Pyrido[4,3-D]pyrimidine derivatives as mutant KRAS G12C inhibitors for cancer treatment

Abstract

This disclosure provides a compound of formula (I) useful for treating or suppressing cancer, for example, cancer characterized by KRAS G12C, for use in the treatment and suppression of cancer. Pharmaceutical formulations containing such compounds and processes for preparing such compounds are also provided. TIFF2026517789000598.tif59165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 464,191, filed on 4 May 2023, and U.S. Provisional Patent Application No. 63 / 615,742, filed on 28 December 2023, the disclosures thereof incorporated herein by reference in their entirety.

[0002] Field of Invention This disclosure provides compounds useful in treating or suppressing cancer, particularly compounds useful in treating or suppressing cancer characterized by KRAS G12C mutations. Also provided are pharmaceutical formulations containing such compounds, processes for preparing such compounds, and methods for using such compounds in the treatment or suppression of cancer. [Background technology]

[0003] background KRAS is a molecular switch. Under normal physiological conditions, the protein is in the "off state" bound to guanosine diphosphate (GDP). In response to signaling via receptor tyrosine kinases (RTKs) such as EGFR, GDP is exchanged for guanosine triphosphate (GTP) in a process facilitated by guanine nucleotide exchange factors (GEFs) such as SOS. The GTP-bound form of KRAS is the "on state," and it interacts with proteins such as RAF and PI3K to enhance downstream signaling that leads to cell division, proliferation, and survival. In a process facilitated by GAP (GTPase-activating protein), KRAS can slowly hydrolyze GTP back to GDP and thus return to the "off state."

[0004] KRAS mutations are found in approximately 30% of all human cancers and are extremely common in the three most deadly forms of cancer: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%). Combined, these cancers occur in more than 200,000 patients annually in the United States alone. One specific mutation (a substitution of glycine to cysteine ​​at position 12 (G12C)) occurs in more than 40,000 patients per year. The KRAS G12C mutation impairs the hydrolysis of GTP to GDP, thus trapping KRAS in an "on" state and promoting the proliferation of cancer cells.

[0005] The cysteine ​​residue of G12C offers an opportunity to develop covalent drugs targeted to this mutant KRAS. Early clinical trial results for the KRAS G12C inhibitors AMG 510 and MRTX849 showed promising results for non-small cell lung cancer (NSCLC), but the data for colorectal cancer (CRC) were less compelling. Furthermore, even in cases where patients respond to initial treatment, there are indications of limited duration of response and the potential for rapid resistance development.

[0006] Most inhibitors of KRAS mutations preferentially bind to the GDP-bound form of the protein. For example, Amgen's KRAS inhibitor AMG 510 and Mirati's KRAS inhibitor MRTX849 react at least 1000 times faster to the GDP-bound form of KRAS G12C than to the GTP-bound form of the protein. One form of resistance observed is that cancer cells increase signaling via RTKs, thus increasing the amount of GTP-bound KRAS that is less affected by current inhibitors. Therefore, the creation of molecules that can bind to and inhibit both the GDP-bound and GTP-bound forms of KRAS may have substantial utility.

[0007] What is needed is a compound useful in the treatment of cancer (such as cancer characterized by KRAS G12C). What is needed is a compound useful in the treatment of cancer characterized by KRAS G12C that binds to and inhibits both the inactivated GDP-bound and activated GTP-bound forms of KRAS. What is needed is a compound useful in the treatment of cancer characterized by KRAS G12C that improves the inhibition of the GTP-bound form of KRAS G12C. [Overview of the Initiative]

[0008] overview In one embodiment, the present invention relates to a compound of formula (I): TIFF2026517789000002.tif59165 or its salts, and / or its isotopic substitutions are provided, in the formula, X is either -N(CH3)- or -O-; X 1 is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is either 0 or 1; R 1 This is a 4- to 8-membered saturated heterocyclic group containing one nitrogen atom as the sole heteroatom within the ring atom, where the heterocyclic group has 0, 1, 2, or 3 R atoms. 1A Replaced by; R in each case 1A The R is independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl), or two geminal R 1A However, together with the carbon atoms to which they are bonded, they form C3-C4 cycloalkyl groups substituted with 0, 1, or 2 halos, or two geminal R groups. 1A These combine to form =CH2, =CHF, or =CF2; Ra is H or CH3; R 2 is TIFF2026517789000003.tif52165; R 3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 5 is H or -OH; Y is CH or N; Each R in each case 6 is independently selected from the group consisting of halo, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, and -NH2; and r is 0, 1, 2, or 3; Provided that when q is 0, R 1 is neither TIFF2026517789000004.tif33165 nor any of its enantiomers, and when TIFF2026517789000005.tif40165 is TIFF2026517789000006.tif46165 or any of its enantiomers, R 2 is not TIFF2026517789000007.tif33165, and when TIFF2026517789000008.tif40165 is TIFF2026517789000009.tif40165 or any of its enantiomers, R 2 is not TIFF2026517789000010.tif33165 either.

[0009] In some embodiments, including any of the embodiments described in the preceding paragraphs, the compound is selected from the group consisting of the compounds in Table 1, as well as all of their salts and isotopic substitutions.

[0010] In another embodiment, a pharmaceutical formulation is provided comprising a compound described herein (including, but not limited to, the compounds described in the preceding paragraph) and a pharmaceutically acceptable carrier, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0011] In another embodiment, a method is provided for treating or suppressing cancer, which comprises administering a therapeutically effective amount of a compound described herein (including, but not limited to, the compounds described in the preceding paragraph) or a pharmaceutical formulation (including, but not limited to, the pharmaceutical formulations described in the preceding paragraph) to a subject in need thereof, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt. In some embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In some embodiments, cancer is glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell carcinoma The group is selected from myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In some embodiments encompassing any of the embodiments described above, the method is for treating cancer. In some embodiments encompassing any of the embodiments described above, the method is for suppressing cancer. In some embodiments encompassing any of the embodiments described above, the cancer is a KRAS G12C-mediated cancer. In some embodiments encompassing any of the embodiments described above, the subject is diagnosed with KRAS G12C-mediated cancer.In some embodiments, the method further includes administering a therapeutically effective amount of an additional chemotherapeutic agent to the subject.

[0012] In another embodiment, the use of the compounds described herein (including, but not limited to, any of the embodiments described above) as pharmaceuticals is provided. In another embodiment, the use of the compounds described herein (including, but not limited to, any of the embodiments described above) for treating or suppressing cancer is provided. In another embodiment, the use of the compounds described herein (including, but not limited to, any of the embodiments described above) in the manufacture of a pharmaceutical for use in treating or suppressing cancer is provided. In some embodiments encompassing any of the embodiments described above, the use is for treating cancer. In some embodiments encompassing any of the embodiments described above, the use is for suppressing cancer.

[0013] In another embodiment, compounds described herein (including, but not limited to, any of the embodiments described above) are provided for use in the manufacture of pharmaceuticals for treating or suppressing cancer. In another embodiment, compounds described herein (including, but not limited to, any of the embodiments described above) are provided for use in treating or suppressing cancer. In another embodiment, compounds described herein (including, but not limited to, any of the embodiments described above) are provided for use in the manufacture of pharmaceuticals for treating or suppressing cancer. In some embodiments encompassing any of the embodiments described above, the use is for treating cancer. In some embodiments encompassing any of the embodiments described above, the use is for suppressing cancer.

[0014] The descriptions of compounds, compositions, formulations, and therapeutic methods described herein are understood to include embodiments that "contain ~", "consist of ~", and "essentially consist of ~". In some embodiments, for all compositions described herein and all methods of using compositions described herein, the compositions may contain listed components or steps, or "essentially consist of" listed components or steps. Where a composition is described as "essentially consisting of" listed components, the composition may contain the listed components and other components that do not substantially affect the condition being treated, but not other components other than those explicitly listed that substantially affect the condition being treated; or, if the composition contains surplus components other than those listed that substantially affect the condition being treated, the composition does not contain surplus components in a concentration or quantity sufficient to substantially affect the condition being treated. Where a method is described as "essentially consisting of" the listed steps, the method may contain the listed steps and other steps that do not substantially affect the condition being treated, but the method shall not contain any other steps other than those explicitly listed that substantially affect the condition being treated. As a non-limiting example, where a composition is described as "essentially consisting of" components, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other components that do not substantially affect the condition being treated.

[0015] Additional embodiments, features, and advantages of this disclosure will become apparent from the following embodiments for carrying out the invention and through the practice of this disclosure. [Modes for carrying out the invention]

[0016] Detailed explanation Compounds useful in the treatment of cancer and methods of using such compounds for the treatment of cancer are provided herein. In some embodiments, the compounds are useful in the treatment of cancer characterized by KRAS G12C. In some embodiments, the compounds advantageously inhibit both the inactivated GDP-bound and activated GTP-bound forms of KRAS G12C. In some embodiments, the compounds advantageously have improved inhibition of the GTP-bound form of KRAS G12C.

[0017] definition Unless otherwise specified, abbreviations used herein have their conventional meanings within the fields of chemistry and biology.

[0018] Please understand that the description of compound structures, including possible substitutions, is limited to those that are chemically possible.

[0019] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. The “Examples” column in Table 1 indicates the synthesis example number corresponding to the structure listed in the same row in Table 1. For a set of compounds in Table 1, each having absolute stereochemistry, multiple example numbers may be assigned to the “Examples” column. In such cases, each assigned example produced only one of those compounds. However, the absolute stereochemistry of the compounds is not determined. For example, compounds 7-2 and 7-3 in Table 1 are listed as “22 or 23” in the “Examples” column. This means that only one of compounds 7-2 and 7-3 was obtained from Example 22, and only the other compound was obtained from Example 23. As another example, compounds 15-3, 15-4, 15-5, and 15-6 in Table 1 are listed as “36 or 37” in the “Examples” column. This means that only one of the four compounds was obtained from Example 36, and only one of the other three compounds was obtained from Example 37.

[0020] Compounds marked with (and) in the stereochemistry column of Table 1 are mixtures of enantiomers, and their relative stereochemistry is as shown. Compounds that have a stereocenter whose configuration is not shown in the illustrated structure and are not listed in the stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds that have a stereocenter whose configuration is shown by a solid or dashed wedge in the structure and are not listed in the stereochemistry column of Table 1, or are marked with (abs), are single enantiomers, in which case their absolute stereochemistry is as shown.

[0021] For example, compound 7-2 TIFF2026517789000011.tif52165 is a single enantiomer with the stereochemistry shown.

[0022] The solid or dashed non-wedge (i.e., rectangular) bonds in a compound indicate that the compound is a mixture of different diastereomers having fixed cis or trans configurations.

[0023] For example, compound 7-1 TIFF2026517789000012.tif59165 is compound 7-2 TIFF2026517789000013.tif52165 and 7-3 It is a mixture with TIFF2026517789000014.tif52165.

[0024] In some cases, the stereochemistry column in Table 1 includes different indices selected from (abs) and (and), which represent different stereocenters or pairs of stereocenters of a molecule.

[0025] For example, compound 27-1 In TIFF2026517789000015.tif59165, "amino-pyrrolidine-(abs)" indicates that the compound has a (R,R) stereoconfiguration in which the amino-pyrrolidine head is depicted, and also "R 1-(and) is the R of a compound 1 The group has either (R) or (S) stereochemistry, and as a result, the compound obtained from Example 55 is compound 27-2 TIFF2026517789000016.tif59165 and 27-3 This indicates that it is a mixture with TIFF2026517789000017.tif59165.

[0026] Those skilled in the art will be able to separate racemic compounds into their respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization, and the like. Reference to a racemic compound implies the inclusion of the individual enantiomers contained within the mixture.

[0027] References to values ​​or parameters in this specification that use the term "about" include (and describe) variations in the value or parameter itself. For example, a description referring to "about X" includes a description of "X". As used herein, and unless otherwise specified, the terms "about" and "approximately" mean a dose, amount, or weight percentage that would be recognized by those skilled in the art as providing an equivalent pharmacological effect to that obtained from a specified dose, amount, or weight percentage of an ingredient in a composition or dosage form. Specifically, as used in this context, the terms "about" and "approximately" intend doses, amounts, or weight percentages within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dose, amount, or weight percentage.

[0028] The terms "a" and "an" as used herein mean one or more unless otherwise clearly indicated by the context.

[0029] The terms “subject,” “individual,” and “patient” mean individual organisms, preferably vertebrates, more preferably mammals, and most preferably humans. Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, and horses). In some embodiments, the subject is identified or diagnosed as having cancer or a tumor with a KRAS G12C mutation (determined, for example, using an assay or kit approved by a regulatory agency (e.g., FDA approved)).

[0030] "Treating" a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, to reduce or eliminate the disorder or one or more symptoms of the disorder, to slow the progression of the disorder or one or more symptoms of the disorder, or to reduce the severity of the disorder or one or more symptoms of the disorder.

[0031] "Suppressing" a disorder by the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, to suppress the clinical signs of the disorder or the signs of the adverse symptoms of the disorder. The difference between treatment and suppression is that treatment occurs after the adverse symptoms of the disorder have become apparent in the subject, while suppression occurs before the adverse symptoms of the disorder have become apparent in the subject. Suppression may be partial, substantially complete, or complete. In some embodiments, genetic screening may be used to identify patients at risk of the disorder. The compounds and methods disclosed herein may then be administered to asymptomatic patients at risk of developing the clinical signs of the disorder to suppress the appearance of any adverse symptoms.

[0032] The “therapeutic use” of the compounds discussed herein is defined as the use of one or more of the compounds discussed herein to treat or suppress a disorder as defined herein. The “therapeutic dose” of a compound is the amount of the compound sufficient, when administered to a subject, to reduce or eliminate any of the symptoms of the disorder or one or more of the disorders, to slow the progression of the disorder or one or more of the symptoms of the disorder, to reduce the severity of the disorder or one or more of the symptoms of the disorder, to suppress the clinical signs of the disorder, or to suppress the signs of the adverse symptoms of the disorder. The therapeutic dose may be given in one or more doses.

[0033] In this specification, "KRAS G12C-mediated cancer" is used interchangeably with "cancer characterized by KRAS G12C," indicating that such cancer includes cells containing the KRAS G12C mutation.

[0034] The compounds described herein may be produced and used as neutral (non-salted) compounds, but this specification is intended to encompass all salts of the compounds described herein, as well as methods of using such salts of the compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0035] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable to humans and / or animals and retains at least some of the desired pharmacological activities of the parent compound upon administration. Such salts may be formed by (a) inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like); or by organic acids (such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4 Examples of acid addition salts formed by (b) an acid proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ions, alkaline earth ions, or aluminum ions) or by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like). Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985 (the entire document is incorporated herein by reference).

[0036] Where chemically related, all stereoisomers of a compound, including diastereomers and enantiomers, are included herein. This also includes, but is not limited to, racemic mixtures, of possible stereoisomers in any proportion. Unless stereochemistry is explicitly indicated within a structure, the structure is intended to encompass all possible stereoisomers of the compound shown. If stereochemistry is explicitly indicated for some or more parts of a molecule, but not for other parts or parts of the molecule, the structure is intended to encompass all possible stereoisomers for the parts or parts whose stereochemistry is not explicitly indicated.

[0037] In this specification, “isotope substitution” refers to a compound whose isotopic composition differs from its “natural” isotopic composition. “Isotope composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing those natural isotopic compositions may also be referred to in this specification as “unenriched” atoms. Unless otherwise specified, atoms of compounds listed in this specification are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, it is understood that the position has hydrogen in its natural isotopic composition. The descriptions of compounds in this specification include all isotopic substitutions of all compounds in this specification, and in some embodiments, partially deuterated or fully deuterated analogues. “Isotope-enriched” may also refer to a compound containing at least one atom having an isotopic composition other than that of its natural isotopic composition. "Isotope enrichment" refers to the percentage of a given atom in a molecule that incorporates a specific isotope in place of its naturally occurring isotopic abundance. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that specified position. Since the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using unenriched starting materials is approximately 0.0156%. The isotope enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0038] "Alkyl" refers to a saturated monovalent hydrocarbon radical that has a defined number of carbon atoms and is linear, branched, or a combination thereof. Examples of C1-C4 alkyl groups include methyl, ethyl, propyl, 2-propyl, butyl, and the like.

[0039] "Alkylene" refers to a saturated divalent hydrocarbon radical having a defined number of carbon atoms, in a linear, branched, or combination thereof configuration. Examples of C1-C4 alkylenes include methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and similar compounds.

[0040] "Alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having a defined number of carbon atoms. Examples of C2-C4 alkenyls include vinyl, propa-1-en-2-yl, propa-1-en-1-yl, allyl, and the like.

[0041] "Alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having a defined number of carbon atoms. Examples of C2-C4 alkynes include ethynyl, propynyl, 2-propynyl, butynyl, and similar compounds.

[0042] "alkoxy" is -OR x radical (where R is the radical in the formula) x (where is an alkyl as defined above), or -R x 'OR x '' radical (where R x ' is alkylene and R x '' means an alkyl group as defined above, where the defined number of alkyl carbons in the alkoxy group is R x 'and R x '' is equal to the total number of carbon atoms in the molecule. For example, C1-C4 alkoxys include, for example, methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, iso-butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, the alkoxy is -OR x It is radical. In some embodiments, the alkoxy is -R x 'OR xIt is radical. In some embodiments, when nitrogen is substituted with an alkoxy group, the alkoxy group is not linked to nitrogen via oxygen in the alkoxy group or carbon directly adjacent to oxygen. For example, alkoxy-substituted nitrogen is N-OR x But -CH2-OR x "Not really."

[0043] "alkoxyalkoxy" is -OR y radical (where R is the radical in the formula) y is an alkoxy as defined above, however R y The bond point is not an oxygen atom), or -R y 'OR y '' radical (where R y ' is alkylene and R y '' is an alkoxy group as defined above, however, R y The bond point of '' is not an oxygen atom, where the defined number of alkyl carbons in the alkoxyalkoxy group is R y 'and R y The total number of carbon atoms is equal to the total number of carbon atoms in the molecule. For example, C1-C6 alkalkalk represents, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, and the like. In some embodiments, alkalkalk is -OR y It is radical. In some embodiments, the alkoxyalkoxy is -R y 'OR y It is radical. In some embodiments, when nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not linked to nitrogen via oxygen in the alkoxyalkoxy group or carbon directly adjacent to oxygen. For example, alkoxyalkoxy-substituted nitrogen is N-OR y But N-CH2-OR y "Not really."

[0044] "Aminoalkyl" is -NHRz radical (where R is the radical in the formula) z (is an alkyl as defined above), or -NR z R z 'radical (where R is used in the formula) z and R z ' is an alkyl group as defined above, or -R z 'NH2 radical (wherein -R z '' is an alkylene group as defined above, or -R z ''NHR z radical (where R is the radical in the formula) z '' is an alkylene group as defined above, and R z ' is an alkyl group as defined above, or -R z 'NR z R z 'radical (where R is used in the formula) z '' is an alkylene group as defined above, and R z and R z ' means an alkyl group as defined above, where the defined number of alkyl carbons in the aminoalkyl group is R, where applicable. z , R z ', and R z The total number of carbon atoms is equal to the total number of carbon atoms in the molecule. For example, C1-C6 aminoalkyls include, for example, -NHCH3, -NHCH2CH3, -NHCH2(CH3)2, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -CH2NH2, -CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and the like. In some embodiments, aminoalkyls are -NHR z It is radical. In some embodiments, the aminoalkyl is -NR z R z 'It is a radical. In some embodiments, the aminoalkyl is -R z It is an NH2 radical. In some embodiments, the aminoalkyl is -R z ''NHR zIt is radical. In some embodiments, the aminoalkyl is -R z 'NR z R z 'It is radical. In some embodiments, when oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not linked to oxygen via the nitrogen in the aminoalkyl group or the carbon directly adjacent to the nitrogen. For example, aminoalkyl-substituted oxygen is O-NR z But O-CH2-NHR z But no.

[0045] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided within the aromatic ring system. 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (" 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). In some embodiments, "Aryl" also includes ring systems in which an aryl ring as defined above is condensed with one or more carbocyclyl or heterocyclyl groups, where the radical or bond site is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl and naphthyl, where the bond site can be on any carbon atom. Exemplary aryl groups include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like, where the bond site is on the phenyl group. In some embodiments, "Aryl" excludes ring systems in which an aryl ring as defined above is condensed with one or more carbocyclyl or heterocyclyl groups.

[0046] "Cycloalkyl" refers to a monocyclic saturated monovalent hydrocarbon radical having a defined number of carbon atoms. Examples of C3-C6 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] "Cycloalkylene" refers to a monocyclic saturated divalent hydrocarbon radical having a defined number of carbon atoms. Examples of C3-C6 cycloalkylenes include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0048] "Cyanoalkyl" refers to an alkyl radical, as defined above, that is substituted with a cyano group (-CN). Cyanoalkyl can also be called alkylnitrile.

[0049] "Halo" means fluoro, chloro, bromo, or iodine. In some embodiments, halo is fluoro or chloro.

[0050] "Haloalkyl" refers to an alkyl radical defined as one or more halogen atoms substituted with, for example, 1 to 5 halogen atoms (such as fluorine or chlorine), and includes those substituted with different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the same. When the alkyl is substituted only with fluoro, it may be referred to as fluoroalkyl in this application.

[0051] "Halalkoxy" is -OR a’ radical (where R is the radical in the formula) a’ (is a haloalkyl as defined above) or -R b’ Ure c’ radical (where R is the radical in the formula) b’ and R c’ R means an alkyl group or haloalkyl group as defined above, where the defined number of alkyl carbons in the haloalkoxy group is R b’ and R c’is equal to the total number of carbons therein. The halo atom(s) may be present in R b’ 、R c’ 、or both, provided that at least one of R b’ and R c’ contains a halo atom. For example, C1-C4 haloalkoxy includes, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2, and the like. In some embodiments, the haloalkoxy is a -OR a’ radical. In some embodiments, the haloalkoxy is a -R b’ OR c’ radical. When all of the halo atom(s) in the haloalkoxy group are fluorine, it may be referred to as fluoroalkoxy in the present application. In some embodiments, when nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not linked to nitrogen through oxygen or the carbon directly adjacent to oxygen in the haloalkoxy group. For example, haloalkoxy-substituted nitrogen is neither N-OR a’ nor N-C(H) n (X) m -O-R’’ (where X is a halogen and n and m are integers, provided that n + m = 2).

[0052] "Hydroxyalkyl" means an alkyl radical as defined above substituted with one or more hydroxyl (-OH) groups (e.g., 1 to 3 hydroxyl groups, such as -CH2OH, -CH2CH2OH, -C(OH)(CH3)2, -CH(OH)CH3, and the like).

[0053] Unless otherwise specified, a "heterocyclic group" or "heterocyclic group" means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, where 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the remainder of the ring is carbon. The sulfur group may exist either as -S- or -S(O)2-. Unless otherwise specified, heterocyclic groups include monocyclic and polycyclic systems, including fused, bridging, and spirocyclic systems. A "heterocyclic group" or "heterocyclic group" also includes cyclic systems in which a heterocyclic group as defined above is fused with one or more carbocyclic groups, where the bond site is on either the carbocyclic or heterocyclic group. In some embodiments, “heterocyclic group” or “heterocyclic” also encompasses a ring system in which a heterocyclic group as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on a heterocyclyl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. In some embodiments, the heterocyclic group is a monocyclic ring. In some embodiments, the heterocyclic group comprises two fused rings. In some embodiments, the heterocyclic group comprises two spiro rings. In some embodiments, the heterocyclic group comprises a bridging ring system.

[0054] Unless otherwise specified, "carbocyclic group" or "carbocyclic group" means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, the ring atoms of which are carbon. Unless otherwise specified, carbocyclic groups include monocyclic and polycyclic systems, including fused, bridging, and spirocyclic systems. In some embodiments, the carbocyclic group is monocyclic. In some embodiments, the carbocyclic group contains two fused rings. In some embodiments, the carbocyclic group contains two spirocyclic rings. In some embodiments, the carbocyclic group contains a bridging ring system.

[0055] Unless otherwise specified, “heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical consisting of 5 to 10 ring atoms, where one or more (in some embodiments, 1, 2, or 3) ring atoms are heteroatoms (or multiple) independently selected from N, O, or S, and the remainder of the ring atoms are carbon. In some embodiments, “heteroaryl” also includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocykyl or heterocyclyl groups, where the bond site is on the heteroaryl ring. In such cases, unless otherwise specified, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. In some embodiments, “heteroaryl” also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the bond site is on either the aryl ring or the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and similar groups), the bond site may be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl). In some embodiments, "heteroaryl" excludes ring systems in which the heteroaryl ring is fused with a carbocyclyl group or a heterocyclyl group. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazolyl, tetrazolyl, and similar groups.

[0056] The term "spiro" cycloalkyl group indicates that the cycloalkyl group is linked to the rest of the compound via a spiro linkage. A "spiro" cycloalkyl substituent has two bonding sites that connect to the same carbon atom of the substituted group, forming a spiro linkage. For example, a cyclohexyl group substituted with a "spiro C3-C4 cycloalkyl" group is This shows TIFF2026517789000018.tif27165.

[0057] "Requires treatment," as used herein, means that the patient is being treated by a physician or other caregiver after a diagnosis of the disease or a determination that the patient is at risk of developing the disease. In some embodiments, the patient has been diagnosed with KRAS G12C-mediated cancer. In some embodiments, the patient has been determined to be at risk of developing KRAS G12C-mediated cancer.

[0058] "Administer," "administer," and similar terms refer to bringing a compound of formula (I), formula (I'), or formula (I''), or a pharmaceutically acceptable salt and / or isotopic substitution thereof, a pharmaceutical composition containing the same, or a diagnostic agent into contact with a subject, cell, tissue, organ, or biological fluid, for example, when applied to a patient, cell, tissue, organ, or biological fluid. In the context of cells, administration includes bringing a reagent into contact with cells (e.g., in vitro or ex vivo), as well as bringing a reagent into contact with a fluid where the fluid is in contact with the cell.

[0059] "Optional" or "optional" means that the event or situation described thereafter may or may not occur, and that the description includes both examples in which the event or situation occurs and examples in which it does not occur.

[0060] "Pharmacologically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and useful in preparing a pharmaceutical composition that is not undesirable in either biological or otherwise respect, and includes carriers or excipients acceptable for veterinary and human pharmaceutical use. "Pharmacologically acceptable carrier / excipient" includes both one and more such excipients, as used in the specification and claims.

[0061] The term “disease,” as used herein, is generally synonymous with and intended to be interchangeable with the terms “disorder,” “syndrome,” and “pathological condition” (as in medical pathological conditions), all of which reflect an abnormal condition of one of the human or animal body or part thereof that impairs normal function, typically presents with distinguishing signs and symptoms, and results in a reduction of the duration or quality of life of the human or animal.

[0062] The term “combination therapy” means the administration of two or more therapeutic agents to treat the diseases or disorders described herein. Such administration encompasses the co-administration of these therapeutic agents substantially simultaneously (e.g., in a single capsule or tablet with a fixed ratio of active ingredients, or in multiple separate capsules or tablets for each active ingredient). In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In any case, the treatment regimen will have a beneficial effect of combining drugs in the treatment of the conditions or disorders described herein.

[0063] compound Compounds of formula (I) are provided herein. Unless otherwise required by context, references throughout this specification to “compounds of formula (I)” or “compounds of formula (I)” are, for example, formulas (I'), (I''), (Ia), (Ib), (Ic), (Id), (IA), (IB), (Ia-1), (Ia-2), (Ib-1), (Ib-2), (Ic-1), (Ic-2), (IA-a), (IA-b), (IA-c), (IA This refers to all embodiments of formula (I), including the compounds of (IA-a-1), (IA-a-2), (IA-b-1), (IA-b-2), (IA-c-1), (IA-c-2), (IB-a), (IB-b), (IB-c), (IB-d), (IB-a-1), (IB-a-2), (IB-b-1), (IB-b-2), (IB-c-1), (IB-c-2), and the compounds of Table 1. In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided. In some embodiments, compounds of formula (I) are provided as pharmaceutically acceptable salts. In some embodiments, compounds of formula (I) are provided as corresponding free bases (i.e., not salts).

[0064] In one embodiment, a compound of formula (I): TIFF2026517789000019.tif59165 or its salts, and / or its isotopic substitutions are provided, in the formula, X is either -N(CH3)- or -O-; X 1 is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is either 0 or 1; R 1 This is a 4- to 8-membered saturated heterocyclic group containing one nitrogen atom as the sole heteroatom within the ring atom, where the heterocyclic group has 0, 1, 2, or 3 R atoms. 1A Replaced by; R in each case 1AThe R is independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl), or two geminal R 1A However, together with the carbon atoms to which they are bonded, they form C3-C4 cycloalkyl groups substituted with 0, 1, or 2 halos, or two geminal R groups. 1A These combine to form =CH2, =CHF, or =CF2; R a is either H or CH3; R 2 teeth, The filename is TIFF2026517789000020.tif52165; R 3 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 5 is either H or -OH; Y is either CH or N; R in each case 6 is independently selected from the group consisting of halo, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, and -NH2; and r is 0, 1, 2, or 3.

[0065] In some embodiments, when q is 0, R 1 teeth, Neither TIFF2026517789000021.tif33165 nor any of its enantiomers. In some embodiments, TIFF2026517789000022.tif40165 is If TIFF2026517789000023.tif40165 or any enantiomer thereof, R 2 teeth, It is not TIFF2026517789000024.tif33165. In some embodiments, TIFF2026517789000025.tif40165 is If TIFF2026517789000026.tif40165 or any enantiomer thereof, R 2 teeth, It is not TIFF2026517789000027.tif33165. In some embodiments, TIFF2026517789000028.tif40165 is If TIFF2026517789000029.tif40165 or any enantiomer thereof, 2 teeth, It is not TIFF2026517789000030.tif33165. In some embodiments, R 1 but If TIFF2026517789000031.tif33165 or any enantiomer thereof, R 2 teeth, It is not TIFF2026517789000032.tif32164 either. In some embodiments, TIFF2026517789000033.tif40165 is If TIFF2026517789000034.tif40165 or any enantiomer thereof, R 2 teeth, It's not TIFF2026517789000035.tif34165 either.

[0066] In some embodiments, R 2 teeth, This is TIFF2026517789000036.tif52165. In some embodiments, R 3R is selected from the group consisting of halo, C1-C4 alkyl, and C2-C3 alkynyl. In some embodiments, R 3 R is selected from the group consisting of -F, -Cl, -Et, -C≡CH, and -C≡C-CH3. In some embodiments, R 4 is hydrogen or a halo. In some embodiments, R 4 is hydrogen or -F. In some embodiments, R 5 is -OH. In some embodiments, R 5 H is H.

[0067] In some embodiments, R 2 teeth, This is TIFF2026517789000037.tif71165. In some embodiments, R 2 teeth, The filename is TIFF2026517789000038.tif40165.

[0068] In some embodiments, R 2 teeth, The file is TIFF2026517789000039.tif33165. In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R in each case 6 r is independently selected from the group consisting of -Cl, -OH, -CH3, -CF3, cyclopropyl, and -NH2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0069] In some embodiments, R 2 teeth, This is TIFF2026517789000040.tif40165. In some embodiments, R 2 teeth, This is TIFF2026517789000041.tif40165. In some embodiments, R6A is cyclopropyl or -CF3. In some embodiments, R 6B is -Cl or -CH3. In some embodiments, R 6C It is either -OH or -NH2.

[0070] In some embodiments, R 2 teeth, The filename is TIFF2026517789000042.tif40165.

[0071] In some embodiments, X is -N(CH3)-. In some embodiments, X is -O-.

[0072] In some embodiments, X 1 is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl. In some embodiments, X 1 It is -CH3.

[0073] In some embodiments, the compound The TIFF2026517789000043.tif46165 part is The file is TIFF2026517789000044.tif103165. In some embodiments, the compound The part TIFF2026517789000045.tif46165 is, This is TIFF2026517789000046.tif167165. In some embodiments, the compound The part TIFF2026517789000047.tif46165 is TIFF2026517789000048.tif40165 is used in some embodiments of the compound The TIFF2026517789000049.tif46165 part is The filename is TIFF2026517789000050.tif40165.

[0074] In some embodiments, R 1 is 0, 1, 2, or 3 R 1A Replaced with This is TIFF2026517789000051.tif33165. In some embodiments, R in each case 1A These are independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3. In some embodiments, two geminal R 1A These, together with the carbon atoms to which they are bonded, form cyclopropyls substituted with 0, 1, or 2 fluorocarbons. In some embodiments, two geminal R 1A These combine to form =CH2, =CHF, or =CF2.

[0075] In some embodiments, R 1 teeth, This is TIFF2026517789000052.tif129165. In some embodiments, R 1 teeth, TIFF2026517789000053.tif198165TIFF2026517789000054.tif59165. In some embodiments, R 1 teeth, This is TIFF2026517789000055.tif27165. In some embodiments, R 1 teeth, The filename is TIFF2026517789000056.tif27165.

[0076] In some embodiments, R 1 teeth, This is TIFF2026517789000057.tif103165. In some embodiments, R 1 teeth, The filename is TIFF2026517789000058.tif230165.

[0077] In some embodiments, R aH is H. In some embodiments, R a This is CH3.

[0078] In one embodiment, the compound of formula (I') TIFF2026517789000059.tif52165 or its salts, and / or its isotopic substitutions are provided, in the formula, R 1 R is a 4- to 8-membered saturated carbocyclic or heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; 3 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; and q is either 0 or 1; However, if q is 0, R 1 teeth, It is neither TIFF2026517789000060.tif33165 nor any of its enantiomers.

[0079] In one embodiment, the compound is a compound of formula (IA) or (IB). TIFF2026517789000061.tif52165TIFF2026517789000062.tif52165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0080] In one embodiment, the compound is a compound of formula (IA).

[0081] In one embodiment, the compound is the compound of formula (1B).

[0082] In one embodiment, the compound is a compound of formula (Ia), formula (Ib), or formula (Ic): TIFF2026517789000063.tif52165TIFF2026517789000064.tif52165TIFF2026517789000065.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0083] In one embodiment, the compound is the compound of formula (Ia).

[0084] In one embodiment, the compound is the compound of formula (Ib).

[0085] In one embodiment, the compound is a compound of formula (Ic).

[0086] In one embodiment, the compound is a compound of formula (Ia-1) or formula (Ia-2): TIFF2026517789000066.tif52165TIFF2026517789000067.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0087] In one embodiment, the compound is the compound of formula (Ia-1).

[0088] In one embodiment, the compound is the compound of formula (Ia-2).

[0089] In one embodiment, the compound is a compound of formula (IA-a) or formula (IB-a): TIFF2026517789000068.tif52165TIFF2026517789000069.tif52165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0090] In one embodiment, the compound is a compound of formula (IA-a).

[0091] In one embodiment, the compound is the compound of formula (IB-a).

[0092] In one embodiment, the compound is a compound of formula (IA-a-1), formula (IA-a-2), formula (IB-a-1), or formula (IB-a-2): TIFF2026517789000070.tif52165TIFF2026517789000071.tif52165TIFF2026517789000072.tif52165TIFF2026517789000073.tif52165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0093] In one embodiment, the compound is a compound of formula (IA-a-1).

[0094] In one embodiment, the compound is a compound of formula (IA-a-2).

[0095] In one embodiment, the compound is a compound of formula (IB-a-1).

[0096] In one embodiment, the compound is a compound of formula (IB-a-2).

[0097] In one embodiment, the compound is a compound of formula (Ib-1) or formula (Ib-2): TIFF2026517789000074.tif52165TIFF2026517789000075.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0098] In one embodiment, the compound is the compound of formula (Ib-1).

[0099] In one embodiment, the compound is the compound of formula (Ib-2).

[0100] In one embodiment, the compound is a compound of formula (IA-b) or formula (IB-b): TIFF2026517789000076.tif52165TIFF2026517789000077.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0101] In one embodiment, the compound is the compound of formula (IA-b).

[0102] In one embodiment, the compound is the compound of formula (IB-b).

[0103] In one embodiment, the compound is a compound of formula (IA-b-1), formula (IA-b-2), formula (IB-b-1), or formula (IB-b-2): TIFF2026517789000078.tif52165TIFF2026517789000079.tif52165TIFF2026517789000080.tif52165TIFF2026517789000081.tif52165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0104] In one embodiment, the compound is the compound of formula (IA-b-1).

[0105] In one embodiment, the compound is the compound of formula (IA-b-2).

[0106] In one embodiment, the compound is a compound of formula (IB-b-1).

[0107] In one embodiment, the compound is a compound of formula (IB-b-2).

[0108] In one embodiment, the compound is a compound of formula (Ic-1) or formula (Ic-2): TIFF2026517789000082.tif52165TIFF2026517789000083.tif52165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0109] In one embodiment, the compound is the compound of formula (Ic-1).

[0110] In one embodiment, the compound is the compound of formula (Ic-2).

[0111] In one embodiment, the compound is a compound of formula (IA-c) or formula (IB-c): TIFF2026517789000084.tif52165TIFF2026517789000085.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0112] In one embodiment, the compound is a compound of formula (IA-c).

[0113] In one embodiment, the compound is a compound of formula (IB-c).

[0114] In one embodiment, the compound is a compound of formula (IA-c-1) or (IA-c-2), formula (IB-c-1), or formula (IB-c-2): TIFF2026517789000086.tif52165TIFF2026517789000087.tif52165TIFF2026517789000088.tif52165TIFF2026517789000089.tif52165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0115] In one embodiment, the compound is a compound of formula (IA-c-1).

[0116] In one embodiment, the compound is a compound of formula (IA-c-2).

[0117] In one embodiment, the compound is a compound of formula (IB-c-1).

[0118] In one embodiment, the compound is a compound of formula (IB-c-2).

[0119] In one embodiment, the compound is a compound of formula (Id): TIFF2026517789000090.tif59165 or its salts, and / or its isotopic substitutions, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0120] In one embodiment, the compound is a compound of formula (IA-d) or formula (IB-d): TIFF2026517789000091.tif59165TIFF2026517789000092.tif59165 or its salts, and / or isotopic substitutions thereof, where R 1 , R 3 , and R 4 This is as defined in any of the embodiments described herein.

[0121] In one embodiment, the compound is a compound of formula (IA-d).

[0122] In one embodiment, the compound is a compound of formula (IA-d).

[0123] Generally, as defined herein, each R 3 R is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R 3 R is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl. In one embodiment, each R 3 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R 3 R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R 3 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R3 R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, R 3 R is selected from halo and C1-C4 alkyl. In one embodiment, R 3 is selected from halo and C2-C3 alkynyl. In one embodiment, each R 3 R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R 3 In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R 3 is independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, R 3 is selected from -F, -Cl, -Et, and -C≡CH. In one embodiment, R 3 is selected from -F, -Cl, and -Et. In one embodiment, R 3 R is selected from -F, -Cl, and -C≡CH. In one embodiment, each R 3 is independently selected from the group consisting of -F and -Cl. In one embodiment, R 3 is -F. In one embodiment, R 3 is -Cl. In one embodiment, R 3 is -Et. In one embodiment, R 3 -C ≡ CH.

[0124] Generally, as defined herein, each R 4 R is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R 4 R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R 4 In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R 4is independently selected from the group consisting of -F and -Cl. In one embodiment, R 4 is selected from -H and -F. In one embodiment, R 4 is -H. In one embodiment, R 4 It is -F.

[0125] Generally, as defined herein, R 1 is a 4- to 8-membered saturated carbocyclic or heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, provided that in formula (I), when q is 0, R 1 teeth, It is neither TIFF2026517789000093.tif33165 nor any of its enantiomers.

[0126] In one embodiment, R 1 R is a 4- to 8-membered saturated bicyclic carbocyclic or bicyclic heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. In one embodiment, R 1 R is a 4- to 8-membered saturated heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. In one embodiment, R 1R is a 4- to 8-membered saturated monocyclic heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. In one embodiment, R 1 A is a 4- to 8-membered saturated bicyclic heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0127] In one embodiment, R 1 The carbocyclic or heterocyclic group is either unsubstituted or substituted with one substituent selected from halo, hydroxy, or spiro C3-C4 cycloalkyl. In one embodiment, R 1 The carbocyclic or heterocyclic group is either unsubstituted or substituted with one fluoro or spiro C3-C4 cycloalkyl group. In one embodiment, R 1 teeth, Selected from the group consisting of TIFF2026517789000094.tif33165, in the formula, R d This is as defined in any of the embodiments described herein. In one embodiment, R 1 teeth, TIFF2026517789000095.tif33165, and in the formula, R d This is as described herein. In one embodiment, R 1 teeth, Selected from TIFF2026517789000096.tif27165. In one embodiment, R 1 teeth, Selected from the group consisting of TIFF2026517789000097.tif33165.

[0128] In one embodiment, R 1 teeth, TIFF2026517789000098.tif33165, and in the formula, R d This is as defined in any of the embodiments described herein. In one embodiment, R 1 teeth, This is TIFF2026517789000099.tif27165. In one embodiment, R 1 teeth, Selected from TIFF2026517789000100.tif27165. In one embodiment, R 1 teeth, The filename is TIFF2026517789000101.tif33165.

[0129] In one embodiment, R 1 teeth, This is TIFF2026517789000102.tif27165. In one embodiment, R 1 teeth, The filename is TIFF2026517789000103.tif27165.

[0130] Generally, as defined herein, q is 0 or 1. In one embodiment, q is 0, except in formula (I), when q is 0, R 1 teeth, Neither TIFF2026517789000104.tif33165 nor any of its enantiomers. In one embodiment, q is 1.

[0131] Generally, as defined herein, R d is H or F. In one embodiment, R d H is H. In one embodiment, R d It is F.

[0132] In one embodiment, the compound is selected from the compounds in Table 1, their salts, and / or their isotopic substitutions. In one embodiment, the compound is not a salt.

[0133] In one embodiment, the compound is a salt. In one embodiment, the salt is a formate. In one embodiment, the salt is a trifluoroacetate. In one embodiment, the salt is a pharmaceutically acceptable salt.

[0134] In one embodiment, the compounds listed in Table 1, or salts thereof, and / or isotopic substitutions thereof are provided herein. In some embodiments, the salts are pharmaceutically acceptable salts.

[0135] [Table 1] TIFF2026517789000106.tif229165TIFF2026517789000107.tif192165TIFF202 6517789000108.tif204165TIFF2026517789000109.tif195165TIFF20265177890 00110.tif201165TIFF2026517789000111.tif196165TIFF2026517789000112.t if192165TIFF2026517789000113.tif196165TIFF2026517789000114.tif185165 TIFF2026517789000115.tif224165TIFF2026517789000116.tif198165TIFF202 6517789000117.tif207165TIFF2026517789000118.tif200165TIFF20265177890 00119.tif197165TIFF2026517789000120.tif221165TIFF2026517789000121.t if196165TIFF2026517789000122.tif207165TIFF2026517789000123.tif101165

[0136] In some variations, any of the compounds described herein, such as the compound of formula (I), or the compounds in Table 1, can be deuterated (for example, by substituting a hydrogen atom with a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other methods known in the art.

[0137] Any formula shown herein, such as formula (I), is intended to represent a compound having the structure shown by its structural formula, as well as a specific variant or form. In particular, any compound of any formula shown herein may have a chiral center and therefore may exist in different enantiomer or diastereomer forms. All optical and stereoisomers of a compound of a general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of that formula. Thus, any formula shown herein is intended to represent a racemate, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Furthermore, any formula shown herein is also intended to refer to a hydrate, solvate, and any one of the amorphous and polymorphic forms of such a compound, as well as mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water, and the solvate is a hydrate.

[0138] Representative examples of the compounds detailed herein, including intermediates and final compounds, are shown in the table and elsewhere in this specification. In one embodiment, it will be understood that any of the compounds, including intermediate compounds which may be isolated and administered to an organism if applicable, may be used in the manner detailed herein.

[0139] The compounds shown herein may exist as salts even if the salt is not shown, and it will be understood, as will be readily apparent to those skilled in the art, that the compositions and methods provided herein encompass all salts and solvates of the compounds shown herein, as well as the unsalted and unsolvated forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0140] In one variant, the compounds described herein are synthetic compounds prepared for administration to an individual. In another variant, a composition containing the compound in a substantially pure form is provided. In yet another variant, a pharmaceutical composition comprising the compound detailed herein and a pharmaceutically acceptable carrier is provided. In yet another variant, a method for administering the compound is provided. The purified form, pharmaceutical composition, and method for administering the compound are suitable for any of the compounds detailed herein or their forms.

[0141] R provided herein 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , X, X 1 q, r, R 1A , R 6A , R 6B , R 6C , R x , R x ', R x ''оR y , R y ', R y ''оR z , R z ', R z ''оR a’ , R b’ , or R c’ Any variation or embodiment of R is described individually and specifically as each combination is described separately. 1 , R 2 , R 3 , R 4 , R 5, R 6 , R a , X, X 1 q, r, R 1A , R 6A , R 6B , R 6C , R x , R x ', R x ''оR y , R y ', R y ''оR z , R z ', R z ''оR a’ , R b’ , or R c’ It can be combined with all other variations or embodiments of the same.

[0142] When used herein, if any variable appears multiple times in a chemical formula, its definition in each appearance is independent of its definition in any other appearance.

[0143] Methods for treating cancer Compounds of formula (I) and pharmaceutically acceptable salts and / or isotopic substitutions thereof (including their embodiments disclosed herein) are useful in the treatment of various types of cancer, including, but not limited to, lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. More specifically, cancers that can be treated with compounds of formula (I), and their pharmaceutically acceptable salts and / or isotopic substitutions (including their embodiments disclosed herein) include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute phosphorus Examples of cancers include, but are not limited to, pablastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In some embodiments encompassing any of the embodiments described above, the cancer is a KRAS G12C-mediated cancer. In some embodiments encompassing any of the embodiments described above, the subject is diagnosed with KRAS G12C-mediated cancer. In some embodiments encompassing any of the embodiments described above, the subject is determined to be at risk of developing KRAS G12C-mediated cancer.

[0144] In one embodiment, a compound of formula (I) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, is provided for use as a pharmaceutical.

[0145] In one embodiment, a compound of formula (I) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, is provided for use in treating or suppressing cancer. In one embodiment, if the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The cancers are selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the compound or pharmaceutical formulation is configured for administration in a therapeutically effective dose.

[0146] In one embodiment, a compound of formula (I) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, is provided for use in the manufacture of a pharmacopoeia for treating or suppressing cancer, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The cancers are selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the pharmaceutical comprises a therapeutically effective amount of a compound or pharmaceutical preparation.

[0147] In one embodiment, the use of a compound of formula (I) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, in the manufacture of a medicament for treating or suppressing cancer, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The cancers are selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the pharmaceutical comprises a therapeutically effective amount of a compound or pharmaceutical preparation.

[0148] In one embodiment, the use of a compound of formula (I) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, for treating or suppressing cancer, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0149] In one embodiment, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In one embodiment, the cancer is glioblastoma pleomorphoni, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid cancer, undifferentiated thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine body, squamous cell carcinoma of the cervix and adenocarcinoma of the cervix, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell bone marrow The cancers are selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, use involves a therapeutically effective amount of the compound or composition.

[0150] In some embodiments encompassing any of the embodiments described above, the subject and / or cancer is resistant or refractory to treatment with a particular KRAS inhibitor (e.g., a G12C KRAS inhibitor).

[0151] Compounds of formula (I), and their pharmaceutically acceptable salts and / or isotopic substitutions (including their embodiments disclosed herein), may be used in methods for inhibiting KRAS G12C in cells by contacting cells in which inhibition of KRAS G12C activity is desired with an amount of the compound effective in inhibiting KRAS G12C activity. Inhibition may be partial or complete. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo.

[0152] test Compounds of formula (I), and their pharmaceutically acceptable salts and / or isotopic substitutions (including their embodiments disclosed herein) may be tested by methods described, for example, in the following examples, or by known and generally accepted cell and / or animal models.

[0153] The ability of compounds of formula (I) and their pharmaceutically acceptable salts and / or isotopic substitutions to inhibit the activity of the GTP-bound form of KRAS G12C can be tested using methods such as the in vitro assays described in Examples 69 and 70 below. In Example 69, various compounds were tested for maximum inhibition of half (IC) of binding of the Ras-binding domain (RBD) to cRaf of KRAS G12C loaded with the GTP analog GMPPNP. 50 This section describes how to measure the maximum inhibition of half (IC) of binding to PI3Kα as the Ras-binding domain (RBD) of KRAS G12C loaded with the GTP analog GMPPNP for various compounds. 50 This section describes how to measure ). Example 71 describes testing a compound for its ability to inhibit cell survival in the MCF10A G12C / A59G mutation by inhibiting GTPase activity and thus preventing hydrolysis from GTP to GDP.

[0154] Pharmaceutical composition The terms "pharmaceutical composition" and "pharmaceutical preparation" are used interchangeably throughout this text.

[0155] In general, the compounds of formula (I) of the Disclosure, and their pharmaceutically acceptable salts and / or isotopic substitutions (which may also be referred to herein as “compounds” or “compounds of the Disclosure”) are administered in therapeutically effective doses by any of the acceptable modes of administration of drugs having similar utility. The therapeutically effective dose of the compounds of the Disclosure may range from about 0.01 to about 500 mg per kg of patient body weight per day and may be administered as a single dose or in multiple doses. In some embodiments, preferred dose levels may be about 0.1 to about 250 mg / kg per day; or about 0.5 to about 100 mg / kg per day. Within this range, the dosage may be approximately 0.05 to approximately 0.5, approximately 0.5 to approximately 5, or approximately 5 to approximately 50 mg / kg per day. For oral administration, the composition may be provided in the form of tablets containing approximately 1.0 to approximately 1000 milligrams of the active ingredient (particularly approximately 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient). The actual amount of the compound (i.e., the active ingredient) of this disclosure will depend on a number of factors, including the severity of the disease being treated, the patient's age and relative health, the potency of the compound being used, the route and form of administration, and other factors.

[0156] In general, the compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral administration, systemic administration (e.g., transdermal administration, intranasal administration, or administration by suppository), or parenteral administration (e.g., intramuscular administration, intravenous administration, or subcutaneous administration). The preferred mode of administration is oral administration using a convenient daily dosage regimen, which may be adjusted according to the severity of the disease. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or other suitable compositions.

[0157] The choice of formulation depends on various factors, such as the mode of drug administration (for example, formulations in the form of tablets, pills, or capsules for oral administration, for example, enteric-coated or delayed-release tablets, pills, or capsules are preferred) and the bioavailability of the drug substance.

[0158] The compositions generally consist of the compounds of the Disclosure in combination with at least one pharmaceutically acceptable excipient. The acceptable excipient is non-toxic, aids administration, and does not adversely affect the therapeutic benefits of the compounds of the Disclosure. Such excipients may be gaseous excipients in any solid, liquid, semi-solid, or aerosol composition, which are generally available to those skilled in the art.

[0159] Examples of solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk powder, and similar materials. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils (of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline solution, aqueous dextrose solution, and glycol.

[0160] The compounds may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be provided, for example, in unit dose form in ampoules or in multi-dose containers with added preservatives. Compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulation agents (suspending agents, stabilizers, and / or dispersants, etc.). Formulations may be provided in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in powder form or freeze-dried, requiring only the addition of a sterile liquid carrier (e.g., physiological saline or sterile pyrogen-free water) immediately before use. Solutions and suspensions for immediate injection may be prepared from the types of sterile powders, granules, and tablets previously described.

[0161] Preparations for parenteral administration include sterile aqueous and non-aqueous (oil-based) injectable solutions of the active compound, which may contain antioxidants, buffers, bacteriostatic agents, and solutes (to make the preparation isotonic with the blood of the intended recipient); and sterile aqueous and non-aqueous suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides), or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension (such as sodium carboxymethylcellulose, sorbitol, or dextran). Optionally, suspensions may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0162] In addition to the formulations described above, the compound can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

[0163] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, troches, or conventionally formulated gels. Such compositions may contain the active ingredient in a flavored base (such as sucrose and acacia or tragacanth).

[0164] The compound can also be formulated in rectal compositions (suppositories or retained enemas, etc.) containing, for example, conventional suppository bases (such as cocoa butter or polyethylene glycol or other glycerides).

[0165] Certain compounds in this disclosure may be administered topically, i.e., by non-systemic administration. Such non-systemic administration includes external application of the compound to the epidermis or buccal oral cavity, and infusion of such compound into the auricle, eye, and nose, so as not to significantly enter the bloodstream. In contrast, systemic administration refers to oral administration, intravenous administration, intraperitoneal administration, and intramuscular administration.

[0166] Suitable formulations for topical administration include liquid or semi-liquid preparations (such as gels, liniments, lotions, creams, ointments, or pastes) suitable for penetration through the skin into the site of inflammation, and drops suitable for administration to the eyes, ears, or nose. The active ingredient for topical administration may be present in, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may be present in up to 10% w / w. In other embodiments, the active ingredient may be present in less than 5% w / w. In certain embodiments, the active ingredient may be present in 2% w / w to 5% w / w. In other embodiments, the active ingredient may be present in 0.1% to 1% w / w of the formulation.

[0167] For administration by inhalation, the compound may be conveniently delivered by a ventilator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack may contain a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In the case of pressurized aerosols, the dosage unit may be determined by providing a valve that delivers a measured amount. Alternatively, for administration by inhalation or ventilation, the compound according to this disclosure may take the form of a dry powder composition, e.g., a powder mixture of the compound and a suitable powder base (e.g., lactose or starch). The powder composition may be presented in unit dosage forms, e.g., in capsules, cartridges, gelatin, or blister packs, and the powder from such unit dosage forms may be administered with the assistance of an inhaler or ventilator. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences (Mack Publishing Company, 20th ed., 2000), edited by EW Martin.

[0168] The level of the compound in a formulation can vary within the entire range used by those skilled in the art. Typically, a formulation will contain about 0.01–99.99% by weight of the compound in the formulation, based on the total weight percentage (W%), balanced by one or more suitable pharmaceutical excipients. For example, the compound may be present at levels of about 1–80% by weight.

[0169] Combination and combination therapy The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions in which the compounds of this disclosure or other drugs may be useful. Such other drugs may be administered simultaneously with or sequentially with the compounds of this disclosure. When the compounds of this disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosing form containing such other drugs and the compounds of this disclosure is intended. However, combination therapy may also include treatments in which the compounds of this disclosure and one or more other drugs are administered on different, overlapping schedules. When used in combination with one or more other active ingredients, the compounds of this disclosure and the other active ingredients may be used at lower doses than when each is used alone.

[0170] Therefore, the pharmaceutical compositions of this disclosure also include those containing one or more other drugs in addition to the compounds of this disclosure.

[0171] The above-mentioned combinations include not only the combination of one other drug but also the combination of the compound of this disclosure with two or more other active drugs. Similarly, the compound of this disclosure may be used in combination with other drugs used in the prevention, treatment, control, alleviation, or reduction of risk of diseases or conditions for which the compound of this disclosure is useful. Such other drugs may be administered simultaneously with or sequentially with the compound of this disclosure. When the compound of this disclosure is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure may be used. Thus, the pharmaceutical composition of this disclosure also includes those containing one or more other active ingredients in addition to the compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may vary and will depend on the effective dose of each component. Generally, the therapeutically effective dose of each component will be used.

[0172] If a subject requiring treatment with the compounds disclosed herein has cancer or is at risk of developing cancer, the subject may be treated with the compounds disclosed herein in any combination with one or more other anticancer agents.

[0173] In some embodiments, the compounds of the present disclosure are used in combination with CDK 4 / 6 inhibitors. Examples of CDK 4 / 6 inhibitors suitable for the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidine-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazine-1-yl)pyridine-2-yl)amino)-pyrido[2,3-d]pyrimidine-7(8H)-one) and ribociclib (7-cyclopentyl-N,N-dimethyl-2-((5-(piperazine-1-yl)pyridine-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), while CDK The 4 / 6 inhibitor trilaciclib (2'-((5-(piperazin-1-yl)pyridine-2-yl)amino)-7',8'-dihydro-6'H-spiro-[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one) is in late-stage clinical trials. Another CDK 4 / 6 inhibitor useful in the methods described herein is the CDK 2 / 4 / 6 inhibitor PF-06873600 (pyrido[2,3-d]pyrimidine-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

[0174] In another embodiment, the compounds of the present disclosure are used in combination with Raf family kinase inhibitors. Examples of Raf family kinase inhibitors suitable for the compositions and methods provided include encorafenib (LGX818): methyl(S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamide)phenyl)-1-isopropyl-1H-pyrazole-4-yl)pyrimidine-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidine-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoro Pyrrolidine-1-sulfonamide (;Raf-709:N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridine]-5-yl)-3-(trifluoromethyl)benzamide (;)LXH254:N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide;Sorafenib:4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY 3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido-[2,3-d]pyrimidine-6-yl)phenyl)urea;rifilafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifhioro-methyl)-1H-benzo[d]imidazole- 2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)methyl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one; Tak-632:N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)-phenyl)acetamide)phenoxy)benzo[d]thiazole-2-yl)cyclopropanecarboxamide;Examples include, but are not limited to, CEP-32496:1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-3-yl)urea; CCT196969:1-(3-(tert-butyl)-1-phenyl-1H-pyrazole-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-8-yl)oxy)phenyl)urea; and R05126766:N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methylsulfamide.

[0175] In another embodiment, the compounds of the Disclosure are used in combination with Src family kinases. Examples of Src family kinase inhibitors suitable for the compositions and methods provided include dasatinib (N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazine-1-yl)-2-methylpyrimidine-4-yl)amino)thiazole-5-carboxamide); ponatinib (3-(imidazo[1,2-b]pyridazin-3-ylethinyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoro Methyl(phenyl)benzamide); vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidine-4-yl)methoxy)quinazoline-4-amine); bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazine-1-yl)-propoxy)quinoline-3-carbonitrile); salakatinib (N-(5-chlorobenzo[d][1,3]dioxol-4-yl) )-7-(2-(4-methylpiperazine-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-4-amine);KX2-391(N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide);SU6656((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indole-2-yl)methylene)indoline-5-sulfonamide);PP1( Examples include, but are not limited to, 1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine);WH-4-023(2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)carbamate), and KX-01(N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide). In one embodiment, the Src inhibitor is dasatinib. In one embodiment, the Src inhibitor is salakatinib. In one embodiment, the Src inhibitor is ponatinib.In one embodiment, the Src inhibitor is vandetanib. In another embodiment, the Src inhibitor is KX-01.

[0176] In another embodiment, the compounds of this disclosure are used in combination with an SHP-2 inhibitor, such as SHP-099 (6-(4-amino-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-aminedihydrochloride), RMC-4550 (3(3S,4S)-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichlorophenyl)pyrazine-2-yl)methanol), RMC-4360 (Revolution Medicine), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

[0177] In another embodiment, the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for the compositions and methods provided include everolimus, rapamycin, zotalolimus (ABT-578), ridafololimus (defololimus; MK-8669), sapanicertib (INK128; 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)benzo[d]oxazole-2-amine), and torin-1; 1-(4-(4-propionylpiperazine-1-yl)- 3-(trifluoromethyl)cyclohexyl)-9-(quinoline-3-yl)benzo[h][1,6]naphthyridine-2(1H)-one, dactricib (BEZ235); 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)propanenitrile, buparlicib (5-(2,6-dimorpholine-4-ylpyrimidine-4-yl (L)-4-(trifluoromethyl)pyridine-2-amine); GDC-0941 (pictilisib); 4-[2-(1H-indazole-4-yl)-6-[(4-methylsulfonylpiperazine-1-yl)methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine); GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrid Examples include, but are not limited to, [3,4-d]pyrimidine-2-yl)phenyl)urea), VS-5584 (SB2343) (5-(8-methyl-2-morpholin-4-yl-9-propan-2-yl-purine-6-yl)pyrimidine-2-amine) and bis-tucertib (AZD-2014; 3-(2,4-bis((S)-3-methylmorpholino)pyrido-[2,3-d]pyrimidine-7-yl)-N-methylbenzamide).

[0178] In another embodiment, the compounds of the disclosed herein are used in combination with a pan-ErbB family inhibitor. In one embodiment, the KRAS inhibitor and the pan-ErbB family inhibitor are the sole activators in the provided composition and method. In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for the provided composition and method include afatinib; dacomitinib; canertinib; poziotinib; AV 412(N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazine-1-butyne-1-yl]-6-quinazolinyl]-2-prepenamide); PF 6274484(N-4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide); and HKI Examples include, but are not limited to, 357(N-(2(E)-N-[[4-[[3-chloro-4-[(fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide). In another embodiment, the pan-ErbB family inhibitors are reversible inhibitors.Examples of reversible pan-ErbB family inhibitors suitable for the provided compositions and methods include erlotinib, gefitinib, sapitinib; vallitinib; TAK-285(N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidine-5-yl]ethyl]-3-hydroxy-3-methylbutanamide); AEE788(S)-(6-(4-((4-ethyl Piperazine-1-ylmethyl)phenyl]-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine); talloxotinib(3-[N-[4-(3-bromo-4-chlorophenylamino)-pyrido[3,4-d]pyrimidine-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazole-5-ylmethyl)-2(E)-propene-1-aminium bromide); BMS Examples include, but are not limited to, 599626((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazole-5-yl]amino]-5-methylprolo(methylpurrolo)[2,1-f][1,2,4]triazine-6-yl]carbamate dihydrochloride); and GW 583340(N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[2-[2-(methylsulfonyl)ethylaminomethyl]thiazole-4-yl]quinazoline-4-amine dihydrochloride).

[0179] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, where the EGFR inhibitor and HER2 inhibitor are AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazoline-4-amine hydrochloride); AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl))-N-(3-phenylpropyl)-2-propenamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-propenamide); AG 825 (E-3-[3-benzothiazole-2-ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714(2-Methoxy-N-[(2E)-3-[4-[3-methyl-4-(6-methylpyridine-3-yloxy)phenylamino]quinazoline-6-yl]-2-propen-1-yl]acetamide);BIBU 1361(N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)-piperidine-1-yl]pyrimido[5,4-d]pyrimidine-4-amine dihydrochloride);BIBU 1382;(N 8 -(3-chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)pyrimidino[5,4-d]pyrimidine-4-aminedihydrochloride), JNJ 28871063 (5E-4-amino-6-[4-(benzyloxy)-3-chlorophenylamino]pyrimidine-5-carbaldehyde N-[2-(4-morpholinyl)ethyl]oxime hydrochloride); PD 153035 (4-(3-bromophenylamino)-6,7-dimethoxyquinazoline hydrochloride); and PD 158780 (N 4 -(3-bromophenyl)-N 6 This is a combination of two of the following: -methylpyrido[3,4-d]pyrimidine-4,6-diamine.

[0180] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody. Antibodies, including monoclonal antibodies, antibody conjugates, and bispecific antibodies that target EGFR and / or HER2, are well known, and several antibodies are commercially available for research and human clinical use. Examples of anti-EGFR antibodies suitable for the provided compositions and methods include nesitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for the provided compositions and methods include trastuzumab, trastuzumab, and trastuzumab emtansine.

[0181] In some embodiments, the compounds of this disclosure are used in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors suitable for the compositions and methods provided include, but are not limited to, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors, such as pembrolizumab (Keytruda®), nivolumab (Opdivo®), semiprimab (Libtayo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), relatrimab, opduralag, and dostallimab (Jemperli).

[0182] Compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and salts may be co-administered with other antineoplastic compounds (e.g., chemotherapy) or used as adjuvants in combination with other treatments (such as radiation or surgical intervention) either before or after surgery.

[0183] List of embodiments The following numbered embodiments represent several aspects of the present invention. Set A. Embodiment 1. Compound of formula (I'): TIFF2026517789000124.tif52165 or its salts, and / or its isotopic substitutions, in the formula, R 1 R is a 4- to 8-membered saturated carbocyclic or heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, where the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 3 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; and q is either 0 or 1; However, if q is 0, R 1 teeth, The compound, a salt thereof, and / or an isotopic substitution thereof, which is neither TIFF2026517789000125.tif33165 nor any enantiomer thereof.

[0184] Embodiment 2. The compound is a compound of formula (IA) or formula (IB), The compound according to Embodiment 1, which is TIFF2026517789000126.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0185] Embodiment 3. The compound is the compound of formula (IA) as described in Embodiment 2.

[0186] Embodiment 4. The compound is the compound of formula (IB) as described in Embodiment 2.

[0187] Embodiment 5. The compound is a compound of formula (Ia), formula (Ib), or formula (Ic): The compound according to Embodiment 1, which is TIFF2026517789000128.tif52165TIFF2026517789000129.tif52165TIFF2026517789000130.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0188] Embodiment 6. The compound is the compound of formula (Ia) as described in Embodiment 5.

[0189] Embodiment 7. The compound is the compound of formula (Ib), as described in Embodiment 5.

[0190] Embodiment 8. The compound is the compound of formula (Ic), as described in Embodiment 5.

[0191] Embodiment 9. The compound is a compound of formula (Ia-1) or formula (Ia-2): The compound according to Embodiment 1, which is TIFF2026517789000131.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0192] Embodiment 10. The compound is the compound of formula (Ia-1), as described in Embodiment 9.

[0193] Embodiment 11. The compound is the compound of formula (Ia-2), as described in Embodiment 9.

[0194] Embodiment 12. The compound is a compound of formula (IA-a) or formula (IB-a): The compound according to Embodiment 1, which is TIFF2026517789000133.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0195] Embodiment 13. The compound is the compound of formula (IA-a) as described in Embodiment 12.

[0196] Embodiment 14. The compound described in Embodiment 12, wherein the compound is a compound of formula (IB-a).

[0197] Embodiment 15. The compound is a compound of formula (IA-a-1), formula (IA-a-2), formula (IB-a-1), or formula (IB-a-2): The compound according to Embodiment 1, which is TIFF2026517789000135.tif52165TIFF2026517789000136.tif52165TIFF2026517789000137.tif52165TIFF2026517789000138.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0198] Embodiment 16. The compound is the compound of formula (IA-a-1) as described in Embodiment 15.

[0199] Embodiment 17. The compound is the compound of formula (IA-a-2), as described in Embodiment 15.

[0200] Embodiment 18. The compound is the compound of formula (IB-a-1), as described in Embodiment 15.

[0201] Embodiment 19. The compound is the compound of formula (IB-a-2), as described in Embodiment 15.

[0202] Embodiment 20. The compound is a compound of formula (Ib-1) or formula (Ib-2): The compound according to Embodiment 1, which is TIFF2026517789000139.tif52165TIFF2026517789000140.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0203] Embodiment 21. The compound is the compound of formula (Ib-1), as described in Embodiment 20.

[0204] Embodiment 22. The compound is the compound of formula (Ib-2), as described in Embodiment 20.

[0205] Embodiment 23. The compound is a compound of formula (IA-b) or formula (IB-b): The compound according to Embodiment 1, which is TIFF2026517789000141.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0206] Embodiment 24. The compound described in Embodiment 23, wherein the compound is a compound of formula (IA-b).

[0207] Embodiment 25. The compound described in Embodiment 23, wherein the compound is a compound of formula (IB-b).

[0208] Embodiment 26. The compound is a compound of formula (IA-b-1), formula (IA-b-2), formula (IB-b-1), or formula (IB-b-2): The compound according to Embodiment 1, which is TIFF2026517789000143.tif52165TIFF2026517789000144.tif52165TIFF2026517789000145.tif52165TIFF2026517789000146.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0209] Embodiment 27. The compound is the compound of formula (IA-b-1) as described in Embodiment 26.

[0210] Embodiment 28. The compound described in Embodiment 26, wherein the compound is a compound of formula (IA-b-2).

[0211] Embodiment 29. The compound is the compound of formula (IB-b-1), as described in Embodiment 26.

[0212] Embodiment 30. The compound is the compound of formula (IB-b-2), as described in Embodiment 26.

[0213] Embodiment 31. The compound is a compound of formula (Ic-1) or formula (Ic-2): The compound according to Embodiment 1, which is TIFF2026517789000147.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0214] Embodiment 32. The compound is the compound of formula (Ic-1), as described in Embodiment 31.

[0215] Embodiment 33. The compound is the compound of formula (Ic-2), as described in Embodiment 31.

[0216] Embodiment 34. The compound is a compound of formula (IA-c) or formula (IB-c): The compound according to Embodiment 1, which is TIFF2026517789000149.tif52165TIFF2026517789000150.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0217] Embodiment 35. The compound is the compound of formula (IA-c) as described in Embodiment 34.

[0218] Embodiment 36. The compound is the compound of formula (IB-c), as described in Embodiment 34.

[0219] Embodiment 37. The compound is a compound of formula (IA-c-1), formula (IA-c-2), formula (IB-c-1), or formula (IB-c-2): The compound according to Embodiment 1, which is TIFF2026517789000151.tif52165TIFF2026517789000152.tif52165TIFF2026517789000153.tif52165TIFF2026517789000154.tif52165 or a salt thereof, and / or an isotopic substitution thereof.

[0220] Embodiment 38. The compound is the compound of formula (IA-c-1) as described in Embodiment 37.

[0221] Embodiment 39. The compound is the compound of formula (IA-c-2), as described in Embodiment 37.

[0222] Embodiment 40. The compound is the compound of formula (IB-c-1), as described in Embodiment 37.

[0223] Embodiment 41. The compound is the compound of formula (IB-c-2), as described in Embodiment 37.

[0224] Embodiment 42. The compound is a compound of formula (Id): The compound according to Embodiment 1, which is TIFF2026517789000155.tif59165 or a salt thereof, and / or an isotopic substitution thereof.

[0225] Embodiment 43. The compound is a compound of formula (IA-d) or formula (IB-d): The compound according to Embodiment 1, which is TIFF2026517789000156.tif59165 or a salt thereof, and / or an isotopic substitution thereof.

[0226] Embodiment 44. The compound described in Embodiment 43, wherein the compound is a compound of formula (IA-d).

[0227] Embodiment 45. The compound is the compound of formula (IA-d), as described in Embodiment 43.

[0228] Embodiment 46.R 3 The compound is selected from halo, C1-C4 alkyl, and C2-C3 alkynyl, as described in any one of Embodiments 1 to 45.

[0229] Embodiment 47.R 3 The compound is selected from halo and C1-C4 alkyl groups, as described in any one of Embodiments 1 to 45.

[0230] Embodiment 48.R 3 The compound is selected from a halo and a C2-C3 alkynyl compound, as described in any one of Embodiments 1 to 45.

[0231] Embodiment 49.R 3 The compound is a halo, as described in any one of Embodiments 1 to 45.

[0232] Embodiment 50.R 3 The compound is selected from -F, -Cl, -Et, and -C≡CH, as described in any one of Embodiments 1 to 45.

[0233] Embodiment 51.R 3 The compound is selected from -F, -Cl, and -Et, as described in any one of Embodiments 1 to 45.

[0234] Embodiment 52.R 3 The compound is selected from -F, -Cl, and -C≡CH, as described in any one of Embodiments 1 to 45.

[0235] Embodiment 53.R 3 is a compound selected from -F and -Cl, as described in any one of Embodiments 1 to 45.

[0236] Embodiment 54.R 3 The compound is -F, as described in any one of Embodiments 1 to 45.

[0237] Embodiment 55.R 3The compound is -Cl, as described in any one of Embodiments 1 to 45.

[0238] Embodiment 56.R 3 The compound is -Et, as described in any one of Embodiments 1 to 45.

[0239] Embodiment 57.R 3 The compound is one of any one of Embodiments 1 to 45, wherein -C≡CH.

[0240] Embodiment 58.R 4 The compound is selected from hydrogen and halo, as described in any one of Embodiments 1 to 57.

[0241] Embodiment 59.R 4 is a compound selected from -H and -F, as described in any one of Embodiments 1 to 57.

[0242] Embodiment 60.R 4 The compound is -H, as described in any one of Embodiments 1 to 57.

[0243] Embodiment 61.R 4 The compound is -F, as described in any one of Embodiments 1 to 57.

[0244] Embodiment 62.R 1 The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein is a 4- to 8-membered saturated bicyclic carbocyclic group or bicyclic heterocyclic group containing one nitrogen as the sole heteroatom in the ring atom, and the carbocyclic group or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0245] Embodiment 63.R 1The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein the heterocyclic group is a 4- to 8-membered saturated heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, and the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0246] Embodiment 64.R 1 The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein the heterocyclic group is a 4- to 8-membered saturated monocyclic heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, and the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0247] Embodiment 65.R 1 The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein the heterocyclic group is a 4- to 8-membered saturated bicyclic heterocyclic group containing one nitrogen atom as the sole heteroatom in the ring atom, and the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro-C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0248] Embodiment 66. The R 1 The compound according to any one of Embodiments 62 to 65, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one substituent selected from halo, hydroxy, or spiro C3-C4 cycloalkyl.

[0249] Embodiment 67. The R 1 The compound according to any one of embodiments 62 to 65, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one fluoro or spiro C3-C4 cycloalkyl group.

[0250] Embodiment 68A.R 1 teeth, Selected from the group consisting of TIFF2026517789000158.tif33165, in the formula, R d The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein is H or F.

[0251] Embodiment 68B.R 1 teeth, The compound described in any one of embodiments 1 to 41 and 46 to 61, which is TIFF2026517789000159.tif103165.

[0252] Embodiment 68C.R 1 teeth, The compound according to any one of embodiments 1 to 41 and 46 to 61, which is TIFF2026517789000160.tif230165.

[0253] Embodiment 69.R 1 teeth, TIFF2026517789000161.tif33165, and in the formula, R d The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein is H or F.

[0254] Embodiment 70.R 1 teeth, TIFF2026517789000162.tif33165, and in the formula, R d The compound according to any one of embodiments 1 to 41 and 46 to 61, wherein is H or F.

[0255] Embodiment 71.R d The compound according to any one of embodiments 68 to 70, wherein H is present.

[0256] Embodiment 72.R d The compound is F, as described in any one of embodiments 68 to 70.

[0257] Embodiment 73.R 1 teeth, A compound according to any one of embodiments 1 to 41 and 46 to 61, selected from TIFF2026517789000163.tif27165.

[0258] Embodiment 74.R 1 teeth, A compound according to any one of embodiments 1 to 41 and 46 to 61, which is TIFF2026517789000164.tif27165.

[0259] Embodiment 75.R 1 teeth, The compound according to any one of embodiments 1 to 41 and 46 to 61, which is TIFF2026517789000165.tif27165.

[0260] Embodiment 76.R 1 teeth, The compound according to any one of Embodiments 1 to 61, which is TIFF2026517789000166.tif27165.

[0261] Embodiment 77.R 1 teeth, A compound according to any one of embodiments 1 to 41 and 46 to 61, selected from the group consisting of TIFF2026517789000167.tif33165.

[0262] Embodiment 78.R 1 teeth, The compound according to any one of Embodiments 1 to 61, which is TIFF2026517789000168.tif33165.

[0263] Embodiment 79. The compound is A compound according to any one of Embodiments 1 to 78, selected from the group consisting of TIFF2026517789000169.tif186165TIFF2026517789000170.tif192165 or its salts, and / or its isotopic substitutions.

[0264] Embodiment 80. The compound described in any one of Embodiments 1 to 79, which is not a salt.

[0265] Embodiment 81. The compound according to any one of Embodiments 1 to 79, wherein the compound is a salt.

[0266] Embodiment 82. The compound according to Embodiment 81, wherein the salt is a formate salt.

[0267] Embodiment 83. The compound according to Embodiment 81, wherein the salt is a trifluoroacetate salt.

[0268] Embodiment 84. The compound according to Embodiment 81, wherein the salt is a pharmaceutically acceptable salt.

[0269] Embodiment 85. A pharmaceutical formulation comprising a compound according to any one of Embodiments 1 to 84, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0270] Embodiment 86. A method for treating or suppressing cancer, comprising administering to a subject in need of the treatment an effective amount of a compound described in any one of Embodiments 1 to 84, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt, or a pharmaceutical formulation described in Embodiment 85.

[0271] Embodiment 87. The method according to Embodiment 86, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0272] Embodiment 88. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The method according to Embodiment 86, selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0273] Embodiment 89. The method according to any one of Embodiments 86 to 88, wherein the cancer is a KRAS G12C-mediated cancer.

[0274] Embodiment 90. The method according to any one of Embodiments 86 to 88, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0275] Embodiment 91. The method according to any one of Embodiments 86 to 88, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the subject.

[0276] Embodiment 92. A compound according to any one of Embodiments 1 to 84, or a pharmaceutical formulation according to Embodiment 77, for use as a pharmaceutical.

[0277] Embodiment 93. A compound according to any one of Embodiments 1 to 84, or a pharmaceutical formulation according to Embodiment 77, for use in treating or suppressing cancer, wherein the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0278] Embodiment 94. The compound or pharmaceutical formulation for use according to Embodiment 93, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0279] Embodiment 95. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytic myeloma, and uterine carcinosarcoma. Compounds or pharmaceutical formulations for use as described in Embodiment 93, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0280] Embodiment 96. The compound or pharmaceutical formulation for use according to any one of Embodiments 93 to 95, wherein the cancer is a KRAS G12C-mediated cancer.

[0281] Embodiment 97. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound or pharmaceutical formulation for use according to any one of Embodiments 93 to 95.

[0282] Embodiment 98. The compound or pharmaceutical formulation for use according to any one of Embodiments 93 to 97, wherein the compound or pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0283] Embodiment 99. The compound or pharmaceutical formulation for use according to any one of Embodiments 93 to 98, configured to be administered in a therapeutically effective dose.

[0284] Embodiment 100. A compound according to any one of Embodiments 1 to 84, or a pharmaceutical formulation according to Embodiment 77, for use in the manufacture of a pharmaceutical for treating or suppressing cancer, wherein the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0285] Embodiment 101. The compound or pharmaceutical formulation for use according to Embodiment 100, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0286] Embodiment 102. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytic myeloma, and uterine carcinosarcoma. Compounds or pharmaceutical formulations for use as described in Embodiment 100, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0287] Embodiment 103. The compound or pharmaceutical formulation for use according to any one of Embodiments 100 to 102, wherein the cancer is a KRAS G12C-mediated cancer.

[0288] Embodiment 104. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound or pharmaceutical formulation for use according to any one of Embodiments 100 to 102.

[0289] Embodiment 105. The compound or pharmaceutical formulation for use according to any one of Embodiments 100 to 104, wherein the compound or pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0290] Embodiment 106. The pharmaceutical compound or pharmaceutical formulation for use according to any one of Embodiments 100 to 105, comprising a therapeutically effective amount of the compound or composition.

[0291] Embodiment 107. The use of a compound according to any one of Embodiments 1 to 84, or a pharmaceutical formulation according to Embodiment 77, in the manufacture of a pharmaceutical for treating or suppressing cancer, wherein the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0292] Embodiment 108. The use described in Embodiment 107, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0293] Embodiment 109. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The use described in Embodiment 107, selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0294] Embodiment 110. The use according to any one of Embodiments 107 to 109, wherein the cancer is a KRAS G12C-mediated cancer.

[0295] Embodiment 111. The use described in any one of Embodiments 107 to 109, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0296] Embodiment 112. The use according to any one of Embodiments 107 to 111, wherein the compound or the pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0297] Embodiment 113. The use according to any one of Embodiments 107 to 112, wherein the pharmaceutical product comprises a therapeutically effective amount of the compound or the pharmaceutical preparation.

[0298] Embodiment 114. Use of a compound according to any one of Embodiments 1 to 84, or a pharmaceutical formulation according to Embodiment 77, for the treatment or suppression of cancer, wherein the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0299] Embodiment 115. The use described in Embodiment 114, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0300] Embodiment 116. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The use described in Embodiment 114 is selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0301] Embodiment 117. The use according to any one of Embodiments 114 to 116, wherein the cancer is a KRAS G12C-mediated cancer.

[0302] Embodiment 118. The use described in any one of Embodiments 114 to 116, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0303] Embodiment 119. The use according to any one of Embodiments 114 to 118, wherein the compound or the pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0304] Embodiment 120. The use described in any one of Embodiments 114 to 119, wherein the use is accompanied by a therapeutically effective amount of the compound or composition.

[0305] Set B. Embodiment 1. Compound of formula (I''): TIFF2026517789000171.tif59165 or its salts, and / or its isotopic substitutions, wherein in the formula, X is either -N(CH3)- or -O-; X 1 is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is either 0 or 1; R 1 This is a 4- to 8-membered saturated heterocyclic group containing one nitrogen atom as the sole heteroatom within the ring atom, where the heterocyclic group has 0, 1, 2, or 3 R atoms. 1A Replaced by; R in each case 1A The R is independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl), or two geminal R 1AHowever, together with the carbon atoms to which they are bonded, they form C3-C4 cycloalkyl groups substituted with 0, 1, or 2 halos, or two geminal R groups. 1A These combine to form =CH2, =CHF, or =CF2; R a is either H or CH3; R 2 teeth, The filename is TIFF2026517789000172.tif52165; R 3 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 5 is either H or -OH; Y is either CH or N; R in each case 6 is independently selected from the group consisting of halo, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, and -NH2; and r is 0, 1, 2, or 3; However, if q is 0, R 1 teeth, Neither TIFF2026517789000173.tif33165 nor any of its enantiomers, TIFF2026517789000174.tif40165 is If TIFF2026517789000175.tif40165 or any enantiomer thereof, 2 teeth, Not TIFF2026517789000176.tif33165, and TIFF2026517789000177.tif40165 is If TIFF2026517789000178.tif40165 or any enantiomer thereof, 2 teeth, The compound, its salt, and / or its isotopic substitutions, other than TIFF2026517789000179.tif34165.

[0306] Embodiment 2.R 2 teeth, The compound of Embodiment 1, or a salt thereof, and / or an isotopically substituted thereof, is TIFF2026517789000180.tif52165.

[0307] Embodiment 3.R 3 This refers to a compound according to Embodiment 2, selected from the group consisting of halo, C1-C4 alkyl, and C2-C3 alkynyl, or a salt thereof, and / or an isotopically substituted thereof.

[0308] Embodiment 4.R 3 This refers to a compound according to Embodiment 2, or a salt thereof, and / or an isotopic substituted thereof, selected from the group consisting of -F, -Cl, -Et, -C≡CH, and -C≡C-CH3.

[0309] Embodiment 5.R 4 The compound, salt thereof, and / or isotope-substituted derivative thereof, according to any one of Embodiments 2 to 4, wherein is hydrogen or a halo.

[0310] Embodiment 6.R 4 The compound, a salt thereof, and / or an isotopically substituted thereof, according to any one of Embodiments 2 to 4, wherein is hydrogen or -F.

[0311] Embodiment 7.R 5 The compound, a salt thereof, and / or an isotopically substituted thereof, is -OH.

[0312] Embodiment 8.R 5The compound, a salt thereof, and / or an isotopic substituted thereof, according to any one of Embodiments 2 to 6, wherein H is present.

[0313] Embodiment 9.R 2 teeth, The compound described in Embodiment 2, or a salt thereof, and / or an isotopic variant thereof, which is TIFF2026517789000181.tif71165.

[0314] Embodiment 10.R 2 teeth, The compound of Embodiment 1, or a salt thereof, and / or an isotopically substituted thereof, is TIFF2026517789000182.tif33165.

[0315] Embodiment 11.Y is CH, the compound of Embodiment 10, or a salt thereof, and / or an isotopically substituted thereof.

[0316] Embodiment 12.Y is N, the compound of Embodiment 10, or a salt thereof, and / or an isotopically substituted thereof.

[0317] Embodiment 13. R in each case 6 This is a compound according to any one of Embodiments 10 to 12, or a salt thereof, and / or an isotopic substituted thereof, independently selected from the group consisting of -Cl, -OH, -CH3, -CF3, cyclopropyl, and -NH2.

[0318] Embodiment 14.r is a compound, a salt thereof, and / or an isotopic substituted thereof, according to any one of Embodiments 10 to 13.

[0319] Embodiment 15.R 2 teeth, A compound, a salt thereof, and / or an isotopic variant thereof, as described in any one of Embodiments 10 to 13, which is TIFF2026517789000183.tif40165.

[0320] Embodiment 16.R 2 teeth, TIFF2026517789000184.tif40165, and in the formula, R 6A It is cyclopropyl or -CF3, and R 6B is -Cl or -CH3, and R 6C The compound, a salt thereof, and / or an isotopically substituted thereof, is -OH or -NH2, as described in any one of Embodiments 10 to 13.

[0321] Embodiment 17.R 2 teeth, The compound of Embodiment 10, or a salt thereof, and / or an isotopically substituted thereof, is TIFF2026517789000185.tif40165.

[0322] Embodiment 18.X is a compound, a salt thereof, and / or an isotopic substituted thereof, according to any one of Embodiments 1 to 17, wherein the compound is -N(CH3)-.

[0323] Embodiment 19.X is a compound, a salt thereof, and / or an isotopically substituted thereof, according to any one of Embodiments 1 to 17, wherein the compound is -O-.

[0324] Embodiment 21.X 1 The compound, a salt thereof, and / or an isotopically substituted thereof, is -CH3, as described in any one of Embodiments 1 to 19.

[0325] Embodiment 20.X 1 The compound, a salt thereof, and / or an isotopic substituted thereof, described in any one of Embodiments 1 to 19, wherein is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl.

[0326] Embodiment 22. The compound The TIFF2026517789000186.tif46165 part is A compound, a salt thereof, and / or an isotopic variant thereof, as described in any one of Embodiments 1 to 17, which is TIFF2026517789000187.tif103165.

[0327] Embodiment 23. The compound The TIFF2026517789000188.tif46165 part is A compound, a salt thereof, and / or an isotopic substituted thereof, as described in any one of Embodiments 1 to 17, which is TIFF2026517789000189.tif167165.

[0328] Embodiment 24.R 1 is 0, 1, 2, or 3 R 1A Replaced with A compound, a salt thereof, and / or an isotopic variant thereof, as described in any one of Embodiments 1 to 23, which is TIFF2026517789000190.tif33165.

[0329] Embodiment 25. R in each case 1A These are independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3, or two geminal R 1A However, together with the carbon atoms to which they are bonded, they form cyclopropyls substituted with 0, 1, or 2 fluorocarbons, or 2 geminal R 1A A compound according to any one of Embodiments 1 to 24, or a salt thereof, and / or an isotopic substituted thereof, wherein the compounds combine to form =CH2, =CHF, or =CF2.

[0330] Embodiment 26.R 1 teeth, A compound, a salt thereof, and / or an isotopic variant thereof, as described in any one of Embodiments 1 to 25, which is TIFF2026517789000191.tif103165.

[0331] Embodiment 27.R 1 teeth, A compound, a salt thereof, and / or an isotopic variant thereof, as described in any one of Embodiments 1 to 25, which is TIFF2026517789000192.tif230165.

[0332] Embodiment 28.R a The compound is one of any one of Embodiments 1 to 27, wherein is H.

[0333] Embodiment 29.R a The compound is CH3, as described in any one of Embodiments 1 to 27.

[0334] Embodiment 30. The compound is selected from the group consisting of the compounds in Table 1, the compound described in Embodiment 1, or a salt thereof, and / or an isotopic variant thereof.

[0335] Embodiment 31. The salt is a pharmaceutically acceptable salt, and is a compound, salt thereof, or an isotopic variant thereof, according to any one of Embodiments 1 to 30.

[0336] Embodiment 32. A pharmaceutical formulation comprising a compound described in any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, and a pharmaceutically acceptable carrier.

[0337] Embodiment 33. A method for treating or suppressing cancer, comprising administering a therapeutically effective amount of any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 32, to a subject in need thereof.

[0338] Embodiment 34. The method according to Embodiment 33, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0339] Embodiment 35. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The method according to Embodiment 33, selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0340] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein the cancer is a KRAS G12C-mediated cancer.

[0341] Embodiment 37. The method according to any one of Embodiments 33 to 35, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0342] Embodiment 38. The method according to any one of Embodiments 33 to 35, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the subject.

[0343] Embodiment 39. A compound according to any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 32, for use as a pharmaceutical.

[0344] Embodiment 40. A compound according to any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 32, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0345] Embodiment 41. The cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and the compound for use in Embodiment 40, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0346] Embodiment 42. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, and low-grade brain cancer. Compounds for use as described in Embodiment 40, or pharmaceutically acceptable salts thereof, and / or isotopic substitutions thereof, or pharmaceutical formulations, selected from the group consisting of glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0347] Embodiment 43. The cancer is a KRAS G12C-mediated cancer, and the compound for use described in any one of Embodiments 38-40, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0348] Embodiment 44. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound for use according to any one of Embodiments 40-42, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0349] Embodiment 45. The compound or the pharmaceutical formulation is configured to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent, the compound for use according to any one of Embodiments 40 to 44, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0350] Embodiment 46. The compound or the pharmaceutical formulation is a compound for use according to any one of Embodiments 40 to 45, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation, configured to be administered in a therapeutically effective dose.

[0351] Embodiment 47. A compound according to any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 30, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0352] Embodiment 48. The cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and is a compound for use in Embodiment 47, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0353] Embodiment 49. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, and low-grade brain cancer. Compounds for use as described in Embodiment 47, or pharmaceutically acceptable salts thereof, and / or isotopic substitutions thereof, or pharmaceutical formulations, selected from the group consisting of glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0354] Embodiment 50. The cancer is a KRAS G12C-mediated cancer, and the compound for use described in any one of Embodiments 47 to 49, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0355] Embodiment 51. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound for use according to any one of Embodiments 47-49, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0356] Embodiment 52. The compound or the pharmaceutical formulation is configured to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent, the compound for use according to any one of Embodiments 47 to 51, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

[0357] Embodiment 53. The pharmaceutical is a compound for use according to any one of Embodiments 47 to 52, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation, comprising a therapeutically effective amount of the compound or the composition.

[0358] Embodiment 54. The use of a compound according to any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 32, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0359] Embodiment 55. The use described in Embodiment 54, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0360] Embodiment 56. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The use described in Embodiment 54 is selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0361] Embodiment 57. The use according to any one of Embodiments 54 to 56, wherein the cancer is a KRAS G12C-mediated cancer.

[0362] Embodiment 58. The use described in any one of Embodiments 54 to 56, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0363] Embodiment 59. The use according to any one of Embodiments 54 to 58, wherein the compound or the pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0364] Embodiment 60. The use according to any one of Embodiments 54 to 59, wherein the pharmaceutical product comprises a therapeutically effective amount of the compound or the pharmaceutical preparation.

[0365] Embodiment 61. The use of a compound according to any one of Embodiments 1 to 31, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to Embodiment 30, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0366] Embodiment 62. The use described in Embodiment 61, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0367] Embodiment 63. The cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The use described in Embodiment 61, selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0368] Embodiment 64. The use according to any one of Embodiments 61 to 63, wherein the cancer is a KRAS G12C-mediated cancer.

[0369] Embodiment 65. The use according to any one of Embodiments 61 to 63, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

[0370] Embodiment 66. The use according to any one of Embodiments 61 to 65, wherein the compound or the pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0371] Embodiment 67. The use described in any one of Embodiments 61 to 66, wherein the use is accompanied by a therapeutically effective amount of the compound or composition.

[0372] General synthesis methods The compounds in Table 1 of this disclosure were prepared or can be prepared according to the methods described in the Examples section or variations thereof that are within the scope of knowledge of those skilled in the art.

[0373] The starting materials and reagents used in the preparation of these compounds are either available from commercial suppliers (MilliporeSigma, Bachem, etc.) or prepared by methods known to those skilled in the art, following the procedures outlined in the reference literature (Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), etc.). These schemes are merely examples of some ways in which the compounds of this disclosure may be synthesized, and various modifications to these schemes may be suggested to those skilled in the art who have read this disclosure. The starting materials, intermediates, and final reaction products may be isolated and purified, if desired, using conventional techniques (including but not limited to filtration, distillation, crystallization, chromatography, and similar methods). Such materials may be characterized using conventional means (including physical constants and spectral data).

[0374] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure over a temperature range of approximately 20°C, such as approximately -78°C to approximately 150°C, approximately 0°C to approximately 125°C, and also approximately room temperature (or ambient temperature).

[0375] In some embodiments, the compounds provided herein can be synthesized according to Method 1. Method 1. TIFF2026517789000193.tif154165 where X', q, R 1 , and R 3 This is defined in relation to formula (I) or its variations, as detailed herein.

[0376] An exemplary embodiment of Method 1 is shown in Method 1a. Method 1a. TIFF2026517789000194.tif167165 where X', q, R 1 , and R 3 This is defined in relation to formula (I) or its variations, as detailed herein.

[0377] Exemplary embodiments of Method 1 are further illustrated in the following steps.

[0378] Step 1: tert-butyl-3-(benzyl(methyl)amino)-(X') q -pyrroridine-1-carboxylate TIFF2026517789000195.tif40165 tert-butyl-3-amino-(X') in methanol [0.5M] q To a solution of -pyrrolidine-1-carboxylate (1.0 equivalent), sodium borohydride (2.0 equivalents), acetic acid (1.0 equivalent), and benzaldehyde (1.1 equivalents) were added at 0°C for 1 hour. Next, formaldehyde (3.0 equivalents) was added to the mixture, and the reaction was stirred at 0°C for 2 hours. The reaction mixture was concentrated to dryness under vacuum and purified by column chromatography to obtain tert-butyl-3-[benzyl(methyl)amino]-(X'). q -Pyrrolidine-1-carboxylate was obtained.

[0379] Step 2: tert-butyl-(X') q -3-(methylamino)pyrroridine-1-carboxylate TIFF2026517789000196.tif33165 In a solution of palladium carbon in methanol [0.16M], cis-tert-butyl-3-[benzyl(methyl)amino]-(X') q -Pyrrolidine-1-carboxylate (1.0 equivalent) was added, and the mixture was stirred at 40°C for 2 hours under a hydrogen atmosphere. Next, the reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain tert-butyl-(X') q -3-(methylamino)pyrrolidine-1-carboxylate was obtained.

[0380] Step 3: tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -pyrroridine-1-carboxylate TIFF2026517789000197.tif591651,4-Dioxane [0.24M] contains tert-butyl-(X') q To a solution of -3-(methylamino)pyrrolidine-1-carboxylate (1.0 equivalent) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.18 equivalents), N,N-diisopropylethylamine (3.0 equivalents) was added, and the mixture was stirred at 0°C for 1 hour. Next, the mixture was diluted with water and extracted with ethyl acetate. The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography to obtain tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-carboxylate was obtained.

[0381] Step 4: tert-butyl-3-((7-chloro-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -pyrroridine-1-carboxylate TIFF2026517789000198.tif59165 R in dioxane [0.14M] 1-Methanol (1.5 equivalents) and tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q To a solution of -pyrrolidine-1-carboxylate (1.0 equivalent), N,N-diisopropylethylamine (3.1 equivalents) was added, and the mixture was stirred at 80°C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography to obtain tert-butyl-3-((7-chloro-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-carboxylate was obtained.

[0382] Step 5: tert-butyl-3-((8-fluoro-7-(7-R 3 -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -pyrroridine-1-carboxylate TIFF2026517789000199.tif591651,4-dioxane / water mixture [2:1 v / v, 0.1 M] ((7-R 3 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equivalents) and tert-butyl-3-(((7-chloro-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') qTo a solution of -pyrrolidine-1-carboxylate (1.0 equivalent), potassium phosphate (3.0 equivalent) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.2 equivalent) were added, and the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography and obtained tert-butyl-3-((8-fluoro-7-(7-R 3 -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-carboxylate was obtained.

[0383] Step 6: tert-butyl-3-((7-(8-ethynyl-7-R 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -pyrroridine-1-carboxylate TIFF2026517789000200.tif59165N,N-dimethylformamide [0.07M] contains tert-butyl-3-((8-fluoro-7-(7-R 3 -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q To a solution of -pyrrolidine-1-carboxylate (1.0 equivalent), cesium fluoride (10.0 equivalent) was added, and the mixture was stirred at 20°C for 1 hour. Next, the mixture was diluted with water and extracted with ethyl acetate. The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography to obtain tert-butyl-3-((7-(8-ethynyl-7-R 3-Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-carboxylate was obtained.

[0384] Step 7: 7-(8-ethynyl-7-R) 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)-N-methyl-N-(X') q -pyrroridine-3-yl)pyrido[4,3-d]pyrimidine-4-amine TIFF2026517789000201.tif52165 Dichloromethane [0.063M] containing tert-butyl-3-((7-(8-ethynyl-7-R 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q To a solution of -pyrrolidine-1-carboxylate (1.0 equivalent), trifluoroacetic acid (3.0 equivalents) was added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum, and 7-(8-ethynyl-7-R 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)-N-methyl-N-(X') q -Pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (as trifluoroacetate) was obtained.

[0385] Step 8: ((7-(8-ethynyl-7-R 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-yl)prop-2-en-1-one TIFF2026517789000202.tif59165 7-(8-ethynyl-7-R in a mixture of tetrahydrofuran and water [3:1 v / v, 0.07 M] 3-Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)-N-methyl-N-(X') q To a solution of -pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (trifluoroacetate) (1.0 equivalent), sodium bicarbonate (3.0 equivalents) and acryloyl chloride (0.9 equivalents) were added, and the mixture was stirred at 20°C for 1 hour. Next, the reaction mixture was concentrated to dryness under vacuum and purified by reverse-phase HPLC to obtain ((7-(8-ethynyl-7-R 3 -Naphthalene-1-yl)-8-fluoro-2-((R 1 -Methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-(X') q -Pyrrolidine-1-yl)propa-2-ene-1-one was obtained. [Examples]

[0386] The following preparations of the compound of formula (I) and its pharmaceutically acceptable salts are given to enable those skilled in the art to better understand and practice the present disclosure. They should not be considered as limitations of the scope of the present disclosure, but merely illustrative and representative.

[0387] The following abbreviations will be used in this section. TIFF2026517789000203.tif235165

[0388] All reagents were obtained from commercial suppliers and used without further purification unless otherwise specified.

[0389] Synthesis Examples Example 1-1: Synthesis of Compound 1-1; cis-1-(-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (Method 1) TIFF2026517789000204.tif59165 Step 1: cis-tert-butyl-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of cis-tert-butyl-3-amino-2-methyl-pyrrolidine-1-carboxylate (1 g, 4.99 mmol) in methanol (10 mL), sodium borohydride (627.55 mg, 9.99 mmol), acetic acid (299.84 mg, 4.99 mmol), and benzaldehyde (582.86 mg, 5.49 mmol) were added at 0°C for 1 hour. Then, formaldehyde (1.22 g, 14.98 mmol) was added to the mixture, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) to obtain cis-tert-butyl-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1 g, crude) as a colorless oil, which was used in the next step without further purification: 1 ¹H NMR (400 MHz, chloroform-d) δ 7.32 - 7.28 (m, 1H), 7.27 - 7.24 (m, 3H), 7.20 - 7.16 (m, 1H), 4.08 (s, 1H), 3.99 (br s, 1H), 3.63 - 3.50 (m, 1H), 3.47 - 3.31 (m, 1H), 3.29 - 3.16 (m, 1H), 2.77 - 2.59 (m, 1H), 2.03 - 1.99 (m, 3H), 1.97 (s, 1H), 1.88 - 1.74 (m, 1H), 1.40 (d, J = 2.0 Hz, 9H), 1.14 - 1.06 (m, 3H). LCMS room temperature = 0.338 min, m / z = 304.2 [M + H] + .

[0390] Step 2: cis-tert-butyl-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate TIFF2026517789000206.tif33165 To a solution of palladium carbon (200 mg, 10% purity) in methanol (10 mL), cis-tert-butyl-3-[benzyl(methyl)amino]-2-methyl-pyrrolidine-1-carboxylate (500 mg, 1.6 mmol) was added, and the mixture was stirred at 40°C for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain cis-tert-butyl-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (300 mg, crude) as a colorless oil, which was used in the next step without further purification: 1 H NMR (400 MHz, chloroform-d) δ 4.02 - 3.76 (m, 1H), 3.25 - 2.98 (m, 2H), 2.90 - 2.72 (m, 1H), 2.34 (s, 3H), 1.79 (br s, 2H), 1.36 (s, 9H), 1.02 - 0.88 (m, 3H). LCMS room temperature = 0.295 min, m / z = 214.2 [M + H] + .

[0391] Step 3: cis-tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000207.tif52165 A solution of cis-tert-butyl-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (252.54 mg, 1.18 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (350 mg, 1.39 mmol) in dioxane (5 mL) was mixed with N,N-diisopropylethylamine (537.53 mg, 4.16 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 65-70% ethyl acetate in petroleum ether) to obtain cis-tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (350 mg, 58.67%) as a yellow solid. LCMS at room temperature = 0.651 min, m / z = 429.1 [M + H] + .

[0392] Step 4: cis-tert-butyl-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (66.60 mg, 418.31 μmol) and cis-tert-butyl-3-[(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-methyl-amino]-2-methyl-pyrrolidine-1-carboxylate (120 mg, 278.87 μmol) in dioxane (2 mL), N,N-diisopropylethylamine (108.13 mg, 836.62 μmol) was added, and the mixture was stirred at 80°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 80-100% ethyl acetate in petroleum ether) to obtain cis-tert-butyl-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (150 mg, 97.26%) as a yellow solid. LCMS at room temperature = 1.491 min, m / z = 552.2 [M + H] + .

[0393] Step 5: cis-tert-butyl-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000209.tif52165 Dioxane (2 mL) and water (1 mL) containing ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (306.81 mg, 678.07 μmol) and cis-tert-butyl-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy To a solution of pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (150 mg, 271.23 μmol), potassium phosphate (172.72 mg, 813.68 μmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42.68 mg, 54.25 μmol) were added, and the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 10 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 85-100% ethyl acetate in petroleum ether) to obtain cis-tert-butyl-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (180 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.624 min, m / z = 842.5 [M + H] + .

[0394] Step 6: cis-tert-butyl-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of cis-tert-butyl-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (180 mg, 213.50 μmol) in N,N-dimethylformamide (3 mL), cesium fluoride (324.31 mg, 2.13 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-25% methanol in dichloromethane) to obtain cis-tert-butyl-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (130 mg, crude) as a brown solid, which was used in the next step without further purification. LCMS at room temperature = 0.478 min, m / z = 686.3 [M + H] + .

[0395] Step 7: cis-7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine TIFF2026517789000211.tif46165 A solution of cis-tert-butyl-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (65 mg, 94.65 μmol) in dichloromethane (1.5 mL) was mixed with trifluoroacetic acid (32.38 mg, 283.94 μmol) and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum to obtain cis-7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (65 mg, crude, trifluoroacetate) as a brown oil, which was used in the next step without further purification. LCMS at room temperature = 0.365 min, m / z = 586.3 [M + H] + .

[0396] Step 8: cis-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one To a solution of cis-7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (65 mg, 92.77 μmol, trifluoroacetate) in tetrahydrofuran (1 mL) and water (0.3 mL), sodium bicarbonate (23.38 mg, 278.30 μmol) and acryloyl chloride (7.56 mg, 83.49 μmol) were added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100×30mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40%~70% B, 8.0 min) to obtain cis-1-((2RS,3RS)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (10.11 mg, 15.63%) as a yellow solid.1H NMR (400 MHz, chloroform-d) δ 9.18 (br s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 2.97 (m, 1H), 2.91 - 2.81 (m, 1H), 2.48 - 2.34 (m, 2H), 2.28 - 2.14 (m, 2H), 2.04 - 1.89 (m, 3H), 1.74 - 1.59 (m, 3H), 1.20 - 1.07 (m, 3H). LCMS room temperature = 2.226 min, m / z = 641.3 [M + H]. + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.226 minutes, ESI+ measured value: [M+H] + = 641.3.

[0397] Examples 1-2 and 1-3: Separation of compounds 1-2 and 1-3: 1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-ene -1-one and 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (SFC isolation from Example 1-1) A mixture (100 mg) of the cis-diastereomer of TIFF2026517789000213.tif521651-(cis-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one was purified by SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH4OH)]; B%: 50%, homogeneous concentration elution mode) to obtain the following arbitrarily assigned compounds: Examples 1-2: 1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 1, retention time = 1.467 min) (33.02 mg) (white solid): 1H NMR (400 MHz, chloroform-d) δ = 9.21 - 9.16 (m, 1H), 8.02 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.31 (m, 1H), 6.57 - 6.36 (m, 2H), 5.77 - 5.68 (m, 1H), 5.45 - 5.20 (m, 1H), 5.10 - 4.89 (m, 2H), 4.45 - 4.15 (m, 2H), 3.94 - 3.81 (m, 1H), 3.68 (s, 1H), 3.63 (s, 3H), 3.48 - 3.14 (m, 3H), 3.01 (s, 1H), 2.86 (s, 1H), 2.59 - 2.28 (m, 3H), 2.27 - 2.09 (m, 2H), 2.04 - 1.86 (m, 3H), 1.13 (d, J = 4.9 Hz, 3H); LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.226 minutes, ESI + measured value: [M+H] + = 641.3, and Examples 1-3: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 2, retention time = 1.617 min) (30.58 mg) (white solid): 1H NMR (400 MHz, chloroform-d) δ 9.18 (s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 2.97 (m, 1H), 2.91 - 2.81 (m, 1H), 2.48 - 2.34 (m, 2H), 2.28 - 2.14 (m, 2H), 2.04 - 1.89 (m, 3H), 1.74 - 1.59 (m, 3H), 1.20 - 1.07 (m, 3H); LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.226 minutes, ESI + measured value: [M+H] + = 641.3.

[0398] Example 2: Synthesis of Compound 2-1; 1-((3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000214.tif59165 Step 1: tert-butyl(3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate TIFF2026517789000215.tif33165 The reductive amination reaction was carried out in the same manner as in Method 1, Step 1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate (5.25 g, 70.49%) as a white solid: 1 H NMR (400 MHz, chloroform-d) δ 7.30 - 7.20 (m, 5H), 3.60 - 3.50 (m, 2H), 3.38 - 3.31 (m, 1H), 3.29 - 3.05(m, 3H), 2.79 - 2.66 (m, 1H), 2.38 - 2.24 (m, 1H), 1.97 (s, 3H), 1.39 (s, 9H), 0.99-0.97 (dd, J = 1.6, 6.9 Hz, 3H). LCMS room temperature = 0.323 min, m / z = 304.2 [M + H] + .

[0399] Step 2: tert-butyl(3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate Deprotection of the n group was carried out in the same manner as in Method 1, Step 2. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain tert-butyl(3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate (3.54 g, crude) as a white solid, which was used in the next step without further purification. LCMS at room temperature = 0.282 min, m / z = 214.2 [M + H] + .

[0400] Step 3: tert-butyl(3R,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 3. The crude residue was diluted with a mixture of petroleum ether:ethyl acetate (10:1) (10 mL), and the resulting precipitate was filtered to obtain tert-butyl(3R,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (9.25 g, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.578 min, m / z = 429.1 [M + H]+.

[0401] Step 4: tert-butyl(3R,4R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The mixture was concentrated to dryness under vacuum and purified by reverse-phase HPLC (column: Phenomenex luna C18 250×150 mm×15 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 30%~60% B, 20.0 min) to obtain tert-butyl(3R,4R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (7.77 g, 54.24%, trifluoroacetate) as a yellow solid. LCMS room temperature = 2.194 min, m / z = 552.2 [M + H] + .

[0402] Step 5: tert-butyl(3R,4R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. (TIFF2026517789000219.tif52165) The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 85%~95% B, 8.0 min) to obtain tert-butyl(3R,4R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (285 mg, 75.16%) as a white solid. LCMS at room temperature = 0.639 min, m / z = 842.5 [M + H] + .

[0403] Step 6: tert-butyl(3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The deprotection reaction of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain tert-butyl(3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (110 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.454 min, m / z = 686.3 [M + H] + .

[0404] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4R)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4R)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (110 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.335 min, m / z = 586.3 [M + H] + .

[0405] Step 8: 1-((3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 45%~75% B, 8.0 minutes) to obtain 1-((3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (43.90 mg, 39.87%) as a white solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.30 - 9.17 (m, 1H), 8.21 - 8.07 (m, 2H), 7.74 - 7.64 (m, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.27 (dd, J = 2.1, 16.7 Hz, 1H), 5.71 (dd, J = 1.9, 10.4 Hz, 1H), 5.66 - 5.44 (m, 1H), 5.39 - 5.16 (m, 1H), 4.27 - 4.19 (m, 1H), 4.16 - 4.10 (m, 1H), 4.08 - 3.91 (m, 2H), 3.56 - 3.48 (m, 1H), 3.47 - 3.30 (m, 3H), 3.30 - 3.24 (m, 1H), 3.16 (br d, J = 4.6 Hz, 2H), 3.08 (s, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.86 (m, 1H), 2.24 - 2.14 (m, 3H), 2.12 (br d, J = 2.6 Hz, 1H), 2.10 - 2.02 (m, 1H), 1.90 - 1.81 (m, 2H), 1.21 - 1.07 (m, 3H). LCMS room temperature = 2.997 min, m / z = 640.3 [M + H] + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.997 minutes, ESI+ measured value: [M+H]+ = 640.3.

[0406] Example 3: Synthesis of Compounds 2-3; 1-((3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000223.tif52165 Step 1: tert-butyl(3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate TIFF2026517789000224.tif33165 The reductive amination reaction was carried out in the same manner as in Method 1, Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) to obtain tert-butyl(3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate (5g, 67.13%) as a yellow oil. LCMS at room temperature = 0.298 min, m / z = 304.2 [M + H]+.

[0407] Step 2: tert-butyl(3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate Deprotection of the Bn group was carried out in the same manner as in Method 1, Step 2. The reaction mixture was concentrated under vacuum to obtain tert-butyl(3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate (3.2 g, crude) as a white oil, which was used in the next step without further purification. LCMS at room temperature = 0.508 min, m / z = 214.2 [M + H]+.

[0408] Step 3: tert-butyl(3R,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 3. The mixture was filtered and concentrated under vacuum to obtain tert-butyl(3R,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (5.7 g, 66.88%) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.572 min, m / z = 429.1 [M + H] + .

[0409] Step 4: tert-butyl(3R,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The mixture was concentrated to dryness under vacuum and purified by reverse-phase HPLC (column: Welch Xtimate C18 250×100mm×10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 15%~45% B, 20.0 min) to obtain tert-butyl(3R,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (2.5 g, 34.74%) as a yellow solid. LCMS room temperature = 0.406 min, m / z = 552.2 [M + H] + .

[0410] Step 5: tert-butyl(3R,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 30-100% ethyl acetate in petroleum ether) to obtain tert-butyl(3R,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (400 mg, 52.48%) as a yellow solid, which was used in the next step without further purification. LCMS room temperature = 0.616 min, m / z = 842.5 [M + H] + .

[0411] Step 6: tert-butyl(3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The mixture was filtered and concentrated to dryness under vacuum to obtain tert-butyl(3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (400 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.451 min, m / z = 686.3 [M + H] + .

[0412] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4S)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Phenomenex luna C18 100×40mm×3um; mobile phase: [water (0.1% TFA)-ACN]; gradient: 10%~40% B, 8.0 min) to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4S)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (300 mg, 73.51%, trifluoroacetate) as a yellow oil. LCMS at room temperature = 0.358 min, m / z = 586.3 [M + H] + .

[0413] Step 8: 1-((3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 45%~75% B, 8.0 min) to obtain 1-((3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (56.50 mg, 29.62%) as a yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.31 - 9.17 (m, 1H), 8.23 ​​- 8.09 (m, 2H), 7.76 - 7.64 (m, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.61 (ddd, J = 10.5, 13.1, 16.8 Hz, 1H), 6.33 - 6.21 (m, 1H), 5.77 - 5.66 (m, 1H), 5.41 - 5.17 (m, 1H), 5.12 - 4.89 (m, 1H), 4.27 - 4.20 (m, 1H), 4.19 - 4.14 (m, 1H), 4.13 (br d, J = 3.3 Hz, 2H), 3.73 - 3.51 (m, 1H), 3.46 (s, 3H), 3.34 - 3.27 (m, 1H), 3.16 (br d, J = 6.2 Hz, 2H), 3.10 - 3.05 (m, 1H), 2.96 - 2.86 (m, 1H), 2.84 - 2.62 (m, 1H), 2.22 - 2.17 (m, 3H), 2.13 (br d, J = 2.4 Hz, 1H), 2.08 (br s, 1H), 1.89 (br dd, J = 7.0, 11.0 Hz, 2H), 1.17 (d, J = 6.5 Hz, 3H). LCMS room temperature = 2.993 min, m / z = 640.3 [M + H] + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.993 minutes, ESI+ measured value: [M+H]+ = 640.3.

[0414] Example 4: Synthesis of Compound 3-1; 1-((2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000232.tif52165 Step 1: tert-butyl(2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 3. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (800 mg, 93.87%) as a yellow oil: 1 H NMR (400 MHz, chloroform-d) δ 8.93 (s, 1H), 5.21 - 5.11 (m, 1H), 3.96 - 3.84 (m, 2H), 3.36 (s, 3H), 3.30 (t, J = 10.3 Hz, 1H), 2.53 - 2.45 (m, 1H), 1.78 - 1.69 (m, 1H), 1.42 (s, 9H), 1.33 (d, J = 6.0 Hz, 3H). LCMS room temperature = 0.568 min, m / z = 429.1 [M + H] + .

[0415] Step 2: tert-butyl(2S,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2S,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (300 mg, 31.12%) as a yellow solid: 1 H NMR 1H NMR (400 MHz, chloroform-d) δ 8.79 (s, 1H), 5.32 - 5.14 (m, 1H), 5.11 - 5.01 (m, 1H), 4.22 (br s, 2H), 3.95 - 3.81 (m, 2H), 3.29 (s, 3H), 3.27 - 3.23 (m, 1H), 3.22 - 3.09 (m, 2H), 2.93 (br s, 1H), 2.49 - 2.41 (m, 1H), 2.28 -2.13 (m, 2H), 2.09 (br d, J = 3.0 Hz, 1H), 1.96 - 1.69 (m, 5H), 1.42 (s, 9H), 1.32 (br d, J = 5.9 Hz, 3H). LCMS room temperature = 1.605 min, m / z = 552.2 [M + H] + .

[0416] Step 3: tert-butyl(2S,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2S,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (300 mg, 65.60%) as a yellow solid. LCMS room temperature = 0.639 min, m / z = 842.5 [M + H] + .

[0417] Step 4: tert-butyl(2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The TIPS group was deprotected in the same manner as in Method 1, Step 6. The mixture was filtered and purified by reverse-phase HPLC (column: 3_Phenomenex Luna C18 75×30mm×3um; mobile phase: [water (0.1% TFA)-ACN]; gradient: 30%~60% B, 8.0 min) to obtain tert-butyl(2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (120 mg, 84.23%, trifluoroacetate) as a yellow solid. LCMS at room temperature = 1.839 min, m / z = 686.3 [M + H] + .

[0418] Step 5: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (80 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.341 min, m / z = 586.3 [M + H] + .

[0419] Step 6: 1-((2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 30%~60% B, 8.0 min) to obtain 1-((2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (29.99 mg, 36.19%) as a pale yellow amorphous solid: 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 9.18 (d, J = 2.3 Hz, 1H), 8.17 - 8.11 (m, 2H), 7.72 - 7.66 (m, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.68 - 6.51 (m, 1H), 6.31 - 6.19 (m, 1H), 5.74 - 5.64 (m, 1H), 5.36 - 5.10 (m, 2H), 4.38 - 4.24 (m, 1H), 4.19 (br s, 2H), 4.14 - 4.10 (m, 1H), 3.75 - 3.54 (m, 1H), 3.47 (s, 3H), 3.30 - 3.24 (m, 1H), 3.20 - 3.11 (m, 2H), 3.07 (s, 1H), 2.95 - 2.87 (m, 1H), 2.76 - 2.53 (m, 1H), 2.25 - 2.18 (m, 1H), 2.13 - 2.00 (m, 3H), 1.94 - 1.90 (m, 1H), 1.89 - 1.82 (m, 2H), 1.44 (d, J = 6.1 Hz, 3H) LCMS room temperature = 2.976 min, m / z = 640.3 [M + H] +LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.976 minutes, ESI+ measured value: [M+H]+ = 640.3.

[0420] Example 5: Synthesis of Compound 3-3; 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000239.tif52165 Step 1: tert-butyl(2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000240.tif33165 The reductive amination reaction was carried out in the same manner as in Method 1, Step 1. The reaction mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (720 mg, 47.37%) as a colorless oil: 1 H NMR (400 MHz, methanol-d4) δ 7.35 - 7.23 (m, 5H), 4.00 (quin, J = 6.6 Hz, 1H), 3.65 - 3.60 (m, 1H), 3.58- 3.47 (m, 2H), 3.29 - 3.15 (m, 2H), 2.12 (s, 3H), 2.08 - 1.86 (m, 2H), 1.47 (s, 9H), 1.19 (br d, J = 6.4 Hz, 3H).

[0421] Step 2: tert-butyl(2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1-carboxylate Deprotection of the n group was carried out in the same manner as in Method 1, Step 2. The reaction mixture was concentrated under vacuum to obtain tert-butyl(2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1-carboxylate (510 mg, crude) as a yellow oil, which was used directly in the next step: 1 H NMR (400 MHz, methanol-d4) δ 3.95 (br s, 1H), 3.55 (br s, 1H), 3.31 - 3.09 (m, 2H), 2.35 (s, 3H), 1.94 -1.80 (m, 2H), 1.46 (s, 9H), 1.20 (br d, J = 6.3 Hz, 3H).

[0422] Step 3: tert-butyl(2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 3. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (700 mg, 85.03%) as a yellow solid. LCMS at room temperature = 0.572 min, m / z = 429.1 [M + H] + .

[0423] Step 4: tert-butyl(2R,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (580 mg, 70.51%) as a yellow solid. LCMS at room temperature = 0.657 min, m / z = 552.2 [M + H] + .

[0424] Step 5: tert-butyl(2R,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The mixture was concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (790 mg, 95.96%) as a brown solid. LCMS room temperature = 1.041 m / z = 842.5 [M + H] + .

[0425] Step 6: tert-butyl(2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The deprotection reaction of the TIPS group was carried out in the same manner as in Method 1, Step 6. The mixture was concentrated to dryness under vacuum to obtain tert-butyl(2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (590 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 1.838 min, m / z = 686.3 [M + H] + .

[0426] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5R)-5-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5R)-5-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (180 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.347 min, m / z = 586.3 [M + H]+ .

[0427] Step 8: 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 45%~75% B, 8.0 min) to obtain 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (75.66 mg, 39.76%) as a pale yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.17 - 9.11 (m, 1H), 8.16 - 8.07 (m, 2H), 7.71 - 7.61 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.25 (dt, J = 1.8, 16.9 Hz, 1H), 5.67 (ddd, J = 2.3, 10.4, 12.7 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.36 - 5.17 (m, 1H), 4.42 (br d, J = 3.3 Hz, 1H), 4.22 - 4.11 (m, 2H), 4.11 - 3.83 (m, 1H), 3.79 - 3.61 (m, 1H), 3.39 (s, 3H), 3.28 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.04 (m, 1H), 2.93 - 2.85 (m, 1H), 2.63 - 2.36 (m, 1H), 2.23 - 2.12 (m, 3H), 2.09 - 1.98 (m, 2H), 1.89 - 1.83 (m, 2H), 1.34 - 1.24 (m, 3H). LCMS room temperature = 2.976 min, m / z = 640.3 [M + H] + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.976 minutes, ESI+ measured value: [M+H]+ = 640.3.

[0428] Example 6: Synthesis of Compound 2-2; 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000248.tif59165 Step 1: tert-butyl(3S,4S)-3-[benzyl(methyl)amino]-4-methyl-pyrrolidine-1-carboxylate TIFF2026517789000249.tif33165 The reductive amination reaction was carried out in the same manner as in Method 1, Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, ethyl acetate in petroleum ether, 10-20%) to obtain tert-butyl(3S,4S)-3-[benzyl(methyl)amino]-4-methylpyrrolidine-1-carboxylate (850 mg, 55.92%) as a colorless oil: 1 H NMR (400 MHz, chloroform-d) δ 7.36 - 7.24 (m, 5H), 3.75 (br t, J = 6.2 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.55 (dd, J = 7.6, 9.8 Hz, 1H), 3.44 (br dd, J = 5.3, 9.7 Hz, 1H), 3.36 - 3.30 (m, 1H), 3.29 - 3.17 (m, 1H), 2.84 - 2.75(m, 1H), 2.44 - 2.37 (m, 1H), 2.05 (s, 3H), 1.48 (s, 9H), 1.07 (br d, J = 6.5 Hz, 3H).

[0429] Step 2: tert-butyl(3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate Deprotection of the n group was carried out in the same manner as in Method 1, Step 2. The reaction mixture was concentrated under vacuum to obtain tert-butyl(3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate (580 mg, crude) as a colorless oil, which was used in the next step without further purification: 1 ¹H NMR (400 MHz, chloroform-d): δ 3.50 - 3.38 (m, 2H), 3.28 - 3.03 (m, 3H), 2.42 (s, 3H), 2.37 - 2.28 (m, 1H), 1.45 (s, 9H), 1.00 - 0.95 (m, 3H).

[0430] Step 3: tert-butyl(3S,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(3S,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (930 mg, 87.39%) as a yellow solid. LCMS at room temperature = 2.354 min, m / z = 429.11 [M + H] + .

[0431] Step 4: tert-butyl(3S,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 50-100% ethyl acetate in petroleum ether) to obtain tert-butyl(3S,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (1.02 g, 95.62%) as a yellow solid. LCMS at room temperature = 0.427 min, m / z = 552.2 [M + H] + .

[0432] Step 5: tert-butyl(3S,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(3S,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (490 mg, 80.36%) as a brown solid. LCMS at room temperature = 1.122 min, m / z = 842.5 [M + H] + .

[0433] Step 6: tert-butyl(3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The filtrate was concentrated to dryness under vacuum to obtain tert-butyl(3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (450 mg, crude) as a brown solid, which was used in the next step without further purification. LCMS at room temperature = 0.451 min, m / z = 686.3 [M + H] + .

[0434] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3S,4S)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of the Boc group was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated to dryness under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((3S,4S)-4-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (220 mg, crude, trifluoroacetate) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.358 min, m / z = 586.3 [M + H] + .

[0435] Step 8: 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 30%~65% B, 8.0 min) to obtain 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one (24.23 mg, 21.42%) as a yellow amorphous solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.23 - 9.18 (m, 1H), 8.15 - 8.08 (m, 2H), 7.70 - 7.63 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.25 (dd, J = 2.0, 16.8 Hz, 1H), 5.69 (br d, J = 10.4 Hz, 1H), 5.63 - 5.43 (m, 1H), 5.36 - 5.15 (m, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 3.97 (m, 2H), 3.96 - 3.82 (m, 2H), 3.51 - 3.46 (m, 1H), 3.44 (t, J = 4.4 Hz, 3H), 3.36 - 3.28 (m, 1H), 3.27 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.09 - 3.03 (m, 1H), 3.01 - 2.86 (m, 2H), 2.19 - 2.16 (m, 1H), 2.10 (br d, J = 2.6 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.92 - 1.81 (m, 2H), 1.11 (t, J = 7.7Hz, 3H). LCMS room temperature = 2.992 min, m / z = 640.3 [M + H] + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.992 minutes, ESI+ measured value: [M+H]+ = 640.3.

[0436] Example 7: Synthesis of Compound 5; 1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)propa-2-en-1-one (Method 1) TIFF2026517789000257.tif59165 Step 1: (S)-(5-methyl-5-azaspiro[2,4]heptan-6-yl)methanol To a solution of (6S)-5-methyl-5-azaspiro[2.4]heptan-6-carboxylic acid (300 mg, 1.93 mmol) in tetrahydrofuran (10 mL), lithium aluminum hydride (2.5 M, 1.16 mL) (in tetrahydrofuran) was added at 0°C. The mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched at 0°C with sodium sulfate decahydrate (100 mg) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain (S)-(5-methyl-5-azaspiro[2.4]heptan-6-yl)methanol (260 mg, crude) as a white solid, which was used in the next step without further purification: 1 H NMR (400 MHz, chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 -2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4,12.5 Hz, 1H), 0.54 - 0.40 (m, 4H).

[0437] Step 2: tert-butyl(R)-3-((7-chloro-8-fluoro-2-(((S)-5-methyl-5-azapiro[2,4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane in methanol) to obtain tert-butyl(R)-3-((7-chloro-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 31.96%) as a white solid. LCMS at room temperature = 0.633 min, m / z = 520.24 [M + H] + .

[0438] Step 3: tert-butyl(R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((S)-5-methyl-5-azapiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane in ethyl acetate) to obtain tert-butyl(R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 64.24%) as a brown solid: 1H NMR (400 MHz, chloroform-d) δ 9.13 (br s, 1H), 7.90 - 7.80 (m, 2H), 7.54 - 7.45 (m, 2H), 7.27 (t, J = 8.8Hz, 1H), 5.34 (br d, J = 6.3 Hz, 1H), 4.69 - 4.25 (m, 2H), 3.92 - 3.45 (m, 3H), 3.34 (br d, J = 4.0 Hz, 3H), 2.66 - 2.43(m, 3H), 2.32 (br d, J = 3.3 Hz, 1H), 2.18 - 2.06 (m, 2H), 1.80 - 1.49 (m, 3H), 1.42 (s, 9H), 1.20 - 1.16 (m, 3H), 1.03 -0.86 (m, 2H), 0.83 - 0.78 (m, 18H), 0.53 - 0.46 (m, 4H). LCMS room temperature = 0.628 min, m / z = 810.5 [M + H] + .

[0439] Step 4: tert-butyl(R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azapiro[2,4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The mixture was concentrated to dryness under vacuum to obtain tert-butyl(R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (100 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS at room temperature = 0.468 min, m / z = 654.3 [M + H] + .

[0440] Step 5: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-N-methyl-2-(((S)-5-methyl-5-azapiro[2,4]heptan-6-yl)methoxy)-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-N-methyl-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (90 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.353 min, m / z = 554.3 [M + H] + .

[0441] Step 6: 1-((R)-3-((7-(8-ethinyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azapiro[2,4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 25%~75% B, 8.0 min) to obtain 1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azapiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)prop-2-en-1-one (23.41 mg, 24.53%) as a yellow amorphous solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.17 (br s, 1H), 8.16 - 8.08 (m, 2H), 7.71 - 7.65 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H), 6.66 - 6.52 (m, 1H), 6.25 (br d, J = 16.8 Hz, 1H), 5.73 - 5.64 (m, 1H), 5.45 - 5.29 (m, 1H), 4.57 - 4.51 (m, 1H), 4.40 - 4.34 (m, 1H), 4.14 - 3.93 (m, 1H), 3.92 - 3.79 (m, 1H), 3.74 - 3.62 (m, 1H), 3.61 - 3.45 (m, 1H), 3.43 (s, 3H), 3.32 - 3.25 (m, 1H), 2.93 - 2.85 (m, 1H), 2.66 (br d, J = 8.9 Hz, 1H), 2.52 (br d, J = 8.8 Hz, 1H), 2.41 (d, J = 1.9 Hz, 3H), 2.33 - 2.24 (m, 2H), 2.05 (br dd, J = 8.0, 12.4 Hz, 1H), 1.69 (br dd, J = 7.5, 12.5 Hz, 1H), 0.62 - 0.48 (m, 4H). LCMS room temperature = 2.928 min, m / z = 608.3 [M + H] + LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.928 minutes, ESI+ measured value: [M+H]+ = 608.3.

[0442] Example 8: Synthesis of Compounds 2-4; 1-((3S,4R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpyrrolidine-1-yl)prop-2-en-1-one TIFF2026517789000264.tif52165 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.22 - 9.15 (m, 1H), 8.15 - 8.09 (m, 2H), 7.70 - 7.62 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.57 (ddd, J = 10.4, 13.3, 16.8 Hz, 1H), 6.27 - 6.20 (m, 1H), 5.67 (ddd, J = 2.2, 4.2, 10.4 Hz, 1H), 5.37 - 5.16 (m, 1H), 5.08 - 4.86 (m, 1H), 4.21 - 4.16 (m, 1H), 4.15 - 4.01 (m, 2H), 4.01 - 3.93 (m, 1H), 3.70 - 3.46 (m, 1H), 3.45 - 3.42 (m, 3H), 3.30 - 3.23 (m, 1H), 3.20 - 3.11 (m, 2H), 3.05 (s, 1H), 2.93 - 2.84 (m, 1H), 2.81 - 2.61 (m, 1H), 2.23 - 2.15 (m, 2H), 2.11 - 2.03 (m, 2H), 1.91 - 1.81 (m, 3H), 1.17 - 1.11 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.998 minutes, ESI+ measured value: [M+H]+ = 641.3.

[0443] Example 9: Synthesis of Compounds 3-4; 1-((2S,4S)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one TIFF2026517789000265.tif52165 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.14 (s, 1H), 8.16 - 8.07 (m, 2H), 7.66 (d, J = 5.4 Hz, 2H), 7.44 (t, J = 9.1 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.33 - 6.18 (m, 1H), 5.74 - 5.62 (m, 1H), 5.60 - 5.46 (m, 1H), 5.35 - 5.17 (m, 1H), 4.49 - 4.34 (m, 1H), 4.24 - 4.18 (m, 1H), 4.15 - 4.11 (m, 1H), 3.94 - 3.66 (m, 1H), 3.39 (s, 3H), 3.30 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.06 (s, 1H), 2.93 - 2.85 (m, 1H), 2.64 - 2.36 (m, 1H), 2.24 - 2.16 (m, 2H), 2.10 (br d, J = 3.1 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.90 - 1.76 (m, 3H), 1.34 - 1.25 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.985 minutes, ESI+ measured value: [M+H] + = 641.3.

[0444] Example 10: Synthesis of Compound 3-2; 1-((2R,4S)-4-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one TIFF2026517789000266.tif52165 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.16 - 9.12 (m, 1H), 8.14 - 8.08 (m, 2H), 7.66 (d, J = 5.6 Hz, 2H), 7.44 (t, J = 9.1 Hz, 1H), 6.68 - 6.47 (m, 1H), 6.21 (d, J = 16.9 Hz, 1H), 5.65 (d, J = 7.8 Hz, 1H), 5.34 - 5.06 (m, 2H), 4.33 - 4.16 (m, 2H), 4.12 - 4.08 (m, 1H), 3.71 - 3.46 (m, 1H), 3.44 (s, 3H), 3.28 - 3.22 (m, 1H), 3.17 - 3.10 (m, 2H), 3.08 - 3.03 (m, 1H), 2.92 - 2.84 (m, 1H), 2.77 - 2.45 (m, 1H), 2.21 - 2.13 (m, 3H), 2.10 - 2.07 (m, 1H), 2.04 (s, 1H), 1.91 - 1.81 (m, 3H), 1.41 (d, J = 6.3 Hz, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 3.003 minutes, ESI + measured value: [M+H] + = 641.3.

[0445] Example 12: Synthesis of Compound 6; 1-cis-1-(3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2,4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one TIFF2026517789000267.tif59165 1H NMR (400 MHz, chloroform-d) δ 9.30 - 9.10 (m, 1H), 8.01 - 7.93 (m, 2H), 7.66 - 7.58 (m, 2H), 7.35 (t, J = 8.8 Hz, 1H), 6.52 - 6.39 (m, 2H), 5.77 - 5.68 (m, 1H), 5.11 - 4.91 (m, 2H), 4.75 - 4.58 (m, 1H), 4.50 - 4.36 (m, 1H), 3.92 - 3.83 (m, 1H), 3.64 - 3.60 (m, 3H), 3.10 - 2.97 (m, 1H), 2.90 - 2.82 (m, 1H), 2.79 - 2.69 (m, 1H), 2.65 - 2.59 (m, 1H), 2.56 - 2.50 (m, 3H), 2.43 - 2.34 (m, 1H), 2.20 - 2.11 (m, 1H), 1.86 - 1.56 (m, 3H), 1.20 - 1.10 (m, 3H), 0.69 - 0.63 (m, 1H), 0.59 - 0.48 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.982 minutes, ESI + measured value: [M+H] + = 623.3.

[0446] Example 17: Synthesis of Compound 9; 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000268.tif59165 Step 1: tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000269.tif521651,4-Dioxane (40 mL) contained a solution of tert-butyl(2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1.0 g, 2.324 mmol), ((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (1.839 g, 4.64 mmol), and a 4 Å molecular sieve (160 mg). N,N-diisopropylethylamine (901 mg, 6.96 mmol) was added to this solution. The mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 60%~90% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 32.70%) as a white solid: 1H NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 7.58 - 7.50 (m, 4H), 7.41 - 7.25 (m, 6H), 4.95 - 4.78 (m, 1H), 4.51 - 4.32 (m, 2H), 4.13 - 3.93 (m, 1H), 3.70 - 3.46 (m, 2H), 3.45 - 3.25 (m, 5H), 3.06 - 2.93 (m, 1H), 2.85 - 2.57 (m, 1H), 2.54 - 2.33 (m, 1H), 2.31 - 2.20 (m, 2H), 2.17 - 2.07 (m, 2H), 2.06 - 1.95 (m, 2H), 1.94 - 1.73 (m, 2H), 1.40 (s, 9H), 1.03 - 0.95 (m, 12H). LCMS room temperature = 2.396 min, m / z = 789.2 / 790.2 [M + H] + .

[0447] Step 2: tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000270.tif521651,4-Dioxane (1 mL) and water (0.3 mL) contain tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 633.35 μmol), ((2-fluoro-8-(4,4 A mixture of ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethinyl)triisopropylsilane (429.87 mg, 950.03 μmol), potassium phosphate (403.32 mg, 1.90 mmol), and [2-(2-aminophenyl)phenyl]-chloropalladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (45.64 mg, 63.34 μmol) was degassed and purged three times with nitrogen, and then the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase [H2O(0.1% TFA)-ACN]; gradient: 60%~90% B 8.0 min) to obtain tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (420 mg, 55.56%, trifluoroacetate) as a yellow solid: 1¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.39 (d, J = 11.2 Hz, 1H), 8.26 - 8.16 (m, 2H), 7.73 - 7.67 (m, 1H), 7.66 - 7.58 (m, 6H), 7.53 - 7.46 (m, 3H), 7.45 - 7.40 (m, 3H), 4.88 (d, J = 5.5 Hz, 1H), 4.74 (d, J = 10.1 Hz, 1H), 4.63 - 4.52 (m, 1H), 4.45 (d, J = 8.9 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.54 (s, 1H), 3.38 - 3.33 (m, 1H), 2.52 - 2.50 (m, 3H), 2.36 (dd, J = 5.6, 13.7 Hz, 3H), 2.21 (s, 2H), 2.15 (d, J = 11.8 Hz, 2H), 1.79 (s, 4H), 1.46 (s, 9H), 1.39 (d, J = 3.9 Hz, 1H), 1.20 - 1.16 (m, 2H), 1.08 (s, 9H), 1.02 - 1.00 (m, 1H), 0.85 (d, J = 6.4 Hz, 18H), 0.61 (dt, J = 7.0, 14.2 Hz, 3H). LCMS room temperature = 2.706 min, m / z = 1079.5 [M + H] + .

[0448] Step 3: tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of tert-butyl(2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, 185.27 μmol, trifluoroacetate) in N,N-dimethylformaldehyde (1 mL), cesium fluoride (562.86 mg, 3.71 mmol) was added. The mixture was stirred at 50°C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The mixed organic layer was washed with saturated lithium chloride (3 × 5 mL), dried over sodium sulfate, and concentrated under vacuum to obtain tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (126 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.432 min, m / z = 685.2 [M + H] + .

[0449] Step 4: (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidine-3-yl)amino)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)hexahydro-1H-pyrrolidine-2-ol A solution of tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (126 mg, 184.00 μmol) in HCl / ethyl acetate (2 M, 2 mL) was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated to dryness under vacuum to obtain (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidine-3-yl)amino)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)hexahydro-1H-pyrrolidine-2-ol (106 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.339 min, m / z = 585.2 [M + H] + .

[0450] Step 5: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one To a solution of (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidine-3-yl)amino)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)hexahydro-1H-pyrrolidine-2-ol (106 mg, 170.66 μmol, hydrochloride) in tetrahydrofuran (1 mL) and water (0.3 mL), sodium bicarbonate (43.01 mg, 511.98 μmol) and acryloyl chloride (10.81 mg, 119.46 μmol) were added, and the mixture was then stirred at 0°C for 10 minutes under a nitrogen atmosphere. The reaction mixture was concentrated to dryness under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 30%~65% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (8.48 mg, 7.08%) as a yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.24 (d, J = 4.8 Hz, 1H), 8.18 - 8.11 (m, 2H), 7.69 (d, J = 4.8 Hz, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.74 - 5.66 (m, 1H), 5.04 - 4.79 (m, 2H), 4.55 - 4.38 (m, 1H), 4.31 - 4.06 (m, 2H), 3.94 - 3.72 (m, 1H), 3.72 - 3.65 (m, 1H), 3.62 (d, J = 4.9 Hz, 3H), 3.61 - 3.50 (m, 1H), 3.29 (s, 1H), 3.19 - 3.08 (m, 1H), 2.95 (td, J = 5.2, 16.5 Hz, 1H), 2.89 - 2.77 (m, 1H), 2.61 - 2.48 (m, 2H), 2.47 - 2.32 (m, 2H), 1.88 - 1.78 (m, 3H), 1.71 - 1.63 (m, 1H), 1.17 - 1.05 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.705 minutes, ESI + measured value: [M + H] + = 639.3.

[0451] Example 18: Synthesis of Compound 10; 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (Method 1) TIFF2026517789000274.tif59165 Step 1: 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate To a solution of O1-tert-butyl O2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (20 g, 81.54 mmol) in dichloromethane (100 mL), tert-butyl-chloro-dimethyl-silane (13.52 g, 89.70 mmol), N,N-dimethylpyridine-4-amine (996.18 mg, 8.15 mmol) and imidazole (11.10 g, 163.08 mmol) were added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched at 0°C with saturated sodium bicarbonate (500 mL) and extracted with dichloromethane (3 × 200 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (25 g, 85.27%) as a white solid: 1 H NMR (400 MHz, chloroform-d) δ 4.47 - 4.27 (m, 2H), 3.73 (s, 3H), 3.70 - 3.54 (m, 1H), 3.41 - 3.27 (m, 1H), 2.39 - 2.23 (m, 1H), 2.17 - 2.06 (m, 1H), 1.54 - 1.41 (m, 9H), 0.91 - 0.85 (m, 9H), 0.11 - 0.00 (m, 6H). LCMS room temperature = 0.642 min, m / z = 360.1 [M + H] + .

[0452] Step 2: 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate TIFF2026517789000276.tif40165 A solution of 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (20 g, 55.63 mmol) in tetrahydrofuran (300 mL) was mixed with lithium hexamethyldisilazane (83.44 mL, 83.44 mmol, 1 M in tetrahydrofuran). The mixture was stirred at -78°C for 2 hours under a nitrogen atmosphere. Next, 3-chloro-2-(chloromethyl)propa-1-ene (10.43 g, 83.44 mmol) was added to the above solution at -78°C. The mixture was stirred at 20°C for 10 hours under a nitrogen atmosphere. The reaction mixture was quenched at 0°C with saturated ammonium chloride (500 mL) and extracted with ethyl acetate (3 × 100 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (15 g, 60.18%) as a white solid. LCMS at room temperature = 0.716 min, m / z = 448.2 / 450.1 [M + H] + .

[0453] Step 3: 1-(tert-butyl)2-methyl(2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate TIFF2026517789000277.tif40165 A solution of 1-(tert-butyl)2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (11 g, 24.55 mmol) in tetrahydrofuran (15 mL) was mixed with tetrabutylammonium fluoride (29.46 mL, 29.46 mmol, 1 M in tetrahydrofuran). The mixture was stirred at 20°C for 1 hour. The mixture was diluted with saturated sodium chloride (300 mL) and water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain 1-(tert-butyl)2-methyl(2S,4S)-2-(2-chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (6 g, 73.22%) as a white solid. LCMS at room temperature = 0.458 min, m / z = 334.0 / 336.0 [M + H] + .

[0454] Step 4: 1-(tert-butyl)2-methyl(2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate TIFF2026517789000278.tif40165 A solution of 1-(tert-butyl)2-methyl(2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (7 g, 20.97 mmol) in dichloromethane (100 mL) was mixed with (bis-(2-methoxyethyl)amino) trifluoride sulfur (9.28 g, 41.94 mmol) at -78 °C. The mixture was stirred at 20 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with saturated sodium bicarbonate (500 mL) and water (150 mL) and extracted with dichloromethane (3 × 200 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain 1-(tert-butyl)2-methyl(2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (3.7 g, 52.54%) as a white solid: 1 H NMR (400 MHz, chloroform-d) δ 5.47 - 5.33 (m, 1H), 5.29 - 5.04 (m, 2H), 4.22 - 4.09 (m, 2H), 3.94 - 3.68 (m, 5H), 3.33 - 3.16 (m, 1H), 2.86 (d, J = 14.4 Hz, 1H), 2.65 - 2.28 (m, 2H), 1.50 - 1.45 (m, 9H). LCMS room temperature = 0.549 min, m / z = 336.0 / 338.0 [M + H] + .

[0455] Step 5: Methyl(2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain methyl(2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate (2.6 g, crude, trifluoroacetate) as a white solid, which was used in the next step without further purification. LCMS at room temperature = 0.174 min, m / z = 236.0 / 238.0 [M + H] + .

[0456] Step 6: Methyl(2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2026517789000280.tif33165 A solution of methyl(2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate (2.6 g, 11.03 mmol, trifluoroacetate) in methanol (5 mL) was mixed with ammonia (20 mL, 140.00 mmol, 7 M in methanol). The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain methyl(2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.7 g, 77.35%) as a white solid. LCMS room temperature = 0.146 min, m / z = 200.1 [M + H] + .

[0457] Step 7: Methyl(6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5H')-carboxylate To a solution of methyl(2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.6 g, 8.03 mmol) in dichloromethane (50 mL), diethylzinc (40.16 mL, 40.16 mmol, 1 M in toluene) and diiodomethane (21.51 g, 80.31 mmol) were added under nitrogen at 0°C. The mixture was stirred under a nitrogen atmosphere at 20°C for 12 hours. The reaction mixture was quenched at 0°C with saturated ammonium chloride (300 mL) and extracted with dichloromethane (3 × 200 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain methyl(6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (300 mg, 30%) as a white solid: 1 H NMR (400 MHz, chloroform-d) δ 5.29 - 5.12 (m, 1H), 3.67 (s, 3H), 3.25 - 3.21 (m, 1H), 3.17 - 3.09 (m, 2H), 2.84 (dd, J = 1.2, 8.8 Hz, 1H), 2.35 - 2.23 (m, 2H), 2.23 - 2.17 (m, 1H), 2.14 - 2.08 (m, 1H), 0.55 - 0.42 (m, 4H). LCMS room temperature = 0.520 min, m / z = 214.1 [M + H] + .

[0458] Step 8: ((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol TIFF2026517789000282.tif33165 A solution of methyl(6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (250 mg, 1.17 mmol) in tetrahydrofuran (4 mL) was mixed with lithium aluminum tetrahydrogen (1.41 mL, 3.52 mmol, 2.5 M in tetrahydrofuran). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched at 0°C with sodium sulfate decahydrate (200 mg). The mixed organic layers were dried over sodium sulfate and concentrated under vacuum to obtain ((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (200 mg, crude) as a colorless oil, which was used in the next step without further purification: 1 H NMR (400 MHz, chloroform-d) δ 5.35 - 5.14 (m, 1H), 3.51 (d, J = 10.3 Hz, 1H), 3.29 (d, J = 10.5 Hz, 1H), 3.20 - 3.15 (m, 2H), 3.14 - 3.02 (m, 1H), 2.79 (dd, J = 1.1, 9.3 Hz, 1H), 2.28 - 2.21 (m, 1H), 2.21 - 2.13 (m, 1H), 2.11 - 2.06 (m, 1H), 1.45 - 1.41 (m, 1H), 0.59 - 0.47 (m, 4H).

[0459] Step 9: tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (120 mg, 47.98%) as a yellow solid. LCMS at room temperature = 0.422 min, m / z = 579.2 / 581.2 [M + H] + .

[0460] Step 10: tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. (TIFF2026517789000284.tif59165) The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 65%~95% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (20 mg, 13.33%) as a brown solid: 1 H NMR (400 MHz, chloroform-d) δ 9.28 - 9.23 (m, 1H), 7.98 - 7.89 (m, 2H), 7.62 - 7.52 (m, 2H), 7.34 (dt, J = 1.9, 8.7 Hz, 1H), 5.47 - 5.26 (m, 1H), 5.23 - 4.94 (m, 1H), 4.59 - 4.44 (m, 2H), 3.69 - 3.57 (m, 3H), 3.54 (s, 2H), 3.43 (ddd, J = 3.4, 6.8, 10.3 Hz, 1H), 3.34 - 3.23 (m, 2H), 2.47 - 2.30 (m, 4H), 2.29 - 2.18 (m, 2H), 1.83 (d, J = 8.6 Hz, 2H), 1.50 (d, J = 0.8 Hz, 9H), 1.33 - 1.24 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.91 - 0.86 (m, 18H), 0.62 - 0.56 (m, 4H). LCMS room temperature = 2.906 min, m / z = 869.3 [M + H] + .

[0461] Step 11: tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The deprotection reaction of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (8 mg, crude) as a brown solid, which was used in the next step without further purification. LCMS at room temperature = 0.494 min, m / z = 713.4 [M + H] + .

[0462] Step 12: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (7.3 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.376 min, m / z = 613.4 [M + H] + .

[0463] Step 13: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100×30mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 45%~80% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (1.11 mg, 13.77%) as a pale yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.09 (m, 2H), 7.70 - 7.64 (m, 2H), 7.45 (t, J = 9.1 Hz, 1H), 6.64 - 6.53 (m, 1H), 6.32 - 6.19 (m, 1H), 5.68 (dd, J = 2.3, 10.3 Hz, 1H), 5.41 - 5.22 (m, 1H), 4.97 - 4.81 (m, 2H), 4.46 - 4.24 (m, 2H), 3.90 - 3.66 (m, 1H), 3.61 (d, J = 5.4 Hz, 3H), 3.59 - 3.45 (m, 1H), 3.26 (d, J = 8.5 Hz, 1H), 3.16 (d, J = 8.8 Hz, 2H), 3.13 - 3.08 (m, 1H), 2.75 (d, J = 8.0 Hz, 1H), 2.65 - 2.47 (m, 1H), 2.44 - 2.27 (m, 2H), 2.24 (s, 3H), 1.15 - 1.05 (m, 3H), 0.53 (s, 4H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 4.113 minutes, ESI + measured value: [M+H] + = 667.3.

[0464] Example 19: Synthesis of Compound 11; 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000288.tif59165 Step 1: tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (340 mg, 57.48%) as a yellow solid. LCMS at room temperature = 0.391 min, m / z = 509.2 / 510.2 [M + H] + .

[0465] Step 2: tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 40%~70% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (260 mg, 55.21%, trifluoroacetate) as a yellow solid. LCMS room temperature = 0.602 min, m / z = 799.5 [M + H] + .

[0466] Step 3: 8-Fluoro-7-(7-Fluoro-8-((Triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (110 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.507 min, m / z = 699.5 [M + H] + .

[0467] Step 4: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-N-methyl-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-N-methyl-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (81 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.315 min, m / z = 543.2 [M + H] + .

[0468] Step 5: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 30%~60% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (28.48 mg, 31.90%) as a yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.07 (m, 2H), 7.69 - 7.63 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.58 (dd, J = 10.3, 16.8 Hz, 1H), 6.32 - 6.20 (m, 1H), 5.68 (dd, J = 2.2, 10.3 Hz, 1H), 4.99 - 4.79 (m, 2H), 4.53 - 4.41 (m, 1H), 4.37 - 4.25 (m, 1H), 3.88 - 3.65 (m, 1H), 3.62 - 3.46 (m, 4H), 3.28 (s, 1H), 3.07 - 2.97 (m, 1H), 2.68 (d, J = 4.8 Hz, 1H), 2.60 - 2.46 (m, 1H), 2.41 (s, 3H), 2.37 (d, J = 6.3 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.07 - 1.97 (m, 1H), 1.83 - 1.66 (m, 3H), 1.15 - 1.03 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.814 minutes, ESI + measured value: [M+H] + = 597.3.

[0469] Example 20: Synthesis of Compound 12; 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000294.tif52165 Step 1: tert-butyl(2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (220 mg, 88.06%) as a yellow solid. LCMS at room temperature = 0.471 min, m / z = 691.4 [M + H] + .

[0470] Step 2: 7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (181 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.566 min, m / z = 591.3 [M + H] + .

[0471] Step 3: 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40%~70% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (27.03 mg, 14.28%) as a yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.30 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.96 (dd, J = 6.1, 8.9 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.41 (t, J = 9.4 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.29 (dd, J = 10.3, 15.9 Hz, 1H), 5.70 (d, J = 10.0 Hz, 1H), 5.38 - 5.17 (m, 1H), 5.01 - 4.86 (m, 2H), 4.29 - 4.11 (m, 2H), 3.91 - 3.67 (m, 1H), 3.63 (d, J = 6.1 Hz, 3H), 3.60 - 3.48 (m, 1H), 3.20 - 3.05 (m, 3H), 2.96 - 2.85 (m, 1H), 2.68 - 2.46 (m, 2H), 2.43 - 2.20 (m, 3H), 2.12 (s, 1H), 2.07 - 2.00 (m, 1H), 1.93 - 1.80 (m, 3H), 1.17 - 1.06 (m, 3H), 0.88 - 0.79 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 3.261 minutes, ESI+ measured value: [M+H] + = 645.3.

[0472] Example 21: Synthesis of Compound 7-1; 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000298.tif59165 Step 1: tert-butylcis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. (TIFF2026517789000299.tif52165) The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 25%~55% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (25 mg, 33.05%, trifluoroacetate) as a yellow solid. LCMS at room temperature = 1.615 min, m / z = 697.3 / 698.3 [M + H] + .

[0473] Step 2: 7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of the Boc group was carried out in the same manner as in Method 1, Step 7. The mixture was concentrated to dryness under vacuum to obtain 7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (25 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.352 min, m / z = 597.3 / 598.4 [M + H] + .

[0474] Step 3: 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100×25mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 25%~55% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (10.75 mg, 46.88%) as a yellow solid: 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.28 (d, J = 4.2 Hz, 1H), 8.19 - 8.14 (m, 1H), 8.13 - 8.07 (m, 1H), 7.72 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.34 - 6.21 (m, 1H), 5.70 (d, J = 10.4 Hz, 1H), 5.39 - 5.17 (m, 1H), 5.00 - 4.83 (m, 2H), 4.31 - 3.79 (m, 3H), 3.77 - 3.50 (m, 5H), 3.21 - 3.05 (m, 3H), 2.97 - 2.85 (m, 1H), 2.68 - 2.33 (m, 2H), 2.14 - 2.11 (m, 1H), 2.10 - 2.03 (m, 1H), 1.92 - 1.80 (m, 3H), 1.16 - 1.08 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 3.007 minutes, ESI + measured value: [M+H] + = 651.0 / 652.0.

[0475] Examples 22 and 23: Synthesis of compounds 7-2 and 7-3; 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)pro Pa-2-en-1-one and 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (Method 1) TIFF2026517789000302.tif59165 Step 1: cis-tert-butyl-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 25%~55% B, 8.0 min) to obtain cis-tert-butyl-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (110 mg, 39.66%, trifluoroacetate) as a yellow solid. LCMS room temperature = 1.624 min, m / z = 697.3 / 698.3 [M + H] + .

[0476] Step 2: 7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000304.tif46165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (80 mg, crude, trifluoroacetate) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.350 min, m / z = 597.3 / 598.3 [M + H] + .

[0477] Step 3: 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one and 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 45%~75% B, 8.0 minutes) to obtain 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (40 mg, 45.81%) as a white solid: 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 - 3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.957 minutes, ESI + measured value: [M+H] + = 651.4 / 652.4.

[0478] A mixture (30 mg) of the cis-diastereomer of 1-(cis-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one was further purified by SFC [SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, homogeneous concentration elution mode)] to obtain the following arbitrarily assigned compounds: Example 22: 1-((2R,3R)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 1, retention time = 1.508 min) (10.22 mg, 11.69%) (white solid): 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 - 3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H), LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.957 minutes, ESI + measured value: [M+H] + = 651.4 / 652.4; and Example 23: 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 2, retention time = 1.787 min) (10.22 mg, 11.69%) (white solid): 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.29 (d, J = 4.2 Hz, 1H), 8.21 - 8.15 (m, 1H), 8.10 (dd, J = 5.9, 8.9 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.55 (t, J = 9.0 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.35 - 6.19 (m, 1H), 5.70 (d, J = 10.0 Hz, 1H), 5.40 - 5.17 (m, 1H), 5.06 - 4.82 (m, 2H), 4.26 - 4.18 (m, 1H), 3.89 (t, J = 9.5 Hz, 1H), 3.74 - 3.50 (m, 5H), 3.24 - 3.06 (m, 3H), 2.97 - 2.85 (m, 1H), 2.70 - 2.48 (m, 1H), 2.45 - 2.32 (m, 1H), 2.14 - 2.06 (m, 3H), 1.94 - 1.82 (m, 3H), 1.16 - 1.06 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.956 minutes, ESI + measured value: [M+H] + = 651.4 / 652.4.

[0479] Example 24: Synthesis of Compound 8-1; 1-(cis-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000306.tif59165 Step 1: cis-tert-butyl-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 100×40mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 30%~60% B, 8.0 min) to obtain cis-tert-butyl-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (280 mg, 97.42%, trifluoroacetate) as a yellow solid. LCMS room temperature = 0.461 min, m / z = 681.6 [M + H] + .

[0480] Step 2: 7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000308.tif52165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (120 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.332 min, m / z = 581.3 [M + H] + .

[0481] Step 3: 1-(cis-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 35%~65% B, 8.0 min) to obtain 1-(cis-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (54.77 mg, 49.95%) as a pale yellow amorphous solid: 1H NMR (400 MHz, アセトニトリル-d3) δ 9.31 (d, J = 3.8 Hz, 1H), 8.18 - 8.09 (m, 1H), 7.92 (ddd, J = 1.7, 5.0, 9.2 Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.60 - 7.52 (m, 1H), 6.61 (dd, J = 10.2, 16.7 Hz, 1H), 6.28 (dd, J = 9.3, 16.5 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.37 - 5.19 (m, 1H), 4.93 (d, J = 9.0 Hz, 2H), 4.29 - 4.06 (m, 2H), 3.92 - 3.67 (m, 1H), 3.63 (d, J = 6.8 Hz, 3H), 3.59 - 3.42 (m, 1H), 3.20 - 3.11 (m, 2H), 3.08 (s, 1H), 2.95 - 2.87 (m, 1H), 2.64 - 2.35 (m, 2H), 2.14 - 2.03 (m, 3H), 1.94 - 1.88 (m, 2H), 1.87 - 1.79 (m, 1H), 1.12 (s, 3H). LCMS (5~95% のアセトトリル+0.03% bicarbonate アンモニウム in water, 6 minutes), retention time: 2.981 minutes, ESI+ measured value: [M+H] + = 635.1.

[0482] Examples 25 and 26: Synthesis of compounds 8-2 and 8-3; 1-((2R,3R)-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propane 2-en-1-one and 1-((2S,3S)-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (Method 1) A mixture (100 mg) of the cis-diastereomer of TIFF2026517789000310.tif521651-(cis-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one was further purified by SFC (column: DAISEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, homogeneous concentration elution mode) to obtain the following arbitrarily assigned compounds: Example 25: 1-((2R,3R)-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 2, retention time = 1.639 min) (31.69 mg, 14.63%) (white solid): 1H NMR (400 MHz, acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.22 - 8.04 (m, 1H), 7.91 (ddd, J = 1.5, 5.1, 9.1Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.56 (dt, J = 7.7, 9.6 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.28 (dd, J = 8.5, 16.3 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.39 - 5.15 (m, 1H), 4.92 (d, J = 7.3 Hz, 2H), 4.30 - 4.06 (m, 2H), 3.95 - 3.47 (m, 5H), 3.22 - 3.04 (m, 3H), 2.99 - 2.83 (m, 1H), 2.70 - 2.46 (m, 1H), 2.43 - 2.21 (m, 2H), 2.12 (d, J = 3.5 Hz, 2H), 1.94 - 1.82 (m, 3H), 1.12 (s, 3H), LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.910 minutes, ESI + measured value: [M+H] + = 635.3; and Example 26: 1-((2S,3S)-3-((7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (peak 1, retention time = 1.446 min) (29.88 mg, 13.93%) (white solid): 1H NMR (400 MHz, acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.13 (dt, J = 2.2, 4.7 Hz, 1H), 7.92 (ddd, J = 1.5, 5.1, 9.2 Hz, 1H), 7.71 (d, J = 5.4 Hz, 2H), 7.56 (dt, J = 7.6, 9.6 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.28 (dd, J = 9.8, 16.4 Hz, 1H), 5.70 (d, J = 10.1Hz, 1H), 5.41 - 5.16 (m, 1H), 4.92 (s, 2H), 4.32 - 4.03 (m, 2H), 3.94 - 3.50 (m, 5H), 3.21 - 3.04 (m, 3H), 2.99 - 2.86 (m, 1H), 2.72 - 2.47 (m, 1H), 2.46 - 2.20 (m, 2H), 2.14 - 2.05 (m, 2H), 1.94 - 1.79 (m, 3H), 1.12 (s, 3H), LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.908 minutes, ESI + measured value: [M+H] + = 635.4.

[0483] Example 27: Synthesis of compounds 1-4: 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 2) TIFF2026517789000311.tif59165 Step 1: tert-butyl(2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate TIFF2026517789000312.tif33165 To a solution of tert-butyl(2R,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (400 mg, 2.00 mmol), benzaldehyde (233.14 mg, 2.20 mmol), and acetic acid (119.94 mg, 2.00 mmol) in methanol (5 mL), sodium borohydride (251.02 mg, 3.99 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. Next, formaldehyde (486.23 mg, 5.99 mmol, 37% purity in water) was added to the above solution at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched at 0°C with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 × 20 mL). The mixed organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 74.01%) as a colorless oil. LCMS at room temperature = 0.344 min, m / z = 305.2 [M + H] + .

[0484] Step 2: tert-butyl(2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate TIFF2026517789000313.tif33165 A solution of tert-butyl(2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 1.97 mmol) in methanol (6 mL) was mixed with Pd / C (300 mg, 281.9 μmol, 10% purity). The mixture was stirred under hydrogen (50 Psi) at 45°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum to obtain tert-butyl(2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (470 mg, crude) as a yellow oil, which was used in the next step without further purification: 1H NMR (400 MHz, chloroform-d) δ 3.77 - 3.61 (m, 1H), 3.44 - 3.34 (m, 1H), 2.86 - 2.79 (m, 1H), 2.45 - 2.41 (m, 3H), 2.13 - 1.96 (m, 1H), 1.76 - 1.65 (m, 2H), 1.47 - 1.44 (m, 9H), 1.22 (s, 3H). LCMS room temperature = 0.280 min, m / z = 215.3 [M + H] + .

[0485] Step 3: tert-butyl(2R,3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (550 mg, 2.18 mmol) in 1,4-dioxane (8 mL), N,N-diisopropylethylamine (844.69 mg, 6.54 mmol) and tert-butyl(2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (443.53 mg, 2.07 mmol) were added at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (780 mg, 82.37%) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ 9.09 - 8.91 (m, 1H), 5.21 - 5.05 (m, 1H), 4.08 - 3.89 (m, 1H), 3.88 - 3.70 (m, 1H), 3.54 - 3.47 (m, 1H), 3.47 - 3.44 (m, 3H), 2.52 - 2.38 (m, 1H), 2.17 - 2.07 (m, 1H), 1.52 - 1.47 (m, 9H), 1.43 - 1.35 (m, 3H). LCMS room temperature = 0.585 min, m / z = 430.1 / 431.0 [M + H] + .

[0486] Step 4: tert-butyl(2R,3S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (794 mg, 79.11%) as a white solid: 1¹H NMR (400 MHz, chloroform-d) δ 8.87 (s, 1H), 5.39 - 5.19 (m, 1H), 5.10 - 4.94 (m, 1H), 4.37 - 4.17 (m, 2H), 4.08 - 3.90 (m, 1H), 3.86 - 3.65 (m, 1H), 3.51 - 3.41 (m, 1H), 3.38 - 3.35 (m, 3H), 3.30 - 3.20 (s, 3H), 3.05 - 2.94 (m, 1H), 2.47 - 2.35 (m, 1H), 2.32 - 2.17 (m, 2H), 2.17 - 2.05 (m, 2H), 2.02 - 1.87 (m, 3H), 1.51 - 1.47 (m, 9H), 1.36 - 1.31 (m, 3H). LCMS room temperature = 0.421 min, m / z = 553.3 / 555.2 [M + H] + .

[0487] Step 5: tert-butyl(2R,3S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 65.60%) as an orange solid: 1H NMR (400 MHz, chloroform-d) δ 9.30 - 9.11 (m, 1H), 7.97 - 7.89 (m, 2H), 7.62 - 7.52 (m, 2H), 7.34 (t, J = 8.8 Hz, 1H), 5.27 - 5.04 (m, 1H), 4.10 - 3.71 (m, 4H), 3.58 - 3.43 (m, 3H), 3.43 - 3.38 (m, 2H), 3.31 - 3.22 (m, 2H), 3.18 - 2.87 (m, 2H), 2.55 - 2.34 (m, 3H), 2.11 (s, 4H), 2.02 - 1.96 (m, 1H), 1.54 - 1.52 (m, 3H), 1.51 - 1.50 (m,9H), 1.20 (s, 3H), 0.92 - 0.84 (m, 18H). LCMS room temperature = 0.628 min, m / z = 843.4 [M + H] + .

[0488] Step 6: tert-butyl(2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was concentrated under vacuum to obtain tert-butyl(2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (366 mg, crude) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ 9.14 - 9.09 (m, 1H), 8.00 - 7.92 (m, 2H), 7.65 - 7.56 (m, 2H), 7.37 - 7.32 (m, 1H), 5.40 - 5.21 (m, 1H), 5.11 - 5.00 (m, 1H), 4.29 - 4.18 (m, 1H), 4.07 - 3.71 (m, 3H), 3.44 - 3.40 (m, 3H), 3.25 (s, 3H), 3.19 (s, 2H), 3.00 (d, J = 5.4 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.32 - 2.26 (m, 1H), 2.23 - 2.13 (m, 3H), 1.99 - 1.90 (m, 3H), 1.50 (s, 9H), 1.21 (d, J = 6.8 Hz, 3H). LCMS room temperature = 0.474 min, m / z = 687.3 [M + H] + .

[0489] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3S)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000318.tif46165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3S)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (90 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.356 min, m / z = 587.3 [M + H] + .

[0490] Step 8: 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 25%~55% B, 8.0 minutes) to obtain 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (34.94 mg, 34.26%) as a yellow amorphous solid: 1H NMR (400 MHz, chloroform-d) δ 9.14 - 9.09 (m, 1H), 8.03 - 7.90 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.30 (m, 1H), 6.55 - 6.39 (m, 2H), 5.81 - 5.72 (m, 1H), 5.44 - 5.20 (m, 1H), 5.18 - 5.08 (m, 1H), 4.51 - 4.27 (m, 3H), 4.15 - 3.80 (m, 2H), 3.79 - 3.58 (m, 1H), 3.42 (s, 3H), 3.34 - 3.16 (m, 2H), 3.09 - 2.80 (m, 2H), 2.67 - 2.51 (m, 1H), 2.36 - 2.11 (m, 4H), 2.06 - 2.88 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 3.055 minutes, ESI + measured value: [M+H] + = 641.3.

[0491] Example 28: Synthesis of compounds 1-5; 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 2) TIFF2026517789000320.tif59165 Step 1: tert-butyl(2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate Reductive amination was carried out in the same manner as in Method 2, Step 1. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 × 10 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum to obtain tert-butyl(2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (400 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.339 min, m / z = 305.3 [M + H] + .

[0492] Step 2: tert-butyl(2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate The debenzylation reaction was carried out in the same manner as in Method 2, Step 2. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain tert-butyl(2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (250 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0493] Step 3: tert-butyl(2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 2, Step 3. The reaction mixture was concentrated to dryness under vacuum to obtain tert-butyl(2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.583 min, m / z = 430.1 / 432.0 [M + H] + .

[0494] Step 4: tert-butyl(2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, 62.25%) as a yellow solid. LCMS at room temperature = 0.421 min, m / z = 553.3 / 555.2 [M + H] + .

[0495] Step 5: tert-butyl(2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The reaction mixture was concentrated to dryness under vacuum to obtain tert-butyl(2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (280 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS at room temperature = 0.646 min, m / z = 843.5 [M + H] + .

[0496] Step 6: tert-butyl(2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 2, Step 6. The reaction mixture was concentrated under vacuum to obtain tert-butyl(2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (230 mg, crude) as a brown solid, which was used in the next step without further purification. LCMS at room temperature = 0.649 min, m / z = 687.3 [M + H] + .

[0497] Step 7: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2S,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000327.tif46165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((2S,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (90 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.342 min, m / z = 587.2 [M + H] + .

[0498] Step 8: 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 30%~65% B, 8.0 min) to obtain 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (12.41 mg, 97.15%) as a yellow amorphous solid: 1 H NMR (400 MHz, chloroform-d) δ 9.15 (s, 1H), 8.01 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.35 (t, J = 8.8 Hz, 1H), 6.55 - 6.38 (m, 2H), 5.80 - 5.72 (m, 1H), 5.45 - 5.23 (m, 1H), 5.19 - 5.09 (m, 1H), 4.55 - 4.21 (m, 3H), 4.20 - 3.88 (m, 2H), 3.82 - 3.65 (m, 1H), 3.47 - 3.41 (m, 3H), 3.38 - 3.14 (m, 2H), 3.11 - 2.96 (m, 1H), 2.95 - 2.82 (m, 1H), 2.58 (d, J = 9.8 Hz, 1H), 2.44 - 2.17 (m, 4H), 2.11 - 1.89 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 3.056 mins, ESI + measured value: [M+H] + = 641.3.

[0499] Example 29: Synthesis of compound 13-1 or 13-2; 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (Method 1) TIFF2026517789000329.tif59165 Step 1: 1-(tert-butyl)2-methyl(R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate To a solution of potassium tert-butoxide (22.14 g, 197.32 mmol) in N,N-dimethylformamide (210 mL), 2-((fluoromethyl)sulfonyl)pyridine (20.74 g, 118.39 mmol) and 1-(tert-butyl)2-methyl(R)-4-oxopyrrolidine-1,2-dicarboxylate (24 g, 98.66 mmol) were added at -78°C. The mixture was stirred at 30°C for 1 hour. The reaction mixture was quenched at 0°C with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (3 × 500 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 15 μm); mobile phase: [H2O (0.1% TFA); gradient: 30%~65% B, 20.0 mins) to obtain 1-(tert-butyl)2-methyl(R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate (3.4 g, 13.29%) as a yellow oil. LCMS at room temperature = 1.694 min, m / z = 260.1 [M + H] + .

[0500] Step 2: (R)-(4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methanol To a solution of 1-(tert-butyl)2-methyl(R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate (3.4 g, 13.11 mmol) in tetrahydrofuran (80 mL), lithium aluminum hydride (20.98 mL, 2.5 M in tetrahydrofuran, 52.45 mmol) was added at 0°C. The mixture was stirred at 70°C for 1 hour. The reaction mixture was quenched at 0°C with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 100 mL). The mixed organic layer was dried over sodium sulfate and concentrated under vacuum to obtain (R)-(4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methanol (1.3 g, crude) as a yellow oil, which was used in the next step without further purification. LCMS room temperature = 0.137 min, m / z = 146.2 [M + H] + .

[0501] Step 3: tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate and tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was carried out in the same manner as in Method 1, Step 4. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 15%~45% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((R)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (550 mg, 35.25%) as a yellow solid. LCMS room temperature = 1.397 min, m / z = 539.2 / 541.2 [M + H] + .

[0502] A mixture of diastereomers of Z-alkenes and E-alkenes (550 mg) was separated by SFC to obtain the following arbitrarily assigned compounds: tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (peak 2, retention time = 1.618 min) (200 mg, 11.83%) (yellow solid), LCMS at room temperature = 1.397 min, m / z = 539.2 / 541.2 [M + H] + and tert-butyl(2R,3R)-3-((7-chloro-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (peak 1, retention time = 1.411 min) (360 mg, 21.29%) (yellow solid), LCMS at room temperature = 1.397 min, m / z = 539.2 / 541.2 [M + H] + . SFC (Column: DAIEL CHIRALPAK IG (250mm x 30mm, 10um); Mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, homogeneous concentration elution mode).

[0503] Step 4: tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (380 mg, 79.69%) as a yellow solid. LCMS at room temperature = 0.594 min, m / z = 829.4 [M + H] + .

[0504] Step 5: tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was concentrated under vacuum to obtain tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (120 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS at room temperature = 0.439 min, m / z = 673.3 [M + H] + .

[0505] Step 6: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000335.tif52165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (110 mg, crude, hydrochloride) as a white solid, which was used in the next step without further purification. LCMS at room temperature = 0.339 min, m / z = 573.3 [M + H] + .

[0506] Step 7: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40%~65% B, 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (19.05 mg, 16.83%) as a white solid: 1H NMR (400 MHz, acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.09 (m, 2H), 7.69 (d, J = 4.5 Hz, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.83 - 6.53 (m, 2H), 6.36 - 6.21 (m, 1H), 5.77 - 5.63 (m, 1H), 5.08 - 4.82 (m, 2H), 4.62 - 4.33 (m, 2H), 3.94 - 3.67 (m, 1H), 3.63 (d, J = 4.3 Hz, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.28 (s, 1H), 2.90 (dd, J = 2.5, 10.0 Hz, 1H), 2.83 - 2.71 (m, 2H), 2.69 - 2.44 (m, 2H), 2.41 (s, 3H), 2.40 - 2.20 (m, 2H), 1.21 - 1.02 (m, 3H). LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate, 6 minutes), retention time: 2.986 minutes, ESI + measured value: [M+H] + = 627.3.

[0507] Example 30: Synthesis of compound 13-1 or 13-2; 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one (Method 1) TIFF2026517789000337.tif59165 Step 1: tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The Suzuki reaction was carried out in the same manner as in Method 1, Step 5. (TIFF2026517789000338.tif59165) The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 45%~85% B, 8.0 min) to obtain tert-butyl(2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, 72.24%, trifluoroacetate) as a yellow solid. LCMS at room temperature = 2.324 min, m / z = 829.4 [M + H] + .

[0508] Step 2: tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate Deprotection of the TIPS group was carried out in the same manner as in Method 1, Step 6. The reaction mixture was concentrated under vacuum to obtain tert-butyl(2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (180 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.461 min, m / z = 673.2 [M + H] + .

[0509] Step 3: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine The deprotection reaction of TIFF2026517789000340.tif52165Boc was carried out in the same manner as in Method 1, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (180 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS at room temperature = 0.355 min, m / z = 573.2 [M + H] + .

[0510] Step 4: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)propa-2-en-1-one The acylation reaction was carried out in the same manner as in Method 1, Step 8. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 25%~65% B, 8.0 minutes) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one (15.70 mg, 8.94%) as a yellow solid: 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.06 (m, 2H), 7.70 (d, J = 4.8 Hz, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.73 - 6.42 (m, 2H), 6.34 - 6.22 (m, 1H), 5.77 - 5.61 (m, 1H), 5.01 - 4.81 (m, 2H), 4.65 - 4.36 (m, ...

Claims

1. Compound of formula (I): or a salt thereof, and / or an isotope-substituted thereof, in the formula, X is -N(CH ３ ) - or -O-; X １ is, -CH ３ ien-CH ２ CH ３ ien-CH=CH ２ , or cyclopropyl, each of which is halo, -OH, and -OCH ３ Substituted with 0, 1, or 2 substituents independently selected from the group consisting of; q is either 0 or 1; R １ is a 4- to 8-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 R １Ａ groups; R in each case １Ａ is halo, hydroxy, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy and -C(O)(C １ -C ４ Independently selected from the group consisting of alkyls, or two geminal R １Ａ However, together with the carbon atoms to which they are bonded, C is substituted with 0, 1, or 2 halos. ３ -C ４ Forms a cycloalkyl group or two geminal R groups. １Ａ Together, =CH ２ , =CHF, or =CF ２ Forming; R ａ is H or CH ３ And; R ２ teeth, And; R ３ is hydrogen, halo, C １ -C ４ Alkyl, C ３ -C ４ Cycloalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy and C ２ -C ３ Selected from the group consisting of alkynnyls; R ４ is hydrogen, halo, C １ -C ４ Alkyl, C ３ -C ４ Cycloalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy and C ２ -C ３ Selected from the group consisting of alkynnyls; R ５ is either H or -OH; Y is either CH or N; R in each case ６ is a halo, -OH, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ４ Cycloalkyl and -NH ２ Independently selected from the group consisting of; and r is 0, 1, 2, or 3; However, if q is 0, R １ teeth, But it's not that arbitrary enantiomer either, but or any enantiomer thereof, R ２ teeth, Rather, and but or any enantiomer thereof, R ２ teeth, The aforementioned compound, its salt, and / or its isotopically substituted derivatives.

2. R ２ teeth, The compound according to claim 1, or a salt thereof, and / or an isotopically substituted thereof.

3. R ３ Hello, C １ -C ４ Alkyl and C ２ -C ３ A compound according to claim 2, a salt thereof, and / or an isotopic derivative thereof, selected from the group consisting of alkynyl compounds.

4. R ３ These are -F, -Cl, -Et, -C≡CH, and -C≡C-CH ３ A compound according to claim 2, or a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

5. R ４ The compound according to any one of claims 2 to 4, or a salt thereof, and / or an isotopically substituted thereof, wherein is hydrogen or a halo.

6. R ４ The compound according to any one of claims 2 to 4, or a salt thereof, and / or an isotopically substituted thereof, wherein is hydrogen or -F.

7. R ５ The compound according to any one of claims 2 to 6, or a salt thereof, and / or an isotopically substituted thereof, wherein is -OH.

8. R ５ The compound according to any one of claims 2 to 6, or a salt thereof, and / or an isotopic substituted thereof, wherein is H.

9. R ２ teeth, The compound according to claim 2, or a salt thereof, and / or an isotopically substituted thereof.

10. R ２ teeth, The compound according to claim 1, or a salt thereof, and / or an isotopically substituted thereof.

11. The compound of claim 10, or a salt thereof, and / or an isotopically substituted thereof, wherein Y is CH.

12. The compound of claim 10, or a salt thereof, and / or an isotopically substituted thereof, wherein Y is N.

13. R in each case ６ -Cl, -OH, -CH ３ , -CF ３ cyclopropyl and -NH ２ A compound according to any one of claims 10 to 12, or a salt thereof, and / or an isotopic substituted thereof, independently selected from the group consisting of the above.

14. The compound according to any one of claims 10 to 13, or a salt thereof, and / or an isotopically substituted thereof, wherein r is 3.

15. R ２ teeth, The compound according to any one of claims 10 to 13, a salt thereof, and / or an isotopic substituted thereof.

16. R ２ teeth, and in the formula, R ６Ａ is cyclopropyl or -CF ３ and R ６Ｂ is -Cl or -CH ３ and R ６Ｃ is -OH or -NH ２ The compound according to any one of claims 10 to 13, or a salt thereof, and / or an isotopically substituted form thereof.

17. R ２ teeth, The compound according to claim 10, or a salt thereof, and / or an isotopically substituted thereof.

18. X is -N(CH ３ ) - the compound according to any one of claims 1 to 17, or a salt thereof, and / or an isotopic substituted thereof.

19. X is -O-, the compound according to any one of claims 1 to 17, a salt thereof, and / or an isotopic substituted thereof.

20. X １ is -CH ３ , -CH ２ F, -CH ２ OCH ３ , -CH ２ CH ３ , -CH(OH)CH ３ , -CH=CH ２ , or cyclopropyl, the compound according to any one of claims 1 to 19, or a salt thereof, and / or an isotope-substituted form thereof.

21. X １ is, -CH ３ The compound according to any one of claims 1 to 19, a salt thereof, and / or an isotopically substituted thereof.

22. The aforementioned compound The part is, The compound according to any one of claims 1 to 17, a salt thereof, and / or an isotopically substituted thereof.

23. The aforementioned compound The part is, The compound according to any one of claims 1 to 17, a salt thereof, and / or an isotopically substituted thereof.

24. R １ is 0, 1, 2, or 3 R １Ａ Replaced with The compound according to any one of claims 1 to 23, a salt thereof, and / or an isotopically substituted thereof.

25. R in each case １Ａ These are independently -F, -OH, and -CH ３ , -OCH ３ , -OCF ３ , -OCHF ２ , or -C(O)CH ３ or two geminal R １Ａ However, together with the carbon atoms to which they are bonded, they form cyclopropyls substituted with 0, 1, or 2 fluorocarbons, or two geminal R atoms. １Ａ Together, =CH ２ , =CHF, or =CF ２ A compound according to any one of claims 1 to 24, or a salt thereof, and / or an isotopic substituted thereof, which forms a compound.

26. R １ teeth, The compound according to any one of claims 1 to 25, a salt thereof, and / or an isotopic substituted thereof.

27. R １ teeth, The compound according to any one of claims 1 to 25, a salt thereof, and / or an isotopic substituted thereof.

28. R ａ The compound according to any one of claims 1 to 27, wherein is H.

29. R ａ CH ３ The compound according to any one of claims 1 to 27.

30. The compound is selected from the group consisting of the compounds in Table 1, and is a compound according to claim 1, or a salt thereof, and / or an isotope-substituted compound thereof.

31. The compound according to any one of claims 1 to 30, or a salt thereof, and / or an isotopic substituted thereof, wherein the salt is a formate salt.

32. The compound according to any one of claims 1 to 31, a salt thereof, and / or an isotopic variant thereof, wherein the salt is a pharmaceutically acceptable salt.

33. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, and a pharmaceutically acceptable carrier.

34. A method for treating or suppressing cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitute thereof, or a pharmaceutical formulation according to claim 33, to a subject in need thereof.

35. The method according to claim 34, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

36. The aforementioned cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, and mesothelial carcinoma. The method according to claim 34, selected from the group consisting of tumors, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

37. The method according to any one of claims 34 to 36, wherein the cancer is a KRAS G12C-mediated cancer.

38. The method according to any one of claims 34 to 36, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

39. The method according to any one of claims 34 to 38, further comprising administering an additional therapeutically effective amount of chemotherapeutic agent to the subject.

40. A compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to claim 33, for use as a pharmaceutical.

41. A compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic variant thereof, or a pharmaceutical formulation according to claim 33, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt.

42. The aforementioned cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and the compound for use of claim 41, or a pharmaceutically acceptable salt thereof, and / or an isotope substitution thereof, or a pharmaceutical formulation.

43. The aforementioned cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, and diffuse cystadenocarcinoma. A compound for use according to claim 41, or a pharmaceutically acceptable salt thereof, and / or an isotopic variant thereof, or a pharmaceutical formulation, selected from the group consisting of B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

44. The aforementioned cancer is a KRAS G12C-mediated cancer, and the compound for use according to any one of claims 41 to 43, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

45. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound for use according to any one of claims 41 to 43, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

46. The compound or the pharmaceutical formulation is configured to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent, the compound for use according to any one of claims 40 to 45, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

47. The compound or the pharmaceutical preparation is a compound for use according to any one of claims 40 to 46, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical preparation, configured to be administered in a therapeutically effective dose.

48. A compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to claim 33, for use in the manufacture of a pharmaceutical for treating or suppressing cancer in a subject that requires it.

49. The aforementioned cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and the compound for use of claim 48, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

50. The aforementioned cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, and diffuse cystadenocarcinoma. A compound for use according to claim 48, or a pharmaceutically acceptable salt thereof, and / or an isotope substitution thereof, or a pharmaceutical formulation, selected from the group consisting of B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

51. The aforementioned cancer is a KRAS G12C-mediated cancer, and the compound for use according to any one of claims 48 to 50, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

52. The subject is diagnosed with KRAS G12C-mediated cancer and is a compound for use according to any one of claims 48 to 50, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

53. The compound or the pharmaceutical formulation is configured to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent, the compound for use according to any one of claims 48 to 52, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

54. The pharmaceutical product comprises a therapeutically effective amount of the compound or composition, the compound for use according to any one of claims 48 to 53, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation.

55. Use of a compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to claim 33, in the manufacture of a pharmaceutical for treating or suppressing cancer in a subject that requires it.

56. The use according to claim 55, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

57. The aforementioned cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, and mesothelial carcinoma. The use according to claim 55, selected from the group consisting of tumors, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

58. The use according to any one of claims 55 to 57, wherein the cancer is a KRAS G12C-mediated cancer.

59. The use according to any one of claims 55 to 57, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

60. The use according to any one of claims 55 to 59, wherein the compound or the pharmaceutical preparation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

61. The use according to any one of claims 55 to 60, wherein the pharmaceutical product comprises a therapeutically effective amount of the compound or the pharmaceutical preparation.

62. Use of a compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical formulation according to claim 33, for treating or suppressing cancer in a subject that requires it.

63. The use according to claim 62, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

64. The aforementioned cancers include glioblastoma pleomorphism, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, and mesothelial carcinoma. The use according to claim 62, selected from the group consisting of tumors, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

65. The use according to any one of claims 62 to 64, wherein the cancer is a KRAS G12C-mediated cancer.

66. The use according to any one of claims 62 to 64, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

67. The use according to any one of claims 62 to 66, wherein the compound or the pharmaceutical preparation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

68. The use according to any one of claims 62 to 67, with a therapeutically effective amount of the compound or the composition.

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