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

Abstract

This disclosure provides compounds of formulas (I) to (VII) for use in the treatment and suppression of cancer, for example, useful in the treatment or suppression of cancer KRAS G12C. Pharmaceutical formulations containing such compounds and methods for preparing such compounds are also provided. TIFF2026515946000431.tif117128TIFF2026515946000432.tif115128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 464,170, 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 is a compound useful in the treatment of cancer (such as cancer characterized by KRAS G12C). What is needed is a compound useful in the treatment of cancer characterized by KRAS G12C that binds to and inhibits both the inactivated GDP-bound and activated GTP-bound forms of KRAS. What is needed is a compound useful in the treatment of cancer characterized by KRAS G12C that improves the inhibition of the GTP-bound form of KRAS G12C. [Overview of the Initiative]

[0008] overview In one embodiment, the present invention provides compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or salts thereof, and / or isotopic substitutions thereof. [ka] [ka] (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 H, -OCH2R 1A , -OC1~C4 alkyl, -C1~C4 alkyl, and [ka] Selected from the group consisting of, R 1A teeth, [ka] selected from the group consisting of R d is H or F, R 2 is

Chemical formula

[0009] In some embodiments, R of formula (II) e R e2 If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents, and R of formula (III) 1 but [ka] If that is the case, [ka] teeth, [ka] isn't it.

[0010] 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.

[0011] 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.

[0012] A method for treating or suppressing cancer according to another embodiment comprises administering 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) to a subject in need thereof, wherein, if the compound is a salt, the salt is a pharmaceutically acceptable salt. In some embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer. In some embodiments, 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and plasma cell bone marrow. The following are selected from the group consisting of tumors, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade brain glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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 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 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.

[0013] 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.

[0014] 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.

[0015] It is understood that the descriptions of compounds, compositions, formulations, and therapeutic methods described herein include embodiments that “contain,” “consist of,” and “essentially consist of.” In some embodiments, in all compositions described herein and in all methods using compositions described herein, the compositions contain or “essentially consist of” the listed components or steps. Where a composition is described as “essentially consisting of” the listed components, the composition contains the listed components and may contain other components that do not substantially affect the condition being treated, but does not contain other components that substantially affect the condition being treated other than those explicitly listed; 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 contains the listed steps and may contain other steps that do not substantially affect the condition being treated, but does not contain other steps that substantially affect the condition being treated other than those explicitly listed. As a non-limiting example, when 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 medical condition being treated.

[0016] 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]

[0017] 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.

[0018] definition Unless otherwise specified, abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0019] Please understand that the description of compound structures, including possible substitutions, is limited to those that are chemically possible.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The terms "a" and "an," as used herein, mean one or more unless otherwise clearly indicated by the context.

[0024] The terms “subject,” “individual,” and “patient” mean an individual organism, preferably a vertebrate, more preferably a mammal, and most preferably a human. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs, and rabbits, and pet 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).

[0025] "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.

[0026] "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.

[0027] 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.

[0028] 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.

[0029] 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 using such salts of compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0030] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable to humans and / or animals and retains at least some of the desired pharmacological activities of the parent compound upon administration. Such salts may be formed by (a) inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like); or by organic acids (such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4' Examples of acid addition salts formed by (b) an acid proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ions, alkaline earth ions, or aluminum ions) or by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like). Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985 (the entire document is incorporated herein by reference).

[0031] Where chemically related, all stereoisomers of a compound, including diastereomers and enantiomers, are included herein. Also included are mixtures of possible stereoisomers in any ratio, including but not limited to racemic mixtures. Unless stereochemistry is explicitly indicated within a structure, the structure is intended to encompass all possible stereoisomers of the compound shown. If stereochemistry is explicitly indicated for some or more parts of a molecule, but not for other parts or parts of the molecule, the structure is intended to encompass all possible stereoisomers for the parts or parts for which stereochemistry is not explicitly indicated.

[0032] 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 in a particular atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance of a particular 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.

[0033] "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.

[0034] "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.

[0035] "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.

[0036] "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.

[0037] "Alkoxy" is R x ' is an alkyl as defined above -OR x 'Radical, or R x '' is alkylene, R x '" is the alkyl group defined above -R 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 it. 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.

[0038] "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 (here, R y The bond point of " 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. For example, C1~C6 alkalkalk represents, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2OCH3, -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 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.

[0039] "Aminoalkyl" means R z -NHR is the alkyl group defined above. zradical, 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 "Equal to the total number of carbon atoms in it. 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, aminoalkyls are -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 "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 zis a radical. In some embodiments, when oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not bonded to oxygen via nitrogen in the aminoalkyl group or a carbon directly adjacent to nitrogen. For example, an aminoalkyl-substituted oxygen is O-NR z or O-CH2-NHR z is not.

[0040] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an 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 to one or more carbocyclic groups or heterocyclic groups, as defined above, and the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms within the aryl ring system. Exemplary aryl groups include phenyl and naphthyl, and the point of attachment can be on any carbon atom. Exemplary aryl groups also include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like, and the point of attachment is on the phenyl group. In some embodiments, "aryl" excludes a ring system in which an aryl ring is fused to one or more carbocyclic groups or heterocyclic groups, as defined above.

[0041] "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.

[0042] "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.

[0043] "Cyanoalkyl" means an alkyl radical as defined above substituted with a cyano group (-CN). Cyanoalkyl may also be referred to as alkyl nitrile.

[0044] "Halo" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro or chloro.

[0045] "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.

[0046] "Haloalkoxy" means -OR a’ where R is a haloalkyl as defined above, or a radical -R a’ where R b’ 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’ OR c’ radical, and the halogen atom is R b’ and R c’ and the total number of carbons of R b’ and R c’It may be present in both, and R b’ and R c’ At least one of them contains a halo atom. For example, C1-C4 haloalkoxys include, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, and -CH2CH(F)CH2OCHF2. In some embodiments, the haloalkoxy is -OR a’ It is radical. In some embodiments, the haloalkoxy is -R b’ Ure c’ It is radical. If all halo atoms in the haloalkoxy group are fluoro, it may be referred to as a fluoroalkoxy in this application. In some embodiments, when nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not bonded to nitrogen via oxygen in the haloalkoxy group or a carbon directly adjacent to oxygen. For example, haloalkoxy-substituted nitrogen is N-OR a’ or NC(H) n (X) m -Not OR (where X is a halogen, n and m are integers, and m+n=2).

[0047] "Hydroxyalkyl" refers to an alkyl radical as defined above, which is 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.

[0048] 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.

[0049] 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.

[0050] 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), 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.

[0051] 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, [ka] This indicates.

[0052] 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.

[0053] "Administering" or "dosing" refers to bringing a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt and / or isotopic substitution thereof, a pharmaceutical composition 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).

[0054] "Optional" or "optional" means that the event or situation described thereafter may or may not occur, and that the description includes both examples in which the event or situation occurs and examples in which it does not occur.

[0055] "Pharmacologically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and useful in preparing a pharmaceutical composition that is not undesirable in either biological or otherwise respect, and includes carriers or excipients acceptable for veterinary and human pharmaceutical use. "Pharmacologically acceptable carrier / excipient" when used in the specification and claims includes both one and more such excipients.

[0056] 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.

[0057] 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.

[0058] compound This specification provides compounds of formulas (I), (II), (III), (IV), (V), and (VI). Unless otherwise specified in the context, throughout this specification, the phrases "compounds of formula (I), (II), (III), (IV), (V), or (VI)" or "multiple compounds of formula (I), (II), (III), (IV), (V), or (VI)" refer to all embodiments of formulas (I), (II), (III), (IV), (V), and (VI), including, for example, compounds of formulas (Ia), (Ib), (II-a), (II-b), (III-a), (III-b), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), and the compounds of Table 1. In some embodiments, compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), or pharmaceutically acceptable salts thereof are provided. In some embodiments, compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), and formula (VI) are provided as pharmaceutically acceptable salts. In some embodiments, compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), and formula (VI) are provided as the corresponding free bases (i.e., not salts).

[0059] In one embodiment, compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or salts thereof, and / or isotopic substitutions thereof are provided. [ka] [ka] (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 H, -OCH2R 1A , -OC1~C4 alkyl, -C1~C4 alkyl, and [ka] Selected from the group consisting of, R 1A teeth, [ka] Selected from the group consisting of, R d is H or F, R 2 teeth, [ka] And, R e -COOH, -C(O)O-C1~C4alkyl, -C(O)O-C1~C4 haloalkyl, -C(O)-C1~C4alkyl, -C(O)-C1~C4 haloalkyl, -C(O)N(C1~C4alkyl)2, -(C1~C2alkyl)-(C1~C2 alkoxy), -S(O)2-C1~C4alkyl, -S(O)2-C1~C4 haloalkyl, R e1 , -C(R Y1 )(R Y2 )R e1 , R e2 and -C(R Y1 )(R Y2 )R e3 Selected from the group consisting of, R Y1 and R Y2 Each instance is independently either -H or -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 e2This is a 5-6 member heteroaryl group substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halo, hydroxy, and methyl, and C3-C6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, hydroxy, and methyl. R e3 -NR 31 R 32 And, R 31 and R 32 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 -OH, halo, and C1-C4alkyl groups. n is 0, 1, or 2.

[0060] In some embodiments, R of formula (II) e R e2 If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents. In some embodiments, R of formula (II) 1 but [ka] If that is the case, [ka] teeth, [ka] isn't it.

[0061] In some embodiments, formula (II) [ka] teeth, [ka] No. In some embodiments, R in formula (II) 1 but [ka] If that is the case, [ka] teeth, [ka] No. In some embodiments, formula (II) [ka] teeth, [ka] isn't it.

[0062] In some embodiments, formula (III)R 1 but [ka] If that is the case, [ka] teeth, [ka] No. In some embodiments, R in formula (III) e R e2 If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents. In some embodiments, R of formula (III) e R e2 And R 1 but [ka] If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents. In some embodiments, R of formula (III) 1 teeth, [ka] No. In some embodiments, R in formula (III) 1 teeth, [ka] No. In some embodiments, equation (III) [ka] teeth, [ka] isn't it.

[0063] In some embodiments, R e R e2 If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents. In some embodiments, R 1 but [ka] If that is the case, [ka] teeth, [ka] No. In some embodiments, R 1 but [ka] If that is the case, [ka] teeth, [ka] No. In some embodiments, [ka] teeth, [ka] No. In some embodiments, [ka] teeth, [ka] No. In some embodiments, R 1 teeth, [ka] If that is the case, [ka] teeth, [ka] No. In some embodiments, R e R e2 And R 1 but [ka] If R e2 The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents. In some embodiments, R 1 teeth, [ka] No. In some embodiments, R 1 teeth, [ka] No. In some embodiments, [ka] teeth, [ka] isn't it.

[0064] In one embodiment, the compound is the compound of formula (I).

[0065] In one embodiment, the compound is the compound of formula (II).

[0066] In one embodiment, the compound is the compound of formula (III).

[0067] In one embodiment, the compound is the compound of formula (IV).

[0068] In one embodiment, the compound is the compound of formula (V).

[0069] In one embodiment, the compound is the compound of formula (VI).

[0070] In one embodiment, the stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] (That is.)

[0071] In one embodiment, the stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] (That is.)

[0072] As generally defined herein, ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl.

[0073] In one embodiment, ring A is selected from 6-10 membered aryls and 9-10 membered bicyclic heteroaryls having 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0074] 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.

[0075] In one embodiment, ring A is naphthalenyl. In another embodiment, ring B is phenyl.

[0076] 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.

[0077] In one embodiment, ring A is [ka] Selected from the group consisting of, Here, R 3 , R 4 , R 5 , R h , R i , R j , R k , R n , R o , R q , R s , R g、 R m and R p These are defined in any embodiment described herein.

[0078] In one embodiment, ring A is [ka] A group consisting of R is selected, where R 3 , R 4 , R h , R i , R j , R k and R m Each of these is defined in any of the embodiments described herein. In one embodiment, ring A is [ka] And here, R 3 , R 4 and R 5 Each of these is defined in any of the embodiments described herein. In one embodiment, ring A is [ka] And here, R 3 and R 4 Each of these is defined in any of the embodiments described herein. In one embodiment, ring A is [ka] And here, R j , R k and R m Each of these is defined in any of the embodiments described herein. In one embodiment, ring A is [ka] Selected from.

[0079] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] That is the case.

[0080] 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.

[0081] One embodiment, each R aR 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.

[0082] 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 a halo in its own right.

[0083] One embodiment, each R a R is independently selected from -F, -Cl, -OH, -Me, -Et, -cyclopropyl, -CF3 and -C≡CH. In one embodiment, each R a R is independently selected from -F, -Cl, -Me, -Et, -cyclopropyl, -CF3 and -C≡CH. In one embodiment, each R a 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 a These 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 ais -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.

[0084] 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 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.

[0085] 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 3 R 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 R3 These are independently halos. In one embodiment, each R 3 The following are 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.

[0086] 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 4R 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 The following are 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 4 is selected from -H and -F. In one embodiment, R 4 is -H. In one embodiment, R 4 It is -F.

[0087] As generally defined herein, each R 5R 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 5 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 5 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R 5 R is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups. In one embodiment, each R 5 R is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R 5 R is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R 5 R is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R 5 R is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R 5 These are independently halos. In one embodiment, each R 5 The following are independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3 and -C≡CH. In one embodiment, each R 5 These are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 5 These are independently selected from the group consisting of -H and -Me. In one embodiment, each R 5 These are independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 5 These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 5 These are independently selected from the group consisting of -H, -F, -Cl, and -C≡CH. In one embodiment, each R 5These are independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R 5 These are independently selected from the group consisting of -F and -Cl. In one embodiment, each R 5 These are independently -H. In one embodiment, each R 5 It is independently -Me.

[0088] 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 The following are 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 hThese 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 R h 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.

[0089] 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 The following are 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 Ri These are independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R i These 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.

[0090] 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 The following are independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3 and -C≡CH. In one embodiment, each R jThese are independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R j These 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.

[0091] 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 kR is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R k These are independently halos. In one embodiment, each R k The following are 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.

[0092] 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 nR is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R n 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 The following are 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.

[0093] 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 Ro R 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 The following are 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.

[0094] 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.

[0095] One embodiment, each R q These are independently halos. In one embodiment, each R q The following are 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.

[0096] 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 The following are 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 r These are independently selected from the group consisting of -F and -Cl. In one embodiment, Rr 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.

[0097] 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 The following are 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 R sThese 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.

[0098] 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.

[0099] 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.

[0100] 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 These are independently -H. In one embodiment, each R p It is independently -OH.

[0101] As generally defined herein, R 1 H, -OCH2R 1A , -OC1~C4 alkyl, -C1~C4 alkyl and [ka] A group consisting of R is selected, where R 1A This is defined in any of the embodiments described herein. In one embodiment, R 1 H, -OCH2R 1A , -OMe, Me and [ka] Selected from, where R 1A This is defined in any of the embodiments described herein. In one embodiment, R 1 H is H. In one embodiment, R 1 is -OMe. In one embodiment, R 1 is Me. In one embodiment, R 1 teeth, [ka] In one embodiment, R 1 OCH2R 1A And here, R 1A This is defined in any of the embodiments described herein.

[0102] In one embodiment, R 1 teeth, [ka] Selected from the group consisting of R 1 teeth, [ka] In one embodiment, R 1 teeth, [ka] In one embodiment, R 1 teeth, [ka] That is the case.

[0103] As generally defined herein, R 1A teeth, [ka] And here, R d This is defined in any of the embodiments described herein. In one embodiment, R 1A teeth, [ka] Selected from. In one embodiment, R 1A teeth, [ka] Selected from. In one embodiment, R 1A teeth, [ka] In one embodiment, R 1A teeth, [ka] In one embodiment, R 1A teeth, [ka] That is the case.

[0104] As generally defined herein, R d is H or F. In one embodiment, R d H is H. In one embodiment, R d It is F.

[0105] As generally defined herein, R 2 teeth, [ka] And here, R e This is defined in any of the embodiments described herein. In one embodiment, R 2 teeth, [ka] In one embodiment, R 2 teeth, [ka] That is the case.

[0106] As generally defined herein, R e -COOH, -C(O)O-C1~C4alkyl, -C(O)O-C1~C4 haloalkyl, -C(O)-C1~C4alkyl, -C(O)-C1~C4 haloalkyl, -C(O)N(C1~C4alkyl)2, -(C1~C2alkyl)-(C1~C2 alkoxy), -S(O)2-C1~C4alkyl, -S(O)2-C1~C4 haloalkyl, R e1 , -C(R Y1 )(R Y2 )R e1 , R e2 and -C(R Y1 )(R Y2 )R e3 A group consisting of R is selected, where R e1 , R e2 , R e3, R Y1 and R Y2 This is defined in any of the embodiments described herein.

[0107] In one embodiment, R e is -C(O)O-C1-C4 alkyl, R e1 , -C(R Y1 )(R Y2 )R e1 , R e2 and -C(R Y1 )(R Y2 )R e3 A group consisting of R is selected, where R e1 , R e2 , R e3 , R Y1 and R Y2 This is defined in any of the embodiments described herein.

[0108] In one embodiment, R e -C(O)OMe, R e1 , -CH2R e1 , R e2 and -CH2R e3 A group consisting of R is selected, where R e1 , R e2 and R e3 This is defined in any of the embodiments described herein.

[0109] In one embodiment, R e -C(O)OMe, R e1 , -CH2R e1 and R e2 A group consisting of R is selected, where R e1 and R e2 This is defined in any of the embodiments described herein.

[0110] In one embodiment, R e R e1 , -CH2R e1 and R e2 A group consisting of R is selected, where R e1 and R e2This is defined in any of the embodiments described herein.

[0111] 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 -C(R Y1 )(R Y2 )R e1 And here, R e1 , R Y1 and R Y2 This is defined in any of the embodiments described herein.

[0112] In one embodiment, R e R e2 And here, R e2 This is defined in any of the embodiments described herein.

[0113] In one embodiment, R e -C(R Y1 )(R Y2 ) and here, R e3 , R Y1 and R Y2 This is defined in any of the embodiments described herein.

[0114] In one embodiment, R e teeth, [ka] It is selected from the group consisting of the following.

[0115] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e teeth, [ka] In one embodiment, R e This is -C(O)OMe.

[0116] As generally defined herein, each R Y1 These are independently selected from H and -CH3. In one embodiment, R Y1 is -H. In one embodiment, Y1 It is -Me.

[0117] As generally defined herein, each R Y2 These are independently selected from H and -CH3. In one embodiment, R Y2 is -H. In one embodiment, Y2 It is -Me.

[0118] As generally 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.

[0119] In one embodiment, R e1 This is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom as the sole heteroatom, or containing one nitrogen atom and one oxygen atom, where the monocyclic 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.

[0120] In one embodiment, R e1 This is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom as the sole heteroatom, where the monocyclic 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.

[0121] In one embodiment, R e1 The monocyclic heterocycle is substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl atoms.

[0122] In one embodiment, R e1 The monocyclic heterocycle is substituted with 0 or 1 C1-C4 alkyl groups. In one embodiment, R e1The monocyclic heterocycle is substituted with 0 or 1 methyl group.

[0123] In one embodiment, R e1 This is selected from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and morpholinyl, which are substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl molecules.

[0124] In one embodiment, R e1 R is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with 0 or 1 methyl groups. In one embodiment, R e1 This is an azetidinyl substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl molecule.

[0125] In one embodiment, R e1 This is an azetidinyl substituted with 0 or 1 methyl group.

[0126] In one embodiment, R e1 This is N-methylazetidinyl.

[0127] In one embodiment, the bond site of the monocyclic heterocycle is located on a carbon atom.

[0128] In one embodiment, R e1 teeth, [ka] It is selected from the group consisting of the following.

[0129] In one embodiment, R e1 teeth, [ka] That is the case.

[0130] In one embodiment, R e1 teeth, [ka] That is the case.

[0131] 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.

[0132] 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.

[0133] In one embodiment, R e1 This 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.

[0134] In one embodiment, R e1 This is a 6-10 member 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.

[0135] In one embodiment, R e1This 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.

[0136] 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.

[0137] 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-oxaazepane, 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, 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-thi A-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.

[0138] 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.

[0139] In one embodiment, R e1 teeth, [ka] A group consisting of is selected, and each of them 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.

[0140] 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. [ka] Selected from.

[0141] 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. [ka] Selected from.

[0142] 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. [ka] That is the case.

[0143] 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. [ka] That is the case.

[0144] 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. [ka] That is the case.

[0145] 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. [ka] That is the case.

[0146] 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. [ka] That is the case.

[0147] 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. [ka] That is the case.

[0148] 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. [ka] That is the case.

[0149] 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. [ka] That is the case.

[0150] 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. [ka] That is the case.

[0151] 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. [ka] That is the case.

[0152] 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.

[0153] 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.

[0154] In one embodiment, R e1 The 4- to 10-membered complex rings are substituted with 0, 1, or 2 -F elements.

[0155] In one embodiment, R e1 The 4- to 10-member complex rings are substituted with 0 or 1 -OMe.

[0156] In one embodiment, R e1 The 4- to 10-member complex rings are non-permutations.

[0157] In one embodiment, R e1 teeth, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0158] In one embodiment, R e1 teeth, [ka] Selected from.

[0159] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 is non-substituted [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 teeth, [ka] In one embodiment, R e1 is non-substituted [ka] That is the case.

[0160] As generally defined herein, R e2 This is a 5-6 member heteroaryl group that may be substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, a C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and a C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0161] In one embodiment, R e2 The heteroaryl group is a 5-6 membered heteroaryl group containing at least one nitrogen atom, the bonding site of the heteroaryl group is a carbon atom group, and the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl atoms.

[0162] In one embodiment, R e2 These are selected from the group consisting of pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl groups.

[0163] In one embodiment, R e2 The substituents are selected from the group consisting of pyrimidinyl, 1,2,4-oxadiazolyl, and 1H-1,2,4-triazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0164] In one embodiment, R e2 teeth, [ka] Selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0165] In one embodiment, R e2 teeth, [ka] Selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0166] In one embodiment, R e2 teeth, [ka] It is selected from the group consisting of the following.

[0167] In one embodiment, R e2 teeth, [ka] It is selected from the group consisting of the following.

[0168] In one embodiment, R e2 This is a six-membered heteroaryl group substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0169] In one embodiment, R e2 This is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0170] In one embodiment, R e2 is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 C1-C4 alkyl groups. In one embodiment, R e2 is a pyrimidinyl substituted with 0, 1, or 2 C1-C4 alkyl groups. In one embodiment, R e2 This is a pyridazinyl compound substituted with 0, 1, or 2 C1-C4 alkyl groups.

[0171] In one embodiment, R e2 is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 -Me. In one embodiment, R e2 is a pyrimidinyl substituted with 0, 1, or 2 -Me. In one embodiment, R e2 This is a pyridazinyl compound substituted with 0, 1, or 2 -Me units.

[0172] In one embodiment, R e2 teeth, [ka] Selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0173] In one embodiment, R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] It is selected from the group consisting of the following.

[0174] In one embodiment, R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] In one embodiment, R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] In one embodiment, R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] That is the case.

[0175] In one embodiment, R e2 is replaced by 0, 1, or 2 -Me [ka] Selected from the group consisting of Re2 is replaced by 0, 1, or 2 -Me [ka] In one embodiment, R e2 is replaced by 0, 1, or 2 -Me [ka] In one embodiment, R e2 is replaced by 0, 1, or 2 -Me [ka] That is the case.

[0176] In one embodiment, R e2 teeth, [ka] It is selected from the group consisting of the following.

[0177] In one embodiment, R e2 teeth, [ka] Selected from the group consisting of R e2 teeth, [ka] In one embodiment, R e2 teeth, [ka] That is the case.

[0178] In one embodiment, R e2This is a five-membered heteroaryl group containing at least one nitrogen atom, where the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0179] In one embodiment, R e2 The substituents are selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0180] In one embodiment, R e2 teeth, [ka] A group consisting of the following is selected, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0181] In one embodiment, R e2 teeth, [ka] A group consisting of the following is selected, each of which is substituted with one substituent independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with one or two substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with one or two substituents independently selected from halo, hydroxy, and methyl.

[0182] In one embodiment, R e2 teeth, [ka] A selection is made from the group consisting of the following, and each of them is substituted with one C1-C4 alkyl group.

[0183] In one embodiment, R e2 teeth, [ka] It is selected from the group consisting of the following.

[0184] In one embodiment, R e2 teeth, [ka] It is selected from the group consisting of the following.

[0185] In one embodiment, R e2 teeth, [ka] In one embodiment, R e2 teeth, [ka] That is the case.

[0186] As generally defined herein, R e3 -NR 31 R 32 And here, R 31 and R 32 This is defined in any of the embodiments described herein. In one embodiment, R e3 teeth, [ka] Selected from. In one embodiment, R e3 teeth, [ka] In one embodiment, R e3 teeth, [ka] That is the case.

[0187] As generally defined herein, R 31 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 31This is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 membered heterocycle containing 1-2 atoms independently selected from N, O, and S, including S(O)2.

[0188] In one embodiment, R 31 is a C1-C4 alkyl group. In one embodiment, R 31 It is -Me.

[0189] As generally defined herein, R 32 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 32 This is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 alkyl substituted with a 3-6 membered heterocycle containing 1-2 atoms independently selected from N, O, and S, including S(O)2.

[0190] In one embodiment, R 32 is a C1-C4 alkyl group or a C1-C4 alkyl group substituted with a 3-6 membered heterocycle. In one embodiment, R 32 is a C1-C4 alkyl group substituted with a 3-6 membered heterocycle. In one embodiment, R 32 is a C1-C4 alkyl group substituted with a heterocycle selected from azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, and morpholine. In one embodiment, R 32 is a C1-C4 alkyl group substituted with oxetane. In one embodiment, R 32 teeth, [ka] In one embodiment, R 32 is a C1-C4 alkyl group. In one embodiment, R 32 This is Me.

[0191] 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.

[0192] 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.

[0193] In one embodiment, the compound is a compound of formula (Ia), formula (II-a), formula (III-a), formula (IV-a), formula (Va), or formula (VI-a), or a salt thereof, and / or an isotopic substitution thereof. [ka] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R x This is defined in any of the embodiments described herein.

[0194] In one embodiment, the compound is the compound of formula (Ia).

[0195] In one embodiment, the compound is the compound of formula (II-a).

[0196] In one embodiment, the compound is the compound of formula (III-a).

[0197] In one embodiment, the compound is the compound of formula (IV-a).

[0198] In one embodiment, the compound is the compound of formula (Va).

[0199] In one embodiment, the compound is the compound of formula (Va).

[0200] In one embodiment, the stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] (That is.)

[0201] In one embodiment, the stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] (That is.)

[0202] In one embodiment, the compound is a compound of formula (Ib), formula (II-b), formula (III-b), formula (IV-b), formula (Vb), or formula (VI-b).

[0203] [ka] [ka] In the formula, R 1 , R 2 , R j , R k , R m , R x and n are as defined in any of the embodiments described herein.

[0204] In one embodiment, the compound is the compound of formula (Ib).

[0205] In one embodiment, the compound is the compound of formula (II-b).

[0206] In one embodiment, the compound is the compound of formula (III-b).

[0207] In one embodiment, the compound is the compound of formula (IV-b).

[0208] In one embodiment, the compound is the compound of formula (Vb).

[0209] In one embodiment, the compound is the compound of formula (VI-b).

[0210] In one embodiment, the stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] (That is.)

[0211] In one embodiment, the stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] (That is.)

[0212] In one embodiment, the compound is selected from the compounds or salts thereof listed in Table 1, and / or isotopic substitutions thereof. In one embodiment, the compound is not a salt.

[0213] 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.

[0214] In some variations, any of the compounds described herein, such as those of formula (I), (II), (III), (IV), (V), or (VI), 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.

[0215] Any formula shown herein, for example, formulas (I), (II), (III), (IV), (V), or (VI), is intended to represent compounds having the structure shown by the structural formula and specific variations or forms. 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. Therefore, any formula shown herein is intended to represent a racemate, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof in any ratio. Furthermore, certain particular structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Furthermore, any formula shown herein is intended to refer to any one of such a compound, including its hydrate, solvate, amorphous, and polymorphic forms, as well as mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water, and the solvate is the hydrate.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] The R provided herein 1 , R 1A , R d , R 2 , R Y1 , R Y2 , R e , R e1 , R e2 , R e3 , R 31 , R 32 , R 3 , R 4 , R 5 , R 6 , R h , R i , R j , R k , R n , R o , Rq , R r , R s , R g , R m , R p , R a , R x , ring A, m, n, R x ', R x ''оR x "', R y , R y ', R y ", R 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 1A , R d , R 2 , R Y1 , R Y2 , R e , R e1 , R e2 , R e3 , R 31 , R 32 , R 3 , R 4 , R 5 , R 6 , 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 "', R y , R y ', R y ", R z , R z ', R z ''оR a’ , R b’ or Rc’ It can be combined with all other variations or embodiments of the same.

[0220] 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.

[0221] Methods of treating cancer Compounds of formulas (I), (II), (III), (IV), (V), and (VI), 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 formulas (I), (II), (III), (IV), (V), and (VI), as well as 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 children Cancers include, but are not limited to, cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic 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 pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, 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.

[0222] In one embodiment, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) as described in any of the embodiments described herein is provided for use as a pharmaceutical, or a pharmaceutical formulation as described in any of the embodiments described herein.

[0223] In one embodiment, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, is provided for use in treating or suppressing cancer. In one embodiment, if the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and 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 pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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 composition is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the compound or pharmaceutical composition is configured for administration in a therapeutically effective dose.

[0224] In one embodiment, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) 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, is provided for use in the manufacture of a pharmaceutical for treating or suppressing cancer. 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, 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and 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 pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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 composition is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the pharmaceutical comprises a therapeutically effective amount of a compound or pharmaceutical composition.

[0225] In one embodiment, the use of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) as described in any of the embodiments described herein, or a pharmaceutical formulation as described in any of the embodiments described herein, is provided, wherein 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and 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 pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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 composition is configured for administration with an additional therapeutically effective dose of a chemotherapeutic agent. In one embodiment, the pharmaceutical comprises a therapeutically effective amount of a compound or pharmaceutical composition.

[0226] In one embodiment, a use is provided for treating or suppressing cancer of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) as described in any of the embodiments described herein, wherein the compound is a salt and the salt is a pharmaceutically acceptable salt.

[0227] 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, the cancer is 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, 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 pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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 composition 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. In some embodiments, which encompass 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).

[0228] Compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), and their pharmaceutically acceptable salts and / or isotopic substitutions (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.

[0229] test Compounds of formulas (I), (II), (III), (IV), (V), and (VI), and their pharmaceutically acceptable salts and / or isotopic substitutions (including the 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.

[0230] The ability of compounds of formulas (I), (II), (III), (IV), (V), and (VI), and their pharmaceutically acceptable salts and / or isotopic substitutions, to inhibit the GTP-bound activity of KRAS G12C can be tested using methods such as the in vitro assays described in Examples 16 and 17 below. Example 16 shows that for various compounds, the 50% maximum inhibition (IC) of KRAS G12C loaded with the GTP analog GMPPNP was tested. 50 ) is determined from the binding to cRaf as the Ras-binding domain (RBD). Example 17 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 18 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).

[0231] Pharmaceutical composition The terms "pharmaceutical composition" and "pharmaceutical preparation" are used interchangeably.

[0232] In general, the compounds of formulas (I), (II), (III), (IV), (V), and (VI) 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 agents that perform 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.

[0233] In general, the compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral administration, systemic administration (e.g., transdermal administration, intranasal administration, or administration by suppository), or parenteral administration (e.g., intramuscular administration, intravenous administration, or subcutaneous administration). The preferred mode of administration is oral administration using a convenient daily dosage regimen, which may be adjusted according to the severity of the disease. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or other suitable compositions.

[0234] The choice of formulation depends on various factors, such as the mode of drug administration (for example, formulations in the form of tablets, pills, or capsules for oral administration, for example, enteric-coated or delayed-release tablets, pills, or capsules are preferred) and the bioavailability of the drug substance.

[0235] The compositions generally consist of the compounds of the present disclosure combined 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 present disclosure. Such excipients may be gaseous excipients in any solid, liquid, semi-solid, or aerosol composition, as are commonly available to those skilled in the art.

[0236] Examples of solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk powder, and similar materials. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils. Oils can be petroleum, animal, plant, or synthetic, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water, physiological saline, glucose solution, and glycol are particularly suitable liquid carriers for injection solutions.

[0237] 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.

[0238] 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.

[0239] 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).

[0240] 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).

[0241] 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).

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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%.

[0246] 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.

[0247] Therefore, the pharmaceutical compositions of this disclosure also include those containing one or more other drugs in addition to the compounds of this disclosure.

[0248] 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.

[0249] 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.

[0250] 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]).

[0251] In another embodiment, the compounds of the present disclosure are used in conjunction 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-methylpropane-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.

[0252] 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.

[0253] In another embodiment, the compounds of this disclosure are used in conjunction 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).

[0254] In another embodiment, the compounds of this disclosure are used in conjunction 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).

[0255] In another embodiment, the compounds of this disclosure are used in conjunction with a pan-ErbB family inhibitor. In one embodiment, the KRAS inhibitor and the pan-ErbB family inhibitor are the sole activators in the provided composition and method. In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for the provided composition and method include afatinib, dacomitinib, canertinib, poziotinib, AV 412(N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazine-1-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).

[0256] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, where the EGFR inhibitor and HER2 inhibitor are AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazoline-4-amine hydrochloride); AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-propenamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-propenamide); AG 825 (E-3-[3-benzothiazole-2-ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714(2-Methoxy-N-[(2E)-3-[4-[3-methyl-4-(6-methylpyridine-3-yloxy)phenylamino]quinazoline-6-yl]-2-propen-1-yl]acetamide);BIBU 1361(N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)-piperidine-1-yl]pyrimido[5,4-d]pyrimidine-4-amine dihydrochloride);BIBU 1382;(N 8 -(3-chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)pyrimidino[5,4-d]pyrimidine-4-aminedihydrochloride), JNJ 28871063 (5E-4-amino-6-[4-(benzyloxy)-3-chlorophenylamino]pyrimidine-5-carbaldehyde N-[2-(4-morpholinyl)ethyl]oxime hydrochloride); PD 153035 (4-(3-bromophenylamino)-6,7-dimethoxyquinazoline hydrochloride); and PD 158780 (N 4 -(3-bromophenyl)-N 6 This is a combination of two of the following: -methylpyrido[3,4-d]pyrimidine-4,6-diamine.

[0257] 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.

[0258] In some embodiments, the compounds of this disclosure are used in conjunction with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors suitable for the compositions and methods provided include, but are not limited to, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors (such as pembrolizumab (Keytruda®), nivolumab (Opdivo®), semiprimab (Libtayo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), relatrimab, opduralag, and dostallimab (Jemperli)).

[0259] 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).

[0260] List of embodiments The following listed embodiments represent several aspects of the present invention.

[0261] Embodiment 1. Compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or salts thereof, and / or isotopic substituted thereof. [ka] [ka] (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 H, -OCH2R 1A , -OC1~C4 alkyl, -C1~C4 alkyl and [ka] Selected from the group consisting of, R 1A teeth, [ka] Selected from the group consisting of, R d is H or F, R 2 teeth, [ka] And, R e -COOH, -C(O)O-C1~C4alkyl, -C(O)O-C1~C4 haloalkyl, -C(O)-C1~C4alkyl, -C(O)-C1~C4 haloalkyl, -C(O)N(C1~C4alkyl)2, -(C1~C2alkyl)-(C1~C2 alkoxy), -S(O)2-C1~C4alkyl, -S(O)2-C1~C4 haloalkyl, R e1, -C(R Y1 )(R Y2 )R e1 , R e2 and -C(R Y1 )(R Y2 )R e3 Selected from the group consisting of, R Y1 and R Y2 Each instance, it is independently selected from -H and -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 This is a 5-6 member heteroaryl group substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, and methyl. R e3 -NR 31 R 32 And, R 31 and R 32 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 member heterocycle. Each R x It is selected from -OH, halo, and C1-C4 alkyl groups. n is 0, 1, or 2.

[0262] Embodiment 2. The compound is the compound of formula (I), as described in Embodiment 1.

[0263] Embodiment 3. The compound is the compound of formula (II), as described in Embodiment 1.

[0264] Embodiment 4. The compound is the compound of formula (III) as described in Embodiment 1.

[0265] Embodiment 5. The compound is the compound of formula (IV) as described in Embodiment 1.

[0266] Embodiment 6. The compound is the compound of formula (V), as described in Embodiment 1.

[0267] Embodiment 7. The compound is the compound of formula (VI), as described in Embodiment 1.

[0268] Embodiment 8. The stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] The compound described in any one of Embodiments 1, 2, and 5.

[0269] Embodiment 9. The stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] The compound described in any one of Embodiments 1, 3, and 4.

[0270] Embodiment 10. The compound according to any one of Embodiments 1 to 9, 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.

[0271] Embodiment 11. The compound according to any one of Embodiments 1 to 9, wherein ring A is selected from the group consisting of naphthalenyl, phenyl, isoquinolinyl, indazolyl, and pyridinyl.

[0272] Embodiment 12. Ring A is a compound according to any one of Embodiments 1 to 9, selected from the group consisting of naphthalenyl and phenyl.

[0273] Embodiment 13. The compound according to any one of Embodiments 1 to 9, wherein ring A is naphthalenyl.

[0274] Embodiment 14. The compound according to any one of Embodiments 1 to 9, wherein ring A is phenyl.

[0275] Embodiment 15. The compound according to any one of Embodiments 1 to 9, wherein ring A is selected from the group consisting of naphthalene-1-yl, phenyl, isoquinoline-1-yl, indazole-4-yl, and pyridine-1-yl.

[0276] Embodiment 16. The compound according to any one of Embodiments 1 to 9, wherein ring A is selected from the group consisting of naphthalene-1-yl and phenyl.

[0277] Embodiment 17. The compound according to any one of Embodiments 1 to 9, wherein ring A is naphthalene-1-yl.

[0278] Embodiment 18. 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 17.

[0279] Embodiment 19. 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 17.

[0280] Embodiment 20. Each R a The compound is independently selected from halo and C1-C4 alkyl groups, as described in any one of Embodiments 1-17.

[0281] Embodiment 21. Each R a The compounds are independently selected from halo and C3-C4 cycloalkyl groups, as described in any one of Embodiments 1 to 17.

[0282] Embodiment 22. Each R a This is a compound according to any one of Embodiments 1 to 17, independently selected from halo and C1-C4 haloalkyl.

[0283] Embodiment 23. 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 17.

[0284] Embodiment 24. Each R a The compound according to any one of Embodiments 1 to 17 is independently a halo.

[0285] Embodiment 25. Each R a The compound is independently selected from -F, -Cl, -OH, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH, as described in any one of Embodiments 1 to 17.

[0286] Embodiment 26. Each R a The compound is independently selected from -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH, as described in any one of Embodiments 1 to 17.

[0287] Embodiment 27. 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 17.

[0288] Embodiment 28. Each R aThe compound is independently selected from -F, -Cl, -Me, and -Et, as described in any one of Embodiments 1 to 17.

[0289] Embodiment 29. Each R a The compound is independently selected from -Cl and -cyclopropyl, as described in any one of Embodiments 1 to 17.

[0290] Embodiment 30. Each R a This is a compound independently selected from -Cl and -CF3, as described in any one of Embodiments 1 to 17.

[0291] Embodiment 31. Each R a The compound is independently selected from -F, -Cl, and -C≡CH, as described in any one of Embodiments 1 to 17.

[0292] Embodiment 32. Each R a The compound is independently selected from -F and -Cl, as described in any one of Embodiments 1 to 17.

[0293] Embodiment 33.m is a compound according to any one of Embodiments 1 to 32, wherein m is 1, 2, or 3.

[0294] Embodiment 34.m is a compound according to any one of Embodiments 1 to 32, wherein m is 1 or 2.

[0295] Embodiment 35.m is a compound according to any one of Embodiments 1 to 32, wherein m is 2 or 3.

[0296] Embodiment 36.m is a compound according to any one of Embodiments 1 to 32, wherein m is 1.

[0297] Embodiment 37.m is a compound according to any one of Embodiments 1 to 32, wherein m is 2.

[0298] Embodiment 38.m is a compound according to any one of Embodiments 1 to 32, wherein m is 3.

[0299] Embodiment 39. Ring A is, [ka] Selected from the group consisting of, During the ceremony, R 3 , R 4 , R 5 , 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. R g 、 R m and R p Each of these compounds 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, according to any one of Embodiments 1 to 9.

[0300] Embodiment 40.R 3 , R 4 , R 5 , 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 39.

[0301] Embodiment 41.R 3 , R4 , R 5 , 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 alkyl, as described in Embodiment 39.

[0302] Embodiment 42.R 3 , R 4 , R 5 , 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 39.

[0303] Embodiment 43.R 3 , R 4 , R 5 , 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 39.

[0304] Embodiment 44.R 3 , R 4 , R 5 , R h , R i , R j , R k , R n , R o , R q , R r and Rs is, independently, a compound according to Embodiment 39 selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl.

[0305] Embodiment 45.R 3 , R 4 , R 5 , R h , R i , R j , R k , R n , R o , R q , R r and R s are, independently, a compound according to Embodiment 39 selected from the group consisting of hydrogen and halo.

[0306] Embodiment 46.R 3 , R 4 , R 5 , R h , R i , R j , R k , R n , R o , R q , R r and R s are, independently, a compound according to Embodiment 39 that is halo.

[0307] Embodiment 47.R 3 , R 4 , R 5 , R h , R i , R j , R k , R n , R o , R q , R r and R s are, independently, a compound according to Embodiment 39 selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH.

[0308] Embodiment 48.R 3 , R 4 , R 5 , Rh 、R i 、R j 、R k 、R n 、R o 、R q 、R r and R s are each independently a compound as described in Embodiment 39 selected from the group consisting of -H, -F, -Cl, -Me and -Et.

[0309] Embodiment 49. R 3 、R 4 、R 5 、R h 、R i 、R j 、R k 、R n 、R o 、R q 、R r and R s are each independently a compound as described in Embodiment 39 selected from the group consisting of -H, -F, -Cl and -cyclopropyl.

[0310] Embodiment 50. R 3 、R 4 、R 5 、R h 、R i 、R j 、R k 、R n 、R o 、R q 、R r and R s are each independently a compound as described in Embodiment 39 selected from the group consisting of -H, -F, -Cl and -CF3.

[0311] Embodiment 51. R 3 、R 4 、R 5 、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 -C≡CH, as described in Embodiment 39.

[0312] Embodiment 52.R 3 , R 4 , R 5 , 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 39.

[0313] Embodiment 53.R 3 , R 4 , R 5 , 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 -F and -Cl, as described in Embodiment 39.

[0314] Embodiment 54.R g 、 R m and R p Each of these is a compound according to any one of embodiments 39 to 53, independently selected from the group consisting of -H and -OH.

[0315] Embodiment 55.R g 、 R m and R p Each of these is independently a compound according to any one of embodiments 39 to 53, wherein each is -H.

[0316] Embodiment 56.R g 、 R m and Rp Each of these is independently a -OH compound according to any one of embodiments 39 to 53.

[0317] Embodiment 57. Ring A is, [ka] A compound according to any one of embodiments 39 to 56, selected from the group consisting of the following.

[0318] Embodiment 58. Ring A is, [ka] The compound according to any one of embodiments 39 to 56.

[0319] Embodiment 59. Ring A is, [ka] The compound according to any one of embodiments 39 to 56.

[0320] Embodiment 60. Ring A is, [ka] The compound according to any one of embodiments 39 to 56.

[0321] Embodiment 61. Ring A is, [ka] A compound selected from any one of Embodiments 1 to 9.

[0322] Embodiment 62. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0323] Embodiment 63. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0324] Embodiment 64. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0325] Embodiment 65. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0326] Embodiment 66. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0327] Embodiment 67. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0328] Embodiment 68. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0329] Embodiment 69. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0330] Embodiment 70. Ring A is, [ka] The compound according to any one of Embodiments 1 to 9.

[0331] Embodiment 71. The compound is a compound of formula (Ia), formula (II-a), formula (III-a), formula (IV-a), formula (Va), or formula (VI-a), or a salt thereof, and / or an isotopic substituted thereof. [ka] [ka] During the ceremony, R 3 This is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. R 4 The compound described in Embodiment 1 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.

[0332] Embodiment 72. The compound is the compound of formula (Ia) as described in Embodiment 71.

[0333] Embodiment 73. The compound is the compound of formula (II-a) as described in Embodiment 71.

[0334] Embodiment 74. The compound is the compound of formula (III-a) as described in Embodiment 71.

[0335] Embodiment 75. The compound is the compound of formula (IV-a) as described in Embodiment 71.

[0336] Embodiment 76. The compound is the compound of formula (Va) as described in Embodiment 71.

[0337] Embodiment 77. The compound is the compound of formula (Va) as described in Embodiment 71.

[0338] Embodiment 78. The stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] The compound described in any one of embodiments 71, 72, and 75.

[0339] Embodiment 79. The stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] The compound described in any one of embodiments 71, 73, and 74.

[0340] Embodiment 80.R 3 The compound is selected from halo, C1-C4 alkyl, and C2-C3 alkynyl, as described in any one of embodiments 39, 57, 59, and 71-79.

[0341] Embodiment 81.R 3 The compound is selected from halo and C1-C4 alkyl groups, as described in any one of embodiments 39, 57, 59 and 71-79.

[0342] Embodiment 82.R 3 The compound is selected from a halo and a C2-C3 alkynyl compound, as described in any one of embodiments 39, 57, 59 and 71-79.

[0343] Embodiment 83.R 3 The compound is a halo, as described in any one of embodiments 39, 57, 59 and 71-79.

[0344] Embodiment 84.R 3 The compound is selected from -F, -Cl, -Et, and -C≡CH, as described in any one of embodiments 39, 57, 59, and 71-79.

[0345] Embodiment 85.R 3 The compound is selected from -F, -Cl, and -Et, as described in any one of embodiments 39, 57, 59, and 71-79.

[0346] Embodiment 86.R 3 The compound is selected from -F, -Cl, and -C≡CH, as described in any one of embodiments 39, 57, 59, and 71-79.

[0347] Embodiment 87.R 3 The compound is selected from -F and -Cl, as described in any one of embodiments 39, 57, 59 and 71-79.

[0348] Embodiment 88.R 3 The compound is -F, as described in any one of embodiments 39, 57, 59 and 71-79.

[0349] Embodiment 89.R 3 The compound is -Cl, as described in any one of embodiments 39, 57, 59 and 71-79.

[0350] Embodiment 90.R 3 The compound is -Et, as described in any one of embodiments 39, 57, 59 and 71-79.

[0351] Embodiment 91.R 3 The compound is one of the embodiments described in any one of 39, 57, 59 and 71-79, wherein -C≡CH.

[0352] Embodiment 92.R 4 The compound is selected from hydrogen and a halo, as described in any one of embodiments 39, 57, 59 and 71-91.

[0353] Embodiment 93.R 4 The compound is selected from -H and -F, as described in any one of embodiments 39, 57, 59 and 71-91.

[0354] Embodiment 94.R 4 The compound is -H, as described in any one of embodiments 39, 57, 59 and 71-91.

[0355] Embodiment 95.R 4 The compound is -F, as described in any one of embodiments 39, 57, 59 and 71-91.

[0356] Embodiment 96. The compound is a compound of formula (Ib), formula (II-b), formula (III-b), formula (IV-b), formula (Vb), or formula (VI-b), or a salt thereof, and / or an isotopic substituted thereof. [ka] [ka] During the ceremony, 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 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 mThe compound described in Embodiment 1 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.

[0357] Embodiment 97. The compound is the compound of formula (Ib), as described in Embodiment 96.

[0358] Embodiment 98. The compound is the compound of formula (II-b) as described in Embodiment 96.

[0359] Embodiment 99. The compound described in Embodiment 96, wherein the compound is a compound of formula (III-b).

[0360] Embodiment 100. The compound is the compound of formula (IV-b) as described in Embodiment 96.

[0361] Embodiment 101. The compound is the compound of formula (Vb), as described in Embodiment 96.

[0362] Embodiment 102. The compound is the compound of formula (VI-b) as described in Embodiment 96.

[0363] Embodiment 103. The stereochemistry of pyrrolidine is (R) (i.e., [ka] The part that is represented as [ka] The compound described in any one of Embodiments 96, 97, and 100.

[0364] Embodiment 104. The stereochemistry of the cyanomethyl group is (S) (i.e., [ka] The part that is represented as [ka] The compound according to any one of embodiments 96, 98, and 99.

[0365] Embodiment 105.R j The compound is selected from C3-C4 cycloalkyl and C1-C4 haloalkyl, as described in any one of embodiments 39, 57, 60 and 80-104.

[0366] Embodiment 106.R j The compound is selected from cyclopropyl, -CHF2, and -CF3, as described in any one of Embodiments 39, 57, 60, and 80-104.

[0367] Embodiment 107.R j The compound is selected from cyclopropyl and -CF3, as described in any one of embodiments 39, 57, 60 and 80-104.

[0368] Embodiment 108.R j The compound is cyclopropyl, as described in any one of embodiments 39, 57, 60 and 80-104.

[0369] Embodiment 109.R j The compound is -CHF2, as described in any one of embodiments 39, 57, 60 and 80-104.

[0370] Embodiment 110.R j The compound is -CF3, as described in any one of embodiments 39, 57, 60 and 80-104.

[0371] Embodiment 111.R k The compound is selected from hydrogen and halo, as described in any one of embodiments 39, 57, 60 and 80-110.

[0372] Embodiment 112.R kThe compound is selected from -H and -Cl, as described in any one of embodiments 39, 57, 60 and 80-110.

[0373] Embodiment 113.R k The compound is -H, as described in any one of embodiments 39, 57, 60 and 80-110.

[0374] Embodiment 114.R k The compound is -Cl, as described in any one of embodiments 39, 57, 60 and 80-110.

[0375] Embodiment 115.R m The compound is selected from -H and -OH, as described in any one of embodiments 39, 57, 60 and 80-114.

[0376] Embodiment 116.R m The compound is -H, as described in any one of embodiments 39, 57, 60 and 80-114.

[0377] Embodiment 117.R m The compound is one of the embodiments 39, 57, 60 and 80-114, wherein the compound is -OH.

[0378] Embodiment 118.R d The compound according to any one of Embodiments 1 to 117, wherein is H.

[0379] Embodiment 119.R d The compound is F, as described in any one of Embodiments 1 to 117.

[0380] Embodiment 120.R 1A teeth, [ka] The compound described in any one of Embodiments 1 to 117.

[0381] Embodiment 121.R 1A teeth, [ka] A compound according to any one of embodiments 1 to 117, selected from the above.

[0382] Embodiment 122.R 1A teeth, [ka] The compound described in any one of Embodiments 1 to 117.

[0383] Embodiment 123.R 1A teeth, [ka] The compound described in any one of Embodiments 1 to 117.

[0384] Embodiment 124.R 1 H, -OCH2R 1A , -OMe, Me and [ka] A compound according to any one of embodiments 1 to 123, selected from the above.

[0385] Embodiment 125.R 1 The compound according to any one of Embodiments 1 to 123, wherein is H.

[0386] Embodiment 126.R 1 The compound is -OMe, as described in any one of Embodiments 1 to 123.

[0387] Embodiment 127.R 1 The compound is Me, as described in any one of Embodiments 1 to 123.

[0388] Embodiment 128.R 1 teeth, [ka] The compound according to any one of Embodiments 1 to 123.

[0389] Embodiment 129.R 1 OCH2R 1A The compound according to any one of Embodiments 1 to 123.

[0390] Embodiment 130.R 1 teeth, [ka] A compound according to any one of embodiments 1 to 123, selected from the group consisting of the following.

[0391] Embodiment 131.R 1 teeth, [ka] The compound according to any one of Embodiments 1 to 123.

[0392] Embodiment 132.R 1 teeth, [ka] The compound according to any one of Embodiments 1 to 123.

[0393] Embodiment 133.R 1 teeth, [ka] The compound according to any one of Embodiments 1 to 123.

[0394] Embodiment 134.R 2 teeth, [ka] The compound according to any one of Embodiments 1 to 133.

[0395] Embodiment 135.R2 teeth, [ka] The compound according to any one of Embodiments 1 to 133.

[0396] Embodiment 136.R Y1 The compound is -Me, as described in any one of Embodiments 1 to 123.

[0397] Embodiment 137.R Y1 The compound is one of any one of Embodiments 1 to 123, wherein is -H.

[0398] Embodiment 138.R Y2 The compound is one of any one of Embodiments 1 to 137, wherein is -H.

[0399] Embodiment 139.R Y2 The compound is -Me, as described in any one of embodiments 1 to 137.

[0400] Embodiment 140.R e R is -C(O)O-C1~C4 alkyl, R e1 , -C(R Y1 )(R Y2 )R e1 , R e2 and -C(R Y1 )(R Y2 )R e3 A compound according to any one of embodiments 1 to 139, selected from the group consisting of the following.

[0401] Embodiment 141.R e -C(O)OMe, R e1 , -CH2R e1 , R e2 and -CH2R e3 A compound according to any one of embodiments 1 to 139, selected from the group consisting of the following.

[0402] Embodiment 142.R e -C(O)OMe, R e1 , -CH2Re1 and R e2 A compound according to any one of embodiments 1 to 139, selected from the group consisting of the following.

[0403] Embodiment 143.R e R e1 , -CH2R e1 and R e2 A compound according to any one of embodiments 1 to 139, selected from the group consisting of the following.

[0404] Embodiment 144.R e R e1 or -C(R Y1 )(R Y2 )R e1 The compound according to any one of Embodiments 1 to 139.

[0405] Embodiment 145.R e1 The compound according to any one of Embodiments 1 to 144, wherein the compound contains a nitrogen atom as the sole heteroatom, or a 4- to 7-membered monocyclic heterocycle containing one nitrogen atom and one oxygen atom, wherein the monocyclic 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.

[0406] Embodiment 146.R e1 The compound according to any one of Embodiments 1 to 144, wherein the compound is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom as the sole heteroatom, where the monocyclic 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.

[0407] Embodiment 147.R e1The compound according to Embodiment 145 or 146, wherein the monocyclic heterocycle is substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl.

[0408] Embodiment 148.R e1 The compound according to embodiment 145 or 146, wherein the monocyclic heterocycle is substituted with 0 or 1 C1-C4 alkyl groups.

[0409] Embodiment 149.R e1 The compound according to embodiment 145 or 146, wherein the monocyclic heterocycle is substituted with 0 or 1 methyl group.

[0410] Embodiment 150.R e1 The compound according to Embodiment 145, which is selected from azetidinyl, pyrrolidinyl, tetrahydrofuranil, and morpholinyl substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl.

[0411] Embodiment 151.R e1 The compound according to Embodiment 145, which is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with 0 or 1 methyl groups.

[0412] Embodiment 152.R e1 The compound according to Embodiment 145 or 146, wherein is an azetidinyl substituted with 0 or 1 methyl, ethyl, isopropyl, or methoxyethyl.

[0413] Embodiment 153.R e1 The compound according to Embodiment 145 or 146, wherein is an azetidinyl substituted with 0 or 1 methyl group.

[0414] Embodiment 154.R e1 The compound according to Embodiment 145 or 146, wherein the compound is N-methylazetidinyl.

[0415] Embodiment 155. The compound according to Embodiments 145-154, wherein the bond site of the monocyclic heterocyclic ring is located on a carbon atom.

[0416] Embodiment 156.R e1 teeth, [ka] A compound according to Embodiment 155, selected from the group consisting of the following.

[0417] Embodiment 157.R e1 teeth, [ka] The compound described in Embodiment 155.

[0418] Embodiment 158.R e1 teeth, [ka] The compound described in Embodiment 155.

[0419] Embodiment 159.R e R e1 The compound described in any one of Embodiments 145 to 158.

[0420] Embodiment 160.R e1 The compound according to any one of Embodiments 1 to 144, 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.

[0421] Embodiment 161.R e1The compound according to Embodiment 160, 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.

[0422] Embodiment 162.R e1 The compound according to Embodiment 160, 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.

[0423] Embodiment 163.R e1 The compound according to Embodiment 160, 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.

[0424] Embodiment 164.R e1 The compound according to Embodiment 160, 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.

[0425] Embodiment 165.R e1The compound according to Embodiment 160, 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.

[0426] Embodiment 166.R e1These include azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxaazepane, 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, 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-thi A-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 160, 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.

[0427] Embodiment 167.R e1 The compound according to Embodiment 160, wherein the compound 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.

[0428] Embodiment 168.R e1 The compounds according to embodiments 160 to 167, wherein the bonding site is a nitrogen atom of the heterocycle.

[0429] Embodiment 169.R e1 teeth, [ka] The compound according to Embodiment 168, selected from the group consisting of, 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.

[0430] Embodiment 170.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. [ka] A compound selected from the compounds described in Embodiment 168.

[0431] Embodiment 171.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. [ka] A compound selected from the compounds described in Embodiment 168.

[0432] Embodiment 172.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. [ka] The compound described in Embodiment 168.

[0433] Embodiment 173.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. [ka] The compound described in Embodiment 168.

[0434] Embodiment 174.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. [ka] The compound described in Embodiment 168.

[0435] Embodiment 175.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. [ka] The compound described in Embodiment 168.

[0436] Embodiment 176.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. [ka] The compound described in Embodiment 168.

[0437] Embodiment 177.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. [ka] The compound described in Embodiment 168.

[0438] Embodiment 178.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. [ka] The compound described in Embodiment 168.

[0439] Embodiment 179.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. [ka] The compound described in Embodiment 168.

[0440] Embodiment 180.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. [ka] The compound described in Embodiment 168.

[0441] Embodiment 181.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. [ka] The compound described in Embodiment 168.

[0442] Embodiment 182.R e1 The compound according to any one of Embodiments 160 to 181, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F, -OMe, and -Me.

[0443] Embodiment 183.R e1The compound according to any one of embodiments 160 to 181, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from -F and -OMe.

[0444] Embodiment 184.R e1 The compound according to any one of embodiments 160 to 181, wherein the 4- to 10-membered heterocycle is substituted with 0, 1, or 2 -F atoms.

[0445] Embodiment 185.R e1 The compound according to any one of embodiments 160 to 181, wherein the 4- to 10-membered heterocycle is substituted with 0 or 1 -OMe.

[0446] Embodiment 186.R e1 The compound according to any one of embodiments 160 to 181, wherein the 4- to 10-membered heterocycle is unsubstituted.

[0447] Embodiment 187.R e1 teeth, [ka] [ka] [ka] A compound according to embodiment 168, selected from the group consisting of the following.

[0448] Embodiment 188.R e1 teeth, [ka] A compound selected from the compounds described in Embodiment 168.

[0449] Embodiment 189.R e1 teeth, [ka] A compound selected from the compounds described in Embodiment 168.

[0450] Embodiment 190.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0451] Embodiment 191.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0452] Embodiment 192.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0453] Embodiment 193.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0454] Embodiment 194.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0455] Embodiment 195.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0456] Embodiment 196.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0457] Embodiment 197.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0458] Embodiment 198.R e1 teeth, [ka] The compound described in Embodiment 168.

[0459] Embodiment 199.R e1 teeth, [ka] The compound described in Embodiment 168.

[0460] Embodiment 200.R e1 teeth, [ka] The compound described in Embodiment 168.

[0461] Embodiment 201.R e1 teeth, [ka] The compound described in Embodiment 168.

[0462] Embodiment 202.R e1 teeth, [ka] The compound described in Embodiment 168.

[0463] Embodiment 203.R e1 teeth, [ka] The compound described in Embodiment 168.

[0464] Embodiment 204.R e1 is non-substitutive [ka] The compound described in Embodiment 168.

[0465] Embodiment 205.R e -C(R Y1 )(R Y2 )R e1 The compound according to any one of embodiments 160 to 204.

[0466] Embodiment 206.R e -CH2R e1 The compound according to any one of embodiments 160 to 204.

[0467] Embodiment 207.R e R e2 The compound according to any one of Embodiments 1 to 139.

[0468] Embodiment 208.R e2 The compound according to any one of embodiments 1 to 143, 145 to 204 and 207, wherein is a 5-6 membered heteroaryl group containing at least one nitrogen atom, the bonding site of the heteroaryl group is a carbon atom group, and the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl atoms.

[0469] Embodiment 209.R e2 The compound is selected from the group consisting of pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents, as described in any one of Embodiments 1-143, 145-204, and 207.

[0470] Embodiment 210.R e2 The compound is selected from the group consisting of pyrimidinyl, 1,2,4-oxadiazolyl, and 1H-1,2,4-triazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents, as described in any one of Embodiments 1-143, 145-204, and 207.

[0471] Embodiment 211.R e2 teeth, [ka] A compound according to any one of Embodiments 1 to 143, 145 to 204 and 207, selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0472] Embodiment 212.R e2 teeth, [ka] A compound according to any one of Embodiments 1 to 143, 145 to 204 and 207, selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0473] Embodiment 213.R e2 teeth, [ka] A compound selected from the group consisting of, one of embodiments 1 to 143, 145 to 204, and 207.

[0474] Embodiment 214.R e2 teeth, [ka] A compound selected from the group consisting of, one of embodiments 1 to 143, 145 to 204, and 207.

[0475] Embodiment 215.R e2 The compound according to any one of embodiments 1 to 143, 145 to 204 and 207, wherein is a six-membered heteroaryl group substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0476] Embodiment 216.R e2The compound according to Embodiment 215, wherein is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0477] Embodiment 217.R e2 The compound according to Embodiment 215, wherein is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 C1-C4 alkyl groups.

[0478] Embodiment 218.R e2 The compound according to Embodiment 215, wherein is a pyrimidinyl substituted with 0, 1, or 2 C1-C4 alkyl groups.

[0479] Embodiment 219.R e2 The compound according to Embodiment 215, wherein is a pyridadinyl substituted with 0, 1, or 2 C1-C4 alkyl groups.

[0480] Embodiment 220.R e2 The compound according to Embodiment 215, wherein is a pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 -Me.

[0481] Embodiment 221.R e2 The compound according to Embodiment 215, wherein is a pyrimidinyl substituted with 0, 1, or 2 -Me.

[0482] Embodiment 222.R e2 The compound according to Embodiment 215, wherein is a pyridazinyl substituted with 0, 1, or 2 -Me.

[0483] Embodiment 223.R e2 teeth, [ka] The compound according to Embodiment 215, selected from the group consisting of, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl which may be substituted with one or two fluoro or methyl substituents.

[0484] Embodiment 224.R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] A compound according to Embodiment 215, selected from the group consisting of the following.

[0485] Embodiment 225.R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] The compound described in Embodiment 215.

[0486] Embodiment 226.R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] The compound described in Embodiment 215.

[0487] Embodiment 227.R e2 is substituted with 0, 1, or 2 C1-C4 alkyl groups. [ka] The compound described in Embodiment 215.

[0488] Embodiment 228.R e2 is replaced by 0, 1, or 2 -Me [ka] A compound according to Embodiment 215, selected from the group consisting of the following.

[0489] Embodiment 229.R e2 is replaced by 0, 1, or 2 -Me [ka] The compound described in Embodiment 215.

[0490] Embodiment 230.R e2 is replaced by 0, 1, or 2 -Me [ka] The compound described in Embodiment 215.

[0491] Embodiment 231.R e2 is replaced by 0, 1, or 2 -Me [ka] The compound described in Embodiment 215.

[0492] Embodiment 232.R e2 teeth, [ka] A compound according to Embodiment 215, selected from the group consisting of the following.

[0493] Embodiment 233.R e2 teeth, [ka] A compound according to Embodiment 215, selected from the group consisting of the following.

[0494] Embodiment 234.R e2 teeth, [ka] The compound described in Embodiment 215.

[0495] Embodiment 235.R e2 teeth, [ka] The compound described in Embodiment 215.

[0496] Embodiment 236.R e2 The compound according to any one of embodiments 1 to 143, 145 to 204 and 207, wherein the heteroaryl is a five-membered heteroaryl group containing at least one nitrogen atom, where the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0497] Embodiment 237.R e2 The compound is selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl which may be substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, as described in any one of Embodiments 1-143, 145-204, and 207.

[0498] Embodiment 238.R 35 However, C3-C6 heterocyclyls that may be substituted with one or two substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halo, hydroxy, and methyl, and C3-C6 cycloalkyls that may be substituted with one or two substituents independently selected from halo, hydroxy, and methyl, each substituted with 0, 1, or 2 substituents independently selected from [ka] A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 271, selected from the group consisting of the above.

[0499] Embodiment 239.R e2 teeth, [ka] A compound according to any one of Embodiments 1 to 143, 145 to 204, and 207, selected from the group consisting of, each of which is substituted with one substituent independently selected from halo, hydroxy, C1 to C4 alkyl, C1 to C4 hydroxyalkyl, C1 to C6 alkoxy, C1 to C4 haloalkyl, C1 to C4 haloalkoxy, C3 to C6 heterocyclyl which may be substituted with one or two substituents independently selected from halo, hydroxy, and methyl, and C3 to C6 cycloalkyl which may be substituted with one or two substituents independently selected from halo, hydroxy, and methyl.

[0500] Embodiment 240.R e2 teeth, [ka] A compound selected from the group consisting of the following, each of which is substituted with one C1-C4 alkyl group, according to any one of embodiments 1-143, 145-204, and 207.

[0501] Embodiment 241.R e2 teeth, [ka] A compound selected from the group consisting of, one of embodiments 1 to 143, 145 to 204, and 207.

[0502] Embodiment 242.R e2 teeth, [ka] A compound selected from the group consisting of, one of embodiments 1 to 143, 145 to 204, and 207.

[0503] Embodiment 243.R e2 teeth, [ka] The compound described in any one of embodiments 1 to 143, 145 to 204, and 207.

[0504] Embodiment 244.R e2 teeth, [ka] The compound described in any one of embodiments 1 to 143, 145 to 204, and 207.

[0505] Embodiment 245.R e -C(R Y1 )(R Y2 )R e3 The compound according to any one of Embodiments 1 to 139.

[0506] Embodiment 246. In one embodiment, R 31 and R32 The compound is one of any one of embodiments 1 to 143, 145 to 204, and 208 to 245, which is independently selected from the group consisting of C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4 haloalkoxy, and C1 to C4 alkyl substituted with a 3 to 6 member heterocycle containing 1 to 2 atoms independently selected from N, O, and S, including S(O)2.

[0507] Embodiment 247.R 31 The compound is a C1-C4 alkyl compound as described in any one of embodiments 1-143, 145-204, and 208-245.

[0508] Embodiment 248.R 31 The compound is -Me, as described in any one of embodiments 1 to 143, 145 to 204, and 208 to 245.

[0509] Embodiment 249.R 32 The compound is one of any one of embodiments 1 to 143, 145 to 204, and 208 to 248, wherein is a C1 to C4 alkyl or a C1 to C4 alkyl substituted with a 3 to 6 membered heterocycle.

[0510] Embodiment 250.R 32 The compound is a C1-C4 alkyl group substituted with a 3-6 membered heterocycle, as described in any one of embodiments 1-143, 145-204, and 208-248.

[0511] Embodiment 251.R 32 The compound is one of any one of Embodiments 1 to 143, 145 to 204, and 208 to 248, wherein is a C1 to C4 alkyl substituted with a heterocycle selected from azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, and morpholine.

[0512] Embodiment 252.R 32 The compound is a C1-C4 alkyl group substituted with oxetane, as described in any one of Embodiments 1-143, 145-204, and 208-248.

[0513] Embodiment 253.R 32 teeth, [ka] The compound described in any one of embodiments 1 to 143, 145 to 204, and 208 to 248.

[0514] Embodiment 254.R 32 The compound is a C1-C4 alkyl compound as described in any one of embodiments 1-143, 145-204, and 208-248.

[0515] Embodiment 255.R 32 The compound is one of the embodiments described in any one of embodiments 1 to 143, 145 to 204, and 208 to 248, wherein the compound is Me.

[0516] Embodiment 256.R e3 teeth, [ka] A compound selected from any one of embodiments 1 to 143, 145 to 204, and 208 to 245.

[0517] Embodiment 257.R e3 teeth, [ka] The compound described in any one of embodiments 1 to 143, 145 to 204, and 208 to 245.

[0518] Embodiment 258.R e3 teeth, [ka] The compound described in any one of embodiments 1 to 143, 145 to 204, and 208 to 245.

[0519] Embodiment 259.R e teeth, [ka] A compound according to any one of embodiments 1 to 139, selected from the group consisting of the following.

[0520] Embodiment 260.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0521] Embodiment 261.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0522] Embodiment 262.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0523] Embodiment 263.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0524] Embodiment 264.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0525] Embodiment 265.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0526] Embodiment 266.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0527] Embodiment 267.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0528] Embodiment 268.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0529] Embodiment 269.R e teeth, [ka] The compound according to any one of Embodiments 1 to 139.

[0530] Embodiment 270.R e The compound is -C(O)OMe, as described in any one of Embodiments 1 to 139.

[0531] Embodiment 271.R x The compound is selected from -F and -Me, as described in any one of Embodiments 1 to 270.

[0532] Embodiment 272.R x The compound is one of any one of Embodiments 1 to 270, wherein is -OH.

[0533] Embodiment 273.R x The compound is -Me, as described in any one of Embodiments 1 to 270.

[0534] Embodiment 274.R x The compound is -F, as described in any one of Embodiments 1 to 270.

[0535] Embodiment 275.n is a compound according to any one of Embodiments 1 to 274, wherein the compound is 0 or 1.

[0536] Embodiment 276.n is a compound according to any one of Embodiments 1 to 274, wherein the compound is 0.

[0537] Embodiment 277.n is a compound according to any one of Embodiments 1 to 274, wherein the compound is 1.

[0538] Embodiment 278.n is a compound according to any one of Embodiments 1 to 274, wherein the compound is 2.

[0539] Embodiment 279. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound, a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

[0540] Embodiment 280. A compound according to any one of Embodiments 1 to 279, which is not a salt.

[0541] Embodiment 281. A compound according to any one of Embodiments 1 to 279, which is a salt.

[0542] Embodiment 282. The compound of Embodiment 281, wherein the salt is a formate salt.

[0543] Embodiment 283. The compound of Embodiment 281, wherein the salt is a trifluoroacetate salt.

[0544] Embodiment 284. The salt is a pharmaceutically acceptable salt of the compound of Embodiment 281.

[0545] Embodiment 285. A pharmaceutical formulation comprising a compound described in any one of Embodiments 1 to 284 (if the compound is a salt, the salt is a pharmaceutically acceptable salt) and a pharmaceutically acceptable carrier.

[0546] Embodiment 286. A method for treating or suppressing cancer, comprising administering a therapeutically effective amount of any one compound from Embodiments 1 to 284 (if the compound is a salt, the salt is a pharmaceutically acceptable salt), or the pharmaceutical formulation described in Embodiment 285, to a subject in need thereof.

[0547] Embodiment 287. The method according to Embodiment 286, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0548] Embodiment 288. 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, and children. The method according to Embodiment 286, selected from the group consisting of miya carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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.

[0549] Embodiment 289. The method according to any one of Embodiments 286 to 288, wherein the cancer is a KRAS G12C-mediated cancer.

[0550] Embodiment 290. The method according to any one of Embodiments 286 to 288, relating to a patient diagnosed with KRAS G12C-mediated cancer.

[0551] Embodiment 291. The method according to any one of Embodiments 286 to 288, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the target.

[0552] Embodiment 292. A pharmaceutical formulation according to Embodiment 285 or any one compound from Embodiments 1 to 284, to be used as a pharmaceutical.

[0553] Embodiment 293. A pharmaceutical formulation according to Embodiment 285 or any one of the compounds in Embodiments 1 to 284 or the embodiment 285, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt.

[0554] Embodiment 294. The cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and is a compound or pharmaceutical formulation used in Embodiment 293.

[0555] Embodiment 295. 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, Compounds or pharmaceutical formulations used in Embodiment 293, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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.

[0556] Embodiment 296. The cancer is a KRAS G12C-mediated cancer, and the compound or pharmaceutical formulation used in any one of Embodiments 292 to 295.

[0557] Embodiment 297. The subject is a compound or pharmaceutical preparation used in any one of Embodiments 292 to 295, diagnosed with KRAS G12C-mediated cancer.

[0558] Embodiment 298. A compound or pharmaceutical formulation used in any one of Embodiments 292 to 297, configured to be administered together with an additional therapeutically effective dose of a chemotherapeutic agent.

[0559] Embodiment 299. A compound or pharmaceutical formulation used in any one of Embodiments 292 to 298, configured for administration in a therapeutically effective dose.

[0560] Embodiment 300. A pharmaceutical formulation according to Embodiment 285 or any one of the compounds in Embodiments 1 to 284 or the one described in Embodiment 285, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt.

[0561] Embodiment 301. The cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer, and is a compound or pharmaceutical formulation used in Embodiment 300.

[0562] Embodiment 302. 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, Compounds or pharmaceutical formulations used in Embodiment 300, selected from the group consisting of mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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.

[0563] Embodiment 303. The cancer is a KRAS G12C-mediated cancer, and the compound or pharmaceutical formulation used in any one of Embodiments 300 to 303.

[0564] Embodiment 304. The subject is a compound or pharmaceutical preparation used in any one of Embodiments 300 to 303, diagnosed with KRAS G12C-mediated cancer.

[0565] Embodiment 305. A compound or pharmaceutical formulation used in any one of Embodiments 300 to 304, configured to be administered together with an additional therapeutically effective dose of a chemotherapeutic agent.

[0566] Embodiment 306. The pharmaceutical is a compound or pharmaceutical preparation according to any one of Embodiments 300 to 305, comprising a therapeutically effective amount of the compound or composition.

[0567] Embodiment 307. Use of any one compound from Embodiments 1 to 284 or the pharmaceutical formulation described in Embodiment 285 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.

[0568] Embodiment 308. The use described in Embodiment 307, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0569] Embodiment 309. 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytosis myeloma, and children. The use described in Embodiment 307, selected from the group consisting of miya carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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.

[0570] Embodiment 310. The use according to any one of Embodiments 307 to 309, wherein the cancer is a KRAS G12C-mediated cancer.

[0571] Embodiment 311. The subject is diagnosed with KRAS G12C-mediated cancer, and the use is as described in any one of Embodiments 307 to 309.

[0572] Embodiment 312. The use according to any one of Embodiments 307 to 311, wherein the compound or pharmaceutical composition is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0573] Embodiment 313. The use described in any one of Embodiments 307 to 312, wherein the pharmaceutical product comprises a therapeutically effective amount of the compound or pharmaceutical composition.

[0574] Embodiment 314. Use of any one compound from Embodiments 1 to 284 or the pharmaceutical formulation described in Embodiment 285 for the treatment or suppression of cancer, wherein the compound is a salt, and the salt is a pharmaceutically acceptable salt.

[0575] Embodiment 315. The use as described in Embodiment 314, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

[0576] Embodiment 316. 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, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, and children. The use described in Embodiment 314, selected from the group consisting of miya carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, 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.

[0577] Embodiment 317. The use according to any one of Embodiments 314 to 316, wherein the cancer is a KRAS G12C-mediated cancer.

[0578] Embodiment 318. The subject is diagnosed with KRAS G12C-mediated cancer, and the use is as described in any one of Embodiments 314 to 316.

[0579] Embodiment 319. The use according to any one of Embodiments 314 to 318, wherein the compound or pharmaceutical composition is configured to be administered together with an additional therapeutically effective amount of chemotherapeutic agent.

[0580] Embodiment 320. Use according to any one of Embodiments 314 to 319 relating to a therapeutically effective amount of a compound or composition.

[0581] General synthesis methods Compounds 1-58 in Table 1 of this disclosure were prepared according to the methods described in the Examples section, or variations thereof within the scope of the knowledge of those skilled in the art.

[0582] 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 by following the 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 examples of some ways in which the compounds of this disclosure may be synthesized, and various modifications to these schemes may be suggested to those skilled in the art who have read this disclosure. The starting materials, intermediates, and final reaction products can be isolated and purified, if desired, using conventional techniques (including, but not limited to, filtration, distillation, crystallization, chromatography, and similar methods). Such materials can be characterized using conventional methods such as physical constants and spectral data.

[0583] 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]

[0584] The following preparations of the compounds of formulas (I), (II), (III), (IV), (V), and (VI), 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.

[0585] The following abbreviations are used in this section. TIFF2026515946000306.tif170165

[0586] All reagents were obtained from commercial suppliers and used without further purification unless otherwise specified.

[0587] Synthesis Examples [ka] Example 1: Synthesis of compound 49, (S,Z)-2-(1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves tert-butyl(2S)-4-(7-chloro-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate (1.5 g, 3.40 mmol) in methanol (20 mL), sodium methoxide (734.54 mg, 4.08 mmol) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain tert-butyl(2S)-4-(7-chloro-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (950 mg, 63.97%) as a yellow solid, which was used in the next step without further purification. LCMS Rt=0.511min,m / z=436.1[M+H] + . [ka] Step 2 involves tert-butyl(2S)-2-(cyanomethyl)-4-[8-fluoro-7-[7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate A mixture of tert-butyl(2S)-4-(7-chloro-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (300 mg, 686.71 μmol), 2-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethinyltriisopropylsilane (683.59 mg, 1.51 mmol), [2-(2-aminophenyl)phenyl]chloropalladium, bis(1-adamantyl)butylphosphane (45.92 mg, 68.67 μmol), potassium phosphate (437.29 mg, 2.06 mmol) in dioxane (3 mL), and water (1 mL) was degassed, purged three times with nitrogen, and then stirred under a nitrogen atmosphere at 80°C for 1 hour. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 3 mL). The combined organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 75%~95%, 8 min) to obtain tert-butyl(2S)-2-(cyanomethyl)-4-[8-fluoro-7-[7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate (77 mg, 15.43%) as a brown solid. LCMS Rt=2.20 min, m / z=726.4 [M+H] + . [ka] Step 3 involves tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[8-fluoro-7-[7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate (67 mg, 92.17 μmol) in acetonitrile (1.5 mL), cesium fluoride (70.00 mg, 460.84 μmol) was added. The mixture was stirred at 25°C for 0.5 hours.

[0588] The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate (53 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.57 min, m / z=570.2 [M+H] + . [ka] In step 4, 2-[(2S)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-2-yl]acetonitrile A solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-1-carboxylate (53 mg, 92.89 μmol) in dichloromethane (1 mL) was mixed with trifluoroacetic acid (0.3 mL). The mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under vacuum to obtain 2-[(2S)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-2-yl]acetonitrile (54 mg, crude, trifluoroacetate) as a yellow oily substance, which was used in the next step without further purification. LCMS Rt=0.471min,m / z=470.2[M+H] + . [ka] In step 5, (S,Z)-2-(1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile To a solution of 2-[(2S)-4-[7-(8-ethynyl-7-fluoro-1-naphthyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazin-2-yl]acetonitrile (54 mg, 92.39 μmol, trifluoroacetate) in N,N-dimethylformaldehyde (1 mL), N,N-diisopropylethylamine (35.82 mg, 277.16 μmol), (Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-enoic acid (36.25 mg, 184.77 μmol), and 2-chloro-1,3-dimethylimidazolinium chloride (39.92 mg, 277.16 μmol) were added. The mixture was stirred at 25°C for 10 minutes, and the reaction mixture was concentrated to dryness under vacuum. The obtained residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm, mobile phase: [H2O (10mM NH4HCO3)-ACN], gradient: 40%-60% B over 8.0 minutes) to obtain (S,Z)-2-(1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazin-2-yl)acetonitrile (21.68 mg, 35.24%) as a yellow solid. 1 H NMR(400MHz,acetonitrile-d3)δ 9.10(d,J=8.0Hz,1H),8.12(dd,J=5.8,8.9Hz,2H),7.71-7.64(m,2H),7.50-7.4 1(m,2H),6.54-6.38(m,1H),4.92(dt,J=1.5,6.3Hz,1H),4.62-4.39(m,2H),4.2 6-4.10(m,1H),4.04(d,J=2.5Hz,3H),3.98-3.86(m,1H),3.85-3.67(m,2H),3.3 0-3.22(m,1H),3.15-3.05(m,1H),3.04-2.90(m,1H),2.59(s,3H),2.47(s,3H). LCMS Rt=2.937min,m / z=648.2[M+H] +LCMS (5-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.937 minutes, ESI+ measured value [M+H] = 648.2.

[0589] [ka] Example 2, Synthesis of compound 5, 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-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves (S)-tert-butyl4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-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 2 of method #1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain (S)-tert-butyl 4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (4.8 g, 76.46%) as a brown solid. LCMS Rt=0.685 min, m / z=707.3 [M+H] + . [ka] In step 2, 2-((S)-4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of the Boc group was performed 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-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (600.00 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.519min, m / z=607.2[M+H] + . [ka] Step 3 involves 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-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35%~65%, 8 minutes) 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)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (163.03 mg, 25.41%) as an amorphous solid. 1 H NMR(400MHz,acetonitrile-d3)δ 9.26-8.99(m,1H),8.70(d,J=5.3Hz,1H),8.18-8.09(m,1H),8.06(dd,J=5.9,9.1Hz,1H),7.79-7.61(m,2H),7.59-7.35(m,2H),6.64-6 .34(m,1H),5.37-5.16(m,1H),5.04-4.82(m,1H),4.69-4.39(m,2H),4.33-4.09(m,3H),3.96-3.61(m,3H),3.24-3.12(m,2H),3.08(br s,1H),3.02(br d,J=7.8Hz,1H),2.99-2.86(m,2H),2.66-2.52(m,3H),2.20(br s,1H),2.12(br s,1H),2.09-2.04(m,1H),1.92-1.81(m,3H). LCMS Rt=2.236min,m / z=771.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.236 minutes, ESI+ measured value [M+H] = 771.3.

[0590] [ka] Example 3, Synthesis of compound 9, 2-((S)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves (S)-tert-butyl 2-(cyanomethyl)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of Method 1. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna C18 (250*70 mm, 15 μm), mobile phase: [water (TFA)-ACN], B%: 33%~60%, 22 minutes) to obtain (S)-tert-butyl 2-(cyanomethyl)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate (1.5 g, 20.74%, trifluoroacetate) as a yellow oily substance. 1H NMR(400MHz,acetonitrile-d3)δ 9.20(d,J=6.8Hz,1H),8.08(br d,J=8.1Hz,1H),7.95(dd,J=5.9,8.9Hz,1H),7.61-7.54(m,1H),7.52-7.47(m,1H),7.41(t,J=9.4Hz,1H),5.57-5.41(m,1H) ,4.66-4.61(m,3H),4.45-4.39(m,1H),4.05-3.98(m,2H),3.71-3.62(m,2H),3.36-3.27(m,2H),2.87-2.82(m,2H),2.58(br d,J=10.0Hz,1H),2.50(br s,1H),2.37(br d,J=5.3Hz,1H),2.29-2.22(m,3H),2.13-2.07(m,1H),1.49(s,9H),1.47(br d,J=2.4Hz,3H),1.33-1.25(m,1H),0.85-0.79(m,3H) LCMS Rt=0.796min,m / z=701.3[M+H] + .

[0591] [ka] Step 2 involves 2-((S)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of the Boc group 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-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (400.00 mg, crude, trifluoroacetate) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=0.515min, m / z=601.3[M+H] + . [ka] Step 3 involves 2-((S)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35%~65%, 8 minutes) to obtain 2-((S)-4-(7-(8-ethyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (130.0 mg, 30.22%) as an amorphous solid. 1 ¹H NMR (400MHz, dimethyl sulfoxide-d6) δ 9.24-9.17 (m, 1H), 8.83-8.75 (m, 1H), 8.13 (br d, J=8.0Hz, 1H), 8.03 (dd, J=6.1, 9.0Hz, 1H), 7.63-7.57 (m, 2H), 7.52-7.46 (m, 2H), 6.65-6.47 (m, 1H), 5.38-5.18 (m, 1H), 4.99-4.86 (m, 1H), 4.61-4.39 (m, 2H), 4.22-4.06 (m, 3H),4.00-3.65(m,3H),3.17-3.00(m,5H),2.89-2.78(m,1H),2.64(s,3H),2.46-2.37( m,1H),2.25-2.12(m,2H),2.08-2.00(m,2H),1.88-1.76(m,3H),0.77(q,J=7.4Hz,3H). LCMS Rt=3.216min,m / z=765.3[M+H]+ LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.216 minutes, ESI+ measured value [M+H] = 765.3.

[0592] [ka] Example 4, Synthesis of compound 11, 2-((S)-4-(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)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves (S)-tert-butyl 2-(cyanomethyl)-4-(7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The residue was purified by flash column (ISCO 25g silica, 0% to 30% ethyl acetate in petroleum ether, gradient over 30 minutes) to obtain (S)-tert-butyl 2-(cyanomethyl)-4-(7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate (4.5g, 87.42%) as a yellow, gum-like substance. 1H NMR(400MHz,chloroform-d)δ 9.00(s,1H),7.89(br d,J=7.9Hz,1H),7.67-7.61(m,1H),7.58-7.50(m,2H),7.36-7.28(m,1H),5.30-5.12(m,1H),4.62-4.35(m,3H),4.25(br dd,J=5.1,10.3Hz,1H),4.16(br d,J=10.4Hz,1H),3.79-3.59(m,2H),3.38-3.27(m,1H),3.24-3.16(m,2H),3.14-3.09(m,1H),2.96-2.88(m,1H),2.75(br d,J=6.8Hz,1H),2.71-2.63(m,1H),2.39(br dd,J=6.6,14.1Hz,1H),2.21-2.07(m,3H),1.90-1.80(m,3H),1.45(s,9H). LCMS Rt=0.638min,m / z=691.3[M+H] + . [ka] Step 2 involves ((S)-4-(7-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of the Boc group 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-(7,8-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (181.00 mg, crude, trifluoroacetate) as a brown, gum-like substance, which was used in the next step without further purification. LCMS Rt=0.539min, m / z=591.2[M+H] + . [ka] Step 3 involves 2-((S)-4-(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)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 30%~60%, 8 minutes) to obtain 2-((S)-4-(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)-1-((Z)-2-fluoro-3-(2-methylpyrimidine-4-yl)acryloyl)piperazine-2-yl)acetonitrile (82.53 mg, 32.30%) as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d)δ 9.12-9.05 (m, 1H), 8.72 (d, J=5.3Hz, 1H), 7.99 (br d, J=7.8Hz, 1H), 7.76-7.69 (m, 1H), 7.67-7.58 (m, 2H), 7.51 (d, J=5.1Hz, 1H), 7.45-7.37 (m, 1H), 6.88-6.63 (m, 1H), 5.40-5.22 (m, 1H), 5.08-4.92 (m, 1H), 4.85 (br s,1H),4.80-4.72(m,1H),4.61-4.46(m,2H),4.39-4.30(m,2H),4.13-3.96(m,1H),3.96-3.76(m,2H),3.37-3.32(m ,1H),3.27-3.21(m,1H),3.14-2.97(m,2H),2.95-2.87(m,1H),2.76(s,3H),2.33-2.16(m,3H),2.03-1.93(m,3H). LCMS Rt=3.013min,m / z=755.3[M+H] +LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.013 minutes, ESI+ measured value [M+H] = 755.3.

[0593] [ka] Example 5, Synthesis of compound 55, (S,Z)-2-(4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves tert-butyl(2S)-4-[7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [H2O(10mM NH4HCO3)-ACN], gradient: 35%~70% B over 8.0 minutes) to obtain tert-butyl(2S)-4-[7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (65 mg, 19.96%) as a white solid. LCMS Rt=0.547min, m / z=568.2[M+H] + . [ka] Step 2 involves 2-[(2S)-4-[7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazine-2-yl]acetonitrile Deprotection of the Boc group was performed in the same manner as in step 4 of method #1. The reaction mixture was concentrated to dryness under vacuum to obtain 2-[(2S)-4-[7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl]piperazin-2-yl]acetonitrile (51 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.438min, m / z=468.2[M+H] + . [ka] Step 3 involves (S,Z)-2-(4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The residue was purified by preparative HPLC using a Waters Xbridge C18 150*50mm*10μm mobile phase [H2O (10mM NH4HCO3)], gradient: 30% to 60% B over 8.0 minutes to obtain (S,Z)-2-(4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile (11.97 mg, 20.73%) as a white solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.10 (s,1H), 7.44 (s,1H), 6.99 (d,J=2.6Hz,1H), 6.84 (d,J=2.5Hz,1H), 6.52-6.39 (m,1H), 4.91 (br s,1H), 4.55-4.39 (m,2H), 4.26-4.08 (m,1H), 4.03 (s,3H), 4.02-3.86 (m,1H), 3.85-3.67 (m,2H), 3.10-3.01 (m,1H), 2.97-2.90 (m,1H), 2.59 (s,3H), 2.47 (s,3H), 1.88-1.79 (m,1H), 0.60 (br d,J=6.6Hz,2H),0.02(br s,2H). LCMS Rt=2.864min,m / z=646.2[M+H] + LCMS (5-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.864 minutes, ESI+ measured value [M+H] = 646.2.

[0594] [ka] Example 6, Synthesis of compound 32, 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-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves 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 2 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) 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%) as a yellow solid. LCMS Rt=0.446 min, m / z=679.3 [M+H] + . [ka] Step 2 involves 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)piperazine-2-yl)acetonitrile Deprotection of the Boc group 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-(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 (407 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.353min, m / z=579.2[M+H] + . [ka] In 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-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [H2O (10mM NH4HCO3)-ACN], gradient: 40%~70% 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-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile (118.11 mg, 23.60%) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 9.14-9.04(m,1H),7.50(d,J=7.8Hz,1H),7.41-7.35(m,2H),7.34-7.29(m,1H),6.82-6.63(m,1H),5.43-5.18(m,1H),5. 03-4.81(m,1H),4.61-4.44(m,2H),4.41-4.13(m,3H),3.93-3.68(m,2H),3.40-3.16(m,3H),3.12-2.98(m,2H),2.89(br dd,J=4.9,16.6Hz,1H),2.72(s,3H),2.56(s,3H),2.36-2.15(m,3H),2.14-1.87(m,5H),0.72(br d,J=7.1Hz,2H),0.23-0.07(m,2H). LCMS Rt=3.175min,m / z=757.3[M+H] +LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.175 minutes, ESI+ measured value [M+H] = 757.3.

[0595] [ka] Example 7, Synthesis of compound 37, (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(2-methylpyrimidine-4-yl)prop-2-en-1-one (Method 1) [ka] Step 1 involves tert-butyl(R)-3-((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)(methyl)amino)pyrrolidine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to obtain tert-butyl(R)-3-((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)(methyl)amino)pyrrolidine-1-carboxylate (1.96 g, 79.41%) as a yellow solid. LCMS Rt=0.749 min, m / z=664.3 [M+H] + . [ka] Step 2 involves 7-(8-chloronaphthalene-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 the Boc group was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain 7-(8-chloronaphthalene-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 (40 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.483min, m / z=564.2[M+H] + . [ka] In step 3, (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(2-methylpyrimidine-4-yl)prop-2-en-1-one The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 40%~70%, 8 minutes) to obtain (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(2-methylpyrimidine-4-yl)prop-2-en-1-one (14.11 mg, 31.36%) as a yellow solid. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 9.34-9.16 (m,1H), 8.76-8.66 (m,1H), 8.21-8.13 (m,1H), 8.10-8.01 (m,1H), 7.74-7.68 (m,1H), 7.68-7.61 (m,2H), 7.60-7.51 (m,2H), 6.79-6.61 (m,1H), 5.45-5.16 (m,2H), 4.35-4.18 (m,2H), 4.16 (br d,J=3.8Hz,2H),3.90-3.80(m,1H),3.73-3.59(m,1H),3.52-3.44(m,3H),3.20-3.14(m,1H),3.13-3 .02(m,2H),2.96-2.84(m,1H),2.67(d,J=3.9Hz,3H),2.46-2.31(m,2H),2.11-1.99(m,2H),1.94(br s,4H). LCMS Rt=3.022min,m / z=728.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.022 minutes, ESI+ measured value [M+H] = 728.3.

[0596] [ka] Example 8, Synthesis of compound 41, (Z)-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)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one (Method 1) [ka] Step 1 involves 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 The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) 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 (642 mg, 86.51%) as a yellow solid. LCMS Rt=0.431 min, m / z=666.3[M+H] + . [ka] Step 2 involves 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 Deprotection of the Boc group was prepared in the same manner as in step 4 of method #1. 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 (150 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.474min, m / z=566.2[M+H] + . [ka] In step 3, (Z)-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)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 30%~60%, 8 minutes) to obtain (Z)-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)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one (8.25 mg, 10.05%) as a yellow solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.25 (s, 1H), 8.16-8.10 (m, 1H), 7.92 (ddd, J=1.6, 5.0, 9.2Hz, 1H), 7.75-7.68 (m, 2H), 7.56 (dt, J=7.6, 9.6Hz, 1H), 7.46 (br d,J=9.6Hz,1H),6.78-6.56(m,1H),5.47-5.14(m,2H),4.26-4.13(m,2H),4.12-3.94(m,1H),3. 93-3.72(m,2H),3.71-3.56(m,1H),3.47(s,3H),3.13-3.04(m,2H),3.02-2.80(m,2H),2.61(br s,3H),2.49(br d,J=6.9Hz,3H),2.44-2.32(m,2H),2.14-2.01(m,3H),1.92-1.76(m,3H). LCMS Rt=2.806min,m / z=744.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.806 minutes, ESI+ measured value [M+H] = 744.3.

[0597] [ka] Example 9, Synthesis of compound 44, (Z)-3-(2,6-dimethylpyrimidine-4-yl)-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)-2-fluoroprop-2-en-1-one (Method 1) [ka] Step 1 involves 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 2 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in petroleum ether) 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 (480 mg, 52.01%) as a yellow solid. LCMS Rt=0.584 min, m / z=828.4 [M+H] + . [ka] Step 2 involves 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 Deprotection of the TIPS group was prepared in the same manner as in step 3 of method #1. The reaction mixture was concentrated under vacuum 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 (600 mg, crude) as a white solid, which was used in the next step without further purification. LCMS Rt=0.663min, m / z=672.3[M+H] + . [ka] Step 3 involves 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 the Boc group was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain 7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidine-3-yl)pyrido[4,3-d]pyrimidine-4-amine (153 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.328 min, m / z=572.3[M+H] + . [ka] In step 4, (Z)-3-(2,6-dimethylpyrimidine-4-yl)-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)-2-fluoroprop-2-en-1-one The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Phenomenex Luna C18 200*40mm*10μm, mobile phase: [water (FA)-ACN], B%: 25%~60%, 8 minutes) to obtain (Z)-3-(2,6-dimethylpyrimidine-4-yl)-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)-2-fluoroprop-2-en-1-one (25.43 mg, 12.18%, formate) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 9.15(s,1H),8.03-7.92(m,2H),7.66-7.57(m,2H),7.41-7.31(m,2H),6.81(s,1H),5.49-5 .38(m,1H),4.51-4.27(m,2H),4.19-3.95(m,2H),3.85-3.63(m,2H),3.49(s,3H),2.93(br s,2H),2.72(s,3H),2.56-2.52(m,3H),2.44-2.28(m,3H),2.12-1.89(m,3H),1.73-1.50(m,6H). LCMS Rt=2.214min,m / z=750.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.214 minutes, ESI+ measured value [M+H] = 750.3.

[0598] [ka] In Example 10, compound 46, (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one, was synthesized (Method 1). [ka] Step 1 involves tert-butyl(R)-3-((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)(methyl)amino)pyrrolidine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to obtain tert-butyl(R)-3-((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)(methyl)amino)pyrrolidine-1-carboxylate (330 mg, 60.63%) as a yellow solid. LCMS Rt=0.497 min, m / z=654.3 [M+H] + . [ka] Step 2 involves 7-(3-chloro-2-cyclopropylphenyl)-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 the Boc group was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain 7-(3-chloro-2-cyclopropylphenyl)-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 (130 mg, crude, hydrochloride) as a yellow oily substance, which was used in the next step without further purification. LCMS Rt=0.377min, m / z=554.2[M+H] + . [ka] In step 3, (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [A: H2O (10mM NH4HCO3)], B%: 40.00%~70.00%, 8.00 min) to obtain (Z)-1-((R)-3-((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)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one (39.79 mg, 24.42%) as a yellow solid. 1¹H NMR (400MHz, chloroform-d) δ 9.17(s,1H),7.49(dd,J=1.3,7.9Hz,1H),7.42-7.35(m,2H),7.34-7.28(m,1H),6.98-6.83(m,1H),5.53-5.15(m,2H),4.42-4.21(m,2H),4.18-4.08(m,1H),4.08-3.87(m,1H),3.86 -3.61(m,2H),3.53-3.44(m,3H),3.42-3.08(m,3H),3.08-2.91(m,1H),2.72(s,3H),2.60 -2.50(m,3H),2.49-2.11(m,5H),2.09-1.84(m,4H),0.83-0.61(m,2H),0.26-0.04(m,2H). LCMS Rt=3.195min,m / z=732.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.195 minutes, ESI+ measured value [M+H] = 732.3.

[0599] [ka] Example 11, Synthesis of compound 56, (R,Z)-1-(3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one (Method 1) [ka] Step 1 involves tert-butyl(R)-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to obtain tert-butyl(R)-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (150 mg, 56.78%) as a yellow solid. LCMS Rt=0.574 min, m / z=543.2 [M+H] + . [ka] In step 2, (R)-3-chloro-4-cyclopropyl-5-(8-fluoro-2-methoxy-4-(methyl(pyrrolidine-3-yl)amino)pyrido[4,3-d]pyrimidine-7-yl)phenol Deprotection of the Boc group was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain (R)-3-chloro-4-cyclopropyl-5-(8-fluoro-2-methoxy-4-(methyl(pyrrolidine-3-yl)amino)pyrido[4,3-d]pyrimidine-7-yl)phenol (130 mg, crude, hydrochloride) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.364 min, m / z=443.2 [M+H] + . [ka] Step 3 involves 3-chloro-4-cyclopropyl-5-(4-(((R)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)pyrrolidine-3-yl)(methyl)amino)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-7-yl)phenyl(Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacrylate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was concentrated under vacuum to obtain 3-chloro-4-cyclopropyl-5-(4-(((R)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)pyrrolidine-3-yl)(methyl)amino)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-7-yl)phenyl(Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacrylate (150 mg, crude) as a brown oily substance, which was used in the next step without further purification. LCMS Rt=2.017min, m / z=799.3[M+H] + . [ka] In step 4, (R,Z)-1-(3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one 3-Chloro-4-cyclopropyl-5-(4-(((R)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)pyrrolidine-3-yl)(methyl)amino)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-7-yl)phenyl(Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacrylate (200 mg, 249.93 μmol) was dissolved in water (2 mL) and lithium hydrate (2 M, 374.89 μL) was added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [H2O (10mM NH4HCO3)-ACN], gradient: 20%~50% B over 8.0 minutes) to obtain (R,Z)-1-(3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroprop-2-en-1-one (5.72 mg, 3.36%) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 9.17(s,1H),7.41-7.32(m,1H),6.86(br d,J=2.5Hz,3H),5.56-5.31(m,1H),4.12(s,3H),4.07-3.92(m,1H),3.89-3.60(m,2H),3.42(br s,3H),2.77-2.62(m,3H),2.54(br d,J=8.5Hz,3H),2.42-2.13(m,2H),1.97-1.90(m,1H),1.38-1.23(m,2H),0.72-0.57(m,2H),0.17-0.02(m,2H). LCMS Rt=2.869min,m / z=621.2[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.869 minutes, ESI+ measured value [M+H] = 621.2.

[0600] [ka] Example 12, Synthesis of compound 16, 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-((Z)-2-fluoro-3-(1-methylazetidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile (Method 2) [ka] Step 1 involves tert-butyl 2-((Z)-3-((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-yl)-2-fluoro-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was purified by reverse-phase HPLC (column: Phenomenex Luna C18 250*50mm*10μm, mobile phase: [water (TFA)-ACN], B%: 25%~55%, 10 minutes) to obtain tert-butyl 2-((Z)-3-((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-yl)-2-fluoro-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (280 mg, 53.43%, trifluoroacetate) as a white solid. LCMS Rt=0.812min,m / z=834.3[M+H] + . [ka] Step 2 involves 2-((2S)-1-((Z)-3-(azetidine-2-yl)-2-fluoroacryloyl)-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 the Boc group was performed in the same manner as in step 4 of method #1. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under vacuum to obtain 2-((2S)-1-((Z)-3-(azetidine-2-yl)-2-fluoroacryloyl)-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 (70 mg, crude, trifluoroacetate) as a brown oily substance, which was used in the next step without further purification. LCMS Rt = 0.639 min, m / z = 734.3 [M + H] + . [ka] Step 3 involves 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-((Z)-2-fluoro-3-(1-methylazetidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile 2-((2S)-1-((Z)-3-(azetidine-2-yl)-2-fluoroacryloyl)-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)aceto To a methanol (5 mL) solution of nitrile (80 mg, 94.21 μmol), N,N-diisopropylethylamine (36.53 mg, 282.62 μmol), sodium borohydride cyanohydride (17.76 mg, 282.62 μmol), acetic acid (565.7 μg, 9.42 μmol), and formaldehyde (15.29 mg, 188.41 μmol) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm, 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-((Z)-2-fluoro-3-(1-methylazetidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile (9.98 mg, 13.98%) as a white solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.13-9.06 (m, 1H), 8.16-8.11 (m, 1H), 8.07 (dd, J=5.7, 9.1Hz, 1H), 7.70-7.64 (m, 2H), 7.52 (dt, J=1.8, 8.9Hz, 1H), 5.85-5.63 (m, 1H), 5.39-5.16 (m, 1H), 4.85 (br d,J=0.9Hz,1H),4.61-4.38(m,2H),4.26-4.06(m,3H),3.89(q,J=8.0Hz,1H),3.83-3.50(m,3H),3.35-3.27(m,1H),3. 20-3.11(m,2H),3.07(s,1H),3.03-2.96(m,1H),2.95-2.87(m,2H),2.85-2.69(m,1H),2.24(d,J=2.8Hz,3H),2.11(br d,J=2.9Hz,3H),2.08-2.00(m,2H),1.92-1.83(m,3H). LCMS Rt=2.021min,m / z=748.3[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.1% trifluoroacetic acid over 6 minutes), retention time 2.021 minutes, ESI+ measured value [M+H] = 748.3.

[0601] [ka] Example 13, Synthesis of compound 29, 2-((S)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (Method 1) [ka] Step 1 involves tert-butyl(S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The mixture was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to obtain tert-butyl(S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate (180 mg, 71.52%) as a brown solid. LCMS Rt=0.919 min, m / z=853.4 [M+H] + . [ka] Step 2 involves tert-butyl(S)-2-(cyanomethyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate Deprotection of the TIPS group was performed in the same manner as in step 3 of method #1. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to obtain tert-butyl(S)-2-(cyanomethyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-carboxylate (200 mg, 98%) as a brown oil. LCMS Rt=0.727 min, m / z=697.3 [M+H] + . [ka] Step 3 involves 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of the Boc group 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-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)piperazine-2-yl)acetonitrile (80 mg, crude, hydrochloride) as a yellow solid, which was used in the next step without further purification. LCMS Rt=0.712 min, m / z=597.3[M+H] + . [ka] In step 4, 2-((S)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35%~65%, 8 minutes) to obtain 2-((S)-1-((Z)-3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (16.83 mg, 16.56%) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δ 9.09-9.03 (m,1H), 8.03-7.93 (m,2H), 7.68-7.56 (m,2H), 7.42-7.33 (m,2H), 6.90-6.64 (m,1H), 5.46-5.20 (m,1H), 5.05-4.81 (m,1H), 4.60-4.44 (m,2H), 4.42-4.31 (m ,2H),4.24-4.12(m,1H),4.00-3.77(m,2H),3.46-3.28(m,2H),3.27-3.10(m,2H),3 .08-2.99(m,2H),2.94-2.89(m,1H),2.77-2.68(m,3H),2.60-2.53(m,3H),2.32(br s, 1H), 2.27-2.16 (m, 2H), 2.07-1.88 (m, 4H). LCMS Rt=3.028min,m / z=775.3[M+H] +LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 3.028 minutes, ESI+ measured value [M+H] = 775.3.

[0602] [ka] In Example 14, compound 54, (S,Z)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile, was synthesized (Method 1). [ka] Step 1 involves tert-butyl(S)-4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The Suzuki reaction product was prepared in the same manner as in step 2 of method #1. The mixture was purified by reverse-phase HPLC (column: Waters Xbridge C18 150*50mm*10μm, mobile phase: [H2O(10mM NH4HCO3)-ACN], gradient: 55%~75% B over 8.0 minutes) to obtain tert-butyl(S)-4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (75 mg, 28.20%) as a yellow oil. LCMS Rt=0.581min, m / z=580.2[M+H] + . [ka] In step 2, (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile Deprotection of the Boc group was prepared in the same manner as in step 4 of method #1. The reaction mixture was concentrated under vacuum to obtain (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile (55 mg, crude, trifluoroacetate) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.389min, m / z=480.1[M+H] + . [ka] In step 3, (S,Z)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazine-2-yl)acetonitrile The amide coupling reaction product was prepared in the same manner as in step 5 of method #1. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm, mobile phase: [H2O (10mM NH4HCO3)-ACN], gradient: 35%~65% B over 8.0 minutes) to obtain (S,Z)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-8-fluoro-2-methoxypyrido[4,3-d]pyrimidine-4-yl)-1-(3-(2,6-dimethylpyrimidine-4-yl)-2-fluoroacryloyl)piperazin-2-yl)acetonitrile (25.46 mg, 41.52%) as a white solid. 1¹H NMR (400MHz, acetonitrile-d3) δ 9.12 (d, J=4.9Hz, 1H), 8.17-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.77-7.61 (m, 2H), 7.55-7.48 (m, 1H), 7.45 (s, 1H), 6.54-6.40 (m, 1H), 4.99-4.87 (m, 1H), 4.61-4.41 (m, 2H), 4.27-4.09 (m, 1H), 4.06-4.03 (m, 3H), 3.96-3.66 (m, 3H), 3.12-3.02 (m, 1H), 3.00-2.89 (m, 1H), 2.59 (s, 3H), 2.47 (s, 3H). LCMS Rt=2.994min,m / z=658.2[M+H] + LCMS (5%-95% acetonitrile aqueous solution + 0.03% ammonium bicarbonate over 6 minutes), retention time 2.994 minutes, ESI+ measured value [M+H] = 658.2.

[0603] Example 15, Other Results TIFF2026515946000368.tif213165TIFF2026515946000369.tif213165TIFF2026515946000370.tif228165 TIFF2026515946000371.tif208165TIFF2026515946000372.tif197165TIFF2026515946000373.tif228165 TIFF2026515946000374.tif242165TIFF2026515946000375.tif238165TIFF2026515946000376.tif238165 TIFF2026515946000377.tif238165TIFF2026515946000378.tif238165TIFF2026515946000379.tif222165

[0604] Biological examples Example 16, 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 with 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% Triton X-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 luminescence 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 AlphaScreen donor and acceptor beads, respectively. IC 50 This was determined using a nonlinear regression approximation of the inhibitor and the response (four parameters).

[0605] 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.

[0606] The results for the compounds are shown in Table 1. [Table 1] TIFF2026515946000381.tif241165TIFF2026515946000382.tif190165TIFF2026515946000383.tif191165TIFF2026515946000384.tif201165 TIFF2026515946000385.tif191165TIFF2026515946000386.tif196165TIFF2026515946000387.tif180165TIFF2026515946000388.tif191165 TIFF2026515946000389.tif191165TIFF2026515946000390.tif190165TIFF2026515946000391.tif212165TIFF2026515946000392.tif217165 TIFF2026515946000393.tif207165TIFF2026515946000394.tif217165TIFF2026515946000395.tif232165TIFF2026515946000396.tif190165

[0607] Example 17, KRAS G12C and inhibition of PI3Ka binding AlphaScreen technology enables compound inhibition of ICs for 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 examined, and the emission is 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. The IC50 is determined using nonlinear regression fitting of [inhibitor] vs. response (four parameters).

[0608] 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.

[0609] Example 18, 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 and processed in Dotmatics, and EC50 is calculated by differential gradient using the Lavenberg-Marquardt 4-parameter fitting procedure.

[0610] Example 19: 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.

[0611] All publications, patents, patent applications and published patent applications referenced herein by identifying reference are incorporated herein by reference in their entirety.

[0612] 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), formula (III), formula (IV), formula (V), or formula (VI), or salts thereof, and / or isotopic substitutions thereof: During the ceremony, 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 to C ４ alkyl, C ３ to C ４ cycloalkyl, C １ to C ４ alkoxy, C １ to C ４ haloalkyl, C １ to C ４ haloalkoxy and C ２ to C ３ alkynyl, and is selected from the group consisting of m is 0, 1, 2, or 3. R １ H, -OCH ２ R １Ａ , -OC １ ~C ４ Alkyl, -C １ ~C ４ Alkyl and Selected from the group consisting of, R １Ａ teeth, Selected from the group consisting of, R ｄ is H or F, R ２ teeth, And, R ｅ is -COOH, -C(O)OC １ ~C ４ Alkyl, -C(O)O-C １ ~C ４ Haloalkyl, -C(O)-C １ ~C ４ Alkyl, -C(O)-C １ ~C ４ Haloalkyl, -C(O)N(C) １ ~C ４ Alkyl) ２ , - (C １ ~C ２ (Alkyl)-(C １ ~C ２ Alkoxy), -S(O) ２ -C １ ~C ４ Alkyl, -S(O) ２ -C １ ~C ４ Haloalkyl, R ｅ１ , -C(R Ｙ１ ) (Caution Ｙ２ ) R ｅ１ , R ｅ２ and -C(R Ｙ１ ) (Caution Ｙ２ ) R ｅ３ Selected from the group consisting of, R Ｙ１ and R Ｙ２ Each instance, independently, is either -H or -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 It is halo, hydroxy, and C １ ~C ４ Alkyl and C １ ~C ４ Hydroxyalkyl and C １ ~C ４ Alkoxy and C １ ~C ４ Haloalkyl and C １ ~C ４ Haloalkoxys and C substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, hydroxy, and methyl ３ ~C ６ A heterocycline and a C substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, hydroxy, and methyl. ３ ~C ６ A 5-6 member heteroaryl group substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cycloalkyl groups, R ｅ３ -NR ３１ R ３２ And, R ３１ and R ３２ are each independently hydrogen, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkoxy, and C １ -C ４ alkyl substituted with a 3- to 6-membered heterocyclic ring, selected from the group consisting of: Each R ｘ is independently selected from the group consisting of -OH, halo, and C １ to C ４ alkyl n is 0, 1, or 2. However, R in equation (II) ｅ R ｅ２ If so, the R ｅ２ The 5-6 member heteroaryl group is substituted with 1, 2, or 3 substituents, and R of formula (III) １ but If that is the case, teeth, isn't it.

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

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

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

8. The stereochemistry of pyrrolidine is (R) (i.e., The part that is represented as The compound, salt thereof, and / or isotope-substituted thereof, according to any one of claims 1, 2, and 5.

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

10. 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 9, or a salt thereof, and / or an isotopic substituted thereof.

11. 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 9, a salt thereof, and / or an isotopic substituted thereof.

12. Each R ａ These are independently: halo, -OH, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ４ Haloalkyl and C ２ ~C ３ A compound selected from alkynyl, according to any one of claims 1 to 11, a salt thereof, and / or an isotopic derivative thereof.

13. Each R ａ These are independently -F, -Cl, -OH, -Me, -Et, -cyclopropyl, -CF ３ A compound according to any one of claims 1 to 11, selected from -C≡CH, or a salt thereof, and / or an isotopic substituted thereof.

14. Ring A is, Selected from the group consisting of, During the ceremony, R ３ , R ４ , R ５ , R ６ , 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 These are, independently, hydrogen, halo, -OH, and -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 Selected from the group consisting of alkynnyls, A compound according to any one of claims 1 to 9, a salt thereof, and / or an isotopically substituted thereof.

15. R ３ , R ４ , R ５ , R ６ , 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 Selected from the group consisting of , and -C≡CH, R ｇ , R ｍ , and R ｐ The compound according to claim 14, wherein each is independently -H or -OH.

16. Ring A is, The compound according to claim 14 or 15, a salt thereof, and / or an isotopically substituted thereof.

17. Ring A is, The compound according to claim 14 or 15, a salt thereof, and / or an isotopically substituted thereof.

18. Ring A is, The compound according to any one of claims 1 to 9, a salt thereof, and / or an isotope-substituted thereof.

19. R ３ H, Halo, C １ ~C ４ Alkyl, or C ２ ~C ３ It is alkinyl, R ４ The compound according to claim 14 or 15, or a salt thereof, and / or an isotopic substituted thereof, wherein is H or a halo.

20. R ３ is H, -F, -Cl, -Me, -Et, or -C≡CH, and R ４ The compound according to claim 14 or 15, or a salt thereof, and / or an isotopic substituted thereof, wherein is H or -F.

21. R ｊ C ３ ~C ４ Cycloalkyl or C １ ~C ４ It is a haloalkyl, R ｋ H or halo, R ｍ The compound according to claim 14 or 16, or a salt thereof, and / or an isotopically substituted thereof, wherein is H or -OH.

22. R ｊ is cyclopropyl or -CF ３ And R ｋ is H or -Cl, and R ｍ The compound according to claim 14 or 16, or a salt thereof, and / or an isotopically substituted thereof, wherein is H or -OH.

23. R ｄ The compound according to any one of claims 1 to 22, or a salt thereof, and / or an isotopic substituted thereof, wherein is H.

24. R ｄ The compound according to any one of claims 1 to 22, or a salt thereof, and / or an isotopic substituted thereof, wherein F is the compound.

25. R １Ａ teeth, The compound according to any one of claims 1 to 22, a salt thereof, and / or an isotope-substituted thereof.

26. R １Ａ teeth, The compound according to any one of claims 1 to 22, a salt thereof, and / or an isotope-substituted thereof.

27. R １ H, -OCH ２ R １Ａ , -OMe, Me, or The compound according to any one of claims 1 to 22, a salt thereof, and / or an isotope-substituted thereof.

28. R １ teeth, A compound according to any one of claims 1 to 22, or a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

29. R ２ teeth, The compound according to any one of claims 1 to 28, a salt thereof, and / or an isotope-substituted thereof.

30. R ２ teeth, The compound according to any one of claims 1 to 28, a salt thereof, and / or an isotope-substituted thereof.

31. R Ｙ１ is -H, and R Ｙ２ The compound according to any one of claims 1 to 30, or a salt thereof, and / or an isotopic substituted thereof, wherein is -H.

32. R ｅ is -C(O)O-C １ -C ４ Alkyl, R ｅ１ , -C(R Ｙ１ ) (Caution Ｙ２ ) R ｅ１ , R ｅ２ , and -C(R Ｙ１ ) (Caution Ｙ２ ) R ｅ３ A compound according to any one of claims 1 to 31, or a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

33. R ｅ１ teeth, A 4- to 7-membered monocyclic heterocycle containing only a nitrogen atom as a heteroatom, or containing one nitrogen atom and one oxygen atom; or a 6- to 10-membered bridging heterocycle. And, The aforementioned 4- to 7-membered monocyclic heterocycle or the aforementioned 6- to 10-membered bridging heterocycle 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 Substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkoxys, A compound according to any one of claims 1 to 31, a salt thereof, and / or an isotopically substituted thereof.

34. R ｅ１ The compound according to any one of claims 1 to 31, or a salt thereof, and / or an isotopic substituted thereof, is selected from the group consisting of azetidinil, pyrrolidinil, tetrahydrofuranil, and morpholinil, each of which is substituted with zero or one methyl, ethyl, isopropyl, or methoxyethyl.

35. R ｅ R ｅ１ or -C(R Ｙ１ ) (Caution Ｙ２ ) R ｅ１ The compound according to any one of claims 1 to 34, a salt thereof, and / or an isotopic substituted thereof.

36. 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 35, or a salt thereof, and / or an isotopically substituted thereof, which is substituted with 0, 1, 2, 3, or 4 substituents selected from haloalkoxys.

37. R ｅ R ｅ２ The compound according to any one of claims 1 to 30, a salt thereof, and / or an isotopically substituted thereof.

38. R ｅ２ This is a 5-6 membered heteroaryl group containing at least one nitrogen atom, and the bonding site of the heteroaryl group is a carbon atom group. The aforementioned heteroaryl is halo, C １ ~C ４ Alkyl, C １ ~C ４ Hydroxyalkyl, C １ ~C ６ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ C may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys, fluorosulfates, and methyls. ３ ~C ６ Substituted with 0, 1, or 2 substituents independently selected from the group consisting of cycloalkyl groups, The compound according to claim 37, or a salt thereof, and / or an isotopically substituted thereof.

39. R ｅ２ The group is selected from pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is a halo, C １ ~C ４ Alkyl, C １ ~C ４ Hydroxyalkyl, C １ ~C ６ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ C may be substituted with one or two substituents independently selected from haloalkoxys, fluoro, and methyl. ３ ~C ６ The compound according to claim 37, or a salt thereof, and / or an isotopically substituted thereof, which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of cycloalkyl compounds.

40. R ｅ２ teeth, A group consisting of is selected, and each of them is Halo, C １ ~C ４ Alkyl, C １ ~C ４ Hydroxyalkyl, C １ ~C ６ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ C may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys, fluorosulfates, and methyls. ３ ~C ６ The compound according to claim 37, or a salt thereof, and / or an isotopically substituted thereof, which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of cycloalkyl compounds.

41. R ｅ teeth, A compound according to any one of claims 1 to 30, or a salt thereof, and / or an isotope-substituted compound thereof, selected from the group consisting of the above.

42. R ｘ The compound according to any one of claims 1 to 41, or a salt thereof, and / or an isotopic substituted thereof, wherein is -OH.

43. The compound according to any one of claims 1 to 41, or a salt thereof, and / or an isotopically substituted thereof, wherein n is 0.

44. 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.

45. The compound according to any one of claims 1 to 44, or a salt thereof, and / or an isotopic substituted thereof, wherein the salt is a formate salt.

46. The compound according to any one of claims 1 to 45, or a salt thereof, and / or an isotopic variant thereof, wherein the salt is a pharmaceutically acceptable salt.

47. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 46, a pharmaceutically acceptable salt thereof, and / or an isotopic substitution thereof, and a pharmaceutically acceptable carrier.

48. 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 46, or a pharmaceutically acceptable salt thereof, and / or an isotopic variant thereof, or a pharmaceutical preparation according to claim 47.

49. The method according to claim 48, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma cancer, cervical cancer, and bladder cancer.

50. 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 cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, clear cell carcinoma of the kidney, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine body, squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytotic myeloma, uterine carcinosarcoma, mesothelioma, The method according to claim 48, selected from the group consisting of adrenocortical carcinoma, low-grade cerebral glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal pigmentophobic carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic carcinoma, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

51. The method according to any one of claims 48 to 50, wherein the cancer is KRAS G12C-mediated cancer, or the subject is diagnosed with KRAS G12C-mediated cancer, or both.

52. The method according to any one of claims 48 to 51, further comprising administering a therapeutically effective amount of an additional chemotherapeutic agent to the subject.

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