Kras inhibitors, methods of making and using the same

Abstract

The present application provides a kind of compound with inhibitory effect on KRAS mutation, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, as shown in formula (I), wherein the definition of each group is detailed in the specification.In addition, the present application also discloses a pharmaceutical composition comprising the compound, and its use in the preparation of a kit for treating cancer, immune diseases or cancer patient prognosis evaluation.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, and in particular to a compound with KRAS inhibitory activity, a pharmaceutical composition, its use and preparation method. Background Technology

[0002] Kirsten rat sarcoma 2 virus 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, they enhance GTP binding and activate it, thereby activating KRas and downstream signaling pathways (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 persistently activate downstream cellular signaling, promoting cell proliferation, migration, and anti-apoptosis, and inducing tumorigenesis.

[0003] KRAS mutations are closely related to tumor formation and development. The role of KRAS in malignant tumors was observed more than 30 years ago (e.g., see Santos et al., (1984) Science 223:661-664). Approximately 20% of all human tumors exhibit aberrant KRAS expression, and KRAS mutations are detected in 25-30% of lung adenocarcinomas (e.g., see Samatarand Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). 80% of KRAS mutations occur at codon 12, causing a single amino acid substitution, the most prevalent being G12C and G12D. KRAS G12C mutation refers to the mutation of glycine at position 12 of the protein into cysteine. The frequency of tumor occurrence is as follows: pancreatic cancer (57%), colorectal cancer (35%), bile duct cancer (28%), small bowel cancer (17%), lung cancer (16%), endometrial cancer (15%) and ovarian cancer (14%), etc. (Seminars in Cancer Biology. 2019 Jun 27 .pii:S1044-579X(18)30060-9). KRAS G12D mutation refers to the mutation of glycine at position 12 of the protein into aspartic acid. The tumor incidence is as follows: 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%) (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831.Dataset Version 4). In addition to G12C and G12D, KRAS has several other mutations, such as G12V, G12A, G12R, G12S, G13D, and Y96D. The frequency of different KRAS mutations varies in different types of cancer cells.

[0004] KRAS has become a popular anticancer target in the pharmaceutical industry due to the frequent mutations found in various tumor types (see MeCormick (2015) Clin cancer Res. 21(8):1797-1801). The development of small molecule KRAS inhibitors generally falls into three categories: (i) competitive ligand blocking GTP binding; (ii) locking KRAS G12C in an inactive state through allosteric modulation; and (iii) disrupting KRAS with its effector proteins and guanine nucleotide exchange factors (GEFs) (such as son of sevenless (SOS), RAF, and PI3K) through protein-protein interaction inhibitors.

[0005] For decades, drug development targeting KRAS largely failed, leading to its initial perception as undruggable. However, recent breakthroughs in biology and protein structure, including comparative studies of mutant and wild-type KRAS proteins, have resulted in clinical success for small-molecule inhibitors targeting KRAS G12C. Amgen's first-in-class KRAS G12C inhibitor, AMG 510, was approved by the FDA on May 28, 2021, for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations. Mirati and several other biopharmaceutical companies both domestically and internationally are also developing drugs targeting KRAS, but the vast majority focus on KRAS G12C or KRAS G12D mutations. As mentioned above, besides KRAS G12C or KRAS G12D mutations, KRAS has several other mutations, such as G12V, G12A, G12R, G12S, G13D, and Y96D. These KRAS mutations play a crucial role in the formation and development of various types of cancer. Therefore, the development of drugs targeting these KRAS mutations is urgently needed. Furthermore, with the successful launch of drugs targeting KRAS G12C, we anticipate that cancer patients receiving these treatments will develop drug resistance. Therefore, developing innovative next-generation broad-spectrum KRAS inhibitors that target multiple KRAS mutations and combat drug resistance mechanisms is of great significance in addressing these unmet clinical needs. Summary of the Invention

[0006] In one aspect, the present invention provides a novel substituted fused-ring aromatic compound that exhibits high inhibitory activity as a selective and broad-spectrum inhibitor of KRAS mutations.

[0007] In one aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof:

[0008]

[0009] Formula (I)

[0010] In equation (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 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 group;

[0011] R 1 for or ;

[0012] R 5 R 6 Each can be independently -H, -D, halogen, -CF3, -OH, =O, -CN, -NR a R b -C(O)OR a Or C 1-6 alkoxy group, R at each substitution position 7 Each is independently 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 The alkynyl group, p is optionally 0, 1, 2, 3, 4, 5 or 6;

[0013] This indicates the absence of chemical bonds, either single or double bonds.

[0014] W is selected from N, C, O, or S atoms;

[0015] n can be any value of 0, 1, or 2;

[0016] m and q can each be independently chosen as 0 or 1;

[0017] R 2 Selected from 5- to 6-membered monocyclic heteroaryl groups, C6-10 Aryl, 8- to 10-membered bicyclic heteroaryl;

[0018] R 3 Selected from H, D, -C 1-3 Alkoxy-C 3-9 cycloalkyl, -C 1-3 Alkoxy-3 to 9-membered heterocyclic alkyl, -C 1-3 Alkoxy-5 to 6-membered monocyclic heteroaryl, -C 1-3 Alkoxy-C6- 10 Aryl or -C 1-3 Alkoxy-8 to 10-membered bicyclic heteroaryl groups;

[0019] And the C mentioned above 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl, C6- 10 The aryl or 8- to 10-membered bicyclic heteroaryl group is optionally surrounded by 0, 1, 2, or 3 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 Substituents of the substituents;

[0020] The R a R b Each is independently H, D, C 1-6 Alkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl or -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl groups;

[0021] The heterocyclic alkyl, monocyclic heteroaryl, and bicyclic heteroaryl groups have at least one heteroatom selected from N, O, and S as a ring atom;

[0022] The halogen is selected from F, Cl, Br or I.

[0023] In one implementation, in formula (I), R 1 Selected from or , where R 5 R 6 R 7 R a The definitions of n, p, and W are the same as those described above.

[0024] In one implementation, in formula (I), R 2 for , where R is the replacement position for each position 8 R 9 Each is 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, and g and f are each independently selected as 0, 1, 2 or 3, with g and f each preferably being 0, 1 or 2.

[0025] In one implementation, in formula (I), R 3 for Where d can be 1, 2 or 3 at will, 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 groups.

[0026] In a preferred embodiment, in formula (I), R 1 Selected from the following structures:

[0027] , , , , , , , , .

[0028] In a preferred embodiment, in formula (I), R 2 Selected from the following structures:

[0029] , , , , , .

[0030] In a preferred embodiment, in formula (I), R 3 Selected from the following structures:

[0031] , , , .

[0032] In one embodiment, the compound of formula (I) is shown as that of formula (II-a), (II-b), (II-c), or (II-d).

[0033]

[0034] Equation (II-a) Equation (II-b)

[0035]

[0036] Equation (II-c) Equation (II-d)

[0037] In the formula, R 2 R 3 R 4 R 5 R 6 R 7 R a R b The custom values ​​for m, n, q, and p are as described above.

[0038] In a preferred embodiment, the compound of formula (I) is as shown in formula (II-e), formula (II-f), formula (II-g), formula (II-h), or formula (II-i).

[0039]

[0040] Equation (II-e) Equation (II-f)

[0041]

[0042] Formula (Ⅱ-g) Formula (Ⅱ-h)

[0043]

[0044] Formula (II-i)

[0045] R 2 R 3 R 4 R 5 R 6 R 7 R a R b The definitions of m, n, q, and p are as described above.

[0046] In one embodiment, the compound of formula (I) is as shown in formula (III-a) or formula (III-b).

[0047]

[0048] Equation (Ⅲ-a) Equation (Ⅲ-b)

[0049] R 1 R 2 R4 R 5 R 6 R 7 The definitions of m, n, q, and p are as described above, as are the definitions of d and A-ring.

[0050] In a preferred embodiment, the compound of formula (I) is as shown in formula (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), (III-k), or (III-l).

[0051]

[0052] Equation (Ⅲ-c) Equation (Ⅲ-d)

[0053]

[0054] Equation (Ⅲ-e) Equation (Ⅲ-f)

[0055]

[0056] Formula (Ⅲ-g) Formula (Ⅲ-h)

[0057]

[0058] Equation (Ⅲ-i) Equation (Ⅲ-j)

[0059]

[0060] Equation (Ⅲ-k) Equation (Ⅲ-l)

[0061] R 1 R 2 R 4 R 5 R 6 R 7 The definitions of m, n, q, and p are as described above, as are the definitions of d and A-ring.

[0062] In a preferred embodiment, the compound is as shown in formula (Ⅲ-m), formula (Ⅲ-n), formula (Ⅲ-o), or formula (Ⅲ-p).

[0063]

[0064] Equation (Ⅲ-m) Equation (Ⅲ-n)

[0065]

[0066] Equation (Ⅲ-o) Equation (Ⅲ-p)

[0067] R 1 R 2 R 4 R 5 R 6 R 7 The definitions of m, n, q, and p are as described above, as are the definitions of d and A-ring.

[0068] 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.

[0069] In one embodiment, the compound of formula (I) includes, but is not limited to, the structures listed below, or their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] .

[0076] In another aspect, the present invention provides a method for preparing the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, comprising the following steps,

[0077]

[0078] (1) Compound (I-1) and compound (R) 1'H) undergoes a substitution reaction to generate compound (I-2), wherein R 1' H is selected from R 1 Or Boc replaces R 1 ;

[0079] (2) The compound (I-2) and compound or Following a Suzuki coupling reaction, compound (Ma) is generated, wherein R... 2' H is selected from R 2 or R substituted with protecting group 2 ;

[0080] (3) The compound (Ma) and compound (R) 3 H) undergoes a coupling reaction to generate compound (Mb);

[0081] (4) The compound (Mb) is deprotected under acidic conditions to generate compound (M);

[0082] The R 1 R 2 R 3 The definition is as described above.

[0083] In another aspect, the present invention provides a pharmaceutical composition comprising the above-described compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a compound prepared by the above-described method, and a pharmaceutically acceptable excipient.

[0084] In one embodiment, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases.

[0085] In another aspect, the present invention provides the use of the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-described method in the preparation of a kit for treating cancer, immune diseases, or for prognostic assessment of cancer patients.

[0086] In another aspect, the present invention provides the use of the above-described pharmaceutical composition in the preparation of a kit for treating cancer, immune diseases, or for prognostic assessment of cancer patients.

[0087] In one embodiment, the use is for use in diseases associated with KRAS mutations.

[0088] In one implementation, the cancers include, but are not limited to, pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer.

[0089] In a preferred embodiment, the cancer includes, but is not limited to, pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, small bowel cancer, endometrial cancer, and ovarian cancer.

[0090] In one embodiment, the immune disease is a KRAS-mediated immune disease.

[0091] In another aspect, the present invention provides the use of the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-described method in the preparation of a KRAS inhibitor.

[0092] In another aspect, the present invention provides the use of the above-described pharmaceutical composition in the preparation of a KRAS inhibitor.

[0093] Preferably, the KRAS inhibitor is a KRAS G12D inhibitor.

[0094] In another aspect, the present invention provides a method for inhibiting KRAS mutations in a biological sample, comprising contacting the biological sample with the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or a compound prepared by the above method, or the above-described pharmaceutical composition. Detailed Implementation

[0095] Based on the content of this disclosure, and in accordance with common technical knowledge and practices in the art, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas described in this disclosure.

[0096] I. Definition

[0097] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0098] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomer, and enantiomers are all included within the scope of this disclosure.

[0099] The disclosed compounds also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0100] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0101] The range of numbers in this article refers to the integers within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C 3-6 "" means that the group can have 3, 4, 5 or 6 carbon atoms.

[0102] The terms "substituted" or "substituted" refer to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the particular atom or group is normal and the resulting compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0103] In this disclosure, when any variable (e.g., R) n When a substituent appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0104] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group. The present disclosure preferably includes methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0105] 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. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0106] "Alynyl" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, cyano, nitro, phenolic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0107] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, wherein the cycloalkyl ring contains at least 3 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0108] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated monocyclic cyclic hydrocarbon substituent in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Non-limiting examples of heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenel, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazacycloheptyl, and piperazinyl.

[0109] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0110] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) 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 benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0111] The aryl group can be substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0112] The term "heteroaryl" refers to a heteroaryl system containing a heteroatom and a carbon atom, wherein the heteroatom is selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl.

[0113] The heteroaryl group can be optionally substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0114] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally 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, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0115] "Alkylthio-alkyl" refers to an alkylthio group attached to an alkyl group, where the alkyl and alkylthio groups are as defined above; "alkylaminocarbonyl" refers to (alkyl)-NC(O)-, where the alkyl group is defined as described above; "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above; "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above; "haloalkoxy" refers to an alkylthio group substituted with one or more halogens, where the alkylthio group is as defined above; "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, where the alkyl group is as defined above.

[0116] All hydrogen atoms described in this disclosure can be replaced by their isotope deuterium.

[0117] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0118] In this disclosure, " "" refers to the point where chemical bonds are joined.

[0119] Drug or pharmaceutical composition

[0120] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0121] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0122] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0123] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0124] For oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or alginate), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical component may 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, esters, ethanol, or fractionated vegetable oils), and a preservative (e.g., methylparaben, propylparaben, or sorbic acid). Stabilizers such as antioxidants (BHA, BHT, propyl iodide, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0125] Tablets containing the active compound can be coated using methods well known in the art. The compositions of this disclosure containing a compound of formula I as the active compound can also incorporate beads, microspheres, or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations 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 prior to use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0126] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0127] The pharmaceutical or pharmaceutical composition disclosed herein can also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0128] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0129] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those 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 the compound is compared to a response in a subject or cell not treated with the compound.

[0130] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0131] The term "excipient" is used herein to include any other compound that is not therapeutic or biologically active and may be contained in or on microparticles. Therefore, excipients should be pharmaceutically or biologically acceptable or relevant, for example, excipients that are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include multiple compounds.

[0132] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0133] Use and treatment method

[0134] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, that comply with the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a person.

[0135] According to the methods disclosed herein, compounds or compositions may be administered in any amount and via any route of administration that are effective in treating KRAS-related diseases or reducing their severity.

[0136] This disclosure relates to a method for inhibiting KRAS in a biological sample, comprising the step of contacting the biological sample with a compound of this disclosure or a composition containing the compound.

[0137] The term "biological sample" includes (but is not limited to) cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily 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.

[0138] The present disclosure discloses a method for inhibiting KRAS in a patient, comprising the step of administering the disclosed compound or a composition comprising the compound to the patient.

[0139] The provided compounds are KRAS inhibitors and therefore can be used to treat one or more conditions associated with KRAS activity. Therefore, in some embodiments, this disclosure provides a method for treating KRAS-mediated conditions, comprising the step of administering the disclosed compounds or pharmaceutically acceptable combinations thereof to a patient in need.

[0140] As used herein, the term "KRAS-mediated" refers to any disease, ailment, and / or symptom where KRAS or its mutants are known to act. Therefore, another embodiment of this disclosure relates to treating or reducing the severity of one or more diseases for which KRAS or its mutants are known to act.

[0141] This disclosure provides a method for treating one or more conditions, diseases, and / or symptoms, wherein the condition, disease, or symptom is a proliferative disease, such as cancer, inflammatory conditions, or viral infections.

[0142] In some embodiments, this disclosure provides a method of treating cancer or another proliferative condition, comprising administering a compound or composition of the disclosed invention to a patient suffering from cancer or another proliferative condition. In some embodiments, the method of treating cancer or another proliferative condition comprises administering a compound or composition of the disclosed invention to a mammal. In some embodiments, the mammal is a human.

[0143] As used herein, the terms “cancer inhibition” and “cancer cell proliferation inhibition” refer to inhibiting the growth, division, maturation, or survival of cancer cells, and / or causing cancer cell death through cytotoxicity, nutrient depletion, or induction of apoptosis, individually or collectively with other cancer cells.

[0144] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and to which the methods described herein are applicable include (but are not limited to) the breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid gland, parathyroid gland, pituitary gland, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, sweat glands, sebaceous glands, muscles, heart, and stomach.

[0145] Cancers treated with the compounds or compositions disclosed herein 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. In some embodiments, the cancer is primary exudative lymphoma (PEL).

[0146] The compounds disclosed herein may be used to treat proliferative diseases selected from the following: benign or malignant tumors or carcinomas of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, or gastrointestinal cancers (especially colon cancer or colorectal adenomas) or tumors of the neck and head; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial-characteristic tumor formation; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; Hodgkin's and non-Hodgkin's lymphomas; breast cancer; follicular carcinoma; undifferentiated tumors; papillary carcinoma; seminoma; melanoma; MYD88-driven diseases; DLBCL; ABC. DLBCL, IL-1 driven diseases, mild or indolent multiple myeloma or leukemia.

[0147] The cancers described in this disclosure include (but are not limited to) leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor). Tumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver tumor, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0148] In some specific embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0149] 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 - pleomorphic astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic glioma, a subependymal ependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal tumor (PNET), or a schwannoma. In some embodiments, the cancer is a type 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 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.

[0150] In another specific embodiment, cancers include (but are not limited to): mesothelioma, hepatobiliary (liver and bile ducts), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal tract (stomach, colon, rectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, and 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 tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more of the aforementioned cancers.

[0151] In some specific embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; bile duct hepatocellular carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0152] The term "primary tumor" is relative to secondary tumors. A primary tumor refers to a tumor that first appears in a certain location, such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0153] The term "inflammatory disease" includes the aforementioned autoimmune, allergic, and inflammatory conditions, such as those 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 allogeneic graft rejection, Bechtel's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, and blistering conditions (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (stage I or II cancer or infection). The aforementioned allergic conditions may be particularly selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and beryllium poisoning. The respiratory conditions mentioned may be selected in particular from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoma, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0154] The term "viral infection" includes, but is not limited to, retroviral infection, hepatitis virus infection, COVID-19 infection, Zika virus infection, dengue virus infection, etc.

[0155] Combined treatment method

[0156] This disclosure provides combination therapies using compounds as described herein in combination with other therapeutic agents. As used herein, the term "combination therapy" includes the sequential administration of these agents, i.e., each therapeutic agent is administered at different times, and the administration of these agents, or at least two agents, substantially simultaneously. The order, or substantially simultaneous administration, of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous routes, and direct absorption through mucosal tissues. Agents may be administered via the same or different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously. Furthermore, selected combinations may be administered intravenously, while other agents in the combination may be administered orally. Alternatively, for example, two or more agents may be administered intravenously or subcutaneously.

[0157] II. Example

[0158] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0159] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0160] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0161] Instruments and reagents:

[0162] NMR: Agilent 400MR DD2 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS: Agilent 1260 Infinity II – InfinityLab LC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high-performance liquid chromatograph (Sunfire C18 5µm 150 x 4.6 mm column).

[0163] Thin-layer chromatography silica gel plates: HSGF254 silica gel plates (Yantai Jiangyou Silica Gel Development Co., Ltd.), specifications 0.9mm-1mm. TLC silica gel plates: GF254 silica gel plates (Yucheng Chemical (Shanghai) Co., Ltd.), specifications 0.2 mm = 0.25 mm. Column chromatography: 300-400 mesh silica gel carrier (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Agilent Claricep Flash amorphous silica gel purification column).

[0164] Reagent: 5,6-amino-2,4-(1 H ,3 H )-Dihydroxypyrimidine, ethyl glyoxylate, phosphorus oxychloride, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, (3-(ethoxymethoxy)-8-fluoronaphth-1-yl)boronic acid, tetrakis(triphenylphosphine)palladium, palladium acetate, ((2 R 7 aS )-2-Fluorohexahydro-1 H -pyrrolizine-7 a --methyl)methanol, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 1-naphthoboric acid, ( S )-(1-methylpyrrolidone-2-yl)methanol, 4,4-difluoropyridine, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), potassium phosphate, (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane, N-methyl-L-prolyl, (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane, 4-methylpiperidin-4-ol, ((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-methyl)methanol, cesium fluoride, thiomorpholine 1,1-dioxide, (1 R 5 S )-8-oxo-3-azabicyclo[3.2.1]octane, 4-methylpiperidin-4-ol, dioxane hydrochloride, ( R The reagents and other reagents and starting materials were purchased from Shanghai Bid, Leyan Reagent Company, Jiangsu Aikon Biomedical R&D Company, Anaiji Chemical Reagent Company, Shanghai McLean Reagent Company, Saen Chemical Reagent Company, etc., or synthesized using methods known in the art.

[0165] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring, in dry nitrogen or argon atmosphere, in dry solvent, and at temperatures in degrees Celsius.

[0166] The following are the intermediate numbers:

[0167]

[0168] (1) Synthesis of intermediate I-1: 2,4,7-triclopteridine

[0169] Step 1: Synthesis of 2,4,7-Trihydroxypterin (I-1a)

[0170] 5,6-amino-2,4(1 H ,3 H 2,4,7-Trihydroxypyrimidine (5 g, 35.21 mmol) and potassium carbonate (5.3 g, 38.71 mmol) were added to water (80 ml), heated to 100 °C, and stirred for 1 hour. The mixture was then cooled to 60 °C and ethyl glyoxylate (4.3 g, 42.21 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours, then heated to 100 °C and stirred for 24 hours. The mixture was filtered while hot, and the filtrate was collected. After cooling, the pH was adjusted to ~3 with dilute hydrochloric acid, filtered again, and 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%.

[0171] Step 2: Synthesis of 2,4,7-triclopteridine (I-1)

[0172] 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. The reaction was carried out at 110 °C for 16 hours under nitrogen protection. Phosphorus oxychloride was removed as much as possible by vacuum distillation, and the residue was diluted with dichloromethane and purified by column chromatography to obtain 3.59 g of the target product, 2,4,7-trichloropteridine (I-1), in 54.81% yield, ESI [M+H]. + =235.0, 237.0.

[0173] (2) Intermediate I-2: tert-butyl(1 R， 5 S Synthesis of 3-(2,7-dichloropterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester

[0174]

[0175] 2,4,7-Trichloropteridine (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, followed by dropwise addition of 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (388 mg, 1.83 mmol) (3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was dissolved in 5 ml of dichloromethane and added dropwise over 10 min). The reaction was carried out at -40 °C for 5 hours. The organic solvent was removed by vacuum distillation. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product tert-butyl (1... R， 5 S 3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (I-2) 421 mg, yield 83.86%, ESI [M+H] + = 411.2, 413.2.

[0176] Example 1: 4-(4-((1) R， 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R， 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7a(5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-fluoronaphthalene-2-ol hydrochloride (1)

[0177]

[0178] Step 1: tert-butyl (1 R 5 S Synthesis of 3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (1-a)

[0179] tert-butyl (1 R 5 S3-(2,7-dichloropterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (I-2, 20 mg, 0.05 mmol), (3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)boronic 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 purged 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 crude product. Purified by silica gel column chromatography, tert-butyl(1 R 5 S 12 mg of 3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluoronaphthyl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (1-a), yield 40%. ESI [M+H] + =595.3

[0180] Step 2: Tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1-b)

[0181] tert-butyl (1 R 5 S )-3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (1-a, 10 mg, 0.017 mmol), ((2 R 7 aS )-2-Fluorohexahydro-1 H -pyrrolizine-7 a1,1'-binaphthyl-2,2'-bis(diphenylphosphine) was dissolved in toluene (0.5 ml) along with methanol (5 mg, 0.034 mmol), palladium acetate (4 mg, 0.018 mmol), cesium carbonate (27 mg, 0.083 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (10 mg, 0.016 mmol). The reaction system was heated to 110 °C under nitrogen atmosphere and reacted for 0.5 h. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (silica gel plate preparation, dichloromethane / methanol = 10 / 1) and high-performance liquid chromatography (HPLC) to obtain tert-butyl (1... R 5 S )-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H 10 mg of 1-(1-b)-(methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1-b), yield 82%. ESI [M+H] + = 717.3

[0182] Step 3: 4-(4-((1) R， 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R， 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-fluoronaphthalene-2-ol hydrochloride (1)

[0183] tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H 4-(4-(1-b, 10 mg, 0.017 mmol) octane-8-carboxylic acid ester (1-b, 10 mg, 0.017 mmol) was dissolved in hydrochloric acid / ethyl acetate (1 ml, 4 M). The reaction solution 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-((1-b) octane-8-carboxylic acid ester (1-b, 10 mg, 0.017 mmol)). R 5 S)-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-fluoronaphthyl-2-ol hydrochloride (1) 6 mg, yield 77%. ESI[M+H] + = 560.3. 1 HNMR (600 MHz, CD3OD) δ 9.01 –8.94 (m, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.41 (s, 1H),7.33 (s, 1H), 7.03 (dd, J = 13.0, 7.7 Hz, 1H), 5.61 (d, J = 51.5 Hz, 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).

[0184] Example 2: 4-(4-((1) R， 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-fluoronaphthalene-2-ol hydrochloride (2)

[0185]

[0186] Step 1: tert-butyl (1 R 5 S Synthesis of 3-(2-chloro-7-(3-(ethoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (2-a)

[0187] tert-butyl (1 R 5 S 3-(2,7-dichloropterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (I-2, 89 mg, 0.22 mmol), (3-(ethoxymethoxy)naphthyl-1-yl)boronic 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 purged 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 crude product. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl (1 R 5 S 3-(2-chloro-7-(3-(ethoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (2-a) 80 mg, yield 63%. ESI [M+H] + =576.3, 1 HNMR (600 MHz, CDCl3) δ 8.94 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.59 (s, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.41 (t, J= 2.02 (s, 2H), 1.84 (d, J =6.2 Hz, 2H), 1.51 (s, 9H), 1.25 (t, J = 7.0, 1.1 Hz, 3H).

[0188] Step 2: Tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)naphth-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (2-b)

[0189] tert-butyl (1 R 5 S )-3-(2-chloro-7-(3-(ethoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (2-a, 17 mg, 0.03 mmol), ((2 R 7 aS 2-fluorohexahydro-1H-pyrrolizin-7α-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'-binaphthyl-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 the crude product. Purification was performed by silica gel column chromatography (dichloromethane / methanol = 14 / 1) to obtain tert-butyl(1... R 5 S )-3-(7-(3-(ethoxymethoxy)naphth-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H 20 mg of (2-b) pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester, yield 95%. ESI [M+H] + 700.3

[0190] Step 3: 4-(4-((1) R， 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-fluoronaphthalene-2-ol hydrochloride (2)

[0191] tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)naphth-1-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H4-(4-(4-(1-(4-(1-(2 ... R 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-fluoronaphthyl-2-ol hydrochloride (2) 15 mg, yield 95%, ESI [M+H] + =542.3. 1 HNMR (600 MHz, CD3OD) δ 9.14 (s,1H), 8.21 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.54 – 7.46 (m, 2H),7.41 – 7.31 (m, 2H), 5.63 (d, J = 51.5 Hz, 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).

[0192] Example 3: 4-((1) R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-(((( S Synthesis of 1-methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pteridine trifluoroacetate (3)

[0193]

[0194] Step 1: tert-butyl (1 R 5 SSynthesis of 3-(2-chloro-7-(naphth-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (3-a)

[0195] tert-butyl (1 R 5 S 3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (I-2, 100 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.048 mmol), potassium carbonate (66 mg, 0.48 mmol), and 1-naphthoic acid (62 mg, 0.36 mmol) were dissolved in toluene (15 ml) and reacted at 60 °C for 4 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the product tert-butyl (1 R 5 S 3-(2-chloro-7-(naphth-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (3-a) 90 mg, yield 74.38%, ESI [M+H] + =503.3.

[0196] Step 2: Tert-butyl (1 R 5 S Synthesis of 3-(2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (3-b)

[0197] tert-butyl (1 R 5 S )-3-(2-chloro-7-(naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (22 mg, 0.036 mmol), cesium carbonate (117 mg, 0.36 mmol) and ( S 1-(1-methylpyrrolidone-2-yl)methanol (41 mg, 0.36 mmol) was dissolved in toluene (5 mL), and the reaction was carried out at 110 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 10 / 1) to obtain the product tert-butyl(1-methylpyrrolidone-2-yl)methanol. R 5 S )-3-(2-((( S1-Methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (3-b) 41 mg, yield 39.05%, ESI [M+H] + = 582.4

[0198] Step 3: 4-((1) R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-(((( S )-1-methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pteridine trifluoroacetate (3)

[0199] tert-butyl (1 R 5 S )-3-(2-((( S 1-Methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (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 vacuum distillation, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-((1 R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl))-2-(((( S 1-Methylpyrrolidone-2-yl)methoxy)-7-(naphth-1-yl)pteridine trifluoroacetate (3) 32 mg, yield 76.19%. ESI[M+H] + =482.4, 1 H NMR (600 MHz, CD3OD- d4) δ 8.99 (d, J = 15.7 Hz, 1H), 8.29 (t, J = 7.8 Hz, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 7.0 Hz, 1H),7.70 (t, J = 7.6 Hz, 1H), 7.64 – 7.56 (m, 2H), 4.93 – 4.88 (m, 2H), 4.72 (dd,J = 12.7, 6.9 Hz, 1H), 4.32 (s, 2H), 3.97 – 3.89 (m, 1H), 3.83 – 3.62 (m, 3H), 3.27 (d, J = 17.0 Hz, 1H), 3.12 (s, 3H), 2.44 (dt, J = 13.1, 7.2 Hz, 1H), 2.31 – 2.06 (m, 8H), 2.05 – 1.89 (m, 1H)

[0200] Example 4: 4-(4-((1) R 5 S Synthesis of trifluoroacetate of 3,8-diazacyclic [3.2.1]octane-3-yl)-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)pterin-7-yl)-5-fluoronaphthyl-2-ol (4)

[0201]

[0202] Step 1: tert-butyl (1 R 5 S Synthesis of 3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (4-a)

[0203] tert-butyl (1 R 5 S3-(2-chloro-7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (1-a, 6 mg, 0.01 mmol), N-methyl-L-prolyl (2 mg, 0.016 mmol), palladium acetate (1 mg, 0.004 mmol), cesium carbonate (7 mg, 0.02 mmol), and 1,1'-binaphthyl-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 crude product. Purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 10 / 1) to obtain product tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)-2-((( S 1-Methylpyrrolidone-2-yl)methoxy)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (4-a) 6 mg, yield 89%. ESI [M+H] + =674.3

[0204] Step 2: 4-(4-((1) R 5 S Synthesis of trifluoroacetate of 3,8-diazacyclic [3.2.1]octane-3-yl)-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)pterin-7-yl)-5-fluoronaphthyl-2-ol (4)

[0205] tert-butyl (1 R 5 S )-3-(7-(3-(ethoxymethoxy)-8-fluoronaphthyl-1-yl)-2-((( S 1-Methylpyrrolidone-2-yl)methoxy)pterin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (4-a, 6 mg, 0.009 mmol) was dissolved in dichloromethane (0.5 ml), and then 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 high performance liquid chromatography to obtain the target product 4-(4-((1 R 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-((( S 3 mg of 1-methylpyrrolidone-2-yl)methoxy)pterin-7-yl)-5-fluoronaphthyl-2-ol trifluoroacetate (4), yield 32%. ESI [M+H] + =516.3, 1HNMR (400 MHz, CD3OD) δ 8.80 (d,J = 3.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.47 – 7.41 (m, 1H), 7.41 – 7.34(m, 1H), 7.26 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 13.1, 7.6 Hz, 1H), 4.87 –4.82 (m, 2H), 4.67 (dd, J = 12.8, 6.9 Hz, 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).

[0206] Example 5: 4-(4,4-difluoropiperidin-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphth-2-ol (5)

[0207]

[0208] Step 1: Synthesis of 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a)

[0209] 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, followed by dropwise addition of 4,4-difluoropyridine (61 mg, 0.54 mmol) (4,4-difluoropyridine dissolved in 5 mL dichloromethane, added over 10 min). The reaction was carried out at -40 °C for 1 hour. The organic solvent was removed by vacuum distillation. The crude product was purified by thin-layer chromatography using silica gel (dichloromethane / methanol = 50 / 1) to obtain 131 mg of 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a), yield 97.76%, ESI [M+H]. + =320.1, 322.0.

[0210] Step 2: Synthesis of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pteridine (5-b)

[0211] The following medications were added: 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 60 mg, 0.19 mmol), [n-butyldi(1-adamantyl)phosphine methanesulfonate](2-amino-1,1'-biphenyl-2-yl)palladium(II) (29 mg, 0.04 mmol), potassium phosphate (81 mg, 0.38 mmol), and (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxane-1,4,5 ... 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 vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to give 7.1 mg of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pteridine (5-b), yield 13.22%, ESI [M+H]. + = 518.3.

[0212] Step 3: 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of )-yl)methoxy)pteridine (5-c)

[0213] The following medications were administered: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pteridine (5-b, 42 mg, 0.08 mmol), palladium acetate (4 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (12 mg, 0.02 mmol), cesium carbonate (52 mg, 0.16 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2-yl)- ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H 11.5 mg of 5-methyl-4-methoxy-4-pteridine (5-c), yield 22.42%, ESI [M+H] + =641.4.

[0214] Step 4: 4-(4,4-difluoropiperidin-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphth-2-ol (5)

[0215] 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-2-(((2))-methyl(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 removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-(((2)) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol (5) 7.45 mg, yield 67.73%. ESI[M+H] + = 597.3, 1 H NMR (600 MHz, CD3OD- d4) δ 8.82 (s, 1H), 7.70 (dd, J = 9.0,5.7 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.12 (d, J = 2.6 Hz, 1H), 5.63 – 5.52 (m,1H), 4.69 (d, J = 12.2 Hz, 2H), 4.63 (d, J = 12.3 Hz, 2H), 3.95 – 3.82 (m,3H), 3.46 (td, J = 11.0, 6.0 Hz, 1H), 2.73 – 2.56 (m, 2H), 2.43 (q, J = 8.5,7.2 Hz, 2H), 2.34 (dq, J = 11.8, 5.8, 4.8 Hz, 3H), 2.24 (dq, J = 12.7, 6.5,5.6 Hz, 5H), 2.17 (dd, J = 9.6, 5.8 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).

[0216] Example 6: 4-(4-((1) R 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphth-2-ol (6)

[0217]

[0218] Step 1: tert-butyl (1 R 5 S Synthesis of 3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (6-a)

[0219] tert-butyl (1 R 5 S)-3-(2,7-dichloropterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylic acid ester (I-2, 20 mg, 0.05 mmol), (2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (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, 0.15 mmol) were dissolved in tetrahydrofuran (1.0 mL) and water (0.1 mL). The reaction system was purged 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 the crude product. Purification was performed by thin-layer chromatography using silica gel plates (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl(1,1'-biphenyl-2-yl)palladium(II) (7 mg, 0.01 mmol) and potassium phosphate (32 mg, 0.15 mmol) R 5 S 19 mg of 3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazahexacyclic [3.2.1]octane-8-carboxylic acid ester (6-a), yield 62%, ESI [M+H] + =609.3.

[0220] Step 2: Tert-butyl (1 R 5 S )-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 3,8-diazacyclic [3.2.1]octane-8-carboxylate (6-b)

[0221] tert-butyl (1 R 5 S )-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pterin-4-yl)-3,8-diazahexacyclic [3.2.1]octane-8-carboxylic acid ester (6-a, 19 mg, 0.03 mmol), ((2 R 7 aS )-2-fluorotetrahydro-1H-pyrrolizine-7 a (5 H1,1'-binaphthyl-2,2'-bis(diphenylphosphine) was dissolved in toluene (3 ml). The reaction system was heated to 110 °C under nitrogen atmosphere and reacted for 0.5 h. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer Prep-HPLC to obtain tert-butyl(1-diphenylphosphine)... R 5 S )-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 10 mg of (6-b) methoxypterin-4-yl)-3,8-diazacyclic [3.2.1]octane-8-carboxylate, yield 45%, ESI [M+H] + =732.3.

[0222] Step 3: 4-(4-((1) R 5 S )-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphth-2-ol (6)

[0223] tert-butyl (1 R 5 S )-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4-(4-(1 ...1-(4-(1-(1-(4-(1-(1-(4-(1-(1-(4-(1-(1-(4-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-( R 5 S)-3,8-diazahexacyclic[3.2.1]octane-3-yl)-2-(((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H (6) 3 mg of (-yl)methoxy)pterin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol trifluoroacetate, yield 31%. ESI[M+H] + = 588.3. 1 HNMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 7.71 (dd, J = 9.0, 5.8 Hz,1H), 7.37 – 7.23 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 5.58 (d, J = 51.9 Hz,1H), 4.67 (q, J = 12.2 Hz, 2H), 4.29 (s, 2H), 4.03 – 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).

[0224] Example 7: 5-ethynyl-6-fluoro-4-(2-(2) R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (7)

[0225]

[0226] Step 1: Synthesis of 2,7-dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a)

[0227] 2,4,7-Trichloropterin (I-1, 140 mg, 0.59 mmol), 4-(trifluoromethyl)piperidine (91.1 mg, 1 eq.), and N,N-diisopropylethylamine (103.6 μL, 1 eq.) were dissolved in dichloromethane (2 mL) and reacted at -40 °C for 30 min. The organic solvent was removed by vacuum distillation, and the residue was diluted with dichloromethane and purified by Flash column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 140 mg of 2,7-dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a), yield 66.83%, ESI [M+H]. + =353.14.

[0228] Step 2: Synthesis of 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-b)

[0229] 2,7-Dichloro-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-a, 100 mg, 0.39 mmol), [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-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (135 mg, 0.39 mmol) were dissolved in tetrahydrofuran (1 ml) and water (0.1 ml), and the mixture was reacted at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain 160 mg of the product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-b), with a yield of 57.24%.

[0230] Step 3: 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-c)

[0231] The following medications were added: 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (28.4 mg, 0.046 mmol), cesium carbonate (111.4 mg, 0.345 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2-)-yl)-2 ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-c) 25.6 mg, yield 13.6%, ESI [M+H] + = 825.01.

[0232] Step 4: 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-d)

[0233] 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)pteroidine (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 to 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 give the product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pteridine (7-d, 20 mg, crude). ESI[M+H] + =669.67

[0234] Step 5: 5-ethynyl-6-fluoro-4-(2-(2) R 7 aS) -2-Fluorotetrahydrofuran-1H-pyrrolidone-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (7)

[0235] 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 5-(2 ... R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (7) 3.21 mg, yield 22.94%. ESI [M+H] + = 625.62. 1H NMR (400 MHz, CD3OD-d4) δ 8.68 (s, 1H), 8.46 (s,1H), 7.86 (td, J = 8.7, 8.2, 4.8 Hz, 1H), 7.46 – 7.38 (m, 1H), 7.37 – 7.31(m, 2H), 7.27 (d, J = 2.5 Hz, 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, 8.9 Hz, 2H), 2.32 (t, J = 8.9 Hz,1H), 2.27 – 2.15 (m, 3H), 2.14 – 1.99 (m, 5H), 1.76 (q, J = 13.7 Hz, 3H), 1.33 – 1.21 (m, 1H).

[0236] Example 8: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (8)

[0237]

[0238] Step 1: Synthesis of 1-(2,7-dichloropterin-4-yl)-4-methylpiperidin-4-ol (8-a)

[0239] 2,4,7-Trichloropteridine (I-1, 50 mg, 0.212 mmol) was dissolved in dichloromethane (0.5 ml), and the reaction mixture was stirred at -40°C for 3 minutes. Then, N,N-diisopropylethylamine (27.4 mg, 0.212 mmol, dissolved in dichloromethane (0.25 ml)) was slowly added dropwise while stirring. After stirring for another 3 minutes, 4-methylpiperidin-4-ol (24.5 mg, 0.212 mmol) dissolved in dichloromethane (0.25 ml) was slowly added dropwise to the reaction mixture. The reaction was carried out at -40°C for 1 hour. The solvent was removed by vacuum distillation as much as possible, and the residue was diluted with dichloromethane and purified by TLC (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.

[0240] Step 2: Synthesis of 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (8-b)

[0241] 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (8-a, 30 mg, 0.0958 mmol), [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)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (34.5 mg, 0.0958 mmol) were dissolved in tetrahydrofuran:water = 10:1 (3.3 ml), and the reaction was carried out at 60 °C for 6 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the product was extracted with water (5 ml) and ethyl acetate (5 ml * 3). The organic phase was then back-extracted with brine. Finally, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by TLC (dichloromethane / methanol = 20 / 1) to obtain the target product 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (8-b, 47 mg, yield 95.92%). ESI [M+H] + =512.2.

[0242] Step 3: 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (8-c)

[0243] The following were added: 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (11.5 mg, 0.018 mmol), cesium carbonate (45 mg, 0.138 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7a (5 H 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2-yl)- ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8-c, 22 mg, yield 37.74%). ESI[M+H] + =634.2

[0244] Step 4: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (8)

[0245] 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2-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 vacuum distillation, and the crude product was purified by preparative liquid chromatography (NH4HCO3: ACN) to obtain 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2-methylpiperidin-4-ol)-2-methylpiperidin-4-ol)-2-methylpiperidin-4-ol. R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H )-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (8, 5.01 mg, yield 24.39%). ESI [M+H] + =591.3. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 7.70 (dd, J = 9.0, 5.8 Hz, 1H), 7.33 – 7.25 (m, 2H), 7.12 (d, J = 2.6 Hz, 1H), 5.33 (d, J = 53.9 Hz, 2H), 4.31 – 4.21 (m, 2H), 3.87 (d, J = 25.2 Hz, 2H), 3.25 (d, J = 20.3 Hz, 3H), 3.04 (tt, J = 9.5, 4.3 Hz, 1H), 2.38 (dd, J =15.0, 4.7 Hz, 2H), 2.32 – 2.12 (m, 5H), 2.01 (dq, J = 12.4, 6.1 Hz, 3H), 1.82 (q, J = 4.6, 4.2 Hz, 4H), 1.33 (s, 5H), 0.85 (t, J = 7.4 Hz, 4H).

[0246] Example 9: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H- Pyrrolidine-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (9)

[0247]

[0248] Step 1: 2-Chloro-4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pteridine(9-a)

[0249] 2,7-Dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 150 mg, 0.47 mmol), [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-dioxane-2-yl)naphth-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 for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (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)naphth-1-yl)pteridine (9-a, 230 mg, yield 74.92%).

[0250] Step 2: 4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1H-pyrrolline-7 a (5 H )-yl)methoxy)pterin(9-b)

[0251] The following medications were administered: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pteridine (9-a, 230 mg, 0.35 mmol), palladium acetate (16 mg, 0.07 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (44 mg, 0.07 mmol), cesium carbonate (228 mg, 0.7 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2-yl)-methyl-2- ... R 7aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 9-β-(9-β), 136 mg, yield 48.92%. ESI[M+H] + = 793.4

[0252] Step 3: 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pteridine (9-c)

[0253] 4-(4,4-difluoropiperidin-1-yl)-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H 4-pyrrolidone-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 to 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 give the target product 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 9-C, 143 mg, crude. ESI [M+H] + =637.3

[0254] Step 4: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (9)

[0255] 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-2-((2-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 removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography (alkaline) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2-yl)methoxy)pteridine. R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (9, 2.15 mg, yield 1.6%). ESI [M+H + =593.3. 1 H NMR (600 MHz, CD3OD- d 4) δ 8.62 (d, J = 6.7 Hz, 1H), 7.88 (dd, J =9.2, 5.6 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 5.36 (d, J =4.5 Hz, 1H), 5.27 (t, J = 3.9 Hz, 1H), 4.29 (d, J = 10.9 Hz, 1H), 4.25 – 4.21(m, 1H), 3.68 (s, 2H), 3.28 – 3.20 (m, 4H), 3.02 (p, J = 5.9 Hz, 1H), 2.37 –2.32 (m, 1H), 2.30 – 2.24 (m, 1H), 2.21 (d, J = 10.7 Hz, 1H), 2.13 (d, J =9.6 Hz, 1H), 2.01 (dq, J = 11.4, 5.3 Hz, 3H), 1.93 – 1.84 (m, 6H).

[0256] Example 10: 4-(4-(1) R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS)-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (10)

[0257]

[0258] Step 1: tert-butyl (1 R 5 S )-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a)

[0259] tert-butyl (1 R 5 S 3-(2,7-dichloropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (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-dioxane-2-yl)naphth-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 for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product tert-butyl(1R,5S)-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a, 215 mg, yield 78.47%).

[0260] Step 2: Tert-butyl (1 R 5 S )-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H)-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-b)

[0261] tert-butyl (1 R 5 S )-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (35 mg, 0.056 mmol), cesium carbonate (182 mg, 0.56 mmol) and ((2 R 7 [[ID=6,2]]aS )-2-fluorotetrahydro-1H-pyrrolline-7 a (5 H 134 mg (0.84 mmol) of methanol was dissolved in toluene (10 mL), and the reaction was carried out at 110 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 10 / 1) to obtain the target product, tert-butyl (1... R 5 S )-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-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

[0262] Step 3: Tert-butyl (1 R 5 S )-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-c)

[0263] tert-butyl (1 R 5 S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-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 to 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 tert-butyl(1 R 5 S )-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-c, 112 mg, crude). ESI [M+H] + =728.4

[0264] Step 4: 4-(4-(1) R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (10)

[0265] tert-butyl (1 R 5 S )-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H4-(4-(1-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 vacuum distillation, and the crude product was purified by preparative liquid chromatography (alkaline) to obtain the target product 4-(4-(1-yl)-(2 ... R 5 S )-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (10, 3.27 mg, yield 3.74%). ESI[M+H] + = 584.4. 1 HNMR (600 MHz, CD3OD- d 4) δ 8.62 (d, J = 6.6 Hz, 1H), 7.88 (dd, J = 9.2, 5.6 Hz,1H), 7.38 – 7.33 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 5.36 (d, J = 4.3 Hz, 1H),5.27 (t, J = 3.8 Hz, 1H), 4.31 – 4.28 (m, 1H), 4.23 (dd, J = 10.6, 3.1 Hz,1H), 3.68 (s, 2H), 3.28 – 3.19 (m, 4H), 3.02 (dd, J = 9.6, 5.6 Hz, 1H), 2.34(dd, J = 15.0, 4.9 Hz, 1H), 2.28 – 2.23 (m, 1H), 2.22 – 2.19 (m, 1H), 2.13(d, J = 9.6 Hz, 1H), 2.01 (ddt, J = 18.2, 12.2, 6.2 Hz, 4H), 1.88 (dd, J =28.8, 9.4 Hz, 6H).

[0266] Example 11: 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 HSynthesis of 1,1-dioxytrifluoroacetate of 1,1-(1-yl)methoxy)pterin-4-yl)thiomorpholine (11)

[0267]

[0268] Step 1: 4-(2,7-dichloropteridin-4-yl)thiomorpholine 1,1-dioxide (11-a)

[0269] 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, followed by dropwise addition of 1,1-thiomorpholine (276 mg, 2.04 mmol) dissolved in 5 mL dichloromethane over 10 min. The reaction was carried out at -40 °C for 1 hour. During the reaction, the product precipitated and was filtered to obtain the target product, 4-(2,7-dichloropteridine-4-yl)thiomorpholine 1,1-dioxide (11-a, 380 mg, yield 66.90%). ESI[M+H] + = 334.0, 336.0

[0270] Step 2: 4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)thiomorpholine 1,1-dioxide (11-b)

[0271] 4-(2,7-dichloropteridin-4-yl)thiomorpholine 1,1-dioxide (11-a, 60 mg, 0.18 mmol), methanesulfonic acid [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-dioxane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (92 mg, 0.18 mmol) were dissolved in 1,4-dioxane (3 ml) and water (0.3 ml), and the reaction was carried out at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product 4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)thiomorpholine 1,1-dioxide (11-b, 90 mg, yield 73.17%).

[0272] Step 3: 4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxide (11-c)

[0273] The following were added: 4-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (16 mg, 0.026 mmol), cesium carbonate (85 mg, 0.26 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2-)-yl)-methyl-2-(2- ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 1,1-dioxide (11-c, 36 mg, yield 34.29%) of methoxy-pterin-4-ylthiomorpholine (ESI [M+H)). + = 807.7

[0274] Step 4: 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxy(11-d)

[0275] 4-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 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 to 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 give the target product 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-)-( ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 1,1-dioxy(11-d, 35 mg, yield 121%). ESI [M+H + =651.7

[0276] Step 5: 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)thiomorpholine 1,1-dioxytrifluoroacetate (11)

[0277] 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 1,1-dioxy(11-d, 35 mg, 0.05 mmol) of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2-)-( ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H1,1-Dioxytrifluoroacetate (11,8.78 mg, yield 24.39%). ESI [M+H + =607.3. 1 H NMR (600 MHz, CD3OD- d 4) δ 8.80 (s,1H), 7.92 (dd, J = 9.1, 5.6 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.31 (d, J = 2.5Hz, 1H), 5.59 (dt, J = 51.6, 3.7 Hz, 1H), 4.99 (s, 3H), 4.73 (dd, J = 12.5,2.2 Hz, 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, 5.0 Hz, 1H), 2.40 – 2.33 (m,2H), 2.18 (dt, J = 13.7, 7.2 Hz, 1H).

[0278] Example 12: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)pterin-7-yl)-5-ethylnaphthalene-2-ol (12)

[0279]

[0280] Step 1: 2-Chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pteridine(12-a)

[0281] 2,7-Dichloro-4-(4,4-difluoropiperidin-1-yl)pterin (5-a, 30 mg, 0.09 mmol), [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-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)silane (45 mg, 0.09 mmol) were dissolved in tetrahydrofuran (3.6 ml) and water (0.36 ml), and the mixture was reacted at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pteridine (12-a, 10 mg, yield 16.95%).

[0282] Step 2: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin(12-b)

[0283] The following medications were administered: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pteridine (12-a, 47 mg, 0.07 mmol), palladium acetate (3 mg, 0.014 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (9 mg, 0.014 mmol), cesium carbonate (46 mg, 0.14 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-2-((2-yl)-methanol (56 mg, 0.35 mmol) was dissolved in toluene (5 ml), and reacted at 110 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 10 / 1) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2-yl)-methanol ...2-yl)-methanol-2-((2-yl)-methanol-2-(2-yl)-methanol-2-((2-yl)-methanol-2- R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a(5 H )-yl)methoxy)-7-(3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin (12-b, 15.5 mg, yield 28.70%). ESI[M+H] + = 775.4

[0284] Step 3: 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pteridine(12-c)

[0285] 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)naphthyl-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 to 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)naphthyl-1-yl)-2-((2-) R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pteridine (12-c, 4 mg, yield 33.33%). ESI[M+H] + =619.3

[0286] Step 4: 4-(4,4-difluoropiperidin-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethylnaphthalene-2-ol trifluoroacetate (12)

[0287] 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4,4-difluoropiperidin-1-yl)-2-((2-methyl)-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 removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-2-((2-methyl)-methoxy)-pteridine. R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H (12, 1.72 mg, yield 35.83%) ESI [M+H] methoxypterin-7-yl)-5-ethylnaphthyl-2-ol trifluoroacetate (ESI). + =575.30. 1 H NMR (600 MHz, CD3OD- d 4) δ 8.75 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.24(d, J = 2.5 Hz, 1H), 5.60 (t, J = 3.8 Hz, 1H), 5.52 (t, J = 3.8 Hz, 1H), 4.45(d, J = 7.0 Hz, 2H), 4.09 – 4.06 (m, 2H), 3.91 (d, J = 13.5 Hz, 2H), 3.42 (d,J = 1.9 Hz, 1H), 3.26 (d, J = 5.1 Hz, 1H), 2.37 – 2.31 (m, 4H), 2.28 – 2.22(m, 6H), 2.04 – 2.00 (m, 1H), 1.33 – 1.31 (m, 2H).

[0288] Example 13: 4-(4-(1) R 5 S )-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (13)

[0289]

[0290] Step 1: (1) R 5 S Synthesis of 3-(2,7-dichloropteridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-a)

[0291] Dissolve 2,4,7-triclopteridine (I-1, 150 mg, 0.64 mmol) in dichloromethane (5 ml), cool to -40 °C, add N,N-diisopropylethylamine (83 mg, 0.64 mmol), and then add (1) dropwise. R 5 S )-8-oxo-3-azabicyclo[3.2.1]octane (72 mg, 0.64 mmol) was reacted at -40 °C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Flash column chromatography (methanol:dichloromethane = 0%~5%) to obtain the target product (1). R 5 S )-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

[0292] Step 2: (1) R 5 S Synthesis of 3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-b)

[0293] (1) R 5 S3-(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-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (153 mg, 0.3 mmol), potassium phosphate (190 mg, 0.9 mmol), and 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 mixture was purged with nitrogen three times and reacted at 60 °C for 6 h. Quenching with water, extraction with ethyl acetate, collection of the organic phase and backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by Flash column chromatography (methanol:dichloromethane = 0%~2%) to obtain the target product (1 R 5 S )-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13-b, 88 mg, yield 46.3%).

[0294] Step 3: (1) R 5 S )-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of [3.2.1]octane (13-c) of pterin-4-yl-8-oxy-3-azabicyclo[3.2.1]octane

[0295] (1) R 5 S )-3-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (88 mg, 0.13 mmol), ((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 HMethanol (42 mg, 0.26 mmol), cesium carbonate (64 mg, 0.2 mmol), palladium acetate (7 mg, 0.03 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (18 mg, 0.03 mmol) were added to toluene. The mixture was purged with nitrogen three times and heated to 110 °C for 16 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Flash column chromatography (methanol:dichloromethane = 0%–10%) to obtain the target product (1...). R 5 S )-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (13-c, 24 mg, yield 23%). ESI [M+H + =785.4

[0296] Step 4: (1) R 5 S )-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of 13-d)-(-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane

[0297] (1) R 5 S )-3-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-8-oxy-3-azabicyclo[3.2.1]octane (24 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (1 ml), and cesium fluoride (46 mg, 0.3 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated and purified by plate preparation to obtain the target product (1 R 5 S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-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

[0298] Step 5: 4-(4-(1) R 5 S )-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (13)

[0299] (1) R 5 S )-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 4-(4-(1-(4-(1-(4-(8 ... R 5 S )-8-oxa-3-azabicyclo[3.2.1]octyl-3-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (13.6 mg, yield 42.8%). ESI[M+H] + =585.3, 1H NMR(400 MHz, DMSO-d6) δ 10.78 (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 = 2.4 Hz, 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 = 7.0 Hz, 2H).

[0300] Example 14: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (14)

[0301]

[0302] Step 1: Synthesis of 1-(2,7-dichloropterin-4-yl)-4-methylpiperidin-4-ol (14-a)

[0303] 2,4,7-Trichloropteridine (I-1, 200 mg, 0.849 mmol) was dissolved in dichloromethane (2 ml), and the reaction mixture was stirred at -40°C for 3 minutes. Then, N,N-diisopropylethylamine (109.6 mg, 0.849 mmol, dissolved in dichloromethane (0.5 ml)) was slowly added dropwise while stirring. After stirring for another 3 minutes, 4-methylpiperidin-4-ol (98 mg, 0.849 mmol) dissolved in dichloromethane (0.5 ml) was slowly added dropwise to the reaction mixture. The reaction was carried out at -40°C for 1 hour. The solvent was removed by vacuum distillation as much as possible, and the residue was diluted with dichloromethane and purified by TLC (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

[0304] Step 2: Synthesis of 1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (14-b)

[0305] 1-(2,7-dichloropteridin-4-yl)-4-methylpiperidin-4-ol (14-a, 75 mg, 0.2396 mmol), [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-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (122.7 mg, 0.2396 mmol) were dissolved in tetrahydrofuran:water = 10:1 (1.5 ml), and the reaction was carried out at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the product was extracted with water (5 ml) and ethyl acetate (5 ml * 3). The organic phase was then back-extracted with brine. Finally, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by TLC (dichloromethane / methanol = 20 / 1) to obtain the target product 1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)-4-methylpiperidin-4-ol (14-b, 125 mg, yield 78.62%). ESI [M+H] + =664.2

[0306] Step 3: 1-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1H-pyrrolline-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (14-c)

[0307] 1-(2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (23 mg, 0.0377 mmol), cesium carbonate (92 mg, 0.283 mmol), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methanol (45 mg, 0.283 mmol) were dissolved in toluene (2 ml), and the reaction was carried out at 110 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the product was extracted with water (5 ml) and ethyl acetate (5 ml * 3). The organic phase was then back-extracted with brine. Finally, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. 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)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-c, 30 mg, yield 20.27%). ESI[M+H] + =787.2

[0308] Step 4: 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H- Pyrrolidine-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (14-d)

[0309] 1-(7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-yl)-4-methylpiperidin-4-ol (14-c, 30 mg, 0.038 mmol), dissolved in N,N-dimethylformamide (2.5 ml) and cesium fluoride (35 mg, 0.229 mmol), was reacted at room temperature for 4 hours. The solvent was removed by vacuum distillation to give the crude product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-yl)-4-methylpiperidin-4-ol (14-c, 30 mg, 0.038 mmol), soluble in N,N-dimethylformamide (2.5 ml) and cesium fluoride (35 mg, 0.229 mmol). R 7 [[ID=

[105] ]aS )-2-fluorotetrahydro-1H-pyrrolline-7 a (5 H )-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14-d, 45mg). ESI)[M+H] = 631.2

[0310] Step 5: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H Synthesis of 4-methylpiperidin-4-ol (14)

[0311] 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2-yl)-methylpiperidin-4-ol (14-d, 43 mg, 0.052 mmol), dissolved in dioxane (1.9 ml) and dioxane hydrochloride (0.38 ml), was reacted at room temperature for 0.5 hours. The solvent was removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography (NH4HCO3: ACN) to obtain 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2-yl)-methylpiperidin-4-ol (14-d, 43 mg, 0.052 mmol), dissolved in dioxane (1.9 ml) and dioxane hydrochloride (0.38 ml), and reacted at room temperature for 0.5 hours. R 7 aS )-2-fluorotetrahydro-1H-pyrrolline-7 a (5 H )-yl)methoxy)pterin-4-yl)-4-methylpiperidin-4-ol (14, 7.89 mg, yield 19.73%). ESI [M+H] + =587.3. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s,1H), 8.60 (s, 1H), 7.99 (dd, J = 9.2, 6.0 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.40(d, J = 2.6 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 5.27 (d, J = 54.5 Hz, 2H), 4.53 (d, J = 5.8 Hz, 1H), 4.17 (s, 1H), 4.06 – 3.98 (m, 2H), 3.74 – 3.56 (m,2H), 3.11 – 2.99 (m, 4H), 2.91 – 2.77 (m, 2H), 2.08 – 2.00 (m, 2H), 1.79 –1.73 (m, 2H), 1.69 – 1.60 (m, 5H), 1.17 (s, 3H).

[0312] Example 15: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolizine-7 a (5 H Synthesis of 4-methylpiperidin-4-ol trifluoroacetate (15)

[0313]

[0314] Step 1: 2,7-Dichloro-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-a)

[0315] 2,4,7-Trichloropteridine (I-1, 100 mg, 0.425 mmol) was dissolved in dichloromethane (1 ml), and the reaction mixture was stirred at -40°C for 3 minutes. Then, N,N-diisopropylethylamine (54.8 mg, 0.425 mmol, dissolved in dichloromethane (0.5 ml)) was slowly added dropwise while stirring. After stirring for another 3 minutes, 4-methylpiperidin-4-ol (43 mg, 0.425 mmol) dissolved in dichloromethane (0.5 ml) was slowly added dropwise to the reaction mixture. The reaction was carried out at -40°C for 1 hour. The solvent was removed by vacuum distillation as much as possible, and the residue was diluted with dichloromethane and purified by TLC (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

[0316] Step 2: 2-Chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-b)

[0317] 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-dioxacyclopentaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (111.4 mg, 0.217 mmol) were dissolved in tetrahydrofuran:water = 10:1 (2 ml), and the reaction was carried out at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the product was extracted with water (5 ml) and ethyl acetate (5 ml * 3). The organic phase was then back-extracted with brine. Finally, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by TLC (dichloromethane / methanol = 20 / 1) to obtain the target product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-N-(tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-b, 90 mg, yield 63.83%). ESI [M+H] + =649.4

[0318] Step 3: 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin(15-c)

[0319] The following substances were added: 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (17 mg, 0.0277 mmol), cesium carbonate (68 mg, 0.208 mmol), and ((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2-)-methyl-2 ... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H (15-C, 15 mg, yield 14.02%). ESI[M+H] + = 773.5

[0320] Step 4: 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine(15-d)

[0321] 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1H -pyrrolidone-7 a (5 H 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-yl)-methoxy)pterin (15-c, 15 mg, 0.019 mmol), dissolved in N,N-dimethylformamide (2.5 ml) and cesium fluoride (17.7 mg, 0.1165 mmol), was reacted at room temperature for 4 hours. The solvent was removed by vacuum distillation to give the product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2-yl)-methoxy)pterin (15-c, 15 mg, 0.019 mmol), 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. R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H (15-3)-(2-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-d, 30 mg). ESI [M+H] + =617.3

[0322] Step 5: 5-ethynyl-6-fluoro-4-(2-((2) R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H Synthesis of trifluoroacetate of )-yl)methoxy)-4-((tetrahydrofuran-2-yl)methyl)amino)pterin-7-yl)naphthalene-2-ol (15)

[0323] 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H )-(tetrazol-2-yl)methoxy)-N-((tetrahydrofuran-2-yl)methyl)pterin-4-amine (15-d, 30 mg, 0.0487 mmol), dissolved in dioxane (2 ml) and dioxane hydrochloride (0.4 ml), reacted at room temperature for 0.5 hours. The solvent was removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography (TFA: ACN) to obtain 5-ethynyl-6-fluoro-4-(2-((2-)-)-methyl)-pterin-4-amine. R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H (15, 8.29 mg, yield 29.76%) ESI[M+H)-(tetrahydrofuran-2-yl)methyl)amino)pterin-7-yl)naphthalene-2-ol trifluoroacetate (ESI[M+H]). + =573.4.1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.30 (s, 1H), 8.94 (q, J = 6.4 Hz, 1H), 8.74 (d, J= 7.7 Hz, 1H), 8.01 (dd, J = 9.2, 5.9 Hz, 1H), 7.49 (t, J = 9.0 Hz, 1H), 7.42(d, J = 2.6 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 5.76 – 5.40 (m, 1H), 4.59 (s,2H), 4.23 – 4.05 (m, 2H), 3.88 – 3.70 (m, 4H), 3.64 (q, J = 7.3 Hz, 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), 2.06 (d, J = 4.1 Hz, 1H), 1.89 (ddt, J = 33.8, 12.9, 6.6 Hz, 3H),1.74 – 1.62 (m, 1H).

[0324] Example 16: 5-ethynyl-6-fluoro-4-(2-(2-) R 7 [[ID=[

[119] ]aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H Synthesis of )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (16)

[0325]

[0326] Step 1: 2,7-Dichloro-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-a)

[0327] 2,4,7-Trichloropterin (I-1, 200 mg, 0.85 mmol), 3-(trifluoromethyl)piperidine (130.2 mg, 1 eq.), and N,N-diisopropylethylamine (148 μL, 1 eq.) were dissolved in dichloromethane (2 mL) and reacted at -40 °C for 2 hours. The organic solvent was removed by vacuum distillation, and the residue was diluted with dichloromethane and purified by Flash column chromatography (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.

[0328] Step 2: 2-Chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine(16-b)

[0329] 2,7-Dichloro-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-a, 80 mg, 0.212 mmol), methanesulfonic acid [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-dioxacyclopentaborane-2-yl)naphth-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 for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-b, 140 mg, yield 94.08%).

[0330] Step 3: 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine(16-c)

[0331] The following were added: 2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-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'-binaphthyl-2,2'-bis(diphenylphosphine) (24.7 mg, 0.04 mmol), cesium carbonate (97.25 mg, 0.298 mmol), and ((2... R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2-)-methyl ...(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-(2-methyl)-methyl)-methyl)-(2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-c, 47 mg, yield 28.67%). ESI [M+H + = 825.01

[0332] Step 4: 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine(16-d)

[0333] 7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H)-(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 to 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 give the target product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pteridine (16-d, 60 mg). ESI[M+H] + = 669.67

[0334] Step 5: 5-ethynyl-6-fluoro-4-(2-(2) R 7 aS )-2-fluorotetrahydrofuran-1H-pyrrolidone-7 a (5 H )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (16)

[0335] 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 5-(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 removed by vacuum distillation, and the crude product was purified by preparative liquid chromatography (FA) to obtain the target product 5-ethynyl-6-fluoro-4-(2-(2-)-yl)-(3-(trifluoromethyl)piperidin-1-yl)pteridine. R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)-4-(3-(trifluoromethyl)piperidin-1-yl)pterin-7-yl)naphth-2-ol (16, 3 mg, yield 6.41%). ESI [M+H] + = 625.62. 1 H NMR (400 MHz, DMSO- d6) δ 10.35 (s, 1H), 8.56 (d,J = 25.7 Hz, 1H), 8.05 – 7.96 (m, 1H), 7.51 (ddd, J = 26.6, 16.9, 8.5 Hz,2H), 7.31 – 7.22 (m, 1H), 7.09 (d, J = 51.0 Hz, 1H), 5.60 (dd, J = 52.7, 12.2Hz, 2H), 4.68 – 4.31 (m, 4H), 4.11 (d, J = 23.6 Hz, 1H), 3.83 (ddd, J = 33.4,25.2, 11.2 Hz, 3H), 2.37 – 1.87 (m, 8H), 1.74 (d, J = 5.2 Hz, 2H), 1.52 (d, J= 7.0 Hz, 2H), 1.23 (s, 2H).

[0336] Example 17: 5-ethynyl-6-fluoro-4-(2-((2) R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidine-7a(5 H )-yl)methoxy)-4-((( R Synthesis of 2-pyrrolidine-2-yl)methyl)amino)pterin-7-yl)naphthalene-2-ol trifluoroacetate (17)

[0337]

[0338] Step 1: tert-butyl ( R )-2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-a)

[0339] Dissolve 2,4,7-triclopteridine (I-1, 150 mg, 0.64 mmol) in anhydrous dichloromethane (5 ml), and slowly add N,N-diisopropylethylamine (83 mg, 0.64 mmol) at -40 °C. Then add (R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester dropwise. R128 mg (0.64 mmol) of tert-butyl(R)-2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester was dissolved in 5 mL of dichloromethane and added dropwise over 10 min. The reaction was carried out at -40 °C for 1 hour. The organic solvent was removed by vacuum distillation. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product tert-butyl(R)-2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-a, 197 mg, yield 76.95%).

[0340] Step 2: Tert-butyl ( R )-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-b)

[0341] tert-butyl ( R 2-((2,7-dichloropteridin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (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-dioxane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (266 mg, 0.3 mmol) were dissolved in 1,4-dioxane (5 ml) and water (0.5 ml), and the reaction was carried out at 60 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 50 / 1) to obtain the target product tert-butyl( R )-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-b, 135 mg, yield 69.23%).

[0342] Step 3: Tert-butyl ( R )-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-c)

[0343] tert-butyl (R )-2-((2-chloro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-b, 130 mg, 0.17 mmol), palladium acetate (8 mg, 0.034 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (21 mg, 0.034 mmol), cesium carbonate (111 mg, 0.34 mmol) and ((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H 135 mg (0.85 mmol) of methanol was dissolved in toluene (10 mL), and the reaction was carried out at 110 °C for 16 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane / methanol = 10 / 1) to obtain the target product, tert-butyl( R )-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H )-yl)methoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (17-c, 48 mg, yield 32.43%). ESI[M+H] + 872.8

[0344] Step 4: tert-butyl ( R )-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H )-ylmethoxy)pterin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid ester (17-d)

[0345] tert-butyl ( R )-2-((7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidone-7 a (5 H1,3-(17-C, 48 mg, 0.055 mmol) pterin-4-ylamino)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 to 50 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product tert-butyl( R )-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(2 R 7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H (17-d, 46 mg, 120% yield) P-methylpyrrolidine-1-carboxylic acid ester (ESI) [M+H + =716.8

[0346] Step 5: 5-ethynyl-6-fluoro-4-(2-((2) R 7 aS )-2-Fluorotetrahydrofuran-1 H -pyrrolidine-7 a (5 H )-yl)methoxy)-4-((( R )-pyrrolidine-2-yl)methyl)amino)pterin-7-yl)naphthalene-2-ol trifluoroacetate (17)

[0347] tert-butyl ( R )-2-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(2R,7 aS )-2-fluorotetrahydro-1 H -pyrrolidine-7 a (5 H 5-(2-( ... R 7 aS It should be noted that there seem to be some irregular or repeated "aS" notations in the original text which might need further clarification in the context. Also, some of the ID numbers in the translation might have incorrect formatting due to the original text's unclear presentation. )-2-Fluorotetrahydrofuran-1 H -pyrrolidine-7 a (5 H)-yl)methoxy)-4-(((R)-pyrrolidine-2-yl)methyl)amino)pterin-7-yl)naphthyl-2-ol trifluoroacetate (17, 7.04 mg, yield 17.17%). ESI [M+H + = 572.3. 1 H NMR (600 MHz, CD3OD- d 4) δ 8.76 (d, J = 42.6 Hz, 1H), 7.92 (dd, J = 9.2, 5.6 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.28 (d, J = 2.5 Hz, 1H), 5.65 – 5.53 (m, 1H), 4.72 (d, J = 3.9 Hz, 2H), 4.11 – 4.06 (m, 1H), 4.01 (d, J = 7.0 Hz, 3H), 3.95 (dq, J = 9.6, 5.2,3.4 Hz, 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, 4.5 Hz, 3H), 2.12 (dd, J = 13.3, 8.0 Hz, 1H), 1.95 (ddt, J =13.5, 8.7, 4.4 Hz, 1H).

[0348] Test Example 1: Phosphorylation-ERK HTRF Test

[0349] A427 cells expressing the KRAS G12D mutation were cultured in MEM medium (Gibco) containing 10% fetal bovine serum (FBS). Once the cells reached the logarithmic growth phase, the A427 cells were resuspended in serum-free medium at a density of 3.125 × 10⁶ cells / year. 5Cells were seeded at 80 μl / well in 96-well cell culture plates (25,000 cells / well) and incubated overnight at 37°C, 5% CO2. The next day, 20 μl of the compound diluted with serum-free medium was added to each well. After incubation at 37°C, 5% CO2 for 4 hours, the culture medium was removed from the 96-well plates, and 50 μl of 1× cell lysis buffer (Cisbio) was added to each well. The plates were then incubated at room temperature with shaking for 30 min. 16 μl of cell lysis buffer was transferred to 384-well plates (Greiner), and 4 μl / well of pre-mixed antibody (Cisbio64AERPEH) was added. The plates were incubated overnight at room temperature, and HTRF signals were read using a Tecan Spark multimode microplate reader. Data were analyzed using a 4-parameter logistic model to calculate the IC50. 50 value.

[0350] The results of phosphorylated-ERK HTRF tests are shown in Table 1:

[0351] Among them, for IC 50 Value, where "+++" indicates IC 50 <10μM; "++" indicates IC 50 Between 10μM and 100μM.

[0352] Table 1

[0353]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) In equation (I), X is N and Y is -CR 4 ;in, R 4 Selected from -H, -D, halogen, -CF3, -OH, -CN; R 1 for ; When W is N, R 1 one of the This means there are no chemical bonds, the other one Represents a single bond, R 5 R 6 One of them is selected from -H, -D, halogen, -CF3, C. 1-6 Alkyl group, the other one is absent; When W is C Represents a single bond, R 5 R 6 Each is independently selected from -H, -D, halogen, -CF3, -OH, -CN, and C. 1-6 alkyl; When W is 0 This means there are no chemical bonds; When W is S Represents a double bond; represent ; R 7 Each is independently selected from -H, -D, halogen, -CF3, -OH, -CN, and C. 1-6 Alkoxy, C 1-6 Alkyl group; p can be 0, 1, 2, or 3. n can be any value of 0, 1, or 2; m and q can each be independently chosen as 0 or 1; R 2 for Among them, R 8 R 9 Each is independently selected from halogen, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, trifluoromethyl, amino, hydroxyl; g and f are each independently selected as 0, 1, 2, or 3; R 3 for Wherein, d can be arbitrarily selected as 1, 2 or 3; ring A is selected from 3 to 9-membered heterocyclic alkyl groups; Furthermore, the 3 to 9-membered heterocyclic alkyl groups are optionally substituted by 0, 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and amino groups; The heterocyclic alkyl group 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.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The halogen is fluorine.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from the following structures: 、 、 、 、 、 。 4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from the following structures: 、 、 、 、 、 。 5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 3 Selected from the following structures: 、 、 、 。 6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is shown in formula (Ⅱ-b). Equation (Ⅱ-b) R 2 R 3 R 4 R 5 R 6 R 7 The definitions of W, m, n, q, and p are as described in claim 1.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compounds are shown in formulas (II-f), (II-g), (II-h), and (II-i). Equation (Ⅱ-f) Formula (Ⅱ-g) Equation (Ⅱ-h) Formula (II-i) R 2 R 3 R 4 R 5 R 6 R 7 The definitions of , n, and p are as described in claim 1.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is shown in formula (Ⅲ-a). Equation (Ⅲ-a) R 1 R 2 R 4 The definitions of rings d and A are as described in claim 1.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is shown in formula (Ⅲ-c). Formula (Ⅲ-c) R 2 R 4 R 5 R 6 R 7 The definitions of rings n, p, d, and A are as described in claim 1.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compounds are shown in formulas (Ⅲ-e), (Ⅲ-g), (Ⅲ-i), and (Ⅲ-k). Equation (Ⅲ-e) Formula (Ⅲ-g) Formula (III-i) Equation (Ⅲ-k) R 2 R 4 R 5 R 6 R 7 The definitions of rings n, p, d, and A are as described in claim 1.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compounds are shown as those of formula (Ⅲ-o) and formula (Ⅲ-p). Formula (Ⅲ-o) Equation (Ⅲ-p) R 1 R 2 R 4 The definition is as described in claim 1.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The pharmaceutically acceptable salt is selected from 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.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following: 。 14. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, comprising the following steps, (1) Compound I-1 and compound R 1' H undergoes a substitution reaction to generate compound I-2, wherein R 1' The group is selected from R 1 Or Boc replaces R 1 ; (2) The compound I-2 and compound or Following the Suzuki coupling reaction, compound Ma is generated, wherein R... 2' The group is selected from R 2 or R substituted with protecting group 2 ; (3) The compound Ma and compound R 3 H undergoes a coupling reaction to generate compound Mb; (4) The compound Mb undergoes deprotection under acidic conditions to generate compound M; The R 1 R 2 R 3 The definition is as described in any one of claims 1-13.

15. A pharmaceutical composition, wherein, The composition comprises a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

16. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating cancer or immune diseases.

17. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating diseases associated with KRAS mutations.

18. The use as described in claim 16, wherein, The cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, or ovarian cancer.

19. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a KRAS inhibitor.

20. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of KRAS G12D and other KRAS mutation inhibitors.

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