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

Abstract

This disclosure provides compounds of formula (I), (II), or (III) that are useful for treating or suppressing cancer, for example, cancer characterized by KRAS G12C, for use in the treatment and suppression of cancer. Also provided are pharmaceutical formulations containing such compounds and processes for preparing such compounds. TIFF2026515945000281.tif145165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 464,175, filed on 4 May 2023, the entire disclosure of which is incorporated herein by reference.

[0002] Areas of disclosure 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 particularly common in the three most fatal cancers: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%). Taken together, these cancers occur in over 200,000 patients annually in the United States alone. One specific mutation (a substitution of glycine to cysteine ​​at position 12 (G12C)) occurs in over 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 are compounds useful in the treatment of cancer (such as cancer characterized by KRAS G12C, etc.). Further needed are compounds useful in the treatment of cancer characterized by KRAS G12C, which bind to and inhibit both the inactivated GDP-binding form and the activated GTP-binding form of KRAS. Further needed are compounds useful in the treatment of cancer characterized by KRAS G12C, which have an improvement in the inhibition of the GTP-binding form of KRAS G12C.

Summary of the Invention

[0008] Summary In one aspect, the present invention provides a compound of formula (I), formula (II), or formula (III): TIFF2026515945000002.tif148165 or a salt thereof, and / or an isotope-substituted form thereof, wherein Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, Each R a is independently selected from the group consisting of halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, m is 0, 1, 2, or 3, R 1 is TIFF2026515945000003.tif32165, R d is H or F, R 2 is TIFF2026515945000004.tif27165, R e is -R e1 or -R e2 and R Y1 and R Y2 are, each time they occur, independently -H or -CH3, provided that R Y1 and R Y2At least one of them is -CH3, R e1 This is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. R e2 -NR 21 R 22 And, R 21 and R 22 These are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 membered heterocycle. Each R x These are independently selected from the group consisting of halo and C1-C4 alkyl, and n is 0, 1, or 2.

[0009] In some embodiments, including any of the embodiments described in the preceding paragraph, the compounds are 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] A method for treating or suppressing cancer according to another embodiment comprises administering to a subject in need a therapeutically effective amount of a compound (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), 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, cervical cancer, and bladder cancer. In some embodiments, the cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, 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, and plasmacytotic myeloma. The following are selected from the group consisting of uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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, which encompass 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 dose 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 the treatment or suppression of 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 pharmaceuticals for use in treating or suppressing cancer is provided. In some embodiments encompassing any of the embodiments described above, the use is for the treatment of cancer. In some embodiments encompassing any of the embodiments described above, the use is for the suppression of 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 or “essentially consist of” the listed components or steps. Where a composition is described as “essentially consisting of” the 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 This specification provides compounds useful for the treatment of cancer and methods for using such compounds in the treatment of cancer. 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 provide improved inhibition of the GTP-bound form of KRAS G12C.

[0017] definition Unless otherwise specified, abbreviations used herein have their conventional meanings in 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 specified, the absolute stereochemistry of all chiral atoms is as shown in the diagram. Compounds with stereocenters whose arrangement is not shown in the diagram are mixtures of enantiomers at that center.

[0020] 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 and chiral recrystallization. Reference to a compound that is a racemic mixture implies the inclusion of the individual enantiomers contained within the mixture.

[0021] References to values ​​or parameters in this specification that use the term "about" include (and describe) variations directed toward the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X". When 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, when 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.

[0022] The terms "a" and "an" as used herein mean one or more unless otherwise clearly indicated by the context.

[0023] 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 has been identified or diagnosed with a cancer or tumor having a KRAS G12C mutation (determined, for example, using a regulatory-approved, e.g., FDA-approved assay or kit).

[0024] "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.

[0025] "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.

[0026] 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.

[0027] 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.

[0028] The compounds described herein exist and can be used as neutral (non-salt) compounds, but the description herein is intended to encompass all salts of the compounds described herein and methods of use of such salts of compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0029] 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 include acid addition salts formed with (b) methylenebis-(3-hydroxy-2-ene-1-carboxylate), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like, etc., or (b) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ions, alkaline earth ions, or aluminum ions) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and 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).

[0030] Where chemically reasonable, all stereoisomers of a compound, including diastereomers and enantiomers, are included herein. Mixtures of possible stereoisomers are also included in any proportion (including, but not limited to, racemic mixtures). Unless stereochemistry is explicitly shown in the structure, the structure is intended to encompass all possible stereoisomers of the illustrated compound. If stereochemistry is explicitly shown for one or more parts of a molecule but not for another part or more parts of the molecule, the structure is intended to encompass all possible stereoisomers for the part or more for which stereochemistry is not explicitly shown.

[0031] 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 herein 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 specified herein, and in some embodiments, partially deuterated or fully deuterated analogs. “Isotope enrichment” may 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 particular position means that 1% of the molecules in a given sample contain deuterium at the 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.

[0032] "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, and butyl.

[0033] "Alkylene" refers to a saturated divalent hydrocarbon radical that has a defined number of carbon atoms and is linear, branched, or a combination thereof. Examples of C1-C4 alkylenes include methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, and butylene.

[0034] "Alkenyl" refers to a monovalent hydrocarbon radical that contains one or more double bonds and has a defined number of carbon atoms, either linear or branched. Examples of C2-C4 alkenyls include vinyl, propa-1-en-2-yl, propa-1-en-1-yl, and allyl.

[0035] "Alkynyl" refers to a monovalent hydrocarbon radical that contains one or more triple bonds and has a defined number of carbon atoms, either linear or branched. Examples of C2-C4 alkynes include ethynyl, propynyl, 2-propynyl, and butynyl.

[0036] "Alkoxy" is R x ' is an alkyl as defined above -OR x 'radical, or R x '' is alkylene, R x -R is the alkyl group defined above. x OR x '''It means radical, and the defined number of alkyl carbons in an 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-, iso-, tert-butoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, etc. In some embodiments, the alkoxy is -OR x 'It is radical. In some embodiments, the alkoxy is -R x OR xIt is a radical. In some embodiments, when nitrogen is substituted with an alkoxy group, the alkoxy group is not bonded to nitrogen via oxygen in the alkoxy group or a carbon directly adjacent to the oxygen. For example, alkoxy-substituted nitrogen is N-OR x 'or N-CH2-OR x '''isn't it.

[0037] "Alkoxyalkoxy" is R y -OR is an alkoxy as defined above y radical (where R y The bond point is not an oxygen atom), or R y ' is alkylene, R y '' is the alkoxy group defined above -R y 'OR y ''radical (where R y The bond point of '' means that it is not an oxygen atom, and the defined number of alkyl carbons in the alkoxyalkoxy group is R y 'and R y It is equal to the total number of carbon atoms in ''. For example, C1~C6 alkalkalk represents, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, etc. In some embodiments, alkalkalk is -OR y It is radical. In some embodiments, the alkoxyalkoxy is -R y 'OR y It is a radical. In some embodiments, when nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy is not bonded to nitrogen via oxygen in the alkoxyalkoxy group or a carbon directly adjacent to the oxygen. For example, alkoxyalkoxy-substituted nitrogen is N-OR y Or N-CH2-OR y ''isn't it.

[0038] "Aminoalkyl" means R z -NHR is the alkyl group defined above.z radical, or R z and R z ' is the alkyl group defined above -NR z R z 'radical, or R z '' is the alkylene group defined above -R z 'NH2 radical, or R z '' is the alkylene group defined above, and R z ' is the alkyl group defined above -R z ''NHR z radical, or R z '' is the alkylene group defined above, and R z and R z ' is the alkyl group defined above -R z 'NR z R z 'R means radical, and the defined number of alkyl carbons in an aminoalkyl group is, if applicable, R z , R z 'and R z The 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, etc. In some embodiments, the aminoalkyl is -NHR z It is radical. In some embodiments, the aminoalkyl is -NR z R z It is radical. In some embodiments, the aminoalkyl is -R z It is an NH2 radical. In some embodiments, the aminoalkyl is -R z ''NHR z It is radical. In some embodiments, the aminoalkyl is -R z 'NR z R z'It is a radical. In some embodiments, when oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not bonded 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 Or O-CH2-NHR z isn't it.

[0039] "Aryl" refers to a ring of 6-14 carbon atoms and an aromatic ring system ("C"). 6~14 The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having zero heteroatoms provided to it. 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 ("C6 aryl"). 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 a ring system in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, and the radical or bond site is on the aryl ring, in which case 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 similar groups, where the bond site is on the phenyl group. In some embodiments, "Aryl" excludes ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above.

[0040] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical having a defined number of carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0041] "Cycloalkylene" means a monocyclic saturated divalent hydrocarbon radical having a defined number of carbon atoms. For example, C3-C6 cycloalkylene includes cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0042] "Cyanoalkyl" means an alkyl radical as defined above substituted with a cyano group (-CN). Cyanoalkyl may also be referred to as alkyl nitrile.

[0043] "Halo" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro or chloro.

[0044] "Haloalkyl" means an alkyl radical as defined above and substituted with one or more halogen atoms, for example 1 to 5 halogen atoms such as fluorine or chlorine, and includes those substituted with different halogens, for example, -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl is substituted with only fluorine, it may be referred to as fluoroalkyl in the present application.

[0045] "Haloalkoxy" means -OR a’ where R is a haloalkyl as defined above, or -R a’ OR b’ where R and R c’ are alkyl or haloalkyl groups as defined above, and the defined number of alkyl carbons in the haloalkoxy group is equal to the total number of carbons of R b’ and R c’ . The halogen atom is R b’ and R c’ . The total number of carbons of R b’ and R c’、 or may be present in both, and R b’ and R c’ at least one of which contains a halo atom. For example, C1-C4 haloalkoxy represents, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2. In some embodiments, the haloalkoxy is -OR a’ radical. In some embodiments, the haloalkoxy is -R b’ OR c’ radical. If all of the halo atoms 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 bonded to nitrogen through oxygen or the carbon directly adjacent to oxygen in the haloalkoxy group. For example, haloalkoxy-substituted nitrogen is not N-OR a’ or N-C(H) n (X) m -O-R’’ (where X is a halogen, n and m are integers, and n + m = 2).

[0046] "Hydroxyalkyl" means an alkyl radical as defined above substituted with one or more hydroxyl (-OH) groups, for example 1 to 3 hydroxyl groups, such as -CH2OH, -CH2CH2OH, -C(OH)(CH3)2, -CH(OH)CH3, etc.

[0047] Unless otherwise specified, a "heterocyclic group" or "heterocyclic group" means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining ring is carbon. The sulfur group can exist as either -S- or -S(O)2-. Unless otherwise specified, heterocyclic groups include monocyclic and polycyclic ring systems such as fused rings, bridging rings, and spirocyclic systems. A "heterocyclic group" or "heterocyclic group" also includes ring systems in which a heterocyclic group is fused with one or more carbocyclic groups, as defined above, and the bond site is on either the carbocyclic or heterocyclic ring. In some embodiments, a "heterocyclic group" or "heterocyclic group" also includes ring systems in which a heterocyclic group is fused with one or more aryl or heteroaryl groups, as defined above, and the bond site is on a heterocyclyl ring. In such cases, the number of ring members continues to indicate the number of ring members within the heterocyclyl ring system. In some embodiments, the heterocyclic group is a monocyclic ring. In some embodiments, the heterocyclic group contains two fused rings. In some embodiments, the heterocyclic group contains two spiro rings. In some embodiments, the heterocyclic group contains a bridging ring system.

[0048] Unless otherwise specified, "carbocyclic group" or "carbocyclic group" refers to a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms (where the ring atoms are carbon). Unless otherwise specified, carbocyclic groups include monocyclic and polycyclic systems such as fused ring systems, bridging ring systems, and spiro-ring 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 spiro-rings. In some embodiments, the carbocyclic group contains a bridging ring system.

[0049] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, where one or more (in some embodiments, one, two, or three) ring atoms are heteroatoms independently selected from N, O, or S, and the remaining ring atoms are carbon. In some embodiments, "heteroaryl" includes a ring system in which a heteroaryl ring is fused with one or more carbocykyl or heterocyclyl groups, as defined above, and 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 a ring system in which a heteroaryl ring is fused with one or more aryl groups, as defined above, and the bond site is on the aryl or heteroaryl ring, in which case, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In the case of bicyclic heteroaryl groups that do not contain a heteroatom on one ring (e.g., indolyl, quinolinyl, carbazolyl, etc.), 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. Typical 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, and tetrazolyl.

[0050] 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, This shows TIFF2026515945000005.tif27165.

[0051] When used herein, "requiring treatment" 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 is diagnosed with KRAS G12C-mediated cancer. In some embodiments, the patient is determined to be at risk of developing KRAS G12C-mediated cancer.

[0052] "Administering" or "dosing" refers to bringing a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt and / or isotopic substitution thereof, a pharmaceutical preparation containing it, 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 not only contact between the reagent and the cell (e.g., in vitro or ex vivo) but also contact between the reagent and the fluid (in which case the fluid is in contact with the cell).

[0053] The terms "optional" or "optional" mean that the event or situation described thereafter may occur, but is not necessarily required, and that the description includes both cases where the event or situation occurs and cases where it does not.

[0054] "Pharmacologically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and useful in preparing a pharmaceutical formulation 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" when used in the specification and claims includes both one and more such excipients.

[0055] 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 bodies or parts 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.

[0056] The term “combination therapy” means administering two or more therapeutic agents to treat the disease or disorder 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 plan will result in the beneficial effect of the combination of agents in treating the symptoms or disorders described herein.

[0057] compound This specification provides compounds of formulas (I), (II), and (III). Unless otherwise specified in the context, throughout this specification, the phrases “compounds of formula (I), (II), or (III)” or “multiple compounds of formula (I), (II), or (III)” refer to all embodiments of formulas (I), (II), and (III), including, for example, the compounds of formulas (Ia), (Ib), (II-a), (II-b), (III-a), (III-b), and the compounds of Table 1. In some embodiments, compounds of formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof are provided. In some embodiments, compounds of formulas (I), (II), and (III) are provided as pharmaceutically acceptable salts. In some embodiments, compounds of formulas (I), (II), and (III) are provided as corresponding free bases (i.e., not salts).

[0058] In one embodiment, a compound of formula (I), formula (II), or formula (III): TIFF2026515945000006.tif151165 or its salts, and / or its isotopic substitutions are provided, in the formula, Ring A is a 6-10 membered aryl or a 5-10 membered heteroaryl. Each R a These are independently selected from the group consisting of halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. m is 0, 1, 2, or 3. R 1 teeth, The filename is TIFF2026515945000007.tif32165. R d is H or F, R 2 teeth, The filename is TIFF2026515945000008.tif27165. R e is, -R e1 or -R e2 And, R Y1 and R Y2 Each instance is independently -H or -CH3, except R Y1 and R Y2 At least one of them is -CH3, R e1 This is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. R e2 -NR 21 R 22 And, R 21 and R 22These are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 membered heterocycle. Each R x These are independently selected from the group consisting of halo and C1-C4 alkyl, and n is 0, 1, or 2.

[0059] As generally defined herein, ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl.

[0060] In one embodiment, ring A is selected from 6- to 10-membered aryls and 9- to 10-membered bicyclic heteroaryls having 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0061] In one embodiment, ring A is selected from the group consisting of naphthalenyl, phenyl, isoquinolinyl, indazolyl, and pyridinyl. In another embodiment, ring A is selected from the group consisting of naphthalenyl and phenyl.

[0062] In one embodiment, ring A is naphthalenyl. In another embodiment, ring B is phenyl.

[0063] In one embodiment, ring A is selected from the group consisting of naphthalene-1-yl, phenyl, isoquinoline-1-yl, indazole-4-yl, and pyridine-1-yl. In one embodiment, ring A is selected from the group consisting of naphthalene-1-yl and phenyl. In one embodiment, ring A is naphthalene-1-yl.

[0064] In one embodiment, ring A is Selected from the group consisting of TIFF2026515945000009.tif42165, where R 3 , R 4 , R h , R i , R j , R k , R n , Ro , R q , R s , R g 、 R m , and R p These are defined herein, respectively.

[0065] In one embodiment, ring A is Selected from the group consisting of TIFF2026515945000010.tif37165, where R 3 , R 4 , R h , R i , R j , R k and R m These are as defined herein. In one embodiment, ring A is The file is TIFF2026515945000011.tif32165, and here, R 3 and R 4 These are as defined herein. In one embodiment, ring A is TIFF2026515945000012.tif32165, where R j , R k and R m These are as defined herein. In one embodiment, ring A is Selected from TIFF2026515945000013.tif32165.

[0066] In one embodiment, ring A is This is TIFF2026515945000014.tif32165. In one embodiment, ring A is This is TIFF2026515945000015.tif32165. In one embodiment, ring A is This is TIFF2026515945000016.tif32165. In one embodiment, ring A is This is TIFF2026515945000017.tif32165. In one embodiment, ring A is This is TIFF2026515945000018.tif27165. In one embodiment, ring A is This is TIFF2026515945000019.tif27165. As generally defined herein, each R a These are independently selected from halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0067] One embodiment, each R a R is independently selected from halo, -OH, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl. In one embodiment, each R a These are independently selected from halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl.

[0068] One embodiment, each R a These are independently selected from halo and C1-C4 alkyl groups. In one embodiment, each R a These are independently selected from halo and C3-C4 cycloalkyl groups. In one embodiment, each R a These are independently selected from halo and C1-C4 haloalkyl. In one embodiment, each R a These are independently selected from halo and C2-C3 alkynyl. In one embodiment, each R a It is, independently, a halo.

[0069] One embodiment, each R s R is independently selected from -F, -Cl, -OH, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R s These are independently selected from -F, -Cl, -Me, and -Et. In one embodiment, each R a These are independently selected from -F, -Cl, and -cyclopropyl. In one embodiment, each R aThese are independently selected from -F, -Cl, and -CF3. In one embodiment, each R a These are independently selected from -F, -Cl, and -C≡CH. In one embodiment, each R a These are independently selected from -F and -Cl. In one embodiment, each R a is -F. In one embodiment, each R a is -Cl. In one embodiment, each R a is -OH. In one embodiment, each R a is -Me. In one embodiment, each R a is -Et. In one embodiment, each R a is cyclopropyl. In one embodiment, each R a is -CF3. In one embodiment, each a -C ≡ CH.

[0070] As generally defined herein, m is 0, 1, 2, or 3. In one embodiment, m is 1, 2, or 3. In one embodiment, m is 1 or 2. In one embodiment, m is 2 or 3. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.

[0071] As generally 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 3R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R 3 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 groups. 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 These are independently halos. In one embodiment, each R 3 R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R 3 These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 3 These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 3 These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 3 These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R 3 These are 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 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.

[0072] As generally 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 These are independently halos. In one embodiment, each R 4 R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R 4 These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 4 These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 4 These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 4 These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R 4 These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R 4 These are independently selected from the group consisting of -F and -Cl. In one embodiment, R 4is selected from -H and -F. In one embodiment, R 4 is -H. In one embodiment, R 4 It is -F.

[0073] As generally defined herein, each R h 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 h 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 h R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R h R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R h R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R h R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R h R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R h These are independently halos. In one embodiment, each R h R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R h These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R h These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R h These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R h These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each Rh These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R h These are independently selected from the group consisting of -F and -Cl.

[0074] As generally defined herein, each R i 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 i 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 i R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R i R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R i R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R i R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R i R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R i These are independently halos. In one embodiment, each R i R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R i These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R i These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R i These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R iThese are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R i These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R i These are independently selected from the group consisting of -F and -Cl.

[0075] As generally defined herein, each R j 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 j 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 j R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R j R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R j R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R j R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R j R is independently selected from the group consisting of hydrogen and halo. In one embodiment, R j The C3-C4 cycloalkyl and C1-C4 haloalkyl groups are selected from C3-C4 cycloalkyl groups. In one embodiment, each R j These are independently halos. In one embodiment, each R j R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R j These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R jThese are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R j These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R j These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R j These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R j These are independently selected from the group consisting of -F and -Cl. In one embodiment, R j R is selected from cyclopropyl, -CHF2, and -CF3. In one embodiment, R j is cyclopropyl. In one embodiment, R j is -CHF2. In one embodiment, R j It is -CF3.

[0076] As generally defined herein, each R k 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 k 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 k R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R k R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R k R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R k R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R k R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R kThese are independently halos. In one embodiment, each R k R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R k These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R k These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R k These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R k These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R k These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R k These are independently selected from the group consisting of -F and -Cl. In one embodiment, R k R is selected from -H and -Cl. In one embodiment, R k is -H. In one embodiment, R k It is -Cl.

[0077] As generally defined herein, each R n 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 n 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 n R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R n R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R n R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each Rn R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R n R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R n These are independently halos. In one embodiment, each R n R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R n These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R n These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R n These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R n These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R n These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R n These are independently selected from the group consisting of -F and -Cl.

[0078] As generally defined herein, each R o 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 o 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 o R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R o R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R oR is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R o R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R o R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R o These are independently halos. In one embodiment, each R o R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R o These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R o These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R o These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R o These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R o These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R o These are independently selected from the group consisting of -F and -Cl.

[0079] As generally defined herein, each R q 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 q 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 q R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R qR is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R q R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R q R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R q R is independently selected from the group consisting of hydrogen and halo. In one embodiment, R q The group is selected from the group consisting of halos and C1-C4 alkyl groups.

[0080] One embodiment, each R q These are independently halos. In one embodiment, each R q R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R q These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R q These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R q These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R q These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R q These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R q These are independently selected from the group consisting of -F and -Cl. In one embodiment, each R q R is selected from the group consisting of hydrogen, -F, -Cl, and -Me. In one embodiment, each R q is selected from the group consisting of -Cl and -Me. In one embodiment, each R q is -Cl. In one embodiment, each R q It is -Me.

[0081] As generally defined herein, each R rR 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 r 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 r R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R r R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R r R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R r R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R r R is independently selected from the group consisting of hydrogen and halo. In one embodiment, R r R is selected from the group consisting of hydrogen and C1-C4 alkyl groups. In one embodiment, each R r These are independently halos. In one embodiment, each R r R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R r These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R r These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R r These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R r These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R r These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R rThese are independently selected from the group consisting of -F and -Cl. In one embodiment, R r is selected from the group consisting of -H and -Me. In one embodiment, R r is -H. In one embodiment, R r It is -Me.

[0082] As generally defined herein, each R s 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 s 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 s R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R s R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R s R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R s R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R s R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R s These are independently halos. In one embodiment, each R s R is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R s These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R s These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R s These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each Rs These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R s These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R s These are independently selected from the group consisting of -F and -Cl. In one embodiment, R s is selected from the group consisting of -H and -F. In one embodiment, R s is -H. In one embodiment, R s It is -F.

[0083] As generally defined herein, each R g R is independently selected from the group consisting of hydrogen, halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R g These are independently selected from the group consisting of -H and -OH. In one embodiment, each R g These are independently -H. In one embodiment, each R g It is independently -OH.

[0084] As generally defined herein, each R m R is independently selected from the group consisting of hydrogen, halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R m These are independently selected from the group consisting of -H and -OH. In one embodiment, each R m These are independently -H. In one embodiment, each R m It is independently -OH.

[0085] As generally defined herein, each R pR is independently selected from the group consisting of hydrogen, halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R p These are independently selected from the group consisting of -H and -OH. In one embodiment, each R p Independently, each R is -H. In one embodiment, each R p It is independently -OH.

[0086] As generally defined herein, R 1 teeth, The file is TIFF2026515945000020.tif32165, and here, R d This is defined herein. In one embodiment, R 1 teeth, Selected from TIFF2026515945000021.tif22165. In one embodiment, R 1 teeth, This is TIFF2026515945000022.tif22165. In one embodiment, R 1 teeth, The filename is TIFF2026515945000023.tif22165.

[0087] As generally defined herein, R d is H or F. In one embodiment, R d is H. In one embodiment, R d It is F.

[0088] As generally defined herein, R 2 teeth, The file is TIFF2026515945000024.tif27165, and here, R e , R Y1 and R Y2 This is defined herein.

[0089] In one embodiment, R 2 teeth, Selected from the group consisting of TIFF2026515945000025.tif99165.

[0090] In one embodiment, R 2 teeth, This is TIFF2026515945000026.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000027.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000028.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000029.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000030.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000031.tif32165. In one embodiment, R 2 teeth, This is TIFF2026515945000032.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000033.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000034.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000035.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000036.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000037.tif27165. In one embodiment, R 2 teeth, This is TIFF2026515945000038.tif27165. In one embodiment, R2 teeth, This is TIFF2026515945000039.tif27165. In one embodiment, R 2 teeth, The filename is TIFF2026515945000040.tif27165.

[0091] As generally defined herein, R e R e1 or R e2 And here, R e1 and R e2 This is defined in any of the embodiments described herein.

[0092] In one embodiment, R e is, -R e1 And here, R e1 This is defined in any of the embodiments described herein. In one embodiment, R e R e2 And here, R 2 This is defined in any of the embodiments described herein.

[0093] In one embodiment, R e teeth, Selected from the group consisting of TIFF2026515945000041.tif48165.

[0094] As generally defined herein, each R Y1 It is independently selected from H and -CH3, however R Y1 and R Y2 At least one of them is -Me. In one embodiment, R Y1 is -H, where R Y2 is -Me. In one embodiment, R Y1 It is -Me.

[0095] As generally defined herein, each R Y2 It is independently selected from H and -CH3, however R Y1 and RY2 At least one of them is -Me. In one embodiment, R Y2 is -H, where R Y1 is -Me. In one embodiment, R Y2 is -Me. As commonly defined herein, R e1 This is a 4- to 10-membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0096] In one embodiment, R e1 This is a 4- to 10-membered heterocycle containing a nitrogen atom and one or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), where the 4- to 10-membered heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0097] In one embodiment, R e1 A is a 4- to 10-membered heterocycle containing a nitrogen atom and one or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), selected from the group consisting of 4- to 8-membered monocyclic heterocycles, 6- to 10-membered fused bicyclic heterocycles, 6- to 10-membered bridging heterocycles and 6- to 10-membered spiroheterocycles, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0098] In one embodiment, R e1This is a 4- to 8-membered monocyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0099] In one embodiment, R e1 This is a 6-10 membered fused bicyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0100] In one embodiment, R e1 This is a 6-10 membered crosslinked heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0101] In one embodiment, R e1 This is a 6-10 membered spiroheterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0102] In one embodiment, R e1These include azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azapiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, and 2-oxa- Xa-5-azabicyclo[2.2.1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa-3-azabicyclo[3. 3.1] Nonane, 9-oxa-3-azabicyclo[3.3.1]nonane, 2-oxa-6-azabispiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia -7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3] Selected from heptane and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0103] In one embodiment, R e1 This is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0104] In one embodiment, R e1 The bonding point is the nitrogen atom of the heterocycle.

[0105] In one embodiment, R e1 teeth, Selected from the group consisting of TIFF2026515945000042.tif176165, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0106] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Selected from TIFF2026515945000043.tif48165. In one embodiment, R e1is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Selected from TIFF2026515945000044.tif27165.

[0107] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000045.tif27165.

[0108] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000046.tif27165.

[0109] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000047.tif27165.

[0110] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000048.tif27165.

[0111] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000049.tif27165.

[0112] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000050.tif27165.

[0113] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000051.tif27165.

[0114] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000052.tif22165.

[0115] In one embodiment, R e1is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000053.tif22165.

[0116] In one embodiment, R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The filename is TIFF2026515945000054.tif27165.

[0117] In one embodiment, R e1 The 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F, -OMe, and -Me.

[0118] In one embodiment, R e1 The 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F and -OMe.

[0119] In one embodiment, R e1 The 4- to 10-membered complex rings are substituted with 0, 1, or 2 -F elements.

[0120] In one embodiment, R e1 The 4- to 10-member complex rings are substituted with 0 or 1 -OMe.

[0121] In one embodiment, R e1 The 4- to 10-member complex rings are non-permutations.

[0122] In one embodiment, R e1 teeth, The selection is made from the group consisting of TIFF2026515945000055.tif202165 and TIFF2026515945000056.tif207165.

[0123] In one embodiment, R e1 teeth, Selected from TIFF2026515945000057.tif53165.

[0124] In one embodiment, R e1 is non-substituted This is TIFF2026515945000058.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000059.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000060.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000061.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000062.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000063.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000064.tif27165. In one embodiment, R e1 is non-substituted This is TIFF2026515945000065.tif22165. In one embodiment, R e1 teeth, This is TIFF2026515945000066.tif32165. In one embodiment, R e1 teeth, This is TIFF2026515945000067.tif32165. In one embodiment, R e1 teeth, This is TIFF2026515945000068.tif32165. In one embodiment, R e1 teeth, This is TIFF2026515945000069.tif32165. In one embodiment, R e1 teeth, This is TIFF2026515945000070.tif32165. In one embodiment, R e1 teeth, This is TIFF2026515945000071.tif32165. In one embodiment, R e1 is non-substituted The filename is TIFF2026515945000072.tif27165.

[0125] As generally defined herein, R e2 -NR 21 R 22 And here, R 21 and R 22 This is defined in any of the embodiments described herein. In one embodiment, R e2 teeth, The filename is TIFF2026515945000073.tif17165.

[0126] As generally defined herein, R 21 R is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 member heterocycle. In one embodiment, R 21 is a C1-C4 alkyl group. In one embodiment, R 21 It is -Me.

[0127] As generally defined herein, R 22 R is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 member heterocycle. In one embodiment, R 22 is a C1-C4 alkyl group. In one embodiment, R 22 This is Me.

[0128] As generally defined herein, n is 0, 1, or 2. In one embodiment, n is 0 or 1. In one embodiment, n is 1 or 2. In one embodiment, n is 0. In one embodiment, n is 0 or 1. In one embodiment, n is 1. In one embodiment, n is 2.

[0129] As generally defined herein, R x R is selected from ⁻¹-halo and C1-C4 alkyl groups. In one embodiment, R x is selected from -F and -Me. In one embodiment, R x is -Me. In one embodiment, R x It is -F.

[0130] In one embodiment, the compound is the compound of formula (I).

[0131] In one embodiment, the compound is the compound of formula (II).

[0132] In one embodiment, the compound is the compound of formula (III).

[0133] In one embodiment, the compound is a compound of formula (Ia), formula (II-a), or formula (III-a): TIFF2026515945000074.tif147165 or its salts, and / or its isotopic substitutions, where R 1 , R 2 , R 3 , R 4 , R x This is defined in any of the embodiments described herein.

[0134] In one embodiment, the compound is the compound of formula (Ia).

[0135] In one embodiment, the compound is the compound of formula (II-a).

[0136] In one embodiment, the compound is the compound of formula (III-a).

[0137] In one embodiment, the compound is a compound of formula (Ib), formula (II-b), or formula (III-b): TIFF2026515945000075.tif167165 or its salts, and / or its isotopic substitutions, where R 1 , R 2 , R j , R k , R m , R x and n are as defined in any of the embodiments described herein.

[0138] In one embodiment, the compound is the compound of formula (Ib).

[0139] In one embodiment, the compound is the compound of formula (II-b).

[0140] In one embodiment, the compound is the compound of formula (III-b).

[0141] In any embodiment of formulas (I), (Ia), (Ib), (II), (II-a), (II-b), (III), (III-a), and (III-b), the stereochemistry of pyrrolidine is (R) (i.e., The part represented as TIFF2026515945000076.tif27165 (TIFF2026515945000077.tif27165). In any one embodiment of formula (I), (Ia), (Ib), (II), (II-a), (II-b), (III), (III-a), and (III-b), the stereochemistry of the cyanomethyl group is (S) (i.e., The part represented as TIFF2026515945000078.tif32165 (This is TIFF2026515945000079.tif32165).

[0142] In one embodiment, the compound is selected from the compounds or salts thereof listed in Table 1, and / or their isotopic substitutions. In one embodiment, the compound is not a salt. 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.

[0143] In some variations, any of the compounds described herein, such as those of formula (I), (II), or (III), or those in Table 1, may be deuterated (e.g., by replacing 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 be replaced with deuterium atoms using other methods known in the art.

[0144] Any formula shown herein, for example, formulas (I), (II), or (III), is intended to represent a compound having the structure shown by its structural formula and a particular variation or form. In particular, compounds of any formula shown herein may exist in different enantiomer or diastereomer forms because they have a chiral center. 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, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), a tautomer, or an atropisomer. Furthermore, any formula shown herein is 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.

[0145] 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.

[0146] 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.

[0147] In one variant, the compounds described herein are synthetic compounds prepared for administration to an organism. In another variant, a composition containing a substantially pure form of the compound 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 preferred for any compound or form of the compound detailed herein.

[0148] The R provided herein 1 , R d , R 2 , R Y1 , R Y2 , R e , R e1 , R e2 , R 21 , R 22 , R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , Rs , R g , R m , R p , R a , R x , ring A, m, n, R x ', R x ''оR 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 as if each combination were described individually and specifically. 1 , R d , R 2 , R Y1 , R Y2 , R e , R e1 , R e2 , R 21 , R 22 , R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , R s , R g , R m , R p , R a , R x , ring A, m, n, R x ', R x ''оR 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.

[0149] When used herein, if any variable appears multiple times in a chemical formula, the definition for each appearance shall be independent of the definition for all other appearances.

[0150] Methods of treating cancer Compounds of formulas (I), (II), and (III), as well as their pharmaceutically acceptable salts and / or isotopic substitutions (including embodiments thereof 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. Cancers that can be treated with compounds of formula (I), formula (II), and formula (III), and their pharmaceutically acceptable salts and / or isotopic substitutions (including the embodiments thereof disclosed herein) include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute phosphorus This includes, but is not limited to, cancers such as pablastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytosis myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary renal cell carcinoma, pheochromocytoma / 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 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 has been diagnosed with KRAS G12C-mediated cancer. In some embodiments encompassing any of the embodiments described above, the subject has been determined to be at risk of developing KRAS G12C-mediated cancer.

[0151] In one embodiment, a compound of formula (I), formula (II), or formula (III) described in any of the embodiments described herein, or a pharmaceutical formulation described in any of the embodiments described herein, is provided for use as a pharmaceutical.

[0152] In one embodiment, a compound of formula (I), formula (II), or formula (III) 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, 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, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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, plasmacytotic myeloma, The cancers are selected from the group consisting of uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary renal cell carcinoma, pheochromocytoma / 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.

[0153] In one embodiment, a compound of formula (I), formula (II), or formula (III) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, for use in the manufacture of a pharmaceutical for treating or suppressing cancer, wherein the compound is a salt and the salt is a pharmaceutically acceptable salt. 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, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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, plasmacytotic myeloma, The cancers are selected from the group consisting of uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary renal cell carcinoma, pheochromocytoma / 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 product comprises a therapeutically effective amount of a compound or pharmaceutical formulation.

[0154] In one embodiment, the use of a compound of formula (I), formula (II), or formula (III) 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 pharmaceutical for treating or suppressing cancer, wherein the compound is a salt and the salt is a pharmaceutically acceptable salt. 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, cervical cancer, and bladder cancer. In one embodiment, cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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, plasmacytotic myeloma, The cancers are selected from the group consisting of uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary renal cell carcinoma, pheochromocytoma / 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 product comprises a therapeutically effective amount of a compound or pharmaceutical formulation.

[0155] In one embodiment, a use is provided for treating or suppressing cancer, wherein the compound of formula (I), formula (II), or formula (III) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, wherein the compound is a salt and the salt is a pharmaceutically acceptable salt.

[0156] 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, cervical cancer, and bladder cancer. In one embodiment, cancer is selected from the group consisting of glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, The cancers are selected from the group consisting of uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary renal cell carcinoma, pheochromocytoma / 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.

[0157] 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).

[0158] Compounds of formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts and / or isotopic substitutions thereof (including embodiments disclosed herein) can be used in methods for inhibiting intracellular KRAS G12C 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.

[0159] test Compounds of formula (I), formula (II), and formula (III), and their pharmaceutically acceptable salts and / or isotopic substitutions (including embodiments disclosed herein) may be tested, for example, by the methods described in the following examples, or by known and generally accepted cell and / or animal models.

[0160] The ability of compounds of formulas (I), (II), and (III), and their pharmaceutically acceptable salts and / or isotopic substitutions, to inhibit the activity of GTP-bound KRAS G12C can be tested using methods such as the in vitro assays described in Examples 13 and 14 below. Example 13 shows that for various compounds, the maximum 50% inhibition (IC) of KRAS G12C loaded with the GTP analog GMPPNP was achieved. 50 ) is determined from the binding to cRaf as the Ras-binding domain (RBD). Example 14 describes the 50% maximum inhibition (IC) of KRAS G12C loaded with the GTP analog GMPPNP for various compounds. 50The method is described as determining the binding of the Ras-binding domain (RBD) to PI3Kα. Example 15 describes testing the compound for its ability to inhibit cell survival in the MCF10A G12C / A59G mutation (which inactivates GTPase activity and thus prevents hydrolysis of GTP to GDP).

[0161] Pharmaceutical composition The terms "pharmaceutical composition" and "pharmaceutical preparation" are used interchangeably throughout this text.

[0162] In general, the compounds of formulas (I), (II), and (III) 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 acceptable mode of administration of a drug that performs a 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 in single or 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.

[0163] In general, the compounds of this disclosure will be administered as pharmaceutical compositions by any of the following routes: oral administration, systemic administration (e.g., transdermal, intranasal, or suppository administration), or parenteral administration (e.g., intramuscular, intravenous, 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.

[0164] The choice of formulation depends on various factors such as the mode of drug administration (e.g., 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.

[0165] 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.

[0166] 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 substances. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils. Oils can be petroleum, animal, plant, or synthetic, such as peanut oil, soybean oil, mineral oil, and sesame oil. Liquid carriers particularly suitable for injection solutions include water, physiological saline, glucose solution, and glycol.

[0167] 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.

[0168] 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.

[0169] 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).

[0170] 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).

[0171] 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).

[0172] 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.

[0173] 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.

[0174] 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.

[0175] The level of the compound in the formulation can be varied within the entire range adopted by those skilled in the art. Typically, the formulation will contain, in weight percent (W%), about 0.01 to 99.99 Wt% of the compound of the Disclosure based on the entire formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound may be present at a level of about 1 to 80 Wt%.

[0176] 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.

[0177] Therefore, the pharmaceutical compositions of this disclosure also include those containing one or more other drugs in addition to the compounds of this disclosure.

[0178] 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.

[0179] 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.

[0180] 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 of the present invention 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]).

[0181] 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-fluor Ropyrroridine-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-(triphenylomethyl)-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;CEP-32496:1-(3-((6,7-Dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea;Examples include, but are not limited to, 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.

[0182] In another embodiment, the compounds of the disclosed herein 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-(trifluoromethyl (Cyl)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(1 Examples include, but are not limited to, -(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 one embodiment, the Src inhibitor is KX-01.

[0183] In another embodiment, the compounds of the present disclosure are used in combination with SHP-099 (6-(4-amino-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride), 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 Medicines), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca), among others, as well as other SHP-2 inhibitors.

[0184] 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, zotarolimus (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).

[0185] In another embodiment, the compounds of this disclosure 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 composition and method provided. In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for the composition and method provided include afatinib, dacomitinib, canertinib, poziotinib, AV 412(N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazine-1-butin-1-yl]-6-quinazolinyl]-2-prepenamide), PF 6274484 N-4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 Examples include, but are not limited to, 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 inhibitor is a reversible inhibitor.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).

[0186] 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-aminedihydrochloride);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.

[0187] 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.

[0188] 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, Opdualag, and dostallimab (Jemperli).

[0189] 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 either before or after surgery in combination with other treatments (such as radiation or surgical intervention).

[0190] List of embodiments The following listed embodiments represent several aspects of the present invention. Embodiment 1. Compound of formula (I), formula (II), or formula (III): TIFF2026515945000080.tif149165 or its salts, and / or its isotopic substitutions, wherein in the formula, Ring A is a 6-10 membered aryl or a 5-10 membered heteroaryl. Each R a These are independently selected from halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. m is 0, 1, 2, or 3. R 1 teeth, The filename is TIFF2026515945000081.tif32165. R d is H or F, R 2 teeth, The filename is TIFF2026515945000082.tif27165. R e is, -R e1 or -R e2 And, R Y1 and R Y2 Each instance, is independently selected from -H and -CH3, except R Y1 and R Y2 At least one of them is -CH3, R e1 This is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. R e2 -NR 21 R 22 And, R 21 and R 22 These are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 membered heterocycle. Each R xIt is selected from halo and C1-C4 alkyl, and n is 0, 1, or 2. The aforementioned compound, its salt, and / or its isotopically substituted derivative. Embodiment 2. The compound is the compound of formula (I), as described in Embodiment 1. Embodiment 3. The compound is the compound of formula (II), as described in Embodiment 1. Embodiment 4. The compound is the compound of formula (III) as described in Embodiment 1. Embodiment 5. The stereochemistry of pyrrolidine is (R) (i.e., The part represented as TIFF2026515945000083.tif27165 The compound according to Embodiment 1 or 2 (TIFF2026515945000084.tif27165). Embodiment 6. The stereochemistry of the cyanomethyl group is (S) (i.e., The part represented as TIFF2026515945000085.tif32165 The compound according to any one of Embodiments 1, 3, and 4 (TIFF2026515945000086.tif32165). Embodiment 7. The compound according to any one of Embodiments 1 to 6, wherein ring A is selected from a 6-10 membered aryl and a 9-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S. Embodiment 8. The compound according to any one of Embodiments 1 to 6, wherein ring A is selected from the group consisting of naphthalenyl, phenyl, isoquinolinyl, indazolyl, and pyridinyl. Embodiment 9. The compound according to any one of Embodiments 1 to 6, wherein ring A is selected from the group consisting of naphthalenyl and phenyl. Embodiment 10. The compound according to any one of Embodiments 1 to 6, wherein ring A is naphthalenyl. Embodiment 11. The compound according to any one of Embodiments 1 to 6, wherein ring A is phenyl. Embodiment 12. The compound according to any one of Embodiments 1 to 6, wherein ring A is selected from the group consisting of naphthalene-1-yl, phenyl, isoquinoline-1-yl, indazole-4-yl, and pyridine-1-yl. Embodiment 13. The compound according to any one of Embodiments 1 to 6, wherein ring A is selected from the group consisting of naphthalene-1-yl and phenyl. Embodiment 14. The compound according to any one of Embodiments 1 to 6, wherein ring A is naphthalene-1-yl. Embodiment 15. Each R a The compound is independently selected from halo, -OH, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl, as described in any one of Embodiments 1 to 14. Embodiment 16. Each R a The compound is independently selected from halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl, as described in any one of Embodiments 1 to 14. Embodiment 17. Each R a The compound is independently selected from halo and C1-C4 alkyl groups, as described in any one of Embodiments 1-14. Embodiment 18. Each R a The compound is independently selected from a halo and a C3-C4 cycloalkyl group, as described in any one of Embodiments 1 to 14. Embodiment 19. Each R a The compound is independently selected from halo and C1-C4 haloalkyl, as described in any one of Embodiments 1-14. Embodiment 20. Each R a The compound is independently selected from a halo and a C2-C3 alkynyl compound, as described in any one of Embodiments 1 to 14. Embodiment 21. Each R a The compound according to any one of Embodiments 1 to 14 is independently a halo. Embodiment 22. Each R aThe compound is independently selected from -F, -Cl, -OH, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH, as described in any one of Embodiments 1 to 14. Embodiment 23. Each R a The compound is independently selected from -F, -Cl, -cyclopropyl, -CF3, and -C≡CH, as described in any one of Embodiments 1 to 14. Embodiment 24. Each R a The compound is independently selected from -F, -Cl, -Me, and -Et, as described in any one of Embodiments 1 to 14. Embodiment 25. Each R a The compound is independently selected from -Cl and -cyclopropyl, as described in any one of Embodiments 1 to 14. Embodiment 26. Each R a The compound is independently selected from -Cl and -CF3, as described in any one of Embodiments 1 to 14. Embodiment 27. Each R a The compound is independently selected from -F, -Cl, and -C≡CH, as described in any one of Embodiments 1 to 14. Embodiment 28. Each R a The compound is independently selected from -F and -Cl, as described in any one of Embodiments 1 to 14. Embodiment 29.m is a compound according to any one of Embodiments 1 to 28, wherein the compound is 1, 2, or 3. Embodiment 30.m is a compound according to any one of Embodiments 1 to 28, wherein m is 1 or 2. Embodiment 31.m is a compound according to any one of Embodiments 1 to 28, wherein m is 2 or 3. Embodiment 32.m is a compound according to any one of Embodiments 1 to 28, wherein m is 1. Embodiment 33.m is a compound according to any one of Embodiments 1 to 28, wherein m is 2. Embodiment 34.m is a compound according to any one of Embodiments 1 to 28, wherein m is 3. Embodiment 35. Ring A is Selected from the group consisting of TIFF2026515945000087.tif42165, During the ceremony, R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these 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, and R g 、 R m , and R p Each of these is independently selected from the group consisting of hydrogen, halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. A compound according to any one of Embodiments 1 to 6. Embodiment 36. 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl, as described in Embodiment 35. Embodiment 37.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R sEach of these compounds is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl, as described in Embodiment 35. Embodiment 38.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl groups, as described in Embodiment 35. Embodiment 39.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl, as described in Embodiment 35. Embodiment 40.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl compounds, as described in Embodiment 35. Embodiment 41.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R sEach of these is independently selected from the group consisting of hydrogen and halos, and is a compound according to Embodiment 35. Embodiment 42.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these is independently a halo, the compound according to Embodiment 35. Embodiment 43. 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s The compound according to Embodiment 35, wherein each is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. Embodiment 44.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et, as described in Embodiment 35. Embodiment 45.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R sEach of these compounds is independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl, as described in Embodiment 35. Embodiment 46.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of -H, -F, -Cl, and -CF3, as described in Embodiment 35. Embodiment 47.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of -H, -F, -Cl, and -C≡CH, as described in Embodiment 35. Embodiment 48.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R s Each of these compounds is independently selected from the group consisting of -H, -F, and -Cl, as described in Embodiment 35. Embodiment 49.R 3 , R 4 , R h , R i , R j , R k , R n , R o , R q , R r , and R sEach of these compounds is independently selected from the group consisting of -F and -Cl, according to Embodiment 35. Embodiment 50.R g 、 R m , and R p Each of these is independently selected from the group consisting of -H and -OH, and is a compound according to any one of embodiments 35 to 49. Embodiment 51.R g 、 R m , and R p Each of these is independently a compound according to any one of embodiments 35 to 49, wherein each is -H. Embodiment 52.R g 、 R m , and R p Each of these is independently a -OH compound according to any one of embodiments 35 to 49. Embodiment 53. Ring A is, A compound according to any one of embodiments 35 to 52, selected from the group consisting of TIFF2026515945000088.tif37165. Embodiment 54. Ring A is, The compound according to any one of embodiments 35 to 52, which is TIFF2026515945000089.tif32165. Embodiment 55. Ring A is, The compound according to any one of embodiments 35 to 52, which is TIFF2026515945000090.tif32165. Embodiment 56. Ring A is, A compound according to any one of Embodiments 1 to 6, selected from TIFF2026515945000091.tif32165. Embodiment 57. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000092.tif32165. Embodiment 58. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000093.tif32165. Embodiment 59. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000094.tif32165. Embodiment 60. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000095.tif32165. Embodiment 61. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000096.tif27165. Embodiment 62. Ring A is, The compound according to any one of Embodiments 1 to 6, which is TIFF2026515945000097.tif27165. Embodiment 63. The compound is a compound of formula (Ia), formula (II-a), or formula (III-a): TIFF2026515945000098.tif145165 or its salts, and / or its isotopic substitutions, in the formula, 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, and 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. The compound described in Embodiment 1. Embodiment 64. The compound is the compound of formula (Ia) as described in Embodiment 63. Embodiment 65. The compound is the compound of formula (II-a) as described in Embodiment 63. Embodiment 66. The compound described in Embodiment 63, wherein the compound is a compound of formula (III-a). Embodiment 67. The stereochemistry of pyrrolidine is (R) (i.e., The part represented as TIFF2026515945000099.tif27165 The compound according to embodiment 63 or 64 (TIFF2026515945000100.tif27165). Embodiment 68. The stereochemistry of the cyanomethyl group is (S) (i.e., The part represented as TIFF2026515945000101.tif32165 The compound according to any one of embodiments 63, 65, and 66 (TIFF2026515945000102.tif32165). Embodiment 69.R 3 The compound is selected from halo, C1-C4 alkyl, and C2-C3 alkynyl, as described in any one of embodiments 35, 53, 54, and 63-68. Embodiment 70.R 3 The compound is selected from halo and C1-C4 alkyl groups, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 71.R 3 The compound is selected from a halo and a C2-C3 alkynyl compound, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 72.R 3 The compound is a halo, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 73.R 3 The compound is selected from -F, -Cl, -Et, and -C≡CH, as described in any one of embodiments 35, 53, 54, and 63-68. Embodiment 74.R 3 The compound is selected from -F, -Cl, and -Et, as described in any one of embodiments 35, 53, 54, and 63-68. Embodiment 75.R 3 The compound is selected from -F, -Cl, and -C≡CH, as described in any one of embodiments 35, 53, 54, and 63-68. Embodiment 76.R 3 The compound is selected from -F and -Cl, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 77.R 3 The compound is -F, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 78.R 3 The compound according to any one of embodiments 35, 53, 54 and 63-68, wherein -Cl. Embodiment 79.R 3 The compound is -Et, as described in any one of embodiments 35, 53, 54 and 63-68. Embodiment 80.R 3 The compound is one of embodiments 35, 53, 54 and 63-68, wherein -C≡CH. Embodiment 81.R 4 The compound is selected from hydrogen and a halo, as described in any one of embodiments 35, 53, 54 and 63-80. Embodiment 82.R 4 The compound is selected from -H and -F, as described in any one of embodiments 35, 53, 54 and 63-80. Embodiment 83.R 4 The compound according to any one of embodiments 35, 53, 54 and 63-80, wherein is -H. Embodiment 84.R 4 The compound is -F, as described in any one of embodiments 35, 53, 54 and 63-80. Embodiment 85. The compound is a compound of formula (Ib), formula (II-b), or formula (III-b): TIFF2026515945000103.tif161165 or its salts, and / or its isotopic substitutions, in the formula, R j 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 k 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 R m This is selected from the group consisting of hydrogen, halo, -OH, -NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. The compound described in Embodiment 1. Embodiment 86. The compound is the compound of formula (Ib) as described in Embodiment 85. Embodiment 87. The compound is the compound of formula (II-b) as described in Embodiment 85. Embodiment 88. The compound described in Embodiment 85, wherein the compound is a compound of formula (III-b). Embodiment 89. The stereochemistry of pyrrolidine is (R) (i.e., The part represented as TIFF2026515945000104.tif27165 The compound described in Embodiment 85 or 86 (TIFF2026515945000105.tif27165). Embodiment 90. The stereochemistry of the cyanomethyl group is (S) (i.e., The part represented as TIFF2026515945000106.tif32165 The compound according to any one of embodiments 85, 87, and 88 (TIFF2026515945000107.tif32165). Embodiment 91.R j The compound is selected from C3-C4 cycloalkyl and C1-C4 haloalkyl, as described in any one of embodiments 35, 53, 55 and 69-90. Embodiment 92.R j The compound is selected from cyclopropyl, -CHF2, and -CF3, as described in any one of embodiments 35, 53, 55, and 69-90. Embodiment 93.R j The compound is selected from cyclopropyl and -CF3, as described in any one of embodiments 35, 53, 55 and 69-90. Embodiment 94.R jThe compound is cyclopropyl, as described in any one of embodiments 35, 53, 55 and 69-90. Embodiment 95.R j The compound is -CHF2, as described in any one of embodiments 35, 53, 55 and 69-90. Embodiment 96.R j The compound is -CF3, as described in any one of embodiments 35, 53, 55 and 69-90. Embodiment 97.R k The compound is selected from hydrogen and a halo, as described in any one of embodiments 35, 53, 55 and 69-96. Embodiment 98.R k The compound is selected from -H and -Cl, as described in any one of embodiments 35, 53, 55 and 69-96. Embodiment 99.R k The compound according to any one of embodiments 35, 53, 55 and 69-96, wherein is -H. Embodiment 100.R k The compound is -Cl, as described in any one of embodiments 35, 53, 55 and 69-96. Embodiment 101.R m The compound is selected from -H and -OH, as described in any one of embodiments 35, 53, 55 and 69-100. Embodiment 102.R m The compound according to any one of embodiments 35, 53, 55 and 69-100, wherein is -H. Embodiment 103.R m The compound according to any one of embodiments 35, 53, 55 and 69-100, wherein the compound is -OH. Embodiment 104.R d The compound according to any one of embodiments 1 to 103, wherein is H. Embodiment 105.R d The compound is F, as described in any one of Embodiments 1 to 103. Embodiment 106.R 1 teeth, A compound according to any one of Embodiments 1 to 103, selected from TIFF2026515945000108.tif22165. Embodiment 107.R 1 teeth, The compound according to any one of Embodiments 1 to 103, which is TIFF2026515945000109.tif22165. Embodiment 108.R 1 teeth, The compound according to any one of Embodiments 1 to 103, which is TIFF2026515945000110.tif22165. Embodiment 109.R Y1 The compound is -Me, as described in any one of embodiments 1 to 108. Embodiment 110.R Y1 The compound according to any one of Embodiments 1 to 108, wherein is -H. Embodiment 111.R Y2 The compound according to any one of Embodiments 1 to 109, wherein is -H. Embodiment 112.R Y2 The compound is -Me, as described in any one of embodiments 1 to 110. Embodiment 113.R e R e1 The compound according to any one of Embodiments 1 to 112. Embodiment 114.R e1 The compound according to any one of Embodiments 1 to 113, wherein the compound is a 4- to 10-membered heterocycle containing a nitrogen atom and one or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), wherein the 4- to 10-membered heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 115.R e1The compound according to Embodiment 114, wherein is a 4- to 10-membered heterocycle containing a nitrogen atom and one or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), and is selected from the group consisting of 4- to 8-membered monocyclic heterocycles, 6- to 10-membered fused bicyclic heterocycles, 6- to 10-membered bridging heterocycles and 6- to 10-membered spiroheterocycles, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 116.R e1 The compound according to Embodiment 114, wherein is a 4-8 membered monocyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 117.R e1 The compound according to Embodiment 114, wherein is a 6-10 membered fused bicyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 118.R e1 The compound according to Embodiment 114, wherein is a 6-10 membered crosslinked heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 119.R e1 The compound according to Embodiment 114, wherein is a 6-10 membered spiroheterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 120.R e1These include azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azapiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, and 2-oxa- Xa-5-azabicyclo[2.2.1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa-3-azabicyclo[3. 3.1] Nonane, 9-oxa-3-azabicyclo[3.3.1]nonane, 2-oxa-6-azabispiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia -7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.The compound according to Embodiment 114, selected from [3]heptane and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 121.R e1 The compound according to Embodiment 114, wherein is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 122.R e1 The compound according to any one of embodiments 114 to 121, wherein the bond site is a nitrogen atom of the heterocycle. Embodiment 123.R e1 teeth, The compound according to Embodiment 122, selected from the group consisting of TIFF2026515945000111.tif176165, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. Embodiment 124.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. A compound according to Embodiment 122, selected from TIFF2026515945000112.tif48165. Embodiment 125.R e1is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. A compound according to Embodiment 122, selected from TIFF2026515945000113.tif27165. Embodiment 126.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000114.tif27165. Embodiment 127.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000115.tif27165. Embodiment 128.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000116.tif27165. Embodiment 129.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000117.tif27165. Embodiment 130.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000118.tif27165. Embodiment 131.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000119.tif27165. Embodiment 132.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000120.tif27165. Embodiment 133.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound according to Embodiment 122, which is TIFF2026515945000121.tif22165. Embodiment 134.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound according to Embodiment 122, which is TIFF2026515945000122.tif22165. Embodiment 135.R e1 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. The compound described in Embodiment 122, which is TIFF2026515945000123.tif27165. Embodiment 136.R e1 The compound according to any one of embodiments 114 to 135, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F, -OMe, and -Me. Embodiment 137.R e1 The compound according to any one of embodiments 114 to 135, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F and -OMe. Embodiment 138.R e1 The compound according to any one of embodiments 114 to 135, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 -F atoms. Embodiment 139.R e1 The compound according to any one of embodiments 114 to 135, wherein the 4- to 10-membered heterocycle is substituted with 0 or 1 -OMe. Embodiment 140.R e1 The compound according to any one of embodiments 114 to 135, wherein the 4- to 10-membered heterocycle is unsubstituted. Embodiment 141.R e1 teeth, A compound according to Embodiment 122, selected from the group consisting of TIFF2026515945000124.tif138165, TIFF2026515945000125, TIFF207165, and TIFF2026515945000126.tif69165. Embodiment 142.R e1 teeth, A compound according to Embodiment 122, selected from TIFF2026515945000127.tif53165. Embodiment 143.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000128.tif27165. Embodiment 144.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000129.tif27165. Embodiment 145.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000130.tif27165. Embodiment 146.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000131.tif27165. Embodiment 147.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000132.tif27165. Embodiment 148.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000133.tif27165. Embodiment 149.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000134.tif27165. Embodiment 150.R e1 is non-substitutive The compound according to Embodiment 122, which is TIFF2026515945000135.tif22165. Embodiment 151.R e1 teeth, The compound according to Embodiment 122, which is TIFF2026515945000136.tif32165. Embodiment 152.R e1teeth, The compound described in Embodiment 122, which is TIFF2026515945000137.tif32165. Embodiment 153.R e1 teeth, The compound described in Embodiment 122, which is TIFF2026515945000138.tif32165. Embodiment 154.R e1 teeth, The compound described in Embodiment 122, which is TIFF2026515945000139.tif32165. Embodiment 155.R e1 teeth, The compound described in Embodiment 122, which is TIFF2026515945000140.tif32165. Embodiment 156.R e1 teeth, The compound described in Embodiment 122, which is TIFF2026515945000141.tif32165. Embodiment 157.R e1 is non-substitutive The compound described in Embodiment 122, which is TIFF2026515945000142.tif27165. Embodiment 158.R e is, -R e2 The compound according to any one of Embodiments 1 to 112. Embodiment 159.R 21 and R 22 The compound is independently a C1-C4 alkyl compound as described in any one of embodiments 1 to 112 and 114 to 158. Embodiment 160.R 21 The compound is -Me, as described in any one of embodiments 1 to 112 and 114 to 158. Embodiment 161.R 22 The compound is one of embodiments 1 to 112 and 114 to 160, wherein the compound is Me. Embodiment 162.R e2 teeth, The compound described in any one of embodiments 1 to 112 and 114 to 158, which is TIFF2026515945000143.tif17165. Embodiment 163.R e teeth, A compound according to any one of Embodiments 1 to 108, selected from the group consisting of TIFF2026515945000144.tif58165. Embodiment 164.R 2 teeth, A compound according to any one of Embodiments 1 to 112, selected from the group consisting of TIFF2026515945000145.tif99165. Embodiment 165.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000146.tif32165. Embodiment 166.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000147.tif32165. Embodiment 167.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000148.tif32165. Embodiment 168.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000149.tif32165. Embodiment 169.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000150.tif32165. Embodiment 170.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000151.tif32165. Embodiment 171.R 2 teeth, The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000152.tif27165. Embodiment 172.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000153.tif27165. Embodiment 173.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000154.tif27165. Embodiment 174.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000155.tif27165. Embodiment 175.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000156.tif27165. Embodiment 176.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000157.tif27165. Embodiment 177.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000158.tif27165. Embodiment 178.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000159.tif27165. Embodiment 179.R 2 is The compound according to any one of Embodiments 1 to 112, which is TIFF2026515945000160.tif27165. Embodiment 180.R x is the compound according to any one of Embodiments 1 to 179, which is selected from -F and -Me. Embodiment 181.R x The compound is -Me, as described in any one of Embodiments 1 to 179. Embodiment 182.R x The compound is -F, as described in any one of Embodiments 1 to 179. Embodiment 183.n is a compound according to any one of Embodiments 1 to 182, wherein the compound is 0 or 1. Embodiment 184.n is a compound according to any one of Embodiments 1 to 182, wherein the compound is 0. Embodiment 185.n is a compound according to any one of Embodiments 1 to 182, wherein the compound is 1. Embodiment 186.n is a compound according to any two of Embodiments 1 to 182, wherein the compound is 2. Embodiment 187. The compound is A compound, a salt thereof, and / or an isotope-substituted compound thereof, as described in any one of Embodiments 1 to 186, selected from the group consisting of TIFF2026515945000161.tif58165TIFF2026515945000162.tif181165TIFF2026515945000163.tif238165TIFF2026515945000164.tif228165TIFF2026515945000165.tif212165TIFF2026515945000166.tif218165TIFF2026515945000167.tif212165. Embodiment 188. A compound according to any one of Embodiments 1 to 187, which is not a salt. Embodiment 189. A compound according to any one of Embodiments 1 to 187, which is a salt. Embodiment 190. The compound according to Embodiment 189, wherein the salt is a formate salt. Embodiment 191. The compound according to Embodiment 189, wherein the salt is a trifluoroacetate salt. Embodiment 192. The compound according to Embodiment 189, wherein the salt is a pharmaceutically acceptable salt. Embodiment 193. A pharmaceutical formulation comprising a compound described in any one of Embodiments 1 to 192 (if the compound is a salt, the salt is a pharmaceutically acceptable salt) and a pharmaceutically acceptable carrier. Embodiment 194. A method for treating or suppressing cancer, comprising administering to a subject in need of such treatment an effective amount of one compound from any of Embodiments 1 to 192 (if the compound is a salt, the salt is a pharmaceutically acceptable salt), or the pharmaceutical formulation described in Embodiment 193. Embodiment 195. The method according to Embodiment 194, 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, cervical cancer, and bladder cancer. Embodiment 196. Cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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 myeloma, and uterine The method according to Embodiment 194, selected from the group consisting of carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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. Embodiment 197. The method according to any one of Embodiments 194 to 196, wherein the cancer is a KRAS G12C-mediated cancer. Embodiment 198. The method according to any one of Embodiments 194 to 196, relating to a patient diagnosed with KRAS G12C-mediated cancer. Embodiment 199. The method according to any one of Embodiments 194 to 196, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the target. Embodiment 200. A pharmaceutical formulation according to Embodiment 193 or any one compound from Embodiments 1 to 192, to be used as a pharmaceutical. Embodiment 201. A pharmaceutical formulation according to Embodiment 193 or any one of the compounds in Embodiments 1 to 192 or Embodiment 193, for use in the treatment or suppression of cancer, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt. Embodiment 202. The compound or pharmaceutical formulation used in Embodiment 201, 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, cervical cancer, and bladder cancer. Embodiment 203. Cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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 myeloma, uterine carcinosarcoma, Compounds or pharmaceutical formulations used in Embodiment 201, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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. Embodiment 204. The cancer is a KRAS G12C-mediated cancer, and the compound or pharmaceutical formulation used in any one of Embodiments 201 to 204. Embodiment 205. The subject is a compound or pharmaceutical formulation used in any one of Embodiments 201 to 204, which is diagnosed with KRAS G12C-mediated cancer. Embodiment 206. A compound or pharmaceutical formulation used in any one of Embodiments 201 to 205, configured to be administered together with an additional therapeutically effective dose of a chemotherapeutic agent. Embodiment 207. A compound or pharmaceutical formulation for use in any one of Embodiments 201 to 206, configured for administration in a therapeutically effective dose. Embodiment 208. A pharmaceutical formulation according to Embodiment 193 or any one of the compounds in Embodiments 1 to 192 or the one described in Embodiment 193, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt. Embodiment 209. The compound or pharmaceutical formulation used in Embodiment 208, 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, cervical cancer, and bladder cancer. Embodiment 210. Cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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, plasmacytosis myeloma, uterine carcinosarcoma, Compounds or pharmaceutical formulations used in Embodiment 208, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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. Embodiment 211. The cancer is a KRAS G12C-mediated cancer, and the compound or pharmaceutical formulation used in any one of Embodiments 208 to 210. Embodiment 212. The subject is a compound or pharmaceutical formulation used in any one of Embodiments 208 to 210, diagnosed with KRAS G12C-mediated cancer. Embodiment 213. A compound or pharmaceutical formulation used in any one of Embodiments 208 to 212, configured to be administered together with an additional therapeutically effective dose of a chemotherapeutic agent. Embodiment 214. The pharmaceutical is a compound or pharmaceutical formulation according to any one of Embodiments 208 to 213, comprising a therapeutically effective amount of the compound or composition. Embodiment 215. Use of any one compound from Embodiments 1 to 192 or the pharmaceutical formulation described in Embodiment 193 in the manufacture of a pharmaceutical product for treating or suppressing cancer, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt. Embodiment 216. The use as described in Embodiment 215, 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, cervical cancer, and bladder cancer. Embodiment 217. Cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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 myeloma, and uterine The use described in Embodiment 215, selected from the group consisting of carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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. Embodiment 218. The use according to any one of Embodiments 215 to 217, wherein the cancer is a KRAS G12C-mediated cancer. Embodiment 219. The subject is diagnosed with KRAS G12C-mediated cancer, and the use is as described in any one of Embodiments 215 to 217. Embodiment 220. The use according to any one of Embodiments 215 to 219, wherein the compound or pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent. Embodiment 221. The use described in any one of Embodiments 215 to 220, wherein the pharmaceutical product comprises a therapeutically effective amount of the compound or pharmaceutical formulation. Embodiment 222. Use of any one compound from Embodiments 1 to 192 or the pharmaceutical formulation described in Embodiment 193 for the treatment or suppression of cancer, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt. Embodiment 223. The use as described in Embodiment 222, 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, cervical cancer, and bladder cancer. Embodiment 224. Cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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 myeloma, and uterine The use described in Embodiment 222, selected from the group consisting of carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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. Embodiment 225. The use according to any one of Embodiments 222 to 224, wherein the cancer is a KRAS G12C-mediated cancer. Embodiment 226. The subject is diagnosed with KRAS G12C-mediated cancer, and the use is as described in any one of Embodiments 222 to 224. Embodiment 227. The use according to any one of Embodiments 222 to 226, wherein the compound or pharmaceutical formulation is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent. Embodiment 228. Use according to any one of Embodiments 222 to 227 relating to a therapeutically effective amount of a compound or composition.

[0191] General synthesis methods Compounds 1–47 in Table 1 of this disclosure were prepared according to the methods described in the Examples section, or variations thereof within the scope of knowledge of those skilled in the art. The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as MilliporeSigma, Bachem, or can be prepared by methods known to those skilled in the art, following procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1–17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vols. 1–5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Vols. 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). These schemes are merely illustrative of some methods by which the compounds of this disclosure may be synthesized, and various modifications to these schemes will be suggested to those skilled in the art who have read this disclosure. Starting materials and intermediates, as well as the final products of the reactions, may be isolated and purified, if desired, using conventional techniques (including but not limited to filtration, distillation, crystallization, chromatography, and the like). Such materials may be characterized using conventional means (including physical constants and spectral data).

[0192] Unless otherwise specified, the reactions described herein occur under atmospheric pressure in a temperature range of approximately -78°C to approximately 150°C, for example, approximately 0°C to approximately 125°C, and even room temperature (or ambient temperature) such as approximately 20°C. [Examples]

[0193] The following preparations of the compounds of formula (I), formula (II), and formula (III), and their pharmaceutically acceptable salts, are provided so that those skilled in the art may better understand and implement this disclosure. These are not intended to limit the scope of the disclosure, but should be considered merely illustrative and representative.

[0194] The following abbreviations are used in this section. TIFF2026515945000168.tif196165

[0195] All reagents were obtained from commercial suppliers and used without further purification unless otherwise specified.

[0196] Synthesis Examples TIFF2026515945000169.tif58165 Example 1: Synthesis of compound 7, (R,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pento-2-en-1-one (Method 1) TIFF2026515945000170.tif27165 Step 1: Ethyl(R,E)-4-((tert-butoxycarbonyl)amino)penta-2-enoic acid To a solution of ethyl 2-diethoxyphosphoryl acetate (3.2 g, 14.27 mmol) in acetonitrile (50 mL), lithium chloride (1.82 g, 42.82 mmol), N,N-diisopropylethylamine (5.53 g, 42.82 mmol), and tert-butyl N-[(1R)-1-methyl-2-oxoethyl]carbamate (4.94 g, 28.55 mmol) were added. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain ethyl(R,E)-4-((tert-butoxycarbonyl)amino)penta-2-enoic acid (4.1 g, crude) as a colorless oil, which was used in the next step without further purification. 1 ¹H NMR (400MHz, chloroform-d): δ 6.80 (dd, J=4.9, 15.7Hz, 1H), 5.83 (dd, J=1.7, 15.7Hz, 1H), 4.54-4.24 (m, 2H), 4.12 (q, J=7.1Hz, 2H), 1.41-1.37 (m, 9H), 1.25-1.17 (m, 6H). LCMS Rt=0.783min, m / z=243.2[M+H] + .

[0197] TIFF2026515945000171.tif27165 Step 2: (R,E)-4-((tert-butoxycarbonyl)amino)pento-2-enoic acid To a solution of ethyl(R,E)-4-((tert-butoxycarbonyl)amino)penta-2-enoic acid (1 g, 4.11 mmol) in tetrahydrofuran (10 mL) and water (10 mL), lithium hydroxide (295.32 mg, 12.33 mmol) was added, and the mixture was stirred at 50°C for 6 hours. The mixture was quenched with saturated potassium bisulfate (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride (30 mL), dried over sodium sulfate, and concentrated under vacuum to obtain (R,E)-4-((tert-butoxycarbonyl)amino)penta-2-enoic acid (740 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=1.137 min, m / z=215.1 [M+H] + .

[0198] TIFF2026515945000172.tif53165 Step 3: tert-butyl(R)-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)pyrrolidine-1-carboxylate Dioxane (6 mL) and water (2 mL) contain tert-butyl(R)-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)pyrrolidine-1-carboxylate (350 mg, 649.33 umol), 2-(7,8-difluoronaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (282.57 A mixture of [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (51.09 mg, 64.93 mg) was degassed, purged three times with nitrogen, and then stirred at 60°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2%-10% methanol in dichloromethane) to obtain tert-butyl(R)-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)pyrrolidine-1-carboxylate (230 mg, 53.13%) as a yellow oily substance. LCMS Rt=0.772 min, m / z=666.3[M+H] + .

[0199] TIFF2026515945000173.tif48165 Step 4: 7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine A mixture of tert-butyl(R)-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)pyrrolidine-1-carboxylate (100 mg, 149.99 umol) in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was stirred at 25°C for 1 hour. 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-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (100 mg, crude, trifluoroacetate) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.609min, m / z=566.2[M+H] + .

[0200] TIFF2026515945000174.tif58165 Step 5: tert-butyl((R,E)-5-((R)-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)pyrrolidine-1-yl)-5-oxopento-3-en-2-yl)carbamate 7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (100 mg, 146.93 μmol, trifluoroacetate) and N,N-diisopropyl in dichloromethane (2 mL) To a solution of ethylamine (56.97 mg, 440.78 umol) and (E,4R)-4-(tert-butoxycarbonylamino)penta-2-enoic acid (94.88 mg, 440.78 umol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide (280.49 mg, 440.78 umol, 50% purity, in ethyl acetate) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with sodium chloride (2 mL), dried over sodium sulfate, and vacuum concentrated to obtain tert-butyl((R,E)-5-((R)-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)pyrrolidine-1-yl)-5-oxopento-3-en-2-yl)carbamate (100 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.772 min, m / z=763.4[M+H] + .

[0201] TIFF2026515945000175.tif58165 Step 6: (R,E)-4-amino-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one A mixture of tert-butyl((R,E)-5-((R)-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)pyrrolidine-1-yl)-5-oxopento-3-en-2-yl)carbamate (100 mg, 130.92 umol) in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was stirred at 25°C for 1 hour. The reaction mixture was vacuum concentrated to obtain (R,E)-4-amino-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one (100 mg, crude, trifluoroacetate) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.626min, m / z=663.3[M+H] + .

[0202] TIFF2026515945000176.tif58165 Step 7: (R,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pento-2-en-1-one (R,E)-4-amino-1-((R)-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)pyrrolidine-1-yl)pento-2-ene To a solution of 1-one (100 mg, 128.58 umol, trifluoroacetate), triethylamine (39.03 mg, 385.74 umol), acetic acid (772.12 ug, 12.86 umol), formaldehyde (31.31 mg, 385.74 umol, 37% purity, in water) and sodium borohydride cyanohydride (24.24 mg, 385.74 umol) were added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (NH4HCO3)-ACN], gradient: 35%~65% B over 8 minutes) to obtain (R,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pento-2-en-1-one (8.27 mg, 7.68%) as a white solid. 1H NMR (400MHz, chloroform-d) δ9.09(s,1H),7.90(br d,J=7.8Hz,1H),7.70-7.60(m,1H),7.59-7.50(m,2H),7.33(br d,J=9.0Hz,1H),6.89(ddd,J=3.8,7.8,15.3Hz,1H),6.17(br t,J=14.2Hz,1H),5.40-5.11(m,2H),4.26-4.10(m,2H),4.08-3.77(m,2H),3.64-3.46(m,2H),3.38(br dd,J=3.6,7.9Hz,3H),3.24-3.02(m,4H),2.95-2.86(m,1H),2.22(br d,J=5.1Hz,8H),2.14-2.03(m,2H),1.93-1.76(m,4H),1.15(t,J=6.3Hz,3H). LCMS Rt=1.953min,m / z=691.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 1.953 minutes, ESI+ measured value [M+H] = 691.3.

[0203] TIFF2026515945000177.tif58165 Example 2: Synthesis of compound 10, (S,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pento-2-en-1-one (Method 1) TIFF2026515945000178.tif58165 Step 1: tert-butyl((S,E)-5-((R)-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)pyrrolidine-1-yl)-5-oxopento-3-en-2-yl)carbamate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% methanol in dichloromethane) to obtain tert-butyl((S,E)-5-((R)-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)pyrrolidine-1-yl)-5-oxopento-3-en-2-yl)carbamate (200 mg, 66.76%) as a yellow oily substance. LCMS Rt=0.643 min, m / z=763.4 [M+H] + .

[0204] TIFF2026515945000179.tif58165 Step 2: (S,E)-4-amino-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one The deprotection product of Boc was prepared in the same manner as in step 6 of method #1. The reaction mixture was concentrated under vacuum to obtain (S,E)-4-amino-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one (100 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.506min, m / z=663.3[M+H] + .

[0205] TIFF2026515945000180.tif58165 Step 3: (S,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pent-2-en-1-one The reduction amination reaction product was prepared in the same manner as in step 7 of method #1. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (NH4HCO3)-ACN], gradient: 30%~60% B over 8 minutes) to obtain (S,E)-1-((R)-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)pyrrolidine-1-yl)-4-(dimethylamino)pento-2-en-1-one (15.6 mg, 16.24%) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δ 9.22-9.11 (m,1H), 8.03-7.93 (m,1H), 7.78-7.69 (m,1H), 7.68-7.57 (m,2H), 7.46-7.35 (m,1H), 7.02-6.91 (m,1H), 6.32-6.19 (m,1H), 5.52-5.38 (m,1H), 5.30 (s,1H), 4.38-4.27 (m,1H), 4.26-4.19 (m,1H), 4.18-4.0 4(m,1H),4.04-3.86(m,1H),3.76-3.64(m,1H),3.64-3.52(m,1H),3.51-3.41(m,3H),3.34-3.22(m,2H),3.22-3.09(m, 2H),3.04-2.93(m,1H),2.57-2.42(m,1H),2.34-2.23(m,8H),2.22-2.10(m,2H),1.99-1.86(m,3H),1.31-1.20(m,3H). LCMS Rt=2.906min,m / z=691.3[M+H]+ . LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.906 minutes, ESI + measured value [M+H] = 691.3.

[0206] TIFF2026515945000181.tif63165 Example 3: Compound 2-((S)-4-(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)-1-((S,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile 19(method Synthesis of compound 20, namely 2-((S)-4-(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)-1-((R,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile TIFF2026515945000182.tif27165 Step 1: (E)-4-bromopent-2-enoic acid To a solution of (E)-pento-2-enoic acid (2 g, 19.98 mmol) in carbon tetrachloride (30 mL), 2-[(E)-(1-cyano-1-methylethyl)azo]-2-methylpropanenitrile (984.12 mg, 5.99 mmol) and 1-bromopyrrolidine-2,5-dione (5.33 g, 29.97 mmol) were added. The mixture was stirred at 80°C for 1 hour. The mixture was concentrated to dryness under vacuum. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain (E)-4-bromopento-2-enoic acid (3.5 g, 97.87%) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d): δ 7.06 (dd, J=8.1, 15.4Hz, 1H), 5.88 (dd, J=0.9, 15.4Hz, 1H), 4.70-4.58 (m, 1H), 1.77 (d, J=6.6Hz, 3H).

[0207] TIFF2026515945000183.tif27165 Step 2: (E)-4-bromopent-2-enoyl chloride A mixture of (E)-4-bromopent-2-enoic acid (800 mg, 4.47 mmol) and thionyl chloride (20 mL) was degassed, purged three times with nitrogen, and then stirred under a nitrogen atmosphere at 80°C for 12 hours. The mixture was concentrated to dryness under vacuum to obtain (E)-4-bromopent-2-enoyl chloride (800 mg, crude) as a yellow oily substance, which was used in the next step without further purification.

[0208] TIFF2026515945000184.tif68165 Step 3: tert-butyl(S)-4-(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)-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 3 of method #1. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(S)-4-(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)-2-(cyanomethyl)piperazine-1-carboxylate (900 mg, 71.68%) as a brown solid. LCMS Rt=0.790 min, m / z=707.3 [M+H] + .

[0209] TIFF2026515945000185.tif53165 Step 4: 2-((S)-4-(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)piperazine-2-yl)acetonitrile Deprotection of Boc was performed in the same manner as in step 4 of method #1. The mixture was concentrated to dryness under vacuum to obtain 2-((S)-4-(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)piperazine-2-yl)acetonitrile (200 mg, crude, trifluoroacetate) as a brown oil, which was used in the next step without further purification. LCMS Rt=0.601min, m / z=607.2[M+H]+ .

[0210] TIFF2026515945000186.tif63165 Step 5: 2-((2S)-1-((E)-4-bromopent-2-enoyl)-4-(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)piperazine-2-yl)acetonitrile A solution of 2-((S)-4-(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)piperazin-2-yl)acetonitrile (200 mg, 328.92 umol) was prepared by adding sodium bicarbonate (82.89 mg, 986.75 umol) and (E)-4-bromopent-2-enoyl chloride (194.84 mg, 986.75 umol) to tetrahydrofuran (4 mL) and water (1 mL). The mixture was stirred at 0°C for 1 hour. The mixture was concentrated to dryness under vacuum to obtain 2-((2S)-1-((E)-4-bromopento-2-enoyl)-4-(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)piperazin-2-yl)acetonitrile (250 mg, crude) as a yellow oily substance, which was used in the next step without further purification. LCMS Rt=0.745min, m / z=767.2[M+H] + .

[0211] TIFF2026515945000187.tif63165 Step 6: 2-((S)-4-(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)-1-((S,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)py Perazin-2-yl)acetonitrile and 2-((S)-4-(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)-1-((R,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazin-2-yl)acetonitrile To a solution of (3S)-3-methoxypyrrolidine (98.64 mg, 975.23 μmol) in tetrahydrofuran (4 mL), N,N-diisopropylethylamine (210.07 mg, 1.63 mmol) and 2-((2S)-1-((E)-4-bromopento-2-enoyl)-4-(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)piperazin-2-yl)acetonitrile (250 mg, 325.08 μmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with sodium carbonate (9 mL), dried over sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by reverse-phase HPLC (neutral conditions: column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35%~65%, 8 minutes) to obtain 2-((2S)-4-(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)-1-((E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile (47 mg, 18.32%) as a yellow solid. The racemic material was further purified at SFC and then arbitrarily assigned.

[0212] 2-((S)-4-(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)-1-((S,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile (peak 1, retention time = 2.767 minutes) (18.13 mg, 45.33%) was obtained as a yellow solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.16 (br s, 1H), 8.22-8.03 (m, 2H), 7.77-7.62 (m, 2H), 7.55 (br t, J=8.9Hz, 1H), 6.81 (br dd, J=8.1, 15.0Hz, 1H), 6.56 (br s,1H),5.45-5.23(m,1H),5.07-4.42(m,3H),4.38-4.17(m,2H),4.10-3.63(m,4H),3.44-3.26( m,3H),3.24(s,3H),3.07-2.62(m,9H),2.39-2.01(m,6H),1.94-1.72(m,2H),1.33-1.25(m,3H). LCMS Rt=3.020min,m / z=788.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.020 minutes, ESI+ measured value [M+H] = 788.3.

[0213] 2-((S)-4-(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)-1-((R,E)-4-((S)-3-methoxypyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile (peak 2, retention time = 3.553 minutes) (12.11 mg, 30.27%) was obtained as a yellow solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.13 (s, 1H), 8.17-8.10 (m, 1H), 8.10-8.04 (m, 1H), 7.72-7.63 (m, 2H), 7.52 (dt, J=1.8, 8.9Hz, 1H), 6.84-6.71 (m, 1H), 6.70-6.59 (m, 1H), 5.49-5.23 (m, 1H), 5.09-4.75 (m, 1H), 4.63-4.37 (m, 4H), 4.17-3.77 (m, 4H), 3.49-3.34 (m, 3H), 3.24 (s, 3H), 3.18-2.85 (m, 9H), 2.42-2.19 (m, 6H), 2.02 (br d,J=6.0Hz,2H),1.27(br s,3H). LCMS Rt=3.019min,m / z=788.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.019 minutes, ESI+ measured value [M+H] = 788.3. SFC (Column: OX, 50 x 4.6 mm ID, 3.0 μm, Mobile phase: A: CO2, B: MeOH (0.1% IPAm, v / v), Gradient: A: B = 60:40, Flow rate: 4 mL / min).

[0214] TIFF2026515945000188.tif63165 Example 4: Synthesis of compound 29, 2-((2S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((E)-4-((R)-3-fluoropyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile (Method 2) TIFF2026515945000189.tif27165 Step 1: (S,E)-4-bromopent-2-enoic acid To a solution of tert-butyl(S,E)-4-bromopent-2-enoate (700 mg, 2.98 mmol) in dichloromethane (7 mL), trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum, and (S,E)-4-bromopent-2-enoic acid (500 mg, crude) was obtained as a white solid, which was used in the next step without further purification.

[0215] TIFF2026515945000190.tif53165 Step 2: tert-butyl(S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 3 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl(S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (890 mg, 76.71%) as a yellow oily substance. 1 H NMR(400MHz,chloroform-d)δ9.06(s,1H),8.04-7.87(m,2H),7.66-7.53(m,4H),7.47-7.40(m,1H),5.37-5.20(m,1H),4.71-4.63(m,1H),4.54(br d,J=13.9Hz,1H),4.47-4.23(m,3H),3.89-3.66(m,2H),3.35-3.15(m,3H),3.03-2 .95(m,1H),2.87-2.70(m,2H),2.32-2.12(m,3H),1.98-1.89(m,3H),1.53(s,10H). LCMS Rt=0.643min,m / z=689.3[M+H] + .

[0216] TIFF2026515945000191.tif53165 Step 3: 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile The deprotection product of Boc was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (360 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS Rt=0.523min, m / z=589.2[M+H] + .

[0217] TIFF2026515945000192.tif63165 Step 4: 2-((S)-1-((S,E)-4-bromopent-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #2. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) to obtain 2-((S)-1-((S,E)-4-bromopento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (130 mg, 30.12%) as a pale yellow gum-like substance. LCMS Rt=1.956 min, m / z=749.2 [M+H] + .

[0218] TIFF2026515945000193.tif63165 Step 5: 2-((2S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((E)-4-((R)-3-fluoropyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile The substitution reaction product was prepared in the same manner as in step 6 of method #2. The resulting residue was purified by reverse-phase HPLC (column: Phenomenex Luna C18 200*40mm*10um, mobile phase: [water (FA)-acetonitrile], B%: 5%~45%, 8 minutes) to obtain 2-((2S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((E)-4-((R)-3-fluoropyrrolidine-1-yl)pento-2-enoyl)piperazine-2-yl)acetonitrile (7 mg, 5.01%, formate) as a yellow solid. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 9.09 (s, 1H), 8.30 (br s, 1H), 8.05-7.98 (m, 1H), 7.89 (d, J=8.1Hz, 1H), 7.69-7.49 (m, 3H), 7.43 (dt, J=2.1, 7.8Hz, 1H), 6.96 (br dd, J=7.6, 15.0Hz, 1H), 6.56-6.32 (m, 1H), 5.47-5.28 (m, 1H), 5.27-5.10 (m, 1H), 5.03 (br d,J=1.4Hz,1H),4.64-4.55(m,1H),4.53-4.41(m,3H),4.14-3.98(m,1H),3.93 -3.68(m,2H),3.67-3.46(m,2H),3.37-3.14(m,2H),3.12-2.77(m,6H),2.60(br d,J=8.5Hz,1H),2.51-2.37(m,3H),2.25-2.02(m,6H),1.39-1.22(m,3H). LCMS Rt=1.929min,m / z=758.3[M+H] +. LC-MS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 1.929 minutes, ESI+ measured value [M+H] = 758.3.

[0219] TIFF2026515945000194.tif63165 Example 5: Synthesis of compound 30, 2-((S)-1-((R,E)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (Method 3) TIFF2026515945000195.tif27165 Step 1: (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanoic acid The substitution reaction product was prepared in the same manner as in step 6 of method #2. The reaction mixture was concentrated to dryness under vacuum to obtain (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanoic acid (3.6 g, crude) as a colorless oil, which was used in the next step without further purification. LCMS Rt=0.209 min, m / z=185.1 [M+H] + .

[0220] TIFF2026515945000196.tif32165 Step 2: (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methoxy-N-methylpropanamide The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The resulting residue was purified by reverse-phase HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 10%~40%, 10 minutes) to obtain (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methoxy-N-methylpropanamide (1 g, 23.18%) as a yellow oil. 1H NMR(400MHz,chloroform-d)δ4.01-3.81(m,2H),3.72(br d,J=1.6Hz,4H),3.64-3.43(m,3H),3.36-2.97(m,4H),2.16-2.01(m,1H),1.92-1.79(m,3H),1.40-1.24(m,3H). LCMS Rt=1.056min,m / z=228.2[M+H] + .

[0221] TIFF2026515945000197.tif27165 Step 3: (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)propanal To a solution of (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methoxy-N-methylpropanamide (200.00 mg, 876.09 umol) in tetrahydrofuran (4 mL), diisobutylaluminum hydride (2.63 mL, 1 M, in tetrahydrofuran) was added, and the mixture was stirred under a nitrogen atmosphere at -78°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness under vacuum to obtain (R)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanal (200 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.587min,m / z=169.1[M+H] + .

[0222] TIFF2026515945000198.tif73165 Step 4: Diethyl (2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The resulting residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 100*40mm*3um, mobile phase: [water (TFA)-acetonitrile], B%: 25%~70%, 8 minutes) to obtain diethyl (2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate (142 mg, 37.65%, trifluoroacetate) as a yellow solid. LCMS Rt=0.632min,m / z=767.3[M+H] + .

[0223] TIFF2026515945000199.tif63165 Step 5: 2-((S)-1-((R,E)-4-((1R,5S)-3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile The Horner-Wadsworth-Emmons reaction product was prepared in the same manner as in step 1 of method #1. The obtained residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 35%~65%, 8 minutes) to obtain 2-((S)-1-((R,E)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile ((10.68 mg, 39.78%) as a yellow solid. 1 H NMR (400MHz, acetonitrile-d3) δ9.16(s,1H),8.17(d,J=7.2Hz,1H),8.06(d,J=8 .3Hz,1H),7.78-7.70(m,1H),7.69-7.62(m,2H),7.59-7.53(m,1H),6.69-6. 47(m,2H),5.39-5.22(m,1H),5.18-4.66(m,2H),4.54-4.41(m,2H),4.28-4. 23(m,1H),4.18-4.12(m,1H),4.10-3.93(m,1H),3.89-3.73(m,2H),3.61(br dd,J=3.1,9.8Hz,2H),3.52(br d,J=9.4Hz,1H),3.46(br d,J=8.7Hz,1H),3.33(br s,1H),3.20-3.15(m,2H),3.13-3.02(m,3H),3.00-2.85(m,3H),2.24-2.21(m,2H),2.15(br s,1H),2.11-2.02(m,2H),1.93-1.79(m,5H),1.15(br d,J=5.9Hz,3H). LCMS Rt=2.993min,m / z=782.4[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.993 minutes, ESI+ measured value [M+H] = 782.4.

[0224] TIFF2026515945000200.tif63165 Example 6: Synthesis of compound 31, 2-((S)-1-((S,E)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (Method 3) TIFF2026515945000201.tif27165 Step 1: (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanoic acid The substitution reaction product was prepared in the same manner as in step 1 of method #3. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um, mobile phase: [water (NH4HCO3)-ACN], B%: 1%~20%, 10 minutes) to obtain (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanoic acid (520 mg, 8.59%) as a white solid. LCMS Rt=0.133min, m / z=185.1[M+H] +

[0225] TIFF2026515945000202.tif32165 Step 2: (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methoxy-N-methylpropanamide The amide coupling reaction product was prepared in the same manner as in step 2 of method #3. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 10%~40%, 10 minutes) to obtain (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methoxy-N-methylpropanamide (180 mg, 28.09%) as a yellow oily substance. 1H NMR(400MHz,chloroform-d)δ3.85(br dd,J=10.5,16.3Hz,2H),3.71(s,3H),3.55(br dd,J=2.1,10.4Hz,2H),3.47(dd,J=1.9,10.4Hz,1H),3.34-3.15(m,4H),3.08(br s,1H),1.94-1.84(m,4H),1.26(d,J=6.6Hz,3H). LCMS Rt=1.041min,m / z=228.2[M+H] + .

[0226] TIFF2026515945000203.tif27165 Step 3: (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)propanal The reduction reaction product was prepared in the same manner as in step 3 of method #3. The reaction mixture was concentrated to dryness under vacuum to obtain (S)-2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propanal (90 mg, crude) as a colorless oil, which was used in the next step without further purification. 1 ¹H NMR (400MHz, chloroform-d): δ 9.43 (d, J=3.6Hz, 1H), 3.72-3.68 (m, 2H), 3.51 (dd, J=2.2, 10.4Hz, 1H), 3.47-3.43 (m, 1H), 3.18-3.13 (m, 1H), 2.95 (br s, 1H), 2.79-2.68 (m, 1H), 1.86-1.81 (m, 4H), 1.11-1.06 (m, 3H). LCMS Rt=0.149min, m / z=169.1[M+H] + .

[0227] TIFF2026515945000204.tif63165 Step 4: 2-((S)-1-((S,E)-4-((1R,5S)-3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile The HWE reaction product was prepared in the same manner as in step 5 of method #3. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 35%~65%, 8 minutes) to obtain 2-((S)-1-((S,E)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pento-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (10.05 mg, 32.22%) as a white solid. 1¹H NMR (400 MHz, acetonitrile-d3) δ 9.15 (br d,J=3.1Hz,1H),8.16(d,J=7.3Hz,1H),8.05(d,J=8.3Hz,1H),7.75-7.69( m,1H),7.68-7.62(m,2H),7.57-7.51(m,1H),6.74-6.46(m,2H),5.44-5.19 (m,1H),5.07-4.66(m,1H),4.59-4.42(m,2H),4.31-4.23(m,1H),4.22-4.1 2(m,1H),4.10-3.70(m,3H),3.67-3.58(m,2H),3.55-3.41(m,2H),3.33(br s,1H),3.23-3.15(m,2H),3.14-2.98(m,4H),2.96-2.86(m,3H),2.12-2.05(m,2H),1.95-1.72(m,8H),1.14(d,J=6.3Hz,3H). LCMS Rt=3.032min,m / z=782.4[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.032 minutes, ESI+ measured value [M+H] = 782.4.

[0228] TIFF2026515945000205.tif58165 Example 7: Synthesis of compound 32, (E)-4-(dimethylamino)-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one (Method 2) TIFF2026515945000206.tif53165 Step 1: tert-butyl(R)-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)pyrrolidine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 3 of method #2. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) to obtain tert-butyl(R)-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)pyrrolidine-1-carboxylate (2.3 g, 99.69%) as a brown solid. LCMS Rt=2.053 min, m / z=828.4 [M+H] + .

[0229] TIFF2026515945000207.tif53165 Step 2: tert-butyl(R)-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)pyrrolidine-1-carboxylate To a solution of tert-butyl(R)-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)pyrrolidine-1-carboxylate (150 mg, 159.05 μmol) in N,N-dimethylformaldehyde (1 mL), cesium fluoride (241.60 mg, 1.59 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with saturated lithium chloride (15 mL) and extracted with dimethyltetrahydrofuran (3 x 5 mL). The combined organic layers were dried over sodium sulfate and vacuum concentrated to obtain tert-butyl(R)-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)pyrrolidine-1-carboxylate (100 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.668min, m / z=672.3[M+H] + .

[0230] TIFF2026515945000208.tif48165 Step 3: 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine Deprotection of Boc was performed in the same manner as in step 4 of method #2. 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-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (100 mg, crude, trifluoroacetic acid) as a brown oil, which was used in the next step without further purification. LCMS Rt=0.522min, m / z=572.3[M+H] + .

[0231] TIFF2026515945000209.tif58165 Step 4: (E)-4-bromo-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one The amide coupling reaction product was prepared in the same manner as in step 5 of method #2. The reaction mixture was concentrated to dryness under vacuum to obtain (E)-4-bromo-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one (110 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.756min, m / z=732.2[M+H] + .

[0232] TIFF2026515945000210.tif58165 Step 5: (E)-4-(dimethylamino)-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one The substitution reaction product was prepared in the same manner as in step 6 of method #2. 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: 30%~60% B over 8.0 minutes) to obtain (E)-4-(dimethylamino)-1-((R)-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)pyrrolidine-1-yl)pento-2-en-1-one (41.13 mg, 39.20%) as a yellow oil. 1¹H NMR (400MHz, dimethyl sulfoxide-d6) δ 9.20-9.15 (m, 1H), 8.25-8.17 (m, 2H), 7.72-7.64 (m, 2H), 7.60 (t, J=9.0Hz, 1H), 6.70-6.61 (m, 1H), 6.38-6.28 (m, 1H), 5.36-5.18 (m, 2H), 4.16-4.11 (m, 1H), 4.09-4.03 (m, 2H), 3.95-3.84 (m, 1H), 3.77-3.56 (m, 2H), 3.55-3.44 (m, 1H), 3.42 (br d,J=2.5Hz,3H),3.14-3.05(m,3H),3.04-2.99(m,1H),2.86-2.78(m,1H),2.40-2.31(m,1H),2.31-2.23(m,1H),2.14(d,J=6.0Hz,7H),2.05(br s,1H),2.02-1.95(m,1H),1.87-1.81(m,1H),1.80-1.71(m,2H),1.10(t,J=6.7Hz,3H). LCMS Rt=1.695min,m / z=697.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 1.695 minutes, ESI + measured value [M+H] = 697.3.

[0233] TIFF2026515945000211.tif63165 Example 8: Synthesis of compound 44, 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile (Method 1) TIFF2026515945000212.tif53165 Step 1: tert-butyl(S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 3 of method #1. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna C8 250*50mm*10um, mobile phase: [H2O(0.1%TFA)-ACN], gradient: 20%~50% B over 10.0 minutes) to obtain tert-butyl(S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (500 mg, 62.19%, trifluoroacetate) as a yellow solid. LCMS Rt=0.443min, m / z=679.3[M+H] + .

[0234] TIFF2026515945000213.tif53165 Step 2: 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (180 mg, crude, hydrochloric acid) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.334min, m / z=579.2[M+H] + .

[0235] TIFF2026515945000214.tif73165 Step 3: Diethyl (2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain diethyl (2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate (150 mg, 71.75%) as a pink solid. LCMS Rt=0.522 min, m / z=757.3 [M+H] + .

[0236] TIFF2026515945000215.tif63165 Step 4: tert-butyl((R,E)-5-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate The Horner-Wadsworth-Emmons reaction product was prepared in the same manner as in step 5 of method #3. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75*30mm*3um, mobile phase: [H2O (0.1% TFA)-ACN], gradient: 20%~50% B over 8.0 minutes) to obtain tert-butyl((R,E)-5-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate (100 mg, 61.78%) as a pale yellow solid. LCMS Rt=0.585min,m / z=776.3[M+H] + .

[0237] TIFF2026515945000216.tif63165 Step 5: 2-((S)-1-((R,E)-4-aminopenta-2-enoyl)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in step 6 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-1-((R,E)-4-aminopenta-2-enoyl)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (100 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.495min, m / z=676.3[M+H] + .

[0238] TIFF2026515945000217.tif63165 Step 6: 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile Reductive amination was prepared in the same manner as in step 7 of method #1. 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: 15% to 60% B over 8.0 minutes) to obtain 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile (15.10 mg, 15.81%) as a yellow oil. 1¹H NMR (400MHz, chloroform-d) δ 9.09 (s, 1H), 7.54-7.47 (m, 1H), 7.41-7.36 (m, 1H), 7.32 (d, J=7.8Hz, 1H), 7.00-6.84 (m, 1H), 6.62-6.12 (m, 1H), 5.46-5.20 (m, 1H), 5.12-4.92 (m, 1H), 4.64-4.52 (m, 1H), 4.51-4.43 (m, 1H), 4.42-4.28 (m, 2H), 4.26-3.96 (m, 2H) ),3.95-3.71(m,2H),3.57-3.35(m,2H),3.34-3.28(m,1H),3.28-3.23(m,1H),3.09-2.98(m,2H),2.67-2.49(m,1H),2.64-2. 45(m,2H),2.44-2.29(m,6H),2.29-2.14(m,3H),2.10-2.03(m,2H),1.36-1.20(m,3H),0.78-0.68(m,2H),0.24-0.10(m,2H). LCMS Rt=2.070min,m / z=704.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 2.070 minutes, ESI+ measured value [M+H] = 704.3.

[0239] TIFF2026515945000218.tif63165 Example 9: Synthesis of compound 45, 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile (Method 1) TIFF2026515945000219.tif63165 Step 1: tert-butyl((S,E)-5-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate The Horner-Wadsworth-Emmons reaction product was prepared in the same manner as in step 1 of method #1. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain tert-butyl((S,E)-5-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate (120 mg, 78.03%) as a pale yellow oily substance. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 9.10 (s, 1H), 7.52-7.47 (m, 1H), 7.41-7.36 (m, 1H), 7.32 (d, J=7.7Hz, 1H), 6.88-6.75 (m, 1H), 6.43-6.25 (m, 1H), 5.53-5.25 (m, 1H), 5.11-4.88 (m, 1H), 4.62-4.47 (m, 3H), 4.47-4.37 (m, 3H), 4.03-3.79 (m, 3H), 3.73-3.63 (m, 2H), 3.18-3.08 (m, 2H), 2.81 (s, 3H), 2.45-2.25 (m, 3H), 2.09 (br d,J=14.3Hz,3H),1.46(s,12H),1.34-1.29(m,4H),0.74(br d,J=5.0Hz,2H),0.21-0.12(m,2H). LCMS Rt=0.471min,m / z=776.3[M+H] + .

[0240] TIFF2026515945000220.tif63165 Step 2: 2-((S)-1-((S,E)-4-aminopenta-2-enoyl)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-1-((S,E)-4-aminopenta-2-enoyl)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (111 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.340 min, m / z=676.3[M+H] + .

[0241] TIFF2026515945000221.tif63165 Step 3: 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile The reduction amination was prepared in the same manner as in step 7 of method #1. 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: 15% to 60% B over 8.0 minutes) to obtain 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazin-2-yl)acetonitrile (6.87 mg, 7.99%) as a yellow solid. 1¹H NMR (400MHz, chloroform-d) δ 9.11-9.06 (m, 1H), 7.52-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.32 (d, J=7.9Hz, 1H), 7.02-6.91 (m, 1H), 6.47-6.30 (m, 1H), 5.39-5.18 (m, 1H), 5.09- 4.93(m,1H),4.59-4.41(m,2H),4.37-4.21(m,2H),4.19-3.63(m,1H),3.35-3.16(m ,4H),3.05-2.89(m,2H),2.84-2.73(m,1H),2.31(s,6H),2.29-2.13(m,3H),1.90(br s,4H),1.23(br d,J=6.4Hz,3H),0.78-0.66(m,2H),0.22-0.09(m,2H). LCMS Rt=3.103min,m / z=704.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 3.103 minutes, ESI+ measured value [M+H] = 704.3.

[0242] TIFF2026515945000222.tif63165 Example 10: Synthesis of compound 46, 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile (Method 1) TIFF2026515945000223.tif53165 Step 1: tert-butyl(S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reactant was prepared in the same manner as in Step 3 of Method #1. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna C8 250*50mm*10um, mobile phase: [H2O(0.1% TFA)-ACN], gradient: 20% - 50% B over 10.0 minutes) to obtain tert-butyl (S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate ((0.42 g, 28.81%, trifluoroacetate salt) as a brown solid. LCMS Rt = 0.447 min, m / z = 708.2 [M+H] + .

[0243] TIFF2026515945000224.tif53165 Step 2: 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in Step 4 of Method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (1.2 g, crude, trifluoroacetate salt) as a white solid, which was used in the next step without further purification. LCMS Rt = 0.511 min, m / z = 608.2 [M+H] + .

[0244] TIFF2026515945000225.tif73165 Step 3: Diethyl (2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain diethyl (2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-2-oxoethyl)phosphonate (730 mg, 55.87%) as a brown solid. LCMS Rt=0.317 min, m / z=786.2 [M+H] + .

[0245] TIFF2026515945000226.tif63165 Step 4: tert-butyl((R,E)-5-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-n-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate The Horner-Wadsworth-Emmons reaction product was prepared in the same manner as in step 5 of method #3. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75*30mm*3um, mobile phase: [H2O (0.1% TFA)-ACN], gradient: 20%~50% B over 8.0 minutes) to obtain tert-butyl((R,E)-5-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin n-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate (220 mg, 53.75%, trifluoroacetate) as a white solid. LCMS Rt=0.424min,m / z=805.3[M+H] + .

[0246] TIFF2026515945000227.tif63165 Step 5: 2-((S)-1-((R,E)-4-aminopent-2-enoyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in step 6 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-1-((R,E)-4-aminopent-2-enoyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (180 mg, crude, trifluoroacetate) as a yellow solid, which was used in the next step without further purification. LCMS Rt=0.326min, m / z=705.2[M+H] + .

[0247] TIFF2026515945000228.tif63165 Step 6: 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile The reduction amination was prepared in the same manner as in step 7 of method #1. 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: 30%~60% B over 8.0 minutes) to obtain 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((R,E)-4-(dimethylamino)penta-2-enoyl)piperazin-2-yl)acetonitrile (38.43 mg, 22.57%) as a yellow solid. 1 H NMR(400MHz,acetonitrile-d3)δ9.24(s,1H),7.89-7.63(m,2H),7.48(br d,J=7.3Hz,1H),6.86-6.65(m,1H),6.62-6.36(m,1H),5.42-5.16(m,1H),5.06-4.70(m,1H),4.53-4.36(m,2H),4.31 -4.12(m,2H),4.08-3.87(m,1H),3.83-3.60(m,2H),3.59-3.24(m,1H),3.23-3.07(m,4H),3.00-2.83(m,3H),2.30(br s,1H),2.24(s,6H),2.21(br d,J=3.1Hz,1H),2.15-2.06(m,2H),1.93-1.86(m,2H),1.19(br d,J=6.6Hz,3H). LCMS Rt=1.985min,m / z=732.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 1.985 minutes, ESI+ measured value [M+H] = 732.3.

[0248] TIFF2026515945000229.tif63165 Example 11: Synthesis of compound 47, 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile (Method 1) TIFF2026515945000230.tif63165 Step 1: tert-butyl((S,E)-5-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-n-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate The HWE reaction product was prepared in the same manner as in step 1 of method #1. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in tetrahydrofuran) to obtain tert-butyl((S,E)-5-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine n-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-yl)-5-oxopento-3-en-2-yl)carbamate (95 mg, 61.83%) as a yellow oily substance. LCMS Rt=0.596 min, m / z=805.3 [M+H] + .

[0249] TIFF2026515945000231.tif63165 Step 2: 2-((S)-1-((S,E)-4-aminopent-2-enoyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of Boc was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-((S)-1-((S,E)-4-aminopent-2-enoyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (86 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.488min, m / z=705.2[M+H] + .

[0250] TIFF2026515945000232.tif63165 Step 3: 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazine-2-yl)acetonitrile The reduction amination was prepared in the same manner as in step 7 of method #1. 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: 30%~60% B over 8.0 minutes) to obtain 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((S,E)-4-(dimethylamino)penta-2-enoyl)piperazin-2-yl)acetonitrile (8.3 mg, 94.43%) as a yellow solid. 1H NMR(400MHz,acetonitrile-d3)δ9.09-9.06(m,1H),7.80-7.67(m,2H),7.45(br d,J=5.9Hz,1H),6.74(dd,J=7.4,15.2Hz,1H),6.61-6.32(m,1H),5.35-5.16(m,1H),5.08-4.72(m,1H),4.40(br s,2H),4.24-4.10(m,2H),3.91(br s,1H),3.90-3.72(m,2H),3.70-3.56(m,1H),3.15-3.05(m,4H),2.92-2.84(m,3H),2.17(br s,6H),2.10(br d,J=2.6Hz,1H),2.07-2.03(m,1H),1.92-1.87(m,2H),1.86-1.79(m,2H),1.15(br d,J=6.6Hz,3H). LCMS Rt=3.061min,m / z=732.3[M+H] + . LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.061 minutes, ESI+ measured value [M+H] = 732.3.

[0251] Example 12: Other Examples TIFF2026515945000233.tif180165TIFF2026515945000234.tif167165TIFF2026515945000235.tif185165TIFF202 6515945000236.tif173165TIFF2026515945000237.tif190165TIFF2026515945000238.tif190165TIFF20265159450 00239.tif179165TIFF2026515945000240.tif196165TIFF2026515945000241.tif179165TIFF2026515945000242.t if202165TIFF2026515945000243.tif202165TIFF2026515945000244.tif202165TIFF2026515945000245.tif179165

[0252] Biological examples Example 13: KRAS G12C and inhibition of cRAF binding AlphaScreen technology enables compound inhibition of the interaction between KRAS G12C (Cys-light (C51S, C80L, and C118S), existing as a shortened version consisting of amino acids 1-169) and cRAF. 50 The compounds were used to determine the following. The compounds were diluted in 100% DMSO, and each compound concentration was spotted at 200 nl / well into a low-volume white 384-well plate. KRAS G12C contained the biotin-AviTag, and cRaf was GST-tagged as the Ras-binding domain (amino acids 50-131, RBD). KRAS G12C was preloaded with the GTP analog guanosine 5'-[β,γ-imide] triphosphate (GMPPNP). KRAS G12C was diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100, and 10 μM GMPPNP, and added at 10 μl / well to the plate spotted with the compound to make a 2% DMSO concentration. The plate was incubated for 2 hours. Next, a mixture of RBD diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100, and 2% DMSO, along with AlphaScreen streptavidin donor beads and glutathione acceptor beads, was added at 10 μl / well. The donor beads were excited at 680 nm, and the mixture was incubated for 60–90 minutes before reading the sample for emission at 570 nm. All incubations were performed at room temperature. The final peak compound concentration was 50 μM, and 1:3 titration was performed for a 10-point dose-response curve. The final assay conditions were 0.5 nM KRAS G12C, 0.75 nM RBD, and 5 μg / ml each of AlphaScreen donor and acceptor beads. IC 50 This was determined using a nonlinear regression approximation of the inhibitor and the response (four parameters).

[0253] A counter-assay was also set up to exclude inhibitors of AlphaScreen technology itself. Compound plates were incubated for 2 hours with buffer only as described above. AlphaScreen beads were added as described above, except that RBD was replaced with biotin-AviTag-GST. Samples were read and analyzed as described above.

[0254] The results for the compounds are shown in Table 1.

[0255] (Table 1) Binding inhibition of KRAS G12C and cRAF (IC 50 ) TIFF2026515945000246.tif219165TIFF2026515945000247.tif228165TIFF2026515945000248.tif228165 TIFF2026515945000249.tif223165TIFF2026515945000250.tif228165TIFF2026515945000251.tif212165 TIFF2026515945000252.tif212165TIFF2026515945000253.tif207165TIFF2026515945000254.tif207165 TIFF2026515945000255.tif223165TIFF2026515945000256.tif212165TIFF2026515945000257.tif170165

[0256] Example 14: KRAS G12C and inhibition of PI3Ka binding AlphaScreen technology enables compound inhibition of the interaction between KRAS G12C (Cys-light (C51S, C80L, and C118S), existing as a shortened version consisting of amino acids 1-169) and PI3Ka. 50This is used to determine the following. The compounds are diluted in 100% DMSO, and each compound concentration is spotted at 200 nl / well into a low-volume white 384-well plate. KRAS G12C contains biotin-AviTag, and PI3Ka is His-tagged as the Ras-binding domain (amino acids 157-300, RBD). KRAS G12C is preloaded with the GTP analog guanosine 5'-[β,γ-imide] triphosphate (GMPPNP). KRAS G12C is diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100, and 10 μM GMPPNP, and added at 10 μl / well to the plate spotted with the compound to a 2% DMSO concentration. The plate is incubated for 2 hours. Next, a mixture of RBD and AlphaScreen streptavidin donor beads and nickel chelate acceptor beads, diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl2, 0.01% Triton X-100, and 2% DMSO, is added at 10 μl / well and incubated for 60–90 minutes. The sample is then luminescence read at 570 nm after excitation of the donor beads at 680 nm. All incubations are performed at room temperature. The final peak compound concentration is 50 μM, and 1:3 titration is performed for a 10-point dose-response curve. The final assay conditions are 1.5 nM KRAS G12C, 100 nM RBD, 1.25 μg / ml AlphaScreen donor beads, and 10 μg / ml AlphaLISA acceptor beads. IC 50 This is determined using nonlinear regression fitting of [inhibitor] vs. response (four parameters).

[0257] A counter-assay has also been established to eliminate inhibitors of the AlphaScreen technology itself. The compound plate is incubated with buffer only for approximately 2 hours as described above. AlphaScreen beads are added as described above, but an unrelated biotinylated His-tagged peptide is used instead of RBD. The sample is read and analyzed as described above.

[0258] Example 15: MCF10A (G12C or G12C-A59G)-KRAS cell viability assay MCF10A (ATCC, catalog CRL-10317) cells are maintained in MEBM (Lonza, catalog CC-3151) containing 1% horse serum (Sigma, catalog H1270), MEGM mammary epithelial cell proliferation medium SingleQuotsKit (Lonza, catalog CC-4146), and 25 ng / ml cholera toxin (Sigma, catalog C8052). These cells are transduced with either KRAS G12C or G12C / A59G, followed by puromycin selection to generate stably expressing cells. For cell viability assays, 1000 cells of either MCF10A KRAS G12C or MCF10A G12C / A59G are plated in 384 wells spheroid microplates (Corning, catalog no. 3830). The following day, cells are treated with the compound (maximum concentration of 10 μM, 3-fold dilution, and 11 doses). 10 μM tremetinib (MCE, catalog no. HY-10999 / CS-0060) is used as a control. The compound is dispensed using Tecan:HP D300E. After 5 days of incubation, cell viability is measured using a BioTek plate reader with the celltiter-glo luminescence assay kit (Promega, catalog no. G7573) according to the manufacturer's protocol. The data is then imported into Dotmatics for processing and EC. 50 This is calculated using the gradient with the Lavenberg-Marquardt 4-parameter fitting procedure.

[0259] Example 16: Treatment of a human patient Human patients with cancer (e.g., KRAS-mediated cancer as disclosed herein) may be administered a therapeutically effective dose of the compounds disclosed herein (e.g., the compounds in Table 1). The treatment may slow or interrupt tumor growth, reduce tumor volume or mass, or eradicate the tumor in the patient.

[0260] All publications, patents, patent applications and published patent applications referenced herein by identifying reference are incorporated herein by reference in their entirety.

[0261] Although the aforementioned invention has been described in some detail by illustrations and examples for the purpose of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications will be put into practice. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. Compounds of formula (I), formula (II), or formula (III): or a salt thereof, and / or an isotope-substituted thereof, in the formula, Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl. Each R ａ is independently selected from the group consisting of halo, -OH, -NH ２ , 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 alkynyl, and is selected from the group consisting of m is 0, 1, 2, or 3. R １ teeth, And, R ｄ is H or F, R ２ teeth, And, R ｅ is, -R ｅ１ or -R ｅ２ And, R Ｙ１ and R Ｙ２ Each instance, independently, is either -H or -CH. ３ And, however, R Ｙ１ and R Ｙ２ At least one of them is -CH ３ And, R ｅ１ is halo, hydroxy, C １ ~C ４ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxyalkoxy, C １ ~C ４ Haloalkyl and C １ ~C ４ A 4- to 10-membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkoxys, R ｅ２ -NR ２１ R ２２ And, R ２１ and R ２２ These are, independently, hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkoxys and carbon substituted with 3-6 member heterocycles １ ~C ４ Selected from the group consisting of alkyl groups, Each R ｘ These are independently Halo and C １ ~C ４ Selected from the group consisting of alkyl, and n is 0, 1, or 2. The aforementioned compound, its salt, and / or its isotopically substituted derivative.

2. The compound is the compound of formula (I) according to claim 1, or a salt thereof, and / or an isotopically substituted thereof.

3. The compound is the compound of formula (II) according to claim 1, or a salt thereof, and / or an isotope-substituted thereof.

4. The compound is the compound of formula (III) according to claim 1, or a salt thereof, and / or an isotopically substituted thereof.

5. The stereochemistry of pyrrolidine is (R) (i.e., The part that is represented as The compound according to claim 1 or 2, or a salt thereof, and / or an isotopically substituted thereof.

6. The stereochemistry of the cyanomethyl group is (S) (i.e., The part that is represented as The compound, salt thereof, and / or isotope-substituted derivative thereof, according to any one of claims 1, 3, and 4.

7. The compound according to any one of claims 1 to 6, or a salt thereof, and / or an isotopic substituted thereof, wherein ring A is selected from the group consisting of 6-10 membered aryls and 9-10 membered bicyclic heteroaryls having 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S.

8. Ring A is selected from the group consisting of naphthalenyl, phenyl, isoquinolinyl, indazolyl, and pyridinyl, and is a compound according to any one of claims 1 to 6, or a salt thereof, and / or an isotopic substituted thereof.

9. Ring A is selected from the group consisting of naphthalene-1-yl and phenyl, and is a compound according to any one of claims 1 to 6, a salt thereof, and / or an isotopic substituted thereof.

10. Each R ａ It is independent, Haro, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ４ Haloalkyl and C ２ ~C ３ A compound according to any one of claims 1 to 9, selected from the group consisting of alkynyl compounds, a salt thereof, and / or an isotopic compound thereof.

11. Each R ａ These are independently -F, -Cl, -cyclopropyl, -CF ３ A compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotope-substituted thereof, selected from the group consisting of -C≡CH.

12. A compound according to any one of claims 1 to 11, or a salt thereof, and / or an isotopic substituted thereof, wherein m is 1 or 2.

13. Ring A is, Selected from the group consisting of, During the ceremony, R ３ , R ４ , R ｈ , R ｉ , R ｊ , R ｋ , R ｎ , R ｏ , R ｑ , R ｒ , and R ｓ These are, independently, hydrogen, halo, and 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 ｇ 、R ｍ 、and R ｐ each independently represents hydrogen, halo, -OH, -NH ２ 2 １ -C ４ 1 ３ -C ４ 3 １ -C ４ 1 １ -C ４ 3 １ -C ４ 1 ２ -C ３ 3 and is selected from the group consisting of alkynyl, It should be noted that in the original text, there are some incomplete or unclear chemical structure notations. The translation is based on the best understanding of the context, but it may need to be further adjusted according to the accurate chemical knowledge. A compound according to any one of claims 1 to 6, a salt thereof, and / or an isotopically substituted thereof.

14. R ３ , R ４ , R ｈ , R ｉ , R ｊ , R ｋ , R ｎ , R ｏ , R ｑ , R ｒ , and R ｓ These are, independently, hydrogen, halo, and C. １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ４ Haloalkyl and C ２ ~C ３ A compound according to claim 13, a salt thereof, and / or an isotopic derivative thereof, selected from the group consisting of alkynyl compounds.

15. R ３ , R ４ , R ｈ , R ｉ , R ｊ , R ｋ , R ｎ , R ｏ , R ｑ , R ｒ , and R ｓ These are, independently, -H, -F, -Cl, -Me, -Et, -cyclopropyl, and -CF ３ A compound according to claim 13, or a salt thereof, and / or an isotopic substituted thereof, selected from the group consisting of -C≡CH.

16. R ｇ 、 R ｍ , and R ｐ Each of these is independently selected from the group consisting of -H and -OH, and is a compound according to any one of claims 13 to 15, a salt thereof, and / or an isotopic substituted thereof.

17. Ring A is, The compound according to any one of claims 13 to 16, a salt thereof, and / or an isotope-substituted thereof.

18. Ring A is, The compound according to any one of claims 13 to 16, a salt thereof, and / or an isotope-substituted thereof.

19. Ring A is, A compound according to any one of claims 1 to 6, or a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

20. R ３ Hello, C １ ~C ４ Alkyl, or C ２ ~C ３ It is alkinyl and R ４ The compound according to claim 17, or a salt thereof, and / or an isotopically substituted thereof, wherein is hydrogen or a halo.

21. R ３ is -F, -Cl, or -C≡CH, and R ４ The compound according to claim 17, or a salt thereof, and / or an isotopically substituted thereof, wherein is -H or -F.

22. R ｊ C ３ ~C ４ Cycloalkyl or C １ ~C ４ It is a haloalkyl, R ｋ is hydrogen or halo, and R ｍ The compound according to claim 18, or a salt thereof, and / or an isotopically substituted thereof, wherein is -H or -OH.

23. R ｊ is cyclopropyl or -CF ３ And R ｋ is -Cl and R ｍ The compound according to claim 18, or a salt thereof, and / or an isotopically substituted thereof, wherein is -H or -OH.

24. R ｄ The compound according to any one of claims 1 to 23, or a salt thereof, and / or an isotopic substituted thereof, wherein F is the compound.

25. R １ teeth, The compound according to any one of claims 1 to 23, a salt thereof, and / or an isotopically substituted thereof.

26. R １ teeth, The compound according to any one of claims 1 to 23, a salt thereof, and / or an isotopically substituted thereof.

27. R Ｙ１ is -Me and R Ｙ２ The compound according to any one of claims 1 to 26, or a salt thereof, and / or an isotopic substituted thereof, wherein is -H.

28. R Ｙ１ is -Me and R Ｙ２ The compound according to any one of claims 1 to 26, or a salt thereof, and / or an isotopic substituted thereof, wherein is -Me.

29. R ｅ is, -R ｅ１ The compound according to any one of claims 1 to 28, a salt thereof, and / or an isotopic substituted thereof.

30. R ｅ１ is halo, hydroxy, C １ ~C ４ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxyalkoxy, C １ ~C ４ Haloalkyl and C １ ~C ４ A 4- to 8-membered monocyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkoxys, or halo, hydroxy, C １ ~C ４ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxyalkoxy, C １ ~C ４ Haloalkyl and C １ ~C ４ The compound according to claim 29, or a salt thereof, and / or an isotopic substituted thereof, which is a 6-10 membered crosslinked heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkoxys.

31. R ｅ１ These include azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, and 2-oxa-5-azabicyclo[2.2.1] Heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa-3-azabicyclo[3.3.1]nonane, 9-oxa-3-azabicyclo[3.3.1]nonane, 2-oxa 6-azabispiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3 Selected from the group consisting of -thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane, and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each of which is a halo, hydroxy, C １ ~C ４ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxyalkoxy, C １ ~C ４ Haloalkyl and C １ ~C ４ The compound according to claim 29, or a salt thereof, and / or an isotopically substituted thereof, which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from the haloalkoxy.

32. R ｅ１ The compound according to any one of claims 29 to 31, or a salt thereof, and / or an isotopic substituted thereof, wherein the bonding site is a nitrogen atom of a heterocycle.

33. R ｅ１ teeth, And each of them independently is a halo, hydroxyl, C １ ~C ４ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxyalkoxy, C １ ~C ４ Haloalkyl and C １ ~C ４ The compound according to claim 29, or a salt thereof, and / or an isotopically substituted thereof, which is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of haloalkoxys.

34. R ｅ１ teeth, The compound according to claim 29, or a salt thereof, and / or an isotopically substituted thereof.

35. R ｅ is, -R ｅ２ The compound according to any one of claims 1 to 28, a salt thereof, and / or an isotopic substituted thereof.

36. R ２１ and R ２２ Each of them is independently C １ ~C ４ The compound according to claim 35, or a salt thereof, and / or an isotopically substituted thereof, wherein the compound is alkyl.

37. R ｅ２ teeth, The compound according to claim 35, or a salt thereof, and / or an isotopically substituted thereof.

38. A compound according to any one of claims 1 to 37, or a salt thereof, and / or an isotopic substituted thereof, wherein n is 0 or 1.

39. The aforementioned compound, A compound according to claim 1, a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

40. The compound according to any one of claims 1 to 39, or a salt thereof, and / or an isotopic substituted thereof, wherein the salt is a formate salt.

41. The compound according to any one of claims 1 to 40, or a salt thereof, and / or an isotopic substituted thereof, wherein the salt is a pharmaceutically acceptable salt.

42. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 41, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, and a pharmaceutically acceptable carrier.

43. A method for treating or suppressing cancer, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, or a pharmaceutical preparation according to claim 42.

44. The method according to claim 43, 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, cervical cancer, and bladder cancer.

45. The aforementioned cancers include glioblastoma multiforme, 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, renal clear cell carcinoma, bladder urothelial carcinoma, 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, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, and other cancers. The method according to claim 43, selected from the group consisting of renal cortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal 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.

46. The method according to any one of claims 43 to 45, wherein the cancer is a KRAS G12C-mediated cancer.

47. The method according to any one of claims 43 to 45, wherein the subject is diagnosed with KRAS G12C-mediated cancer.

48. The method according to any one of claims 43 to 47, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the subject.

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