₄ )δ8.76 (d, J=42.6Hz, 1H), 7.92 (dd, J=9.2, 5.6Hz, 1H), 7.42-7.35 (m, 2H), 7.28 (d, J=2.5Hz, 1H), 5.65-5.53 (m, 1H), 4.72 (d, J=3.9Hz, 2H), 4.11-4.06 (m, 1H), 4.01 (d, J=7.0Hz, 3H), 3.95 (dq, J=9.6, 5.2, 3.4Hz, 2H), 3. 92-3.86 (m, 1H), 3.52-3.45 (m, 3H), 3.38 (dt, J=9.6, 4.2Hz, 1H), 2.76-2.59 (m, 2H), 2.49-2.44 (m, 1H), 2.39-2.30 (m, 3H), 2.19 (dd, J=8.2, 4.5Hz, 3H) , 2.12 (dd, J=13.3, 8.0Hz, 1H), 1.95 (ddt, J=13.5, 8.7, 4.4Hz, 1H).

Test Example 1: Phosphorylation-ERK HTRF Test

A427 cells expressing KRAS G12D mutation were cultured in MEM medium (Gibco) containing 10% fetal bovine serum (Gibco). When the cells were in the logarithmic growth phase, A427 cells were resuspended in serum-free medium to a density of 3.125×10 ⁵ cells/ml, inoculated into 96-well cell culture plates (25,000 cells/well) at 80 μl/well, and placed in a cell culture incubator (37°C, 5% CO ₂ ) for overnight incubation. On the second day, 20 μl of compound diluted in serum-free medium was added to each well. After incubation in a cell culture incubator (37°C, 5% CO ₂ ) for 4 hours, the culture medium in the 96-well plate was removed, and then 50 μL of 1× cell lysis buffer (Cisbio) was added to each well, and the culture plate was incubated at room temperature for 30 minutes with shaking. 16 μL of cell lysate was transferred to a 384-well plate (Greiner), and then 4 μL/well of pre-mixed antibodies (Cisbio64AERPEH) were added, incubated overnight at room temperature, and then the HTRF signal was read in a Tecan Spark multi-mode microplate reader. The data were analyzed using a 4-parameter logistic model to calculate IC ₅₀ values.

The results of the phosphorylated-ERK HTRF test are shown in Table 1:

For IC ₅₀ values, "+++" indicates IC ₅₀ <10 μM; "++" indicates IC ₅₀ between 10 μM and 100 μM.

Table 1

Claims (12)

1. Compounds of formula (I), their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof: In formula (I), X and Y are selected from -CR ⁴ or N, and X and Y are not simultaneously -CR ⁴ or N, where R ⁴ is selected from -H, -D, halogen, -CF ₃ , -OH, -CN, -NR ^a R ^b , -C(O)OR ^a , C _1-6 alkoxy group, C _1-6 alkyl group, C _2-6 alkenyl group or C _2-6 alkynyl group; R ¹ is R ⁵ and R ⁶ are each independently -H, -D, halogen, -CF ₃ , -OH, =O, -CN, -NR ^a R ^b , -C(O)OR ^a or C _1-6 alkoxy group, R ⁷ in each substitution position is independently selected from -H, -D, halogen, -CF ₃ , -OH, -CN, -NR ^a R ^b , -C(O)OR ^a , C _1-6 Alkoxy, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, p is optionally 0, 1, 2, 3, 4, 5 or 6; Represents no chemical bond or single or double bond; W is selected from N, C, O or S atoms; n is optionally 0, 1 or 2; m and q are each independently chosen to be 0 or 1; R ² is selected from 5 to 6-membered monocyclic heteroaryl, C _6-10 aryl, 8 to 10-membered bicyclic heteroaryl; R ³ is selected from H, D, -C _1-3 alkoxy-C _3-9 cycloalkyl, -C _1-3 alkoxy-3 to 9-membered heterocycloalkyl, -C _1-3 alkoxy Base-5 to 6-membered monocyclic heteroaryl, -C _1-3 alkoxy-C _6-10 aryl or -C _1-3 alkoxy-8 to 10-membered bicyclic heteroaryl; And the C _1-6 alkoxy group, C _1-6 alkyl group, C 2-6 alkenyl group, C _2-6 alkynyl group, C _3-9 cycloalkyl group, 3 to ₉ membered heterocycloalkyl group, 5 to 6 membered monocyclic heteroaryl, C _6-10 aryl or 8 to 10 membered bicyclic heteroaryl is optionally selected from halogen, methyl, ethyl, propyl by 0, 1, 2 or 3 independently. Substitution of base, isopropyl, vinyl, 1-allyl, 2-allyl, ethynyl, propynyl, trifluoromethyl, amino, hydroxyl, carboxyl, -C(O)NR ^a R ^b base substitution; The R ^a and R ^b are each independently H, D, C _1-6 alkyl, -C _1-3 alkyl-C _3-9 cycloalkyl or -C _1-3 alkyl-3 to 9 yuan Heterocycloalkyl; The heterocycloalkyl group, monocyclic heteroaryl group, and bicyclic heteroaryl group have at least one heteroatom selected from N, O, and S as a ring atom; The halogen is selected from F, Cl, Br or I. 2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, R ¹ is Wherein R ⁵ , R ⁶ , R ⁷ , R ^a , n, p and W are as defined in claim 1; Preferably, R ² is Wherein, R ⁸ and R ⁹ in each substitution position are independently selected from halogen, methyl, ethyl, propyl, isopropyl, vinyl, 1-allyl, 2-allyl, ethynyl, Propargyl, trifluoromethyl, amino, hydroxyl, carboxyl, -C(O)NR ^a R ^b , the halogen is preferably fluorine, g and f are each independently optionally 0, 1, 2 or 3, g , f are each independently preferably 0, 1 or 2; Preferably, R ³ is wherein d is optionally 1, 2 or 3, and ring A is selected from C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 to 6 membered monocyclic heteroaryl, C _6-10 aryl or 8 to 10-membered bicyclic heteroaryl. 3. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ^R1 is selected from the following structure: Preferably, ^R2 is selected from the following structures: Preferably, ^R3 is selected from the following structures: 4. The compound of formula (I) according to any one of claims 1 to 3, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is such as formula (II- a), formula (Ⅱ-b), formula (Ⅱ-c) or formula (Ⅱ-d), Preferably, the compound is represented by formula (II-e), formula (II-f), formula (II-g), formula (II-h) or formula (II-i), The definitions of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ra , R ^b , ^m , n, q and p are as stated in claim 1 . 5. The compound of formula (I) according to any one of claims 1 to 3, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is such as formula (III- a) or formula (III-b), Preferably, the compound is such as formula (Ⅲ-c), formula (Ⅲ-d), formula (Ⅲ-e), formula (Ⅲ-f), formula (Ⅲ-g), formula (Ⅲ-h), formula (Ⅲ-i), formula (Ⅲ-j), formula (Ⅲ-k) or formula (Ⅲ-l), Preferably, the compound is represented by formula (Ⅲ-m), formula (Ⅲ-n), formula (Ⅲ-o) or formula (Ⅲ-p), R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, q, and p are as defined in claim 1 , and d and A ring are as defined in claim 2 . 6. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the pharmaceutically acceptable salts include hydrochlorides , hydrobromide, sulfate, phosphate, carbonate, acetate, trifluoroacetate, propionate, methanesulfonate, lactate, benzenesulfonate, p-toluenesulfonate, Any one or combination of succinate, maleate, fumarate, tartrate, citrate or malate. 7. The compound of any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the following group: 8. The preparation method of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, including the following steps, (1) Compound (I-1) and compound (R ¹ 'H) undergo a substitution reaction to generate compound (I-2), where the R ¹ ' group is selected from R ¹ or Boc-substituted R ¹ ; (2) The compound (I-2) and the compound After Suzuki coupling reaction, compound (Ma) is generated, and the R ² ' group is selected from R ² or R ² substituted by a protecting group; (3) The compound (Ma) and the compound (R ³ H) undergo a coupling reaction to generate the compound (Mb); (4) The compound (M-b) is deprotected under acidic conditions to generate the compound (M); The definitions of R ¹ , R ² and R ³ are as described in any one of claims 1 to 7. 9. Pharmaceutical composition, characterized in that the composition contains the compound according to any one of claims 1-7, its pharmaceutically acceptable salts, stereoisomers, solvates, its prodrugs and Pharmaceutically acceptable excipients. 10. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs thereof, and the pharmaceutical composition according to claim 9 for the treatment of cancer, Use in kits for prognostic assessment of patients with immune diseases or cancer; Preferably, the pharmaceutical composition also contains another drug for treating cancer or immune diseases; Preferably, use in the preparation of treatments for diseases associated with KRAS mutations; Preferably, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, etc.; More preferably, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, etc. 11. The compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the pharmaceutical composition of claim 9 in the preparation of KRAS inhibitory Use in agents; preferably, use in the preparation of KRASG12D and other KRAS mutation inhibitors. 12. A method for inhibiting mutated KRAS in a biological sample, comprising making the biological sample and a compound according to any one of claims 1-7, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvent The compound, its prodrug or the pharmaceutical composition according to claim 9.