Methods for the treatment of cancer

Abstract

The present disclosure provides compounds and methods useful in the treatment and suppression of cancer, for example, useful in treating or suppressing cancers characterized by KRAS G12C. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 356,927, filed on June 29, 2022, U.S. Provisional Patent Application No. 63 / 464,185, filed on May 4, 2023, and U.S. Provisional Patent Application No. 63 / 465,510, filed on May 10, 2023, and the entire disclosures of these are incorporated herein by reference in their entireties for all purposes.

[0002] Field of the Disclosure The present disclosure provides compounds useful in treating or suppressing cancer, particularly compounds useful in treating or suppressing cancers characterized by the KRAS G12C mutation. Pharmaceutical formulations containing such compounds, processes for preparing such compounds, and methods of using such compounds in the treatment or suppression of cancer are also provided.

Background Art

[0003] Background KRAS is a molecular switch. Under normal physiological conditions, the protein binds to guanosine diphosphate (GDP) in the "off state". 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 in the "on state" and interacts with proteins such as RAF and PI3K to enhance downstream signaling leading to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP in a process facilitated by GAP (GTPase - activating protein), thus returning to the off state.

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

[0005] The cysteine residue of G12C provides an opportunity to develop covalent drugs targeted at this mutant KRAS. The results of initial clinical trials for the KRAS G12C inhibitors AMG 510 and MRTX849 showed promising results for non-small cell lung cancer (NSCLC), but less compelling data for colorectal cancer (CRC). Furthermore, there are signs that even in cases where patients respond to initial treatment, the duration of response may be limited and resistance may develop rapidly.

[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 with the GDP-bound form of KRAS G12C than with the GTP-bound form of the protein. One form of resistance that has been observed is that cancer cells increase signaling via RTKs and thus increase the amount of GTP-bound KRAS that is less affected by current inhibitors. Therefore, the generation of molecules that can bind to and inhibit both the GDP-bound and GTP-bound forms of KRAS may have substantial utility.

[0007] What is needed are compounds useful in the treatment of cancer (such as cancer characterized by KRAS G12C, etc.). Further needed are compounds useful in the treatment of cancer characterized by KRAS G12C, which bind to and inhibit both the inactivated GDP-bound form and the activated GTP-bound form of KRAS. Further needed are compounds useful in the treatment of cancer characterized by KRAS G12C, which have improved inhibition of the GTP-bound form of KRAS G12C.

Summary of the Invention

[0008] Summary In a first aspect, a compound of formula A, formula B, or formula C: TIFF2025523624000001.tif82128 or a salt thereof; and / or an isotopically substituted form thereof [wherein, Ring A is a 6-membered aryl or a 5- to 10-membered heteroaryl; R F is selected from the group consisting of H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; Each R G is independently selected from halo, -OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, and C2-C3 alkynyl; Each GG is independently 0, 1, 2, or 3; R 1 is a 4- to 8-membered saturated carbocyclic group or a heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the carbocyclic group or heterocyclic group is substituted by 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2b R 2c and R 2eselected from the group consisting of; R 2b is -NR 10 R 11 ; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 is -(CH2) w -R 13 ; or R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom within the ring atoms, the second nitrogen of the 4- to 8-membered saturated heterocyclic group is substituted by cyano, and the 4- to 8-membered saturated heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; R 13 is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, the nitrogen is substituted by cyano, and the heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, one of the nitrogens is substituted by cyano, and the heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to the heteroatom; or R 13is a 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) is substituted by cyano, and the heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to the heteroatom; w is 0, 1, or 2; R 2c is -NR 15 R 16 ; R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 16 is -(CH2) y -R 21 ; R 21 is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C(R 19 )=C(R 20 )R 18 , and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms in the ring atoms, wherein one of the nitrogens of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 6-membered saturated heterocyclic group; or a 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms (plural available) of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated heterocyclic group is selected from; R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and R 35 is selected from the group consisting of; R 19 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy selected from the group consisting of; R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 22 and R 23 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 34 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 35 is a 5- to 6-membered heteroaryl group optionally substituted with 0, 1, or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halo, and methyl, and optionally substituted with 1 or 2 substituents independently selected from C3-C6 heterocyclyl optionally substituted with 1 or 2 substituents independently selected from halo and methyl, and C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo and methyl; y is 0, 1, or 2; z is 1 or 2; q is 0 or 1; u is 0, 1, or 2; R 2e is -NR 28 R 29 ; R 28 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 29 is -(CH2)t-R 30 ; R 30 is A 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C≡CR 31 and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; said 4- to 5-membered saturated heterocyclic group; A 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, wherein one of the nitrogens of the heterocyclic group is substituted by -C(O)C≡CR 31 and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; said 6-membered saturated heterocyclic group; and A 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is substituted by -C(O)C≡CR 31 and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, provided that any optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; said 7-membered saturated heterocyclic group selected from; R 31 is selected from the group consisting of -(CH2) v -NR 32 R 33 and -(CH2) p -R 36 ; R 32 and R 33 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; t is 0, 1, or 2; v is 1 or 2; p is 0, 1, or 2; R 36 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl) is provided.

[0009] In some embodiments, including any of the embodiments in the preceding paragraph, the compound is selected from the group consisting of the compounds of Table 1 and all of their salts and isotope substituents.

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

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

[0012] In another aspect, provided is the use of a compound described herein (including, but not limited to, any of the foregoing embodiments) as a medicament. In another aspect, provided is the use of a compound described herein (including, but not limited to, any of the foregoing embodiments) for treating or suppressing cancer. In another aspect, provided is the use of a compound described herein (including, but not limited to, any of the foregoing embodiments) in the manufacture of a medicament for use in treating or suppressing cancer. In some embodiments including any of the foregoing embodiments, the use is for treating cancer. In some embodiments including any of the foregoing embodiments, the use is for suppressing cancer.

[0013] In another aspect, provided is a compound described herein (including, but not limited to, any of the foregoing embodiments) for use in the manufacture of a medicament for treating or suppressing cancer. In another aspect, provided is a compound described herein (including, but not limited to, any of the foregoing embodiments) for use in treating or suppressing cancer. In another aspect, provided is a compound described herein (including, but not limited to, any of the foregoing embodiments) for use in the manufacture of a medicament for treating or suppressing cancer. In some embodiments including any of the foregoing embodiments, the use is for treating cancer. In some embodiments including any of the foregoing embodiments, the use is for suppressing cancer.

[0014] The descriptions of the compounds, compositions, formulations, and treatment methods described herein are understood to encompass embodiments of "comprising", "consisting of", and "consisting essentially of". In some embodiments, for all of the compositions described herein and all of the methods of using the compositions described herein, the composition may include the listed components or steps, or may "consist essentially of" the listed components or steps. When a composition is described as "consisting essentially 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 the explicitly listed components; or if the composition contains excess components other than those listed that substantially affect the condition being treated, the composition does not contain an excess concentration or amount of the excess components sufficient to substantially affect the condition being treated. When a method is described as "consisting essentially 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 the method does not contain other steps that substantially affect the condition being treated other than the explicitly listed steps. By way of non-limiting specific example, when a composition is described as "consisting essentially of" the components, the composition may contain an additional optional amount of a pharmaceutically acceptable carrier, vehicle, or diluent substance, and other components that do not substantially affect the condition being treated.

[0015] Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description of the invention and from the practice of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

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

[0017] Abbreviations used herein have their conventional meanings within the chemical and biological arts, unless otherwise defined.

[0018] It is to be understood that the description of compound structures including possible substitutions is limited to those that are chemically possible.

[0019] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as illustrated. Compounds with the notation (or) in the first column of Table 1 are single enantiomers, where the absolute stereochemistry is arbitrarily assigned (e.g., based on chiral SFC elution described in the Examples section) and the relative stereochemistry is as shown, unless otherwise specified. Compounds with the notation (and) in the first column of Table 1 are mixtures of enantiomers, where the relative stereochemistry is as shown. Compounds having stereocenters not indicated in structures with stereochemistry illustrated and having no notation in the first column of Table 1 are mixtures of enantiomers at that center. Compounds having stereocenters indicated by wedges or hashes in the structure and having no notation or marked with (abs) in the first column of Table 1 are single enantiomers, where the absolute stereochemistry is as shown. For example, Compound 1 is a pure enantiomer with the indicated stereochemistry. TIFF2025523624000002.tif35128

[0020] In some examples, the first column of Table 1 contains different indicators selected from (abs), (or), and (and) to refer to different stereocenters or pairs of stereocenters of the molecule.

[0021] For example, Compound 9 includes the notation “(abs) pyrrolidine, (or) both cyclohexenyl stereocenters” in column 1 of Table 1. TIFF2025523624000003.tif36128

[0022] The compound is a single enantiomer, where the stereochemistry of the pyrrolidine group is (S) as shown, because the pyrrolidine group was prepared from a mirror-image pure starting material, and the stereochemistry of the fused cyclohexenyl is either (R,R) or (S,S), not a mixture of the two, nor a mixture with (R,S) or (S,R), and the stereochemistry was arbitrarily assigned. When a mixture of enantiomers or diastereomers is separated by chromatography into the corresponding single enantiomer or diastereomer, the stereochemistry is often arbitrarily assigned.

[0023] One of ordinary skill in the art would be able to separate a racemic compound into its respective enantiomers using methods known in the art such as chiral chromatography, chiral recrystallization, and the like. A reference to a compound that is a racemic mixture is meant to include the individual enantiomers contained in the mixture.

[0024] References to "about" a value or parameter herein include (and describe) variations that are inherent in the value or parameter itself. For example, a reference to "about X" includes a description of "X". As used herein, unless otherwise specified, the terms "about" and "approximately" are used in connection with the temperature, dosage, amount, or weight percentage of a component of a composition or dosage form and are recognized by those skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage. Specifically, the terms "about" and "approximately" as used in this context are intended to encompass dosages, amounts, or weight percentages within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dosage, amount, or weight percentage.

[0025] As used herein, the terms "a" and "an" mean one or more, unless the context clearly dictates otherwise.

[0026] 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, domestic animals (such as cows, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, and horses). In some embodiments, the subject is identified or diagnosed as having a cancer or tumor having a KRAS G12C mutation (e.g., determined using an assay or kit approved by a regulatory agency (such as approved by the FDA)).

[0027] "Treating" a disorder by the compounds and methods contemplated herein is defined as administering one or more of the compounds contemplated herein, with or without additional therapeutic agents, to reduce or eliminate the disorder or one or more symptoms thereof, or to retard the progression of the disorder or one or more symptoms thereof, or to reduce the severity of the disorder or one or more symptoms thereof.

[0028] "Suppressing" a disorder by the compounds and methods contemplated herein is defined as administering one or more of the compounds contemplated herein, with or without additional therapeutic agents, to suppress the clinical manifestations of the disorder or the manifestations 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 can be partial, substantially complete, or complete. In some embodiments, genetic screening can be used to identify subjects at risk of a disorder. The compounds and methods disclosed herein can then be administered to asymptomatic subjects at risk of developing the clinical manifestations of the disorder to suppress the appearance of any adverse symptoms.

[0029] "Therapeutic use" of a compound contemplated herein is defined as using one or more of the compounds contemplated herein to treat or suppress a disorder as defined herein. A "therapeutically effective amount" of a compound is an amount of the compound that, when administered to a subject, is sufficient to reduce or eliminate the disorder or one or more symptoms thereof, or to retard the progression of the disorder or one or more symptoms thereof, or to reduce the severity of the disorder or one or more symptoms thereof, or to suppress the clinical manifestations of the disorder, or to suppress the manifestations of the adverse symptoms of the disorder. A therapeutically effective amount can be administered in one or more administrations.

[0030] "KRAS G12C-mediated cancer" is used interchangeably herein with "cancer characterized by KRAS G12C", and refers to the cancer containing cells with KRAS G12C mutation.

[0031] The compounds described herein may occur and be used as neutral (non-salt) compounds, but this specification is intended to encompass all salts of the compounds described herein and methods of using such salts of the compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0032] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable for humans and / or animals and that retains at least some of the desired pharmacological activity of the parent compound upon administration. Such salts include (a) those formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like); or organic acids (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'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like); or (b) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or coordinated with an organic base (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like). Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985 (which is hereby incorporated by reference in its entirety).

[0033] When chemically appropriate, all stereoisomers of a compound, including diastereomers and enantiomers, are included herein. Mixtures of the possible stereoisomers are also included in any ratio (including, but not limited to, racemic mixtures). Unless the stereochemistry is explicitly shown in the structure, the structure is intended to encompass all possible stereoisomers of the depicted compound. If the stereochemistry is explicitly shown for a part or parts of the molecule but not for another part or parts of the molecule, the structure is intended to encompass all possible stereoisomers for the part or parts for which the stereochemistry is not explicitly shown.

[0034] As used herein, "isotopically substituted compound" refers to a compound having an isotopic composition different from its "natural" isotopic composition. "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the isotopic composition or abundance that occurs naturally for a given atom. Atoms having their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds recited 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", that position is understood to have hydrogen in its natural isotopic composition. Descriptions of compounds herein include all isotopically substituted compounds of all compounds herein, and in some embodiments also include partially deuterated analogs or fully deuterated analogs. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotope enrichment" refers to the percentage by which a specific isotope amount is incorporated in place of the natural isotopic abundance of a given atom in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the defined position. Since the natural abundance of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotope enrichment of compounds provided herein can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0035] "Alkyl" means a straight-chain, branched-chain, cyclic, or combination thereof saturated monovalent hydrocarbon radical having a defined number of carbons. For example, C1-C4 alkyl includes, for example, methyl, ethyl, propyl, 2-propyl, butyl, cyclopropyl, cyclobutyl, and the like.

[0036] "Alkylene" means a saturated divalent hydrocarbon radical that is linear, branched, cyclic, or a combination thereof having a defined number of carbons. For example, C1-C4 alkylene includes, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and the like. "C0 alkylene" means a bond. For example, C0-C2 alkylene includes a bond, methylene, ethylene, and the like.

[0037] "Alkynyl" means a linear or branched monovalent hydrocarbon radical having a defined number of carbons and at least one carbon-carbon triple bond. For example, C2-C4 alkynes include, for example, ethynyl, propynyl, 2-propynyl, butynyl, and the like.

[0038] "Alkoxy" is -OR o radical (wherein R o is alkyl as defined above) or -R o ’R o ” radical (wherein R o ’ is alkylene and R o ” is an alkyl group as defined above), and wherein the defined number of alkyl carbons in the alkoxy group is equal to the total number of carbons in R o ’ and R o ”. For example, C1-C4 alkoxy includes, for example, methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopropoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, alkoxy is an -OR o radical. In some embodiments, alkoxy is an -R o ’R o ” radical. In some embodiments, when nitrogen is substituted by an alkoxy group, the alkoxy group is not linked to nitrogen through the oxygen or a carbon immediately adjacent to the oxygen in the alkoxy group. For example, alkoxy-substituted nitrogen is N-OR oor N-CH2-OR o is not “

[0039] “Alkoxyalkoxy” means -OR r radical (wherein R r is the alkoxy defined above, provided that the point of attachment of R r is not an oxygen atom) or -R r ’OR r ” radical (wherein R r is alkylene and R r ” is the alkoxy group defined above, provided that the point of attachment of R r ” is not an oxygen atom), and in the formula, the defined number of alkyl carbons in the alkoxyalkoxy group is equal to the total number of carbons in R r ’ and R r ”. For example, C1-C6 alkoxyalkoxy represents, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, and the like. In some embodiments, alkoxyalkoxy is a -OR r radical. In some embodiments, alkoxyalkoxy is a -R r ’OR r ” radical. In some embodiments, when nitrogen is substituted by an alkoxyalkoxy group, the alkoxyalkoxy group is not linked to nitrogen through an oxygen or a carbon immediately adjacent to oxygen in the alkoxyalkoxy group. For example, alkoxyalkoxy-substituted nitrogen is not N-OR r or N-CH2-O-R r ”.

[0040] “Aminoalkyl” means -NHR n radical (wherein R n is the alkyl defined above) or -NR n R n ’ radical (wherein R n and R n’ is an alkyl group as defined above) or -R n ”NH2 radical (wherein R n ” is an alkylene group as defined above) or -R n ”NHR n radical (wherein R n ” is an alkylene group as defined above and R n is an alkyl group as defined above) or -R n ”NR n R n ’ radical (wherein R n ” is an alkylene group as defined above and R n and R n ’ are alkyl groups as defined above), and in the formula, the defined number of alkyl carbons in the aminoalkyl group is, when applicable, equal to the total number of carbons in R n , R n ’ and R n ”. For example, C1-C6 aminoalkyl represents, for example, -NHCH3, -NHCH2CH3, -NHCH2(CH3)2, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -CH2NH2, -CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and the like. In some embodiments, the aminoalkyl is a -NHR n radical. In some embodiments, the aminoalkyl is a -NR n R n ’ radical. In some embodiments, the aminoalkyl is a -R n ”NH2 radical. In some embodiments, the aminoalkyl is a -R n ”NHR n radical. In some embodiments, the aminoalkyl is a -R”NR n R n ’ radical. In some embodiments, when oxygen is substituted by an aminoalkyl group, the aminoalkyl group is not linked to oxygen through nitrogen or a carbon immediately adjacent to nitrogen in the aminoalkyl group. For example, aminoalkyl-substituted oxygen is O-NR nor O-CH2NHR n is not. "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6 to 4 ring carbon atoms and 0 heteroatoms provided in an aromatic ring system ("C 6-14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracyl). In some embodiments, "aryl" also encompasses a ring system in which the aryl ring defined above is condensed with one or more carbocyclic groups or heterocyclic groups, where the radical or point of attachment is on the aryl ring, and in such examples, the number of ring carbon atoms continues to specify the number of ring carbon atoms in 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 the aryl ring defined above is condensed with one or more carbocyclic groups or heterocyclic groups.

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

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

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

[0045] "Haloalkoxy" is -OR a radical (wherein R a is the haloalkyl defined above) or -R b OR c radical (wherein R b and R c are an alkyl group or a haloalkyl group as defined above), and wherein the defined number of alkyl carbons in the haloalkoxy group is equal to the total number of carbons in R b and R c . The halo atom(s) may be present in R b , R c , or both, provided that at least one of R b and R c contains a halo atom. For example, C1-C4 haloalkoxy includes, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2, and the like. In some embodiments, haloalkoxy is -OR a radical. In some embodiments, haloalkoxy is -R b OR cIt is a radical. When all of the halogen atom(s) in the haloalkoxy group is / are fluorine, it can be referred to as fluoroalkoxy in the present application. In some embodiments, when nitrogen is substituted by a haloalkoxy group, the haloalkoxy group is not linked to nitrogen through oxygen or the carbon immediately adjacent to oxygen in the haloalkoxy group. For example, haloalkoxy-substituted nitrogen is not N-OR a or N-C(H) n (X) m -O-R c (wherein X is a halogen, n and m are integers, provided that n + m = 2).

[0046] "Hydroxyalkyl" means an alkyl radical defined as being substituted by one or more hydroxyl (-OH) groups (e.g., 1 to 3 hydroxyl groups, e.g., -CH2OH, -CH2CH2OH, -C(OH)(CH3)2, -CH(OH)CH3, and the like).

[0047] "Heterocyclic group" or "heterocycle" means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, unless otherwise specified, wherein 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the remainder of the ring is C. The sulfur group may be present either as -S- or as -S(O)2-. Unless otherwise specified, the heterocyclic group includes monocyclic and polycyclic systems, including fused ring systems, bridged ring systems, and spiro ring systems. "Heterocyclic group" or "heterocycle" includes a ring system in which the heterocyclic group defined above is condensed with one or more carbocyclic groups, wherein the point of attachment is on either the carbocyclic or heterocyclic ring, and in such an example, the number of ring members continues to specify the number of ring members in the heterocyclic ring system. In some embodiments, "heterocyclic group" or "heterocycle" also includes a ring system in which the heterocyclic group defined above is condensed with one or more aryl groups or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such an example, the number of ring members continues to specify the number of ring members in the heterocyclic ring system. In some embodiments, "heterocyclic group" or "heterocycle" excludes a ring system in which the heterocyclic group defined above is condensed with one or more carbocyclic groups, aryl groups, or heteroaryl groups. In some embodiments, the heterocyclic group is monocyclic. 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 bridged ring system.

[0048] "Carbocyclic group" or "carbocycle" means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, unless otherwise specified, wherein the ring atoms are C. Unless otherwise specified, the carbocyclic group includes monocyclic and polycyclic systems, including fused ring systems, bridged 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 bridged ring system.

[0049] "Heteroaryl", unless otherwise stated, means a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, where one or more (in some embodiments 1, 2, or 3) of the ring atoms are heteroatom(s) independently selected from N, O, or S, and the remainder of the ring atoms are C. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on either the aryl ring or the heteroaryl ring, and in such instances, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, and the like) can have the point of attachment on either ring (i.e., either the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl)). In some embodiments, "heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring. In such instances, unless otherwise specified, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. In some embodiments, "heteroaryl" excludes ring systems in which the heteroaryl ring is fused to a carbocyclic or heterocyclic group. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0050] A "spiro" cycloalkyl group indicates that the cycloalkyl group is linked to the remainder of the compound via a spiro linkage. A "spiro" cycloalkyl substituent has two junctions that connect to the same carbon of the portion being substituted, forming a spiro connection. For example, a cyclohexyl group substituted with a "spiro C3-C4 cycloalkyl" group is Shows TIFF2025523624000004.tif14128.

[0051] "Requiring treatment", as used herein, means that the patient is being treated by a physician or other caregiver after a diagnosis of a disease or a determination that the patient is at risk of developing a disease. In some embodiments, the patient has been diagnosed with KRAS G12C-mediated cancer. In some embodiments, the patient has been determined to be at risk of developing KRAS G12C-mediated cancer.

[0052] "Administer", "administering", and the like refer to contacting, for example, a compound of formula (A), formula (B), or formula (C), or a pharmaceutically acceptable salt and / or isotope-substituted form thereof, a pharmaceutical composition containing the same, or a diagnostic agent to a subject, cell, tissue, organ, or biological fluid when applied thereto, for example, to a patient, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contacting a reagent to the cell (e.g., in vitro or ex vivo), and contacting the reagent to a liquid where the liquid is in contact with the cell.

[0053] "Optional" or "optionally" means that the subsequent described event or circumstance may occur but need not occur, and that the description includes examples where the event or circumstance occurs and examples where it does not occur.

[0054] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers or excipients acceptable for veterinary use and for human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient", when used in the specification and claims, includes one and both of two or more such excipients.

[0055] As used herein, the term "disease" is generally synonymous with the terms "disorder", "syndrome", and "condition" (such as in a medical condition), and is intended to be used interchangeably, and in all of them, it reflects an abnormal condition of one of the human or animal body or a part thereof that impairs normal function, typically presenting distinguishable signs and symptoms, and causing a reduction in the duration of the human or animal lifespan or quality of life.

[0056] The term "combination therapy" means administering two or more therapeutic agents for treating a disease or disorder described in the present disclosure. Such administration encompasses co-administering these therapeutic agents in a substantially simultaneous manner (such as in a single capsule or tablet having a fixed ratio of active ingredients, or in multiple separate capsules or tablets for each active ingredient, etc.). In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In any case, the treatment regimen will provide a beneficial effect of the combination of drugs in the treatment of the condition or disorder described herein.

[0057] Method for the treatment of cancer The compounds of formula (A), formula (B), and formula (C), as well as their pharmaceutically acceptable salts and / or isotope substituents (including the embodiments thereof disclosed herein), are useful for the treatment of various types of cancer, including but not limited to lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. More specifically, cancers treatable by the compounds of formula (A), formula (B), and formula (C), as well as their pharmaceutically acceptable salts and / or isotope substituents (including the embodiments thereof disclosed herein) include glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colorectal adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, cholangiocarcinoma, gallbladder cancer, 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 endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma, among others. In some embodiments, including any of the foregoing embodiments, the cancer is KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject is diagnosed with having KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject is determined to be at risk of developing KRAS G12C-mediated cancer.

[0058] In one aspect, there is provided a compound of formula (A), formula (B), or formula (C) described in any of the embodiments described herein for use as a medicament, or a pharmaceutical formulation described in any of the embodiments described herein.

[0059] In one aspect, there is provided a compound of formula (A), formula (B), or formula (C) described in any of the embodiments described herein for use in the treatment or suppression of cancer, or a pharmaceutical formulation described in any of the embodiments described herein. In one embodiment, when the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder. In one embodiment, the cancer is glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colorectal adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, carcinosarcoma of the uterus, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / stomach cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma. In one embodiment, the cancer is KRAS G12C-mediated cancer. In one embodiment, the subject is diagnosed with having KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the compound or pharmaceutical formulation is configured for administration at a therapeutically effective amount.

[0060] In one aspect, a compound of formula (A), formula (B), or formula (C) described in any of the embodiments described herein for use in the manufacture of a medicament for treating or suppressing cancer, or a pharmaceutical formulation described in any of the embodiments described herein, wherein the salt is a pharmaceutically acceptable salt when the compound is a salt, is provided. In one embodiment, the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder. In one embodiment, the cancer is glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colorectal adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, carcinosarcoma of the uterus, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma. In one embodiment, the cancer is KRAS G12C-mediated cancer. In one embodiment, the subject is diagnosed with having KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with an additional chemotherapeutic agent in a therapeutically effective amount. In one embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

[0061] In one aspect, there is provided the use of a compound of formula (A), formula (B), or formula (C) described in any of the embodiments described herein, or a pharmaceutical formulation described in any of the embodiments described herein, in the manufacture of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder. In one embodiment, the cancer is glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, choroidal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma. In one embodiment, the cancer is KRAS G12C-mediated cancer. In one embodiment, the subject is diagnosed with KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

[0062] In one aspect, there is provided the use of a compound of formula (A), formula (B), or formula (C) described in any of the embodiments described herein for treating or suppressing cancer, or a pharmaceutical formulation described in any of the embodiments described herein, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0063] In one embodiment, the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder. In one embodiment, the cancer is glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, carcinosarcoma of the uterus, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma. In one embodiment, the cancer is KRAS G12C-mediated cancer. In one embodiment, the subject is diagnosed with having KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the use is accompanied by a therapeutically effective amount of the compound or composition.

[0064] In some embodiments, including any of the foregoing embodiments, the subject and / or the cancer is resistant or refractory to treatment with a particular KRAS inhibitor (e.g., a G12C KRAS inhibitor).

[0065] The compounds of formula (A), formula (B), or formula (C), and their pharmaceutically acceptable salts and / or isotope substituents (including the embodiments thereof disclosed herein) can be used for a method of inhibiting KRAS G12C in a cell by contacting the cell in which inhibition of KRAS G12C activity is desired with an effective amount of the compound. The inhibition can be partial or complete. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo.

[0066] Test The compounds of formula (A), formula (B), or formula (C), and their pharmaceutically acceptable salts and / or isotope substituents (including the embodiments thereof disclosed herein) can be tested by, for example, the methods described in the following examples, or by known generally accepted cell models and / or animal models.

[0067] The ability of the compounds of formula (A), formula (B), and formula (C), and their pharmaceutically acceptable salts and / or isotope substituents to inhibit the activity of the GTP-bound form of KRAS G12C can be tested using methods such as the in vitro assay described in Example 179 below. Example 179 describes determining the 50% maximal inhibition (IC 50 ) of KRAS G12C loaded with the GTP analog GMPPNP from its binding to cRaf as the Ras-binding domain (RBD). Example 180 describes the 50% maximal inhibition (IC 50) is described as being determined from the binding to PI3Kα as the Ras binding domain (RBD). Example 181 describes testing compounds for their ability to inhibit cell survival in the MCF10A G12C / A59G mutation (which prevents the hydrolysis of GTP to GDP and thus inactivates GTPase activity).

[0068] Pharmaceutical composition The terms pharmaceutical composition and pharmaceutical formulation are used interchangeably throughout.

[0069] Generally, the compounds of formula (A), formula (B), and formula (C) of the present disclosure, as well as their pharmaceutically acceptable salts and / or isotope substituents (which may also be referred to herein as "compounds" or "compounds of the present disclosure"), will be administered in a therapeutically effective amount by any of the acceptable modes of administration for agents that provide similar utility. The therapeutically effective amount of the compounds of the present disclosure can range from about 0.01 to about 500 mg per kg of patient body weight per day and can be administered in a single dose or multiple doses. In some embodiments, suitable dosage levels can be about 0.1 to about 250 mg / kg per day; or about 0.5 to about 100 mg / kg per day. Suitable dosage levels can be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range, the dosage can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the composition can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient (particularly about 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 of the present disclosure (i.e., the active ingredient) will depend on a number of factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors, etc.

[0070] Generally, the compounds of the present 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 (e.g., intramuscular administration, intravenous administration, or subcutaneous administration). The preferred mode of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. The compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or other suitable compositions.

[0071] The selection of the formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, e.g., enteric-coated or delayed release tablets, pills, or capsules are preferred) and the bioavailability of the drug substance.

[0072] The compositions generally consist of a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic and assist in administration and do not adversely affect the therapeutic benefit of the compounds of the present disclosure. Such excipients can be any solid, liquid, semisolid, or gaseous excipient in the case of any solid, liquid, semisolid, or aerosol composition generally available to those skilled in the art.

[0073] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, corn, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk powder, and the like. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils (of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers include water, saline, aqueous dextrose, and glycols, particularly for injectable solutions.

[0074] The compound can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection can be provided, for example, in unit dosage forms in ampoules or in multiple-dose containers with added preservatives. The composition can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulating agents (such as suspending agents, stabilizing agents, and / or dispersing agents, etc.). The formulation is provided in unit-dose or multiple-dose containers (such as sealed ampoules and vials) and can be stored in powder form or in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier (such as physiological saline or sterile pyrogen-free water) immediately prior to use. Solutions and suspensions for immediate injection can be prepared from sterile powders, granules, and tablets of the previously described types.

[0075] Formulations for parenteral administration can include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which can contain antioxidants, buffers, bacteriostatic substances, and solutes (to render the formulation isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. 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 injection suspensions can contain substances that increase the viscosity of the suspension (such as sodium carboxymethylcellulose, sorbitol, or dextran, etc.). Optionally, the suspension can also contain suitable stabilizing substances or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0076] In addition to the previously described formulations, the compound can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (such as an emulsion in an acceptable oil) or an ion-exchange resin, or as a poorly soluble derivative (such as a poorly soluble salt).

[0077] For buccal or sublingual administration, the composition can take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions can contain the active ingredient in a flavored base (such as sucrose and acacia or tragacanth).

[0078] The compound can also be formulated in a rectal composition (such as suppositories or retention enemas) containing, for example, conventional suppository bases (such as cocoa butter or polyethylene glycol or other glycerides).

[0079] Certain compounds of the present disclosure can be administered locally, i.e., by non-systemic administration. Such non-systemic administration includes applying the compound externally to the epidermis or buccal cavity so that the compound does not significantly penetrate into the bloodstream, as well as instilling such a compound into the auricle, eye, and nose. In contrast, systemic administration refers to oral administration, intravenous administration, intraperitoneal administration, and intramuscular administration.

[0080] Formulations suitable for topical administration include liquid or semi-liquid preparations (such as gels, liniments, lotions, creams, ointments, or pastes) suitable for percutaneous penetration to the site of inflammation, and drops suitable for administration to the eye, auricle, or nose. The active ingredient for topical administration can be included, for example, at 0.001% - 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can be included at up to 10% w / w. In other embodiments, the active ingredient can be included at less than 5% w / w. In certain embodiments, the active ingredient can be included at 2% w / w - 5% w / w. In other embodiments, the active ingredient can be included at 0.1% - 1% w / w of the formulation.

[0081] For administration by inhalation, the compound can be conveniently delivered from an inhaler, a nebulizer pressurized pack, or other convenient means that deliver an aerosol spray. The pressurized pack can contain a suitable propellant (such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, etc.). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a measured amount. Alternatively, for administration by inhalation or ventilation, the compounds according to the present disclosure can be in the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder base (such as lactose or starch, etc.). The powder composition can be presented in unit dosage form in, for example, capsules, cartridges, gelatin, or blister packs, and the powder from the unit dosage form can be administered with the aid of an inhaler or ventilator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th ed., 2000).

[0082] The level of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain from about 0.01 - 99.99 weight percent of the compounds of the present disclosure, based on the total of the formulation, on a weight percent (wt%) basis, and will be balanced with one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1 - 80 weight percent.

[0083] Combination and combination therapies The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or conditions in which the compounds of the present disclosure or other drugs may have utility. Such other drug(s) can be administered simultaneously or sequentially with the compounds of the present disclosure. When the compounds of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions in unit dosage forms containing such other drugs and the compounds of the present disclosure are contemplated. However, combination therapy can also include treatments in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients can be used at lower doses than when each is used alone.

[0084] Accordingly, the pharmaceutical compositions of the present disclosure also include those containing one or more other drugs in addition to the compounds of the present disclosure.

[0085] The above combinations include the combination of the compounds of the present disclosure not only with one other drug but also with two or more other active drugs. Similarly, the compounds of the present disclosure can be used in combination with other drugs used in the prevention, treatment, control, alleviation, or risk reduction of diseases or conditions for which the compounds of the present disclosure are useful. Such other drugs can be administered simultaneously or sequentially with the compounds of the present disclosure. When the compounds of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds of the present disclosure can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those containing one or more other active ingredients in addition to the compounds of the present disclosure. The weight ratio of the compounds of the present disclosure to the second active ingredient can be varied and will depend on the effective doses of each ingredient. Generally, each therapeutically effective dose will be used.

[0086] If a subject in need of treatment with the compounds of the present disclosure has cancer or is at risk of developing cancer, the subject can be treated with the compounds of the present disclosure in any combination with one or more other anti-cancer agents.

[0087] In some embodiments, the compounds of the present disclosure are used in combination with a CDK 4 / 6 inhibitor. Examples of CDK 4 / 6 inhibitors suitable for the provided compositions and methods include abemaciclib (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-l-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one) and ribociclib (7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), but are not limited thereto. On the other hand, the CDK 4 / 6 inhibitor trilaciclib (2’-((5-(piperazin-1-yl)pyridin-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 the late clinical trial stage. Another CDK 4 / 6 inhibitor useful in the methods herein is the CDK 2 / 4 / 6 inhibitor PF-06873600 (pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

[0088] In another embodiment, the compounds of the present disclosure are used in combination with a Raf family kinase inhibitor. Examples of Raf family kinase inhibitors suitable for the provided compositions and methods include encorafenib (LGX818): methyl (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; sorafenib: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl(phenyll))ureido)phenoxy)-N-methylpicolinamide; LY 3009120: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido-[2,3-d]pyrimidin-6-yl)phenyl)urea; riphirafenib (BGB-283); 5-(((1R,1aS,6bS)-1-(6-(trifhioro(trifhioro)-methyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)methyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one; Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)-phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide;CEP-32496: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea; CCT196969: 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea; and R05126766: N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyl-oxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methylsulfamide, but are not limited thereto.;

[0089] In another embodiment, the compounds of the present disclosure are used in combination with Src family kinases. Examples of Src family kinase inhibitors suitable for the provided compositions and methods include dasatinib (N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide); ponatinib (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide); vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine); bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)-propoxy)quinoline-3-carbonitrile); saracatinib (N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine); KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide); SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide); PP1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), but are not limited thereto. In one embodiment, the Src inhibitor is dasatinib. In one embodiment, the Src inhibitor is saracatinib. 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.

[0090] In another embodiment, the compounds of the present disclosure are used in combination with an SHP-2 inhibitor, and examples of such inhibitors include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-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 Medicine), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

[0091] In another embodiment, the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for the provided compositions and methods include everolimus, rapamycin, zotarolimus (ABT-578), ridafolimus (deforolimus; MK-8669), sapitinib (INK128; 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine), torin-1; 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one, dactolisib (BEZ235); 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile, buparlisib (5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine); GDC-0941 (pictilisib); 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine); GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), VS-5584 (SB2343) (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine) and bisphosphonates (AZD-2014; 3-(2,4-bis((S)-3-methylmorpholino)pyrido-[2,3-d]pyrimidin-7-yl)-N-methylbenzamide), but are not limited thereto.

[0092] In another embodiment, the compounds of the present disclosure are used in combination with a pan-ErbB family inhibitor. In one embodiment, the KRAS inhibitor and the pan-ErbB family inhibitor are the only active agents in the provided compositions and methods. In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for the provided compositions and methods include afatinib; dacomitinib; canertinib; poziotinib, AV 412 (N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-1-butyn-1-yl]-6-quinazolinyl]-2-prepenamide); PF 6274484 (N-4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 (N-(2(E)-N-[[4-[[3-chloro-4-[(fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) but are not limited thereto. 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; baricitinib; TAK-285 (N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide); AEE788 (S)-(6-(4-((4-ethylpiperazin-1-ylmethyl)phenyl]-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); tarloxotinib (3-[N-[4-(3-bromo-4-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propen-1-aminium bromide); BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpurrolo[2,1-f][1,2,4]triazin-6-yl]carbamate dihydrochloride); and GW 583340 (N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[2-[2-(methylsulfonyl)ethylaminomethyl]thiazol-4-yl]quinazolin-4-amine dihydrochloride), but are not limited thereto.

[0093] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, and the EGFR inhibitor and the HER2 inhibitor are AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-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-benzothiazol-2-ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714 (2-methoxy-N-[(2E)-3-[4-[3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino]quinazolin-6-yl]-2-propen-1-yl]acetamide); BIBU 1361 (N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)-piperidin-1-yl]pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride); BIBU 1382; (N8-(3-chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride), 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 (N4-(3-bromophenyl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine), and are a combination of two of them.

[0094] 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 that target EGFR and / or HER2, including monoclonal antibodies, antibody conjugates, and bispecific antibodies, 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 necitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for the provided compositions and methods include pertuzumab, trastuzumab, and trastuzumab emtansine.

[0095] In some embodiments, the compounds of the present disclosure are used in combination with immune checkpoint inhibitors. Examples of suitable immune checkpoint inhibitors for the provided compositions and methods include PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors (pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi™), ipilimumab (Yervoy®), relatlimab, oduvalag, dostarlimab (Jemperli), etc.), but are not limited thereto.

[0096] The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-neoplastic compounds (e.g., chemotherapy) or used in combination with other treatments (such as radiation or surgical intervention) as an adjuvant either before or after surgery.

[0097] Selected embodiments Embodiment 1. A compound of formula A, formula B, or formula C: TIFF2025523624000005.tif82128 or a salt thereof; and / or an isotopically substituted form thereof [wherein, Ring A is a 6-membered aryl or 5- to 10-membered heteroaryl; R F is selected from the group consisting of H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; Each R G is independently selected from halo, -OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, and C2-C3 alkynyl; Each GG is independently 0, 1, 2, or 3; R 1 is a 4- to 8-membered saturated carbocyclic group or a heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the carbocyclic group or heterocyclic group is substituted by 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2b , R 2c and R 2e selected from the group consisting of; R 2b is -NR 10 R 11 ; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 is -(CH2) w -R 13 or; R 10 and R 11together with the nitrogen to which they are attached, form a 4- to 8-membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom within the ring atoms, wherein said second nitrogen of said 4- to 8-membered saturated heterocyclic group is substituted by cyano, and said 4- to 8-membered saturated heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; R 13 is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein said nitrogen is substituted by cyano, and said heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, wherein one of said nitrogens is substituted by cyano, and said heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; or R 13 is a 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally, one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of said nitrogen ring atoms is substituted by cyano, and said heterocyclic group may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; w is 0, 1, or 2; R 2c is -NR 15 R 16 ; R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 16 is -(CH2) y -R 21 ; R 21 is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C(R 19 )=C(R 20 )R 18 , and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, wherein one of the nitrogens of the heterocyclic group is substituted by -C(O)C(R 19 )=C(R 20 )R 18 , and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to the heteroatom; or A 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms (s) of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 ) is substituted, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; said 7-membered saturated heterocyclic group selected from; R 18 is selected from the group consisting of hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and R 35 selected from; R 19 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 22 and R 23 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 34 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 35 is a 5- to 6-membered heteroaryl group optionally substituted with 0, 1, or 2 substituents independently selected from a C3-C6 heterocyclyl optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halo and methyl, and a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo and methyl; y is 0, 1, or 2; z is 1 or 2; q is 0 or 1; u is 0, 1, or 2; R 2e is -NR 28 R 29 ; R 28 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 29 is -(CH2)t-R 30 ; R 30 is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C≡CR 31 and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo. A 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom within the ring atoms, wherein one of said nitrogens of said heterocyclic group is -C(O)C≡CR 31 and is substituted by -C(O)C≡CR, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; and A 7-membered saturated heterocyclic group containing one nitrogen, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, as the only heteroatoms within the ring atoms, wherein one of said nitrogen ring atoms (s) of said heterocyclic group is -C(O)C≡CR 31 and is substituted by -C(O)C≡CR, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; said 7-membered saturated heterocyclic group selected from; R 31 is selected from the group consisting of -(CH2) v -NR 32 R 33 and -(CH2) p -R 36 ; R 32 and R 33 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; t is 0, 1, or 2; v is 1 or 2; p is 0, 1, or 2; R 36is 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl].

[0098] Embodiment 2. The compound according to Embodiment 1, which is a compound of Formula A or a salt thereof.

[0099] Embodiment 3. The compound according to Embodiment 1, which is a compound of Formula B or Formula C or a salt thereof.

[0100] Embodiment 4. The compound according to Embodiment 1, which is a compound of Formula B or a salt thereof.

[0101] Embodiment 5. The compound of Formula B is of Formula B1 TIFF2025523624000006.tif25128, the compound according to any one of Embodiments 1, 3, and 4.

[0102] Embodiment 6. The compound according to Embodiment 1, which is a compound of Formula C or a salt thereof.

[0103] Embodiment 7. R F is C1-C4 alkyl, the compound according to any one of Embodiments 1, 3, 4, and 5.

[0104] Embodiment 8. R F is methyl, the compound according to any one of Embodiments 1, 3, 4, and 5.

[0105] Embodiment 9. Ring A is selected from phenyl, pyridinyl, and isoquinolinyl, the compound according to any one of Embodiments 1 to 8.

[0106] Embodiment 10. Ring A is selected from phenyl, pyridin-2-yl, pyridin-4-yl, and isoquinolin-1-yl, the compound according to any one of Embodiments 1 to 8.

[0107] Embodiment 11. The compound according to any one of Embodiments 1 to 8, wherein ring A is selected from phenyl, pyridin-2-yl, and isoquinolin-1-yl.

[0108] Embodiment 12. The compound according to any one of Embodiments 1 to 11, wherein GG is 1, 2, or 3.

[0109] Embodiment 13. The compound according to any one of Embodiments 1 to 11, wherein GG is 1.

[0110] Embodiment 14. The compound according to any one of Embodiments 1 to 11, wherein GG is 2 or 3.

[0111] Embodiment 15. The compound according to any one of Embodiments 1 to 11, wherein GG is 2.

[0112] Embodiment 16. The compound according to any one of Embodiments 1 to 11, wherein GG is 3.

[0113] Embodiment 17. Each part represented by TIFF2025523624000007.tif17128 is The compound according to any one of Embodiments 1 to 8, independently selected from the group consisting of TIFF2025523624000008.tif25128.

[0114] Embodiment 18. Each part represented by TIFF2025523624000009.tif17128 is The compound according to any one of Embodiments 1 to 8, independently selected from the group consisting of TIFF2025523624000010.tif25128.

[0115] Embodiment 19. Each part represented by TIFF2025523624000011.tif17128 is A compound according to any one of Embodiments 1 to 8, independently selected from the group consisting of TIFF2025523624000012.tif25128.

[0116] Embodiment 20. Each part represented by TIFF2025523624000013.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000014.tif24128.

[0117] Embodiment 21. Each part represented by TIFF2025523624000015.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000016.tif22128.

[0118] Embodiment 22. Each part represented by TIFF2025523624000017.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000018.tif22128.

[0119] Embodiment 23. Each part represented by TIFF2025523624000019.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000020.tif22128.

[0120] Embodiment 24. Each part represented by TIFF2025523624000021.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000022.tif23128.

[0121] Embodiment 25. Each RG The compound according to any one of Embodiments 1 to 24, wherein is independently selected from halo, -OH, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl.

[0122] Embodiment 26. Each R G The compound according to any one of Embodiments 1 to 24, wherein is independently selected from -F, -Cl, -OH, -NH2, -Me, -CF3, and cyclopropyl.

[0123] Embodiment 27. Each part represented by TIFF2025523624000023.tif17128 is The compound according to any one of Embodiments 1 to 8, 25, and 26, which is independently selected from the group consisting of TIFF2025523624000024.tif26128.

[0124] Embodiment 28. Each part represented by TIFF2025523624000025.tif17128 is The compound according to any one of Embodiments 1 to 8, 25, and 26, which is independently selected from the group consisting of TIFF2025523624000026.tif27128.

[0125] Embodiment 29. Each part represented by TIFF2025523624000027.tif17128 is independently The compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000028.tif25128.

[0126] Embodiment 30. Each part represented by TIFF2025523624000029.tif17128 is independently The compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000030.tif23128.

[0127] Embodiment 31. Each part represented by TIFF2025523624000031.tif17128 is independently A compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000032.tif23128.

[0128] Embodiment 32. Each part represented by TIFF2025523624000033.tif17128 is independently A compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000034.tif23128.

[0129] Embodiment 33. Each part represented by TIFF2025523624000035.tif17128 is independently A compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000036.tif22128.

[0130] Embodiment 34. Each part represented by TIFF2025523624000037.tif17128 is independently A compound according to any one of Embodiments 1 to 8, 25, and 26, which is TIFF2025523624000038.tif23128.

[0131] Embodiment 35. Each R G A compound according to any one of Embodiments 1 to 34, wherein each is independently selected from -F, -Cl, -Me, -CF3, and cyclopropyl.

[0132] Embodiment 36. Each part represented by TIFF2025523624000039.tif17128 is A compound according to any one of Embodiments 1 to 8, independently selected from the group consisting of TIFF2025523624000040.tif55141.

[0133] Embodiment 37. Each part represented by TIFF2025523624000041.tif17128 is A compound according to any one of Embodiments 1 to 8, independently selected from the group consisting of TIFF2025523624000042.tif55138.

[0134] Embodiment 38. Each part represented by TIFF2025523624000043.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000044.tif24128.

[0135] Embodiment 39. Each part represented by TIFF2025523624000045.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000046.tif24128.

[0136] Embodiment 40. Each part represented by TIFF2025523624000047.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000048.tif23128.

[0137] Embodiment 41. Each part represented by TIFF2025523624000049.tif17128 is independently A compound according to any one of Embodiments 1 to 8, wherein TIFF2025523624000050.tif22128.

[0138] Embodiment 42. Each part represented by TIFF2025523624000051.tif17128 is, independently A compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000052.tif21128.

[0139] Embodiment 43. Each part represented by TIFF2025523624000053.tif17128 is, independently A compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000054.tif26128.

[0140] Embodiment 44. Each part represented by TIFF2025523624000055.tif17128 is, independently A compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000056.tif22128.

[0141] Embodiment 45. Each part represented by TIFF2025523624000057.tif17128 is, independently A compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000058.tif22128.

[0142] Embodiment 46. Each part represented by TIFF2025523624000059.tif17128 is, independently A compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000060.tif21128.

[0143] Embodiment 47. Each part represented by TIFF2025523624000061.tif17128 is, independently The compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000062.tif25128.

[0144] Embodiment 48. Each part represented by TIFF2025523624000063.tif17128 is independently The compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000064.tif25128.

[0145] Embodiment 49. Each part represented by TIFF2025523624000065.tif17128 is independently The compound according to any one of Embodiments 1 to 8, which is TIFF2025523624000066.tif25128.

[0146] Embodiment 50. R 1 is a 4- to 8-membered saturated monocyclic carbocyclic group or a monocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring atoms, and the carbocyclic group or heterocyclic group is independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy The compound according to any one of Embodiments 1 to 49, which is substituted by 0, 1, 2, or 3 substituents.

[0147] Embodiment 51. R 1 is a 4- to 8-membered saturated bicyclic carbocyclic group or a bicyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring atoms, and the carbocyclic group or heterocyclic group is independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy The compound according to any one of Embodiments 1 to 49, which is substituted by 0, 1, 2, or 3 substituents.

[0148] Embodiment 52. R 1is a 4- to 8-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, the compound according to any one of Embodiments 1 to 51.

[0149] Embodiment 53. The R 1 is a 4- to 8-membered saturated carbocyclic group substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, the compound according to any one of Embodiments 1 to 51.

[0150] Embodiment 54. R 1 is an unsubstituted 4- to 8-membered saturated carbocyclic group or a heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, the compound according to any one of Embodiments 1 to 53.

[0151] Embodiment 55. R 1 The carbocyclic group or heterocyclic group of R is unsubstituted or substituted with one halo, hydroxy, or C1-C4 alkyl, the compound according to any one of Embodiments 1 to 53.

[0152] Embodiment 56. R 1 The carbocyclic group or heterocyclic group of R is unsubstituted or substituted with one halo or hydroxy, the compound according to any one of Embodiments 1 to 53.

[0153] Embodiment 57. R 1 The carbocyclic group or heterocyclic group of R is unsubstituted or substituted with one fluoro, the compound according to any one of Embodiments 1 to 53.

[0154] Embodiment 58. R 1The compound according to any one of Embodiments 1 to 53, wherein the carbocyclic group or heterocyclic group is substituted by one fluoro.

[0155] Embodiment 59. R 1 The compound according to any one of Embodiments 1 to 53, wherein the carbocyclic group or heterocyclic group is substituted by one C1-C4 alkyl.

[0156] Embodiment 60. R 1 is selected from the group consisting of TIFF2025523624000067.tif21131, the compound according to any one of Embodiments 1 to 49.

[0157] Embodiment 61. R 1 is selected from the group consisting of TIFF2025523624000068.tif21128, the compound according to any one of Embodiments 1 to 49.

[0158] Embodiment 62. R 1 is selected from the group consisting of TIFF2025523624000069.tif21128, the compound according to any one of Embodiments 1 to 49.

[0159] Embodiment 63. R 1 is selected from the group consisting of TIFF2025523624000070.tif21128, the compound according to any one of Embodiments 1 to 49.

[0160] Embodiment 64. R 1 is TIFF2025523624000071.tif20128, the compound according to any one of Embodiments 1 to 49.

[0161] Embodiment 65. R 1 is The compound according to any one of Embodiments 1 to 49, which is TIFF2025523624000072.tif20128.

[0162] Embodiment 66. R 1 is The compound according to any one of Embodiments 1 to 50, which is TIFF2025523624000073.tif14128.

[0163] Embodiment 67. R 2 is R 2b and R 2c The compound according to any one of Embodiments 1 to 66, which is selected from the group consisting of R

[0164] Embodiment 68. R 2 is R 2b and R 2e The compound according to any one of Embodiments 1 to 66, which is selected from the group consisting of R

[0165] Embodiment 69. R 2 is R 2c and R 2e The compound according to any one of Embodiments 1 to 66, which is selected from the group consisting of R

[0166] Embodiment 70. R 2 is R 2b The compound according to any one of Embodiments 1 to 66.

[0167] Embodiment 71. R 10 The compound according to any one of Embodiments 1 to 68 and 70, wherein R is methyl or ethyl.

[0168] Embodiment 72. R 10 The compound according to any one of Embodiments 1 to 68 and 70, wherein R is methyl.

[0169] Embodiment 73. R 11 is -(CH2) w -R 13The compound according to any one of Embodiments 1 to 68 and 70 to 72.

[0170] Embodiment 74. The compound according to any one of Embodiments 1 to 68 and 70 to 73, wherein w is 0 or 1.

[0171] Embodiment 75. R 13 is a 4- to 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, said nitrogen being substituted by cyano, and said heterocyclic group being optionally further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, or halo. The compound according to any one of Embodiments 1 to 68 and 70 to 74.

[0172] Embodiment 76. The compound according to any one of Embodiments 1 to 68 and 70 to 75, wherein said heterocyclic group of R 13 is not further substituted.

[0173] Embodiment 77. The compound according to any one of Embodiments 1 to 68 and 70 to 75, wherein said heterocyclic group of R 13 is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0174] Embodiment 78. The compound according to any one of Embodiments 1 to 68 and 70 to 75, wherein said heterocyclic group of R 13 is further substituted by one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0175] Embodiment 79. The compound according to any one of Embodiments 1 to 68 and 70 to 75, wherein said heterocyclic group of R 13 is further substituted by methyl, methoxy, or fluoro.

[0176] Embodiment 80. R 11is a compound according to any one of Embodiments 1 to 68 and 70 to 73, selected from the group consisting of TIFF2025523624000074.tif97145.

[0177] Embodiment 81. R 11 is a compound according to any one of Embodiments 1 to 68 and 70 to 73, selected from the group consisting of TIFF2025523624000075.tif24128.

[0178] Embodiment 82. R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom within the ring atoms, the second nitrogen of the 4- to 8-membered saturated heterocyclic group being substituted by cyano, and the 4- to 8-membered saturated heterocyclic group being optionally further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, a compound according to any one of Embodiments 1 to 68 and 70.

[0179] Embodiment 83. R 10 and R 11 together with the nitrogen to which they are attached, the 4- to 8-membered saturated heterocyclic group formed by R 10 and R 11 is selected from the group consisting of TIFF2025523624000076.tif22128, the second nitrogen atom being substituted by cyano, and the heterocyclic group being optionally further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, a compound according to any one of Embodiments 1 to 68 and 70.

[0180] Embodiment 84. R 10 and R 11Together with the nitrogen to which it is attached to form R 10 and R 11 The 4- to 8-membered saturated heterocyclic group formed by TIFF2025523624000077.tif26128, optionally further substituted by one example of -CH2CN, a compound according to any one of embodiments 1 to 68 and 70.

[0181] Embodiment 85. R 2 is R 2c a compound according to any one of embodiments 1 to 66.

[0182] Embodiment 86. R 15 is selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy, a compound according to any one of embodiments 1 to 67, 69, and 71 to 85.

[0183] Embodiment 87. R 15 is selected from the group consisting of methyl, ethyl, and -CH2CH2OCH3, a compound according to any one of embodiments 1 to 67, 69, and 71 to 85.

[0184] Embodiment 88. R 15 is methyl or ethyl, a compound according to any one of embodiments 1 to 67, 69, and 71 to 85.

[0185] Embodiment 89. R 15 is methyl, a compound according to any one of embodiments 1 to 67, 69, and 71 to 85.

[0186] Embodiment 90. y is 0 or 1, a compound according to any one of embodiments 1 to 67, 69, and 71 to 89.

[0187] Embodiment 91. y is 0, a compound according to any one of embodiments 1 to 67, 69, and 71 to 89.

[0188] Embodiment 92. A compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, wherein y is 1.

[0189] Embodiment 93. R 21 is a 4- to 5-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom is substituted by -C(O)C(R 19 )=C(R 20 )R 18 and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; a 6-membered saturated monocyclic heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, wherein one of the nitrogens is substituted by -C(O)C(R 19 )=C(R 20 )R 18 and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to the heteroatom; and a 7-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) is substituted by -C(O)C(R 19 )=C(R 20 )R 18is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated monocyclic heterocyclic group A compound according to any one of embodiments 1 to 67, 69, and 71 to 92, selected from

[0190] Embodiment 94. R 21 is a 4- to 5-membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, said 4- to 5-membered monocyclic saturated heterocyclic group; a 6-membered monocyclic saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, wherein one of the nitrogens of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 6-membered monocyclic saturated heterocyclic group; and A 7-membered saturated bicyclic spirocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein said nitrogen ring atom is -C(O)C(R 19 )=C(R 20 )R 18 substituted, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated bicyclic spirocyclic heterocyclic group A compound according to any one of embodiments 1 to 67, 69, and 71 to 92, selected from

[0191] Embodiment 95. R 21 is a 4- to 5-membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and said nitrogen ring atom of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 substituted, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo. A compound according to any one of embodiments 1 to 67, 69, and 71 to 92

[0192] Embodiment 96. The heterocyclic group of R 21 is unsubstituted. A compound according to any one of embodiments 1 to 67, 69, and 71 to 95

[0193] Embodiment 97. R 21The compound according to any one of Embodiments 1 to 67, 69, and 71 to 95, wherein the hetero ring group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0194] Embodiment 98. R 21 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 95, wherein the hetero ring group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0195] Embodiment 99. R 21 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 95, wherein the hetero ring group is further substituted by one substituent selected from the group consisting of hydroxy, CN, Me, -CH2CN, and F.

[0196] Embodiment 100. R 21 The hetero ring group of is selected from the group consisting of TIFF2025523624000078.tif16128, and the ring nitrogen of the hetero ring group is substituted by -C(O)C(R 19 )=C(R 20 )R 18 and the hetero ring group is either unsubstituted or substituted by one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 92.

[0197] Embodiment 101. R 21 The hetero ring group of is selected from the group consisting of TIFF2025523624000079.tif14128, and the ring nitrogen of the hetero ring group is -C(O)C(R 19 )=C(R20 )R 18 is replaced by, and the heterocyclic group is either unsubstituted or substituted by one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 92.

[0198] Embodiment 102. R 21 wherein the heterocyclic group of is further unsubstituted, the compound according to Embodiment 100 or 101.

[0199] Embodiment 103. R 21 wherein the heterocyclic group of is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo, the compound according to Embodiment 100 or 101.

[0200] Embodiment 104. R 21 wherein the heterocyclic group of is further substituted by one substituent selected from the group consisting of hydroxy, CN, Me, -CH2CN, and F, the compound according to Embodiment 100 or 101.

[0201] Embodiment 105. R 21 wherein the heterocyclic group of is selected from the group consisting of TIFF2025523624000080.tif177145, the compound according to Embodiment 100 or 101.

[0202] Embodiment 106. R 21 wherein the heterocyclic group of is selected from the group consisting of TIFF2025523624000081.tif139150, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 is substituted by, the compound according to Embodiment 100 or 101.

[0203] Embodiment 107. R 21 wherein said heterocyclic group of is selected from the group consisting of TIFF2025523624000082.tif32138, and said ring nitrogen of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0204] Embodiment 108. R 21 wherein said heterocyclic group of is TIFF2025523624000083.tif13128, and said ring nitrogen of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0205] Embodiment 109. R 21 wherein said heterocyclic group of is TIFF2025523624000084.tif13128, and said ring nitrogen of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0206] Embodiment 110. R 21 wherein said heterocyclic group of is TIFF2025523624000085.tif13128, and said ring nitrogen of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0207] Embodiment 111. R 21 wherein said heterocyclic group of is TIFF2025523624000086.tif13128, and said ring nitrogen of said heterocyclic group is -C(O)C(R 19 )=C(R 20 )R18 The compound according to Embodiment 101, which is substituted by

[0208] Embodiment 112. R 21 wherein the heterocyclic group of is TIFF2025523624000087.tif13128, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 The compound according to Embodiment 101, which is substituted by

[0209] Embodiment 113. R 21 wherein the heterocyclic group of is TIFF2025523624000088.tif13128, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 The compound according to Embodiment 101, which is substituted by

[0210] Embodiment 114. R 21 wherein the heterocyclic group of is TIFF2025523624000089.tif13128, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 The compound according to Embodiment 101, which is substituted by

[0211] Embodiment 115. R 21 wherein the heterocyclic group of is TIFF2025523624000090.tif13128, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 The compound according to Embodiment 101, which is substituted by

[0212] Embodiment 116. R 21 wherein the heterocyclic group of TIFF2025523624000091.tif is 13128, and the ring nitrogen of the heteroaryl group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0213] Embodiment 117. The heteroaryl group of R 21 is TIFF2025523624000092.tif is 13128, and the ring nitrogen of the heteroaryl group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0214] Embodiment 118. The heteroaryl group of R 21 is TIFF2025523624000093.tif is 12128, and the ring nitrogen of the heteroaryl group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0215] Embodiment 119. The heteroaryl group of R 21 is TIFF2025523624000094.tif is 12128, and the ring nitrogen of the heteroaryl group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0216] Embodiment 120. The heteroaryl group of R 21 is TIFF2025523624000095.tif is 12128, and the ring nitrogen of the heteroaryl group is -C(O)C(R 19 )=C(R 20 )R 18 and is substituted by, the compound according to Embodiment 101.

[0217] Embodiment 121. R 21 wherein the heterocyclic group is selected from the group consisting of TIFF2025523624000096.tif15128, and the ring nitrogen of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 substituted by, the compound according to Embodiment 101.

[0218] Embodiment 122. R 16 is selected from the group consisting of TIFF2025523624000097.tif93128, and the azetidine group, pyrrolidine group, and 5-azaspiro[2.4]heptane group are either unsubstituted or substituted by one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 89.

[0219] Embodiment 123. R 16 is selected from the group consisting of TIFF2025523624000098.tif31128, and the azetidine group, pyrrolidine group, and 5-azaspiro[2.4]heptane group are either unsubstituted or substituted by one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 89.

[0220] Embodiment 124. The compound according to Embodiment 122 or 123, wherein the azetidine group, pyrrolidine group, and 5-azaspiro[2.4]heptane group are unsubstituted.

[0221] Embodiment 125. The compound according to Embodiment 122 or 123, wherein the azetidine group, pyrrolidine group, and 5-azaspiro[2.4]heptane group are further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0222] Embodiment 126. The compound according to Embodiment 122 or 123, wherein the azetidine group, pyrrolidine group, and 5-azaspiro[2.4]heptane group are further substituted by one substituent selected from the group consisting of hydroxy, CN, Me, -CH2CN, and F.

[0223] Embodiment 127. R 16 is selected from the group consisting of TIFF2025523624000099.tif124145TIFF2025523624000100.tif224145TIFF2025523624000101.tif152144, and is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 89.

[0224] Embodiment 128. R 16 is selected from the group consisting of TIFF2025523624000102.tif30128TIFF2025523624000103.tif224144TIFF2025523624000104.tif60144, and is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 89.

[0225] Embodiment 129. R 16 is selected from the group consisting of TIFF2025523624000105.tif90146, and is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 89.

[0226] Embodiment 130. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000106.tif with a size of 28128.

[0227] Embodiment 131. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000107.tif with a size of 26128.

[0228] Embodiment 132. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000108.tif with a size of 26128.

[0229] Embodiment 133. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000109.tif with a size of 26128.

[0230] Embodiment 134. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000110.tif with a size of 26128.

[0231] Embodiment 135. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000111.tif with a size of 26128.

[0232] Embodiment 136. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000112.tif with a size of 26128.

[0233] Embodiment 137. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000113.tif26128.

[0234] Embodiment 138. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000114.tif26128.

[0235] Embodiment 139. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000115.tif26128.

[0236] Embodiment 140. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000116.tif26128.

[0237] Embodiment 141. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000117.tif26128.

[0238] Embodiment 142. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is TIFF2025523624000118.tif26128.

[0239] Embodiment 143. R 16 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 89, which is selected from the group consisting of TIFF2025523624000119.tif29128.

[0240] Embodiment 144. R 19The compound according to any one of Embodiments 1 to 67, 69, and 71 to 143, wherein it is hydrogen.

[0241] Embodiment 145. R 20 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 144, wherein it is selected from the group consisting of hydrogen and methyl.

[0242] Embodiment 146. R 20 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 144, wherein it is hydrogen.

[0243] Embodiment 147. R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, and R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is selected from the group consisting of.

[0244] Embodiment 148. R 18 is hydrogen, -(CH2) z -NR 22 R 23 , and -(CH2) u -R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is selected from the group consisting of.

[0245] Embodiment 149. R 22 and R 23 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 148, wherein they are independently selected from methyl and ethyl.

[0246] Embodiment 150. R 18is H and -(CH2) u -R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is selected from the group consisting of

[0247] Embodiment 151. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 149, wherein z is 1 or 2.

[0248] Embodiment 152. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 149, wherein z is 1.

[0249] Embodiment 153. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 149, wherein z is 2.

[0250] Embodiment 154. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, wherein u is 0 or 1.

[0251] Embodiment 155. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, wherein u is 0.

[0252] Embodiment 156. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, wherein u is 1.

[0253] Embodiment 157. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, wherein u is 2.

[0254] Embodiment 158. R 18 is H, -CH2NR 22 R 23 -R 34 -CH2R 34 and -R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 149, which is selected from

[0255] Embodiment 159. R 18 is H, -R 34, -CH2R 34 , and -R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, selected from

[0256] Embodiment 160. R 18 is -CH2NR 22 R 23 , -R 34 , -CH2R 34 , and -R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, selected from

[0257] Embodiment 161. R 18 is -R 34 , -CH2R 34 , and -R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 153, selected from

[0258] Embodiment 162. R 34 is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), and the monocyclic heterocycle is independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl The compound according to any one of Embodiments 1 to 67, 69, and 71 to 161, substituted by 0, 1, 2, 3, or 4 substituents

[0259] Embodiment 163. R 34 The monocyclic heterocycle of is substituted by 0 or 1 example of methyl, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 162

[0260] Embodiment 164. R 34The compound according to any one of Embodiments 1 to 67, 69, and 71 to 162, which is selected from azetidinyl, pyrrolidinyl, and morpholinyl, and is substituted with 0 or 1 example of methyl.

[0261] Embodiment 165. R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 162, wherein R is azetidinyl substituted with 0 or 1 example of methyl.

[0262] Embodiment 166. R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 162, wherein R is pyrrolidinyl substituted with 0 or 1 example of methyl.

[0263] Embodiment 167. R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 162, wherein R is morpholinyl substituted with 0 or 1 example of methyl.

[0264] Embodiment 168. R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 162, wherein the bonding point for R is a carbon atom.

[0265] Embodiment 169. R 34 is selected from the group consisting of TIFF2025523624000120.tif19128, the compound according to Embodiment 168.

[0266] Embodiment 170. R 34 is selected from the group consisting of TIFF2025523624000121.tif12128, the compound according to Embodiment 168.

[0267] Embodiment 171. R 34 is TIFF2025523624000122.tif11128, the compound according to Embodiment 168.

[0268] Embodiment 172. R 34 is a 4- to 10-membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), wherein the 4- to 10-membered heterocycle is independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl and is substituted with 0, 1, 2, 3, or 4 substituents, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 161.

[0269] Embodiment 173. R 34 is a 4- to 10-membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), and is selected from the group consisting of a 4- to 8-membered monocyclic heterocycle, a 6- to 10-membered fused bicyclic heterocycle, a 6- to 10-membered bridged heterocycle, and a 6- to 10-membered spiro heterocycle, each of which is independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl and is substituted with 0, 1, 2, 3, or 4 substituents, and the compound according to Embodiment 172.

[0270] Embodiment 174. R 34 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, and the compound according to Embodiment 172.

[0271] Embodiment 175. R 34The compound according to Embodiment 172, which is a 6- to 10-membered fused bicyclic heterocycle substituted by 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0272] Embodiment 176. R 34 The compound according to Embodiment 172, which is a 6- to 10-membered bridged heterocycle substituted by 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0273] Embodiment 177. R 34 The compound according to Embodiment 172, which is a 6- to 10-membered spiro heterocycle substituted by 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0274] Embodiment 178. R 34is azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 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, 2-oxa-5-azabicyclo[2.2.2]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, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3] A compound according to embodiment 172, selected from heptane and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0275] Embodiment 179. R 34 A compound according to embodiment 178, wherein R is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0276] Embodiment 180. R 34 A compound according to any one of embodiments 172 to 179, wherein the point of attachment for R is the nitrogen atom of the heterocycle.

[0277] Embodiment 181. R 34 is A compound according to embodiment 180, selected from the group consisting of TIFF2025523624000123.tif153145, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0278] Embodiment 182. R 34 is A compound according to embodiment 180, selected from the group consisting of TIFF2025523624000124.tif39144, each being substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0279] Embodiment 183. R 34 is A compound according to embodiment 180, selected from the group consisting of TIFF2025523624000125.tif39146, each being substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0280] Embodiment 184. R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl TIFF2025523624000126.tif16128, a compound according to embodiment 181.

[0281] Embodiment 185. R 34 wherein said 4- to 10-membered heterocycle of R is substituted with 0, 1, 2, 3, or 4 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH2N(CH3)2, and -CH2CH2N(CH3)2, a compound according to any one of embodiments 172 to 184.

[0282] Embodiment 186. R 34The 4- to 10-membered heterocycle of any one of Embodiments 172 to 184, which is substituted with 0, 1, or 2 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH2N(CH3)2, and -CH2CH2N(CH3)2.

[0283] Embodiment 187. R 34 The 4- to 10-membered heterocycle of any one of Embodiments 172 to 184, which is substituted with 0, 1, or 2 substituents independently selected from fluoro and methyl.

[0284] Embodiment 188. R 34 The 4- to 10-membered heterocycle of any one of Embodiments 172 to 184, which is unsubstituted.

[0285] Embodiment 189. R 34 is selected from the group consisting of TIFF2025523624000127.tif199149 and TIFF2025523624000128.tif134149, the compound according to any one of Embodiments 172 to 184.

[0286] Embodiment 190. R 34 is unsubstituted TIFF2025523624000129.tif67144, the compound according to any one of Embodiments 172 to 184.

[0287] Embodiment 191. R 34 is unsubstituted TIFF2025523624000130.tif39146, the compound according to any one of Embodiments 172 to 184.

[0288] Embodiment 192. R 34 is unsubstituted The compound according to any one of Embodiments 172 to 184, which is TIFF2025523624000131.tif17128.

[0289] Embodiment 193. The compound according to any one of Embodiments 172 to 192, wherein u is 1.

[0290] Embodiment 194. R 35 is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom, wherein the heteroaryl is independently selected from C3-C6 heterocyclyl optionally substituted by 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 and methyl, and optionally substituted by one or two substituents independently selected from halo and methyl The compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, which is substituted by 0, 1, or 2 substituents selected from C3-C6 cycloalkyl.

[0291] Embodiment 195. R 35 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 independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halo and methyl Optionally substituted by one or two substituents selected from C3-C6 heterocyclyl optionally substituted by one or two substituents, and optionally substituted by one or two substituents independently selected from halo and methyl The compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, which is substituted by 0, 1, or 2 substituents selected from C3-C6 cycloalkyl.

[0292] Embodiment 196. R 35 is selected from the group consisting of pyrimidinyl, oxazolyl, 1,2,4 - oxadiazolyl, imidazolyl, and 1,2,4 - thiadiazolyl, each optionally 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 and methyl, a C3 - C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, a C3 - C6 cycloalkyl, and is substituted with 0, 1, or 2 substituents independently selected from the above, a compound according to any one of Embodiments 1 - 67, 69, and 71 - 147, 149, and 151 - 193.

[0293] Embodiment 197. R 35 is selected from the group consisting of TIFF2025523624000132.tif27136, each optionally 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 and methyl, a C3 - C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, a C3 - C6 cycloalkyl, and is substituted with 0, 1, or 2 substituents independently selected from the above, a compound according to any one of Embodiments 1 - 67, 69, and 71 - 147, 149, and 151 - 193.

[0294] Embodiment 198. R 35 is Selected from the group consisting of TIFF2025523624000133.tif13128, each being optionally 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 and methyl, C3-C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, C3-C6 cycloalkyl, and substituted with 0, 1, or 2 substituents independently selected therefrom, a compound according to any one of embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0295] Embodiment 199. R 35 Is a 6-membered heteroaryl group optionally 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, halo and methyl, C3-C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, C3-C6 cycloalkyl, and substituted with 0, 1, or 2 substituents independently selected therefrom, a compound according to any one of embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0296] Embodiment 200. R 35is pyrimidinyl or pyridazinyl, each optionally 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 and methyl, and C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl, and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl, a compound according to any one of embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0297] Embodiment 201. R 35 is selected from the group consisting of TIFF2025523624000134.tif13128, each optionally 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 and methyl, and C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl, and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl, a compound according to any one of embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0298] Embodiment 202. R 35is a 5-membered heteroaryl group containing at least one nitrogen atom, wherein the heteroaryl is optionally 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 and methyl, C3-C6 heterocyclyl which is optionally 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 and methyl, and C3-C6 cycloalkyl which is optionally substituted with one or two substituents independently selected from halo and methyl, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0299] Embodiment 203. R 35 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 optionally 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 and methyl, C3-C6 heterocyclyl which is optionally 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 and methyl, and C3-C6 cycloalkyl which is optionally substituted with one or two substituents independently selected from halo and methyl, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0300] Embodiment 204. R 35 is Selected from the group consisting of TIFF2025523624000135.tif26138, each being optionally 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 and methyl, a C3-C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, a C3-C6 cycloalkyl, substituted with 0, 1, or 2 substituents independently selected from the group consisting of, one of embodiments 1-67, 69, and 71-147, 149, and 151-193 of the compounds described.

[0301] Embodiment 205. R 35 is Selected from the group consisting of TIFF2025523624000136.tif11128, each being optionally 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 and methyl, a C3-C6 heterocyclyl, and optionally substituted with one or two substituents independently selected from halo and methyl, a C3-C6 cycloalkyl, substituted with 0 or 1 substituents independently selected from the group consisting of, one of embodiments 1-67, 69, and 71-147, 149, and 151-193 of the compounds described.

[0302] Embodiment 206. R 35 The heteroaryl group of is selected from a C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, halo and methyl, and a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl, substituted with 0 or 1 substituents independently selected from the group consisting of, one of embodiments 1-67, 69, and 71-147, 149, and 151-205 of the compounds described.

[0303] Embodiment 207. R 35 wherein the heteroaryl group of R is substituted with 0 or 1 substituent selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, -C(OH)(CH3)2, oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 205.

[0304] Embodiment 208. R 35 is selected from the group consisting of TIFF2025523624000137.tif120150, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0305] Embodiment 209. R 35 is selected from the group consisting of TIFF2025523624000138.tif97145, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0306] Embodiment 210. R 35 is selected from the group consisting of TIFF2025523624000139.tif21145, and the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0307] Embodiment 211. R 35is 1,2,4-oxadiazolyl substituted by one substituent selected from C3-C6 heterocyclyl which may be substituted by 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 and methyl, and C3-C6 cycloalkyl which may be substituted by one or two substituents independently selected from halo and methyl, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0308] Embodiment 212. R 35 is substituted by one substituent selected from C3-C6 heterocyclyl which may be substituted by 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 and methyl, and C3-C6 cycloalkyl which may be substituted by one or two substituents independently selected from halo and methyl TIFF2025523624000140.tif10128, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0309] Embodiment 213. The oxadiazolyl is substituted by one substituent selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, -C(OH)(CH3)2, oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl, the compound according to Embodiment 211 or 212.

[0310] Embodiment 214. R 35 is A compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, selected from the group consisting of TIFF2025523624000141.tif77137.

[0311] Embodiment 215. R 35 is A compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, selected from the group consisting of TIFF2025523624000142.tif22128.

[0312] Embodiment 216. R 35 is pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 methyl groups, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193.

[0313] Embodiment 217. R 35 is A compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, selected from TIFF2025523624000143.tif17128.

[0314] Embodiment 218. R 35 is A compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, selected from TIFF2025523624000144.tif17128.

[0315] Embodiment 219. R 35 is A compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 193, selected from TIFF2025523624000145.tif17128.

[0316] Embodiment 220. R 35The compound according to any one of Embodiments 1 to 67, 69, and 71 to 147, 149, and 151 to 219, wherein the bonding point for is on a carbon atom.

[0317] Embodiment 221. R 18 is -(CH2) u R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, and 162 to 192.

[0318] Embodiment 222. R 18 is -CH2R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, and 162 to 192.

[0319] Embodiment 223. R 18 is R 34 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, and 162 to 192.

[0320] Embodiment 224. R 18 is R 35 The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, and 194 to 220.

[0321] Embodiment 225. R 18 is -CH2N(CH3). The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146.

[0322] Embodiment 226. R 18 is H. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146.

[0323] Embodiment 227. R 18 is not H. The compound according to any one of Embodiments 1 to 67, 69, and 71 to 220.

[0324] Embodiment 228. R 18is hydrogen, -COOH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)N(CH3)2, -C(O)-cyclopropyl, -CH2OCH3, -CH2N(CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropyl, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, selected from the group consisting of TIFF2025523624000146.tif119145.

[0325] Embodiment 229. R 18 is hydrogen, -COOH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)N(CH3)2, -C(O)-cyclopropyl, -CH2OCH3, -CH2N(CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropyl, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, selected from the group consisting of TIFF2025523624000147.tif120145.

[0326] Embodiment 230. R 18 is hydrogen, -CH2N(CH3)2, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, selected from the group consisting of TIFF2025523624000148.tif71137.

[0327] Embodiment 231. R 18 is -CH2N(CH3)2, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 146.

[0328] Embodiment 232. R 18 is TIFF2025523624000149.tif11128, a compound according to any one of Embodiments 1 to 67, 69, and 71 to 146.

[0329] Embodiment 233. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000150.tif11128.

[0330] Embodiment 234. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000151.tif11128.

[0331] Embodiment 235. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000152.tif10128.

[0332] Embodiment 236. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000153.tif10128.

[0333] Embodiment 237. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000154.tif13128.

[0334] Embodiment 238. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000155.tif13128.

[0335] Embodiment 239. R 18 is The compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000156.tif20128.

[0336] Embodiment 240. R18 is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000157.tif12128.

[0337] Embodiment 241. R 18 is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000158.tif10128.

[0338] Embodiment 242. R 18 is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000159.tif12128.

[0339] Embodiment 243. R 18 is the compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is TIFF2025523624000160.tif17128.

[0340] Embodiment 244. R 18 is hydrogen, -CH2N(CH3)2, the compound according to any one of Embodiments 1 to 67, 69, and 71 to 146, which is selected from the group consisting of TIFF2025523624000161.tif49143.

[0341] Embodiment 245. The -C(O)C(R 19 )=C(R 20 )R 18 the compound according to any one of Embodiments 1 to 67, 69, and 71 to 244, wherein the double bond in the part is in the E configuration.

[0342] Embodiment 246. R 2 is R 2e the compound according to any one of Embodiments 1 to 66.

[0343] Embodiment 247. R 28 is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 246, selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy.

[0344] Embodiment 248. R 28 is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 246, selected from the group consisting of methyl, ethyl, and -CH2CH2OCH3.

[0345] Embodiment 249. R 28 is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 246, which is methyl or ethyl.

[0346] Embodiment 250. R 28 is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 246, which is methyl.

[0347] Embodiment 251. A compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 250, wherein t is 0 or 1.

[0348] Embodiment 252. A compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 250, wherein t is 1.

[0349] Embodiment 253. A compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 250, wherein t is 0.

[0350] Embodiment 254. R 30 is a 4- to 5-membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR 31is replaced, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 253.

[0351] Embodiment 255. R 30 The heterocyclic group of is unsubstituted, the compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 253.

[0352] Embodiment 256. R 30 The heterocyclic group of is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 254.

[0353] Embodiment 257. R 30 The heterocyclic group of is selected from the group consisting of TIFF2025523624000162.tif14128, and the ring nitrogen of the heterocyclic group is substituted by -C(O)C≡CR 3 1, and the heterocyclic group is either unsubstituted or substituted by one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 253.

[0354] Embodiment 258. R 30 The heterocyclic group of is unsubstituted, the compound according to Embodiment 257.

[0355] Embodiment 259. R30 The compound according to embodiment 257, wherein the heteroaryl group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0356] Embodiment 260. R 29 is selected from the group consisting of TIFF2025523624000163.tif31128, and the azetidine group and the pyrrolidine group are either unsubstituted or substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, the compound according to any one of embodiments 1-66, 68, 69, 71-84, and 86-250.

[0357] Embodiment 261. The compound according to embodiment 260, wherein the azetidine group and the pyrrolidine group are unsubstituted.

[0358] Embodiment 262. The compound according to embodiment 260, wherein the azetidine group and the pyrrolidine group are further substituted by one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0359] Embodiment 263. The compound according to any one of embodiments 1-66, 68, 69, 71-84, and 86-262, wherein v is 1.

[0360] Embodiment 264. The compound according to any one of embodiments 1-66, 68, 69, 71-84, and 86-262, wherein v is 2.

[0361] Embodiment 265. The compound according to any one of embodiments 1-66, 68, 69, 71-84, and 86-264, wherein p is 0 or 1.

[0362] Embodiment 266. The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 264, wherein p is 0.

[0363] Embodiment 267. The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 264, wherein p is 1.

[0364] Embodiment 268. R 31 is selected from the group consisting of -CH2-NR 32 R 33 and -(CH2) p -R 36 The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 262, and 265 to 267.

[0365] Embodiment 269. R 31 is selected from the group consisting of -CH2-NR 32 R 33 and -CH2-R 36 The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 262.

[0366] Embodiment 270. R 32 and R 33 are independently selected from methyl and ethyl. The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 269.

[0367] Embodiment 271. R 31 is -(CH2) p -R 36 The compound according to any one of Embodiments 11 to 66, 68, 69, 71 to 84, and 86 to 262, and 265 to 267.

[0368] Embodiment 272. R 31 is -(CH2) v -NR 32 R 33 The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 264.

[0369] Embodiment 273. R 31 is -CH2-NR 32 R 33 and is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 264.

[0370] Embodiment 274. R 36 is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom as the only heteroatom, and the monocyclic heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, and is a compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 271.

[0371] Embodiment 275. The 36 monocyclic heterocycle of R is substituted with 0 or 1 example of methyl, and is a compound according to Embodiment 274.

[0372] Embodiment 276. R 36 is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with 0 or 1 example of methyl, and is a compound according to Embodiment 275.

[0373] Embodiment 277. R 36 is azetidinyl substituted with 0 or 1 example of methyl, and is a compound according to Embodiment 275.

[0374] Embodiment 278. R 36 is pyrrolidinyl substituted with 0 or 1 example of methyl, and is a compound according to Embodiment 275.

[0375] Embodiment 279. R 36 is morpholinyl substituted with 0 or 1 example of methyl, and is a compound according to Embodiment 275.

[0376] Embodiment 280. R 36 The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 271, and 274 to 279, wherein the bonding point for is a carbon atom.

[0377] Embodiment 281. R 36 is The compound according to Embodiment 281, which is selected from the group consisting of TIFF2025523624000164.tif19128.

[0378] Embodiment 282. The compound according to any one of Embodiments 274 to 281, wherein p is 0.

[0379] Embodiment 283. R 36 is a 4- to 10-membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), and the 4- to 10-membered heterocycle is independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 271, which is substituted by 0, 1, 2, 3, or 4 substituents.

[0380] Embodiment 284. R 36 is a 4- to 10-membered heterocycle containing a nitrogen atom and 1 or 2 additional heteroatoms 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 bridged heterocycles, and 6- to 10-membered spiroheterocycles, each of which is independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl The compound according to Embodiment 283, which is substituted by 0, 1, 2, 3, or 4 substituents.

[0381] Embodiment 285. R 36 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 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, the compound according to Embodiment 283.

[0382] Embodiment 286. R 36 is a 6- to 10-membered fused bicyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, the compound according to Embodiment 283.

[0383] Embodiment 287. R 36 is a 6- to 10-membered bridged heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, the compound according to Embodiment 283.

[0384] Embodiment 288. R 36 is a 6- to 10-membered spiro heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, the compound according to Embodiment 283.

[0385] Embodiment 289. R 36are azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 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, 2-oxa-5-azabicyclo[2.2.2]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, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3] A compound according to any one of embodiments 283 to 288, selected from heptane and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each being independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl and substituted with 0, 1, 2, 3, or 4 substituents.

[0386] Embodiment 290. R 36 is a morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl, a compound according to embodiment 289.

[0387] Embodiment 291. R 36 where the point of attachment for is the nitrogen atom of the heterocycle, a compound according to any one of embodiments 283 to 290.

[0388] Embodiment 292. R 36 is selected from the group consisting of TIFF2025523624000165.tif154150, each being independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl and substituted with 0, 1, 2, 3, or 4 substituents, a compound according to embodiment 291.

[0389] Embodiment 293. R 36 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl The compound according to Embodiment 292, which is TIFF2025523624000166.tif17128.

[0390] Embodiment 294. R 36 The compound according to any one of Embodiments 283 to 292, wherein the 4- to 10-membered heterocycle of R is substituted with 0, 1, 2, 3, or 4 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH2N(CH3)2, and -CH2CH2N(CH3)2.

[0391] Embodiment 295. R 36 The compound according to any one of Embodiments 283 to 292, wherein the 4- to 10-membered heterocycle of R is substituted with 0, 1, or 2 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH2N(CH3)2, and -CH2CH2N(CH3)2.

[0392] Embodiment 296. R 36 The compound according to any one of Embodiments 283 to 292, wherein the 4- to 10-membered heterocycle of R is substituted with 0, 1, or 2 substituents independently selected from fluoro and methyl.

[0393] Embodiment 297. R 36 The compound according to any one of Embodiments 283 to 292, wherein the 4- to 10-membered heterocycle of R is unsubstituted.

[0394] Embodiment 298. R 36 is The compound according to any one of Embodiments 283 to 292, which is selected from the group consisting of TIFF2025523624000167.tif199149 and TIFF2025523624000168.tif134149.

[0395] Embodiment 299. R 36 is unsubstituted The compound according to any one of Embodiments 283 to 292, which is TIFF2025523624000169.tif68146.

[0396] Embodiment 300. R 36 is unsubstituted The compound according to any one of Embodiments 283 to 292, which is TIFF2025523624000170.tif17128.

[0397] Embodiment 301. The compound according to any one of Embodiments 285 to 300, wherein p is 1.

[0398] Embodiment 302. R 31 is The compound according to any one of Embodiments 1 to 66, 68, 69, 71 to 84, and 86 to 262, which is selected from the group consisting of TIFF2025523624000171.tif19146.

[0399] Embodiment 303. R 31 is The compound according to any one of Embodiments 1 to 67, 69, 70, 72 to 85, and 87 to 263, which is selected from the group consisting of TIFF2025523624000172.tif11128.

[0400] Embodiment 304. Compounds according to Embodiment 1 selected from the group consisting of TIFF2025523624000173.tif90149, TIFF2025523624000174.tif184149, TIFF2025523624000175.tif205149, TIFF2025523624000176.tif187150, TIFF2025523624000177.tif202149, TIFF2025523624000178.tif177150, TIFF2025523624000179.tif190150, TIFF2025523624000180.tif224149, TIFF2025523624000181.tif215149, TIFF2025523624000182.tif191149, TIFF2025523624000183.tif193149, TIFF2025523624000184.tif187149, TIFF2025523624000185.tif206149, TIFF2025523624000186.tif200149, TIFF2025523624000187.tif225149, TIFF2025523624000188.tif186137, TIFF2025523624000189.tif208143, TIFF2025523624000190.tif220134, TIFF2025523624000191.tif225141, TIFF2025523624000192.tif218140, and all their salts and isotope substituents.

[0401] Embodiment 305. The compound according to Embodiment 1, selected from the group consisting of TIFF2025523624000193.tif with 185148, TIFF2025523624000194.tif with 183149, TIFF2025523624000195.tif with 189147, TIFF2025523624000196.tif with 223146, TIFF2025523624000197.tif with 225145, TIFF2025523624000198.tif with 182144, TIFF2025523624000199.tif with 218146, TIFF2025523624000200.tif with 204149, TIFF2025523624000201.tif with 195147, TIFF2025523624000202.tif with 182148, TIFF2025523624000203.tif with 184146, TIFF2025523624000204.tif with 190145, TIFF2025523624000205.tif with 197149, TIFF2025523624000206.tif with 197149, and all their salts and isotope substituents.

[0402] Embodiment 306. The compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000207.tif 185149, TIFF2025523624000208.tif 197149, TIFF2025523624000209.tif 189149, TIFF2025523624000210.tif 192149, TIFF2025523624000211.tif 183150, TIFF2025523624000212.tif 187150, TIFF2025523624000213.tif 184149, TIFF2025523624000214.tif 177150, TIFF2025523624000215.tif 184149, TIFF2025523624000216.tif 203149, TIFF2025523624000217.tif 193149, TIFF2025523624000218.tif 205149, TIFF2025523624000219.tif 198149, TIFF2025523624000220.tif 199148, TIFF2025523624000221.tif 207138, TIFF2025523624000222.tif 193146, TIFF2025523624000223.tif 222147, TIFF2025523624000224.tif 181144, TIFF2025523624000225.tif 73144; and all of their salts and isotope substituents.

[0403] Embodiment 307. The compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000226.tif 126148; and all of their salts and isotope substituents.

[0404] Embodiment 308. The compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000227.tif 225149, TIFF2025523624000228.tif 66128; and all of their salts and isotope substituents.

[0405] Embodiment 309. A compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000229.tif with 125×150, TIFF2025523624000230.tif with 214×150, and TIFF2025523624000231.tif with 172×150; and all of their salts and isotope substituents.

[0406] Embodiment 310. A compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000232.tif with 203×149, TIFF2025523624000233.tif with 199×150, TIFF2025523624000234.tif with 224×149, TIFF2025523624000235.tif with 218×150, TIFF2025523624000236.tif with 188×149, TIFF2025523624000237.tif with 197×149, TIFF2025523624000238.tif with 197×150, TIFF2025523624000239.tif with 311×28; and all of their salts and isotope substituents.

[0407] Embodiment 311. A compound according to Embodiment 1 selected from the group consisting of TIFF2025523624000240.tif with 142×149, TIFF2025523624000241.tif with 193×150, TIFF2025523624000242.tif with 191×149, TIFF2025523624000243.tif with 198×149, TIFF2025523624000244.tif with 219×149, TIFF2025523624000245.tif with 195×131, TIFF2025523624000246.tif with 220×132, TIFF2025523624000247.tif with 151×135, TIFF2025523624000248.tif with 73×131; and all of their salts and isotope substituents.

[0408] Embodiment 312. A compound according to any one of Embodiments 1 to 311 that is not a salt.

[0409] Embodiment 313. A compound according to any one of Embodiments 1 to 311, which is a salt.

[0410] Embodiment 314. The compound according to Embodiment 313, wherein the salt is a formate.

[0411] Embodiment 315. The compound according to Embodiment 313, wherein the salt is a trifluoroacetate.

[0412] Embodiment 316. The compound according to Embodiment 313, wherein the salt is a pharmaceutically acceptable salt.

[0413] Embodiment 317. A pharmaceutical preparation comprising the compound according to any one of Embodiments 1 to 313, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0414] Embodiment 318. A method for treating or suppressing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of Embodiments 1 to 313, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt, or the pharmaceutical preparation according to Embodiment 317.

[0415] Embodiment 319. The method according to Embodiment 318, wherein the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder.

[0416] Embodiment 320. The method according to embodiment 318, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the uterine cervix and endocervical adenocarcinoma, melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, choroidal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0417] Embodiment 321. The method according to any one of embodiments 318 to 320, wherein the cancer is KRAS G12C-mediated cancer.

[0418] Embodiment 322. The method according to any one of embodiments 318 to 320, wherein the subject is diagnosed with having KRAS G12C-mediated cancer.

[0419] Embodiment 323. The method according to any one of embodiments 318 to 322, further comprising administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0420] Embodiment 324. A compound according to any one of Embodiments 1 to 313 or a pharmaceutical preparation according to Embodiment 317 for use in a method of treating or suppressing cancer, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of Embodiments 1 to 313, or when the salt is a pharmaceutically acceptable salt when the compound is a salt, or the pharmaceutical preparation according to Embodiment 317, said compound or said pharmaceutical preparation.

[0421] Embodiment 325. A compound or pharmaceutical preparation for use according to Embodiment 323, wherein the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder.

[0422] Embodiment 326. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, choroidal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / stomach cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma. A compound or pharmaceutical preparation for use according to Embodiment 325.

[0423] Embodiment 327. A compound or pharmaceutical preparation for use according to any one of Embodiments 324 to 326, wherein the cancer is KRAS G12C-mediated cancer.

[0424] Embodiment 328. A compound or pharmaceutical preparation for use according to any one of Embodiments 324 to 327, wherein the subject has been diagnosed with KRAS G12C-mediated cancer.

[0425] Embodiment 329. A compound or pharmaceutical preparation for use according to any one of Embodiments 324 to 328, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0426] Embodiment 330. Use of a compound according to any one of Embodiments 1 to 313 or a pharmaceutical preparation according to Embodiment 318 in the manufacture of a medicament for treating or suppressing the cancer in a subject in need thereof.

[0427] Embodiment 331. Use according to Embodiment 330, wherein the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder.

[0428] Embodiment 332. Use according to Embodiment 331, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the cervix and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, carcinosarcoma of the uterus, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, choroidal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0429] Embodiment 333. Use according to any one of Embodiments 330 to 332, wherein the cancer is a KRAS G12C-mediated cancer.

[0430] Embodiment 334. Use according to any one of Embodiments 330 to 333, wherein the subject is diagnosed with a KRAS G12C-mediated cancer.

[0431] Embodiment 335. Use according to any one of Embodiments 330 to 334, wherein the compound or pharmaceutical formulation is configured for administration with an additional chemotherapeutic agent.

[0432] Embodiment 336. Use of a compound according to any one of Embodiments 1 to 313 or a pharmaceutical formulation according to Embodiment 318 for treating or suppressing the cancer in a subject in need thereof.

[0433] Embodiment 337. Use according to Embodiment 336, wherein the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder.

[0434] Embodiment 338. The use according to Embodiment 336, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma, 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, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma of the uterine cervix and endocervical adenocarcinoma, melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, carcinosarcoma of the uterus, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, choroidal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma.

[0435] Embodiment 339. The use according to any one of Embodiments 336 to 338, wherein the cancer is KRAS G12C-mediated cancer.

[0436] Embodiment 340. The use according to any one of Embodiments 336 to 339, wherein the subject is diagnosed with having KRAS G12C-mediated cancer.

[0437] Embodiment 341. The use according to any one of Embodiments 336 to 340, wherein the compound or pharmaceutical preparation is configured for administration with an additional chemotherapeutic agent.

[0438] General synthetic method The compounds of the present disclosure can be prepared in consideration of the disclosure in the examples shown below.

[0439] The starting materials and reagents used in the preparation of these compounds are either available from commercial suppliers (such as MilliporeSigma, Bachem, etc.) or are prepared by methods known to those skilled in the art according to the procedures described in reference documents (such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), etc.). These schemes are merely illustrative of some of the ways in which the compounds of the present disclosure can be synthesized, and various modifications can be made to these schemes, which would be suggested to those skilled in the art upon reading the present disclosure. The starting materials and intermediates as well as the final products of the reactions can be isolated and purified using conventional techniques (including but not limited to filtration, distillation, crystallization, chromatography, and the like) if desired. Such materials can be characterized using conventional means (including physical constants and spectral data).

[0440] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure over a temperature range of about -78 °C to about 150 °C, about 0 °C to about 125 °C, etc., and also approximately room temperature (or ambient temperature), such as about 20 °C.

Examples

[0441] The following preparations of the compounds of formula (A), formula (B), and formula (C), as well as their pharmaceutically acceptable salts, are provided to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be construed as limiting the scope of the present disclosure, but are merely illustrative and representative thereof.

[0442] Compounds 1 to 264 in Table 1 were prepared using the methods described in the synthesis examples or modifications thereof available to those skilled in the art.

[0443] The following abbreviations are used in this section. TIFF2025523624000249.tif102165

[0444] All reagents were obtained from commercial suppliers and used without further purification unless otherwise stated.

[0445] Synthesis Examples TIFF2025523624000250.tif49128

[0446] Example 1: (E)-1-((R)-3-((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-morpholinobut-2-en-1-one TIFF2025523624000251.tif22128

[0447] Step 1: Ethyl 2-(3-chloro-2-cyano-phenyl)-2-cyano-acetate To a solution of sodium hydride (5.14 g, 128.57 mmol, 60% purity) in N,N-dimethylformaldehyde (30 mL), ethyl 2-cyanoacetate (14.54 g, 128.57 mmol) was added at 0 °C. The mixture was stirred at 55 °C for 1 h, then 2-chloro-6-fluoro-benzonitrile (10 g, 4.29 mmol) was added and the mixture was stirred at 50 °C for 4 h. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give ethyl 2-(3-chloro-2-cyano-phenyl)-2-cyano-acetate (16 g, crude) as a yellow solid, which was used in the next step without further purification. LCMS Rt = 0.812 min, m / z = 248.0 [M + H] + . TIFF2025523624000252.tif20128

[0448] Step 2: 2-chloro-6-(cyanomethyl)benzonitrile A solution of ethyl 2-(3-chloro-2-cyano-phenyl)-2-cyano-acetate (15 g, 60.32 mmol) in dimethyl sulfoxide (20 mL) and water (2 mL) was stirred at 100 °C for 6 h. The reaction mixture was diluted with water (10 mL) and the resulting precipitate was filtered and dried to give 2-chloro-6-(cyanomethyl)benzonitrile (9.4 g, crude) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 7.80 - 7.68 (m, 2H), 7.65 - 7.59 (m, 1H), 4.33 (s, 2H). LCMS Rt = 0.680 min, m / z = 176.0 [M + H] + . TIFF2025523624000253.tif25128

[0449] Step 3: 1-bromo-8-chloro-isoquinolin-3-amine A solution of 2-chloro-6-(cyanomethyl)benzonitrile (9.4 g, 53.23 mmol) in hydrobromic acid acetic acid (316.06 g, 1.29 mol, 33% purity) was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate (300 mL). The resulting precipitate was filtered and dried to give 1-bromo-8-chloro-isoquinolin-3-amine (13 g, crude), which was used in the next step without further purification as a yellow solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.47 - 8.46 (m, 1H), 8.01 - 7.96 (m, 1H), 7.74 - 7.71 (m, 1H), 7.68 - 7.63 (m, 1H). TIFF2025523624000254.tif25128

[0450] Step 4: 1-Bromo-8-chloro-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine The PMB protection reaction was prepared in a manner similar to Example No. 71, Step 1. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give 1-bromo-8-chloro-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine (3 g, 31.04%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.33 - 7.31 (m, 2H), 7.24 - 7.18 (m, 5H), 6.86 (d, J = 8.6 Hz, 4H), 6.49 - 6.45 (m, 1H), 4.74 (s, 4H), 3.80 (s, 6H). LCMS Rt = 3.172 min, m / z = 498.1 [M + H] + . TIFF2025523624000255.tif46128

[0451] Step 5: (R)-tert-butyl 3-((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to obtain (R)-tert-butyl 3-((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (590 mg, 50.81%) as a yellow solid. LCMS Rt = 0.803 min, m / z = 920.4 [M + H] + . TIFF2025523624000256.tif39128

[0452] Step 6: 7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine The de-Boc reaction and PMB protection reaction were prepared in a manner similar to Example No. 71, Step 7. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 5% - 35%, 8 minutes) to obtain 7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (65 mg, 59.08%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 0.456 min, m / z = 580.2 [M + H] + . TIFF2025523624000257.tif50128

[0453] Step 7: Diethyl (2-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate The amide coupling reaction was prepared in a manner similar to Example No. 2, Step 5. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 60%, 8 minutes) to obtain diethyl (2-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate (15 mg, 22.96%) as a yellow solid. LCMS Rt = 0.713 min, m / z = 758.3 [M + H] + . TIFF2025523624000258.tif48128

[0454] Step 8: (E)-1-((R)-3-((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-morpholinobut-2-en-1-one The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 10% - 50%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-morpholinobut-2-en-1-one (8.76 mg, 87.80%) as a yellow amorphous solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.17 - 9.16 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 - 7.18 (m, 1H), 6.95 - 6.89 (m, 1H), 6.80 - 6.64 (m, 1H), 6.48 - 6.33 (m, 1H), 5.44 - 5.17 (m, 2H), 5.17 - 5.10 (m, 2H), 4.24 - 4.17 (m, 1H), 4.16 - 4.08 (m, 1H), 4.08 - 3.89 (m, 1H), 3.88 - 3.76 (m, 1H), 3.68 - 3.58 (m, 5H), 3.57 - 3.43 (m, 1H), 3.40 (br s, 3H), 3.20 - 3.01 (m, 5H), 2.94 - 2.84 (m, 1H), 2.40 (br s, 4H), 2.32 - 2.17 (m, 2H), 2.12 - 2.02 (m, 3H), 1.92 - 1.75 (m, 3H). LCMS Rt = 2.418 min, m / z = 733.3 [M + H] + . LCMS (Over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.418 min, ESI+ measured value [M + H]=733.3. TIFF2025523624000259.tif46128

[0455] Example 2: (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000260.tif24128

[0456] Step 1: (S)-tert-Butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate To a solution of (2S)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (2 g, 9.94 mmol) and N-methoxymethanamine; hydrochloride (1.16 g, 11.93 mmol) in N,N-dimethylformaldehyde (20 mL), 4-methylmorpholine (1.21 g, 11.93 mmol), 1-hydroxybenzotriazole (1.61 g, 11.93 mmol, 1.2 equiv), and 3-(ethyliminomethylideneamino)-N,N-dimethylpropan-1-amine (2.29 g, 11.93 mmol) were added at 0 °C, and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to give (S)-tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (2.1 g, 85.62%) as a colorless solid. 1 H NMR (400 MHz, chloroform-d) δ 5.10 - 4.95 (m, 1H), 4.09 - 3.99 (m, 1H), 3.92 - 3.81 (m, 1H), 3.70 (s, 3H), 3.30 - 3.17 (m, 3H), 2.46 (dtd, J = 6.4, 9.0, 11.1 Hz, 1H), 2.19 - 2.06 (m, 1H), 1.42 (s, 9H). TIFF2025523624000261.tif13128

[0457] Step 2: (S)-tert-Butyl 2-formylazetidine-1-carboxylate To a solution of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (170 mg, 695.90 umol) in tetrahydrofuran (2 mL), bis(2-methylpropyl)alumanylium hydride (1 M, 1.39 mL in toluene) was added at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 0.5 h under a nitrogen atmosphere. The mixture was quenched with 5% potassium bisulfate (2 mL) at 0 °C and extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated sodium bicarbonate (2 mL) and brine (3 mL), dried over sodium sulfate, and concentrated in vacuo to give (S)-tert-butyl 2-formylazetidine-1-carboxylate (90 mg, crude) as a white solid, which was used in the next step without any further purification. TIFF2025523624000262.tif46128

[0458] Step 3: (R)-tert-butyl 3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to give (R)-tert-butyl 3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (1.5 g, 73.08%) as a brown oil. LCMS Rt = 2.675 min, m / z = 904.4 [M + H] + . TIFF2025523624000263.tif41128

[0459] Step 4: 7-(3-(Bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine A mixture of (R)-tert-butyl 3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (270 mg, 298.34 μmol) in hydrochloric acid - ethyl acetate (2 mL, 4M) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to dryness under vacuum to give 7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (270 mg, crude, hydrochloride) as a yellow solid and used in the next step without any further purification. LCMS Rt = 0.896 min, m / z = 804.4 [M + H] + . TIFF2025523624000264.tif60128

[0460] Step 5: Diethyl (2-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate A solution of 7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (270 mg, 320.91 μmol, hydrochloride), 2-diethoxyphosphoryl acetic acid (125.88 mg, 641.82 μmol), and N,N-diisopropylethylamine (124.43 mg, 962.73 μmol) in dichloromethane (3 mL) was added with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (408.43 mg, 641.82 μmol, 50% purity in ethyl acetate). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched at 0 °C with 1 N HCl (5 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 20% methanol in dichloromethane) to give diethyl (2-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate (300 mg, 95.10%) as a brown oil. LCMS Rt = 0.753 min, m / z = 982.4 [M + H]+. TIFF2025523624000265.tif49128

[0461] Step 6: (S)-tert-Butyl 2-((E)-3-((R)-3-((7-(3-(Bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate To a solution of diethyl (2-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate (150 mg, 152.59 μmol), N-ethyl-N-isopropylpropan-2-amine (59.16 mg, 457.77 μmol), and lithium chloride (32.34 mg, 762.95 μmol) in acetonitrile (2 mL) was added (S)-tert-butyl 2-formylazetidine-1-carboxylate (84.79 mg, 457.77 μmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 20% methanol in dichloromethane) to give (S)-tert-butyl 2-((E)-3-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (90 mg, 58.16%) as a white solid. LCMS Rt = 1.173 min, m / z = 1013.5 [M + H] + . TIFF2025523624000266.tif45128

[0462] Step 7: (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one To a solution of (S)-tert-butyl 2-((E)-3-((R)-3-((7-(3-(Bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (80 mg, 78.88 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated to dryness under vacuum. The residue was purified by reverse phase HPLC: column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 5% - 35%, 8 min to give (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one (20 mg, 32.18%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 0.626 min, m / z = 673.3 [M + H] + . TIFF2025523624000267.tif46128

[0463] Step 8: (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one To a solution of (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one (12.7 mg, 16.12 μmol, trifluoroacetate) in methanol (1 mL) were added triethylamine (4.89 mg, 48.37 μmol), acetic acid (968.15 μg (16.12 μmol)), formaldehyde (915.82 μg, 11.29 μmol), and sodium cyanoboranuide (2.53 mg, 40.30 μmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to dryness under vacuum. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 18% - 58%, 8 minutes) to give (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one (1 mg, 8.50%) as a white solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.28 (d, J = 2.8 Hz, 1H), 7.60 - 7.50 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.94 - 6.80 (m, 2H), 6.61 - 6.44 (m, 1H), 5.51 - 5.22 (m, 4H), 4.37 - 4.25 (m, 2H), 4.24 - 4.06 (m, 1H), 4.05 - 3.85 (m, 2H), 3.85 - 3.71 (m, 2H), 3.70 - 3.53 (m, 2H), 3.52 - 3.34 (m, 5H), 3.29 (br d, J = 11.1 Hz, 2H), 3.25 - 3.20 (m, 1H), 3.07 - 2.97 (m, 2H), 2.28 - 2.05 (m, 7H), 1.99 - 1.82 (m, 3H). LCMS Rt = 1.774 min, m / z = 687.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% formic acid) retention time 1.774 min, ESI+ measured value [M + H] = 687.3 TIFF2025523624000268.tif48128

[0464] Example 3: (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000269.tif52128

[0465] Step 1: (R)-tert-Butyl 2-((E)-3-((R)-3-((7-(3-(Bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain (R)-tert-butyl 2-((E)-3-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (155 mg, crude) as an orange gum and used in the next step without further purification. LCMS Rt = 0.459 min, m / z = 1029.5 [M + H] + . TIFF2025523624000270.tif49128

[0466] Step 2: (E)-1-((R)-3-((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-azetidin-2-yl)prop-2-en-1-one The de-Boc reaction and PMB protection reaction were prepared in a manner similar to Example No. 2, Step 7. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 10% - 40%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-azetidin-2-yl)prop-2-en-1-one (40 mg, 29.86%, trifluoroacetate salt) as a black solid. LCMS Rt = 0.601 min, m / z = 689.3 [M + H] + . TIFF2025523624000271.tif48128

[0467] Step 3: (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one The reductive amination reaction was prepared in a manner similar to Example No. 2, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 55%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one (2.7 mg, 8.32%) as a yellow amorphous solid. 1 1H NMR (400 MHz, acetonitrile-d3) δ 9.21 - 9.10 (m, 1H), 7.71 - 7.59 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.25 - 7.14 (m, 1H), 6.96 - 6.83 (m, 1H), 6.80 - 6.69 (m, 1H), 6.45 - 6.30 (m, 1H), 5.45 - 5.30 (m, 2H), 5.17 - 5.29 (m, 2H), 4.57 - 4.26 (m, 1H), 4.16 - 4.08 (m, 2H),, 3.97 - 3.71 (m, 2H), 3.69 - 3.47 (m, 3H), 3.41 - 3.37 (m, 3H), 3.29 - 3.22 (m, 1H), 3.13 (br d, J = 8.3 Hz, 2H), 3.08 - 3.04 (m, 1H), 2.90 - 2.85 (m, 1H), 2.28 - 2.20 (m, 3H), 2.19 - 2.01 (m, 5H), 1.92 - 1.75 (m, 5H). LCMS Rt = 2.704 minutes, m / z = 703.3 [M + H] + . LCMS (5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.704 minutes, ESI+ measured value [M+H] = 703.3. TIFF2025523624000272.tif55128

[0468] Example 4: (E)-1-(3-(((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one TIFF2025523624000273.tif39128

[0469] Step 1: tert-Butyl 3-[[(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-methyl-amino]methyl]azetidine-1-carboxylate The substitution reaction was prepared in a manner similar to Step 3 of Example No. 71. The mixture was concentrated under vacuum to obtain tert-butyl 3-[[(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-methyl-amino]methyl]azetidine-1-carboxylate (7 g, crude), which was obtained as a brown solid and used in the next step without further purification. LCMS Rt = 0.826 min, m / z = 415.1 [M + H] + . TIFF2025523624000274.tif45128

[0470] Step 2: tert-Butyl 3-(((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The substitution reaction was prepared in a manner similar to Example No. 71, Step 4. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 80 - 100% ethyl acetate in petroleum ether) to obtain tert-butyl 3-(((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (2 g, 44.12%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.87 (s, 1H), 5.41 - 5.18 (m, 1H), 4.30 - 4.19 (m, 2H), 4.08 (q, J = 8.3 Hz, 4H), 3.81 - 3.74 (m, 2H), 3.53 - 3.48 (m, 3H), 3.35 - 3.17 (m, 3H), 3.09 - 2.95 (m, 2H), 2.29 - 2.08 (m, 3H), 2.00 - 1.84 (m, 3H), 1.45 (s, 9H). LCMS Rt = 0.645 min, m / z = 538.2 [M + H] + . TIFF2025523624000275.tif45128

[0471] Step 3: tert-butyl 3-(((8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The tin reagent formation was prepared in a manner similar to Example No. 71, Step 5. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 80 - 100% ethyl acetate in petroleum ether) to obtain tert-butyl 3-(((8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (2.5 g, 84.90%) as a yellow oil. LCMS Rt = 2.437 min, m / z = 794.4 [M + H] + . TIFF2025523624000276.tif48128

[0472] Step 4: tert-butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 80 - 100% ethyl acetate in petroleum ether) to obtain tert-butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (1.3 g, 44.91%) as a yellow solid. LCMS Rt = 0.810 min, m / z = 918.4 [M + H] + . TIFF2025523624000277.tif46128

[0473] Step 5: 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the PMB group was prepared in a manner similar to Example No. 71, Step 7. The mixture was purified by reverse phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 35% - 75%, 8 minutes) to obtain 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (700 mg, 71.45%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 0.594 min, m / z = 578.3 [M + H] + . TIFF2025523624000278.tif65128

[0474] Step 6: Diethyl (2-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-2-oxoethyl)phosphonate The amid coupling reaction was prepared in a manner similar to Example No. 2, Step 5. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3) - acetonitrile]; B%: 40% - 70%, 8 minutes) to obtain diethyl (2-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-2-oxoethyl)phosphonate (120 mg, 36.61%) as a colorless oil. LCMS Rt = 0.616 min, m / z = 756.3 [M + H] + . TIFF2025523624000279.tif55128

[0475] Step 7: (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 40% - 70%, 8 minutes) to obtain (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one (19.39 mg, 23.10%) as a yellow solid. 1 1H NMR (400 MHz, acetonitrile-d3) δ 9.22 - 9.16 (m, 1H), 7.72 - 7.62 (m, 1H), 7.11 - 6.99 (m, 1H), 6.60 (br s, 1H), 5.34 - 5.16 (m, 1H), 4.48 (br t, J = 8.3 Hz, 1H), 4.30 - 4.24 (m, 2H), 4.21 (br dd, J = 3.8, 10.3 Hz, 2H), 4.11 (br s, 2H), 3.96 (br dd, J = 5.3, 10.4 Hz, 1H), 3.58 (br s, 3H), 3.23 (br d, J = 7.6 Hz, 2H), 3.19 - 3.14 (m, 2H), 2.91 - 2.85 (m, 1H), 2.66 - 2.59 (m, 3H), 2.43 (br s, 3H), 2.21 - 2.03 (m, 3H), 1.91 - 1.78 (m, 3H). LCMS Rt = 2.760 min, m / z = 730.3 [M + H] + . LCMS (5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.760 minutes, ESI+ measured value [M+H] = 730.3. TIFF2025523624000280.tif41128

[0476] Example 5: 1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025523624000281.tif20128

[0477] Step 1: 6-Bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine The PMB protection reaction was prepared in a manner similar to Step 1 of Example No. 71. The crude product was washed with tert-butyl methyl ether (30 mL) and then filtered to obtain 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (21 g, 58.21%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.14 (m, 4H), 6.90 - 6.82 (m, 4H), 6.62 - 6.58 (m, 1H), 6.20 - 6.15 (m, 1H), 4.69 - 4.62 (m, 4H), 3.86 - 3.76 (m, 6H), 2.17 - 2.10 (m, 3H). LCMS Rt = 0.966 min, m / z = 426.1 [M + H] + . TIFF2025523624000282.tif25128

[0478] Step 2: 6-Bromo-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine To a solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (11 g, 25.74 mmol) in N,N-dimethylformaldehyde (50 mL), N-iodo-succinimide (8.69 g, 38.61 mmol) was added and the reaction was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was washed with ethyl acetate (15 mL) to give 6-bromo-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (10 g, 66.71%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.13 (m, 4H), 6.91 - 6.83 (m, 4H), 6.31 - 6.26 (m, 1H), 4.70 - 4.59 (m, 4H), 3.87 - 3.78 (m, 6H), 2.36 - 2.31 (m, 3H). LCMS Rt = 1.025 min, m / z = 552.0 [M + H] + . TIFF2025523624000283.tif27128

[0479] Step 3: 6-Bromo-5-cyclopropyl-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine To a solution of 6-bromo-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (8 g, 14.46 mmol) in tert-amyl alcohol (80 mL) was added cyclopropylboronic acid (1.28 g, 14.89 mmol), cesium carbonate (14.13 g, 43.38 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.06 g, 1.45 mmol), and the reaction was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 6-bromo-5-cyclopropyl-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (2.2 g, 26.04%) as a white solid. LCMS Rt = 1.011 min, m / z = 466.1 [M + H] + . TIFF2025523624000284.tif41128

[0480] Step 4: (R)-tert-Butyl 3-((7-(6-(bis(4-methoxybenzyl)amino)-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The still reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 40% tetrahydrofuran in petroleum ether) to obtain (R)-tert-butyl 3-((7-(6-(bis(4-methoxybenzyl)amino)-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (1.3 g, 90.97%) as a yellow oil. LCMS Rt = 2.371 min, m / z = 890.5 [M + H] + . TIFF2025523624000285.tif37128

[0481] Step 5: 7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the PMB group was prepared in a manner similar to Example No. 71, Step 7. The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 (250*70mm, 15um); mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 8% - 36%, 22 min) to obtain 7-(6-amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (80 mg, 11.77%) as a white solid. LCMS Rt = 1.069 min, m / z = 550.3 [M + H] + . TIFF2025523624000286.tif41128

[0482] Step 6: 1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 15% - 55%, 8 minutes) to obtain 1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (7.61 mg, 17.27%) as a yellow oil. 11H NMR (400 MHz, acetonitrile-d3) δ 9.19 - 9.14 (m, 1H), 6.64 - 6.52 (m, 1H), 6.48 - 6.44 (m, 1H), 6.27 - 6.19 (m, 1H), 5.71 - 5.62 (m, 1H), 5.40 - 5.15 (m, 2H), 4.77 - 4.74 (m, 1H), 4.24 - 4.16 (m, 1H), 4.14 - 4.09 (m, 1H), 3.94 (dd, J = 8.0, 12.9 Hz, 1H), 3.90 - 3.76 (m, 1H), 3.69 - 3.60 (m, 1H), 3.58 - 3.41 (m, 1H), 3.41 - 3.35 (m, 3H), 3.18 - 3.08 (m, 2H), 3.06 (s, 1H), 2.93 - 2.84 (m, 1H), 2.39 (s, 3H), 2.36 (br d, J = 8.8 Hz, 1H), 2.31 - 2.25 (m, 1H), 2.19 - 2.16 (m, 1H), 2.11 - 1.99 (m, 3H), 1.91 - 1.82 (m, 3H), 1.74 - 1.65 (m, 1H), 0.56 - 0.47 (m, 2H), 0.03 - 0.06 (m, 2H). LCMS Rt = 2.615 min, m / z = 604.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.615 min, ESI+ observed value [M + H] = 604.3. TIFF2025523624000287.tif48128

[0483] Example 6: (E)-1-((R)-3-((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000288.tif41128

[0484] Step 1: 7-(3-(Bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine The de-Boc protection reaction was prepared in a manner similar to Example No. 2, Step 4. The mixture was concentrated to dryness under vacuum to obtain 7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (623 mg, crude, hydrochloride) as a yellow solid and used in the next step without further purification. LCMS Rt = 0.702 min, m / z = 820.3 [M + H] + . TIFF2025523624000289.tif60128

[0485] Step 2: Diethyl (2-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate The amid coupling reaction was prepared in a manner similar to Example No. 2, Step 5. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 15% methanol in dichloromethane) to obtain diethyl (2 - ((R)-3 - ((7-(3-(bis(4 - methoxybenzyl)amino)-8 - chloroisoquinolin - 1 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorohexahydro - 1H - pyrrolidin - 7a - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-2 - oxoethyl)phosphonate (580 mg, 77.66%) as an orange gum. LCMS Rt = 0.777 min, m / z = 998.4 [M + H] + . TIFF2025523624000290.tif53128

[0486] Step 3: (S)-tert - butyl 2 - ((E)-3 - ((R)-3 - ((7-(3-(bis(4 - methoxybenzyl)amino)-8 - chloroisoquinolin - 1 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorohexahydro - 1H - pyrrolidin - 7a - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-3 - oxoprop - 1 - en - 1 - yl)azetidine - 1 - carboxylate The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The mixture was concentrated to dryness under vacuum to obtain (S)-tert-butyl 2-((E)-3-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (150 mg, crude) as an orange gum and used in the next step without further purification. LCMS Rt = 0.801 min, m / z = 1029.5 [M + H] + . TIFF2025523624000291.tif48128

[0487] Step 4: (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one The de-Boc reaction and PMB protection reaction were prepared in a manner similar to Example No. 2, Step 7. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 10% - 35%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one (40 mg, 34.11%, trifluoroacetate salt) as a black solid. LCMS Rt = 0.567 min, m / z = 689.3 [M + H] + . TIFF2025523624000292.tif48128

[0488] Step 5: The reductive amination reaction of (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one was prepared in a manner similar to Example No. 2, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 55%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one (2.1 mg, 7.99%) as a yellow amorphous solid.1 1H NMR (400 MHz, acetonitrile-d3) δ 9.23 - 9.12 (m, 1H), 7.68 - 7.58 (m, 1H), 7.46 - 7.35 (m, 1H), 7.27 - 7.20 (m, 1H), 6.95 - 6.90 (m, 1H), 6.81 - 6.71 (m, 1H), 6.42 - 6.31 (m, 1H), 5.43 - 5.19 (m, 2H), 5.16 (br s, 2H), 4.24 - 4.17 (m, 1H), 4.16 - 4.09 (m, 1H), 4.08 - 3.75 (m, 2H), 3.69 - 3.60 (m, 1H), 3.58 - 3.43 (m, 2H), 3.42 - 3.38 (m, 3H), 3.32 - 3.23 (m, 1H), 3.19 - 3.08 (m, 2H), 3.08 - 3.04 (m, 1H), 2.94 - 2.85 (m, 1H), 2.84 - 2.75 (m, 1H), 2.41 - 2.28 (m, 2H), 2.23 (br d, J = 9.4 Hz, 3H), 2.12 - 1.99 (m, 4H), 1.92 - 1.79 (m, 4H). LCMS Rt = 2.677 min, m / z = 703.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.1% ammonium bicarbonate) retention time 2.677 min, ESI+ measured value [M + H] = 703.3. TIFF2025523624000293.tif46128

[0489] Example 7: (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000294.tif16128

[0490] Step 1: (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate The amid coupling reaction was prepared in a manner similar to Example No. 2, Step 1. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to obtain (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (2.1 g, 85.62%) as a colorless solid. 1 HNMR (400 MHz, chloroform-d) δ 5.10 - 4.95 (m, 1H), 4.09 - 3.99 (m, 1H), 3.92 - 3.81 (m, 1H), 3.70 (s, 3H), 3.30 - 3.17 (m, 3H), 2.46 (dtd, J = 6.4, 9.0, 11.1 Hz, 1H), 2.19 - 2.06 (m, 1H), 1.42 (s, 9H). LCMS Rt = 0.678 min, m / z = 244.1 [M + H] + . TIFF2025523624000295.tif18128

[0491] Step 2: (R)-tert-butyl 2-formylazetidine-1-carboxylate The reduction reaction was prepared in a manner similar to Example No. 2, Step 2. The mixture was concentrated to dryness under vacuum to obtain (R)-tert-butyl 2-formylazetidine-1-carboxylate (220 mg, crude product) as a colorless oil, which was used in the next step without further purification. TIFF2025523624000296.tif49128

[0492] Step 3: (S)-tert-Butyl 2-((E)-3-((R)-3-((7-(3-(Bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% methanol in dichloromethane) to give (S)-tert-butyl 2-((E)-3-((R)-3-((7-(3-(bis(4-methoxybenzyl)amino)-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (90 mg, 58.16%) as a white solid. LCMS Rt = 1.173 min, m / z = 1013.5 [M + H] + . TIFF2025523624000297.tif46128

[0493] Step 4: (E)-1-((R)-3-((7-(3-Amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one The de-Boc reaction and PMB protection reaction were prepared in a manner similar to Example No. 2, Step 7. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 5% - 35%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one (20 mg, 32.18%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 0.626 min, m / z = 673.3 [M + H] + . TIFF2025523624000298.tif46128

[0494] Step 5: (E)-1-((R)-3-((7-(3-amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one The reductive amination reaction was prepared in a manner similar to Example No. 2, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain (E)-1-((R)-3-((7-(3-amino-8-fluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one (5.2 mg, 14.65%) as a yellow solid. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.22 (d, J = 2.6 Hz, 1H), 7.55 - 7.44 (m, 2H), 6.93 (d, J = 2.0 Hz, 1H), 6.89 - 6.74 (m, 2H), 6.45 - 6.35 (m, 1H), 5.40 - 5.32 (m, 1H), 5.24 - 5.15 (m, 2H), 4.29 - 4.21 (m, 1H), 4.17 (br d, J = 2.3 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.99 - 3.89 (m, 1H), 3.88 - 3.76 (m, 1H), 3.71 - 3.47 (m, 3H), 3.44 (d, J = 1.9 Hz, 3H), 3.35 - 3.27 (m, 1H), 3.22 - 3.14 (m, 2H), 3.13 - 3.07 (m, 1H), 2.96 - 2.78 (m, 2H), 2.44 - 2.29 (m, 3H), 2.26 (d, J = 7.9 Hz, 3H), 2.14 (br s, 2H), 2.11 - 2.06 (m, 2H), 1.93 - 1.78 (m, 3H). LCMS Rt = 1.768 minutes, m / z = 687.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.1% ammonium bicarbonate) retention time 1.768 minutes, ESI+ measured value [M + H] = 687.3. TIFF2025523624000299.tif45128

[0495] Example 8: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000300.tif22128

[0496] Step 1: 6-Bromo-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine The PMB protection reaction was prepared in a manner similar to Step 1 of Example No. 71. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to obtain 6-bromo-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (2.5 g, 78.45%) as a yellow oil. LCMS Rt = 1.037 minutes, m / z = 538.0 [M + H] + . TIFF2025523624000301.tif25128

[0497] Step 2: 6-Bromo-5-cyclopropyl-N,N-bis(4-methoxybenzyl)pyridin-2-amine A solution of 6-bromo-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (2.5 g, 4.64 mmol), cyclopropylboronic acid (406.23 mg, 4.73 mmol), and cesium carbonate (4.53 g, 13.91 mmol) in dioxane (10 mL) and water (1 mL) was added with cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (678.51 mg, 927.29 μmol). The mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (column: Welch Xtimate C18 250*70mm #10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 65% - 95%, 17 min) to give 6-bromo-5-cyclopropyl-N,N-bis(4-methoxybenzyl)pyridin-2-amine (800 mg, 38.06%) as a yellow oil. LCMS Rt = 3.036 min, m / z = 452.1 [M + H] + . TIFF2025523624000302.tif41128

[0498] Step 3: (R)-tert-butyl 3-((7-(6-(bis(4-methoxybenzyl)amino)-3-cyclopropylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The still reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 95 - 100% ethyl acetate in petroleum ether) to obtain tert-butyl (3R)-3-[[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-cyclopropyl-2-pyridyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-methyl-amino]pyrrolidine-1-carboxylate (350 mg, 24.07%) as a yellow oil. LCMS Rt = 0.757 min, m / z = 876.5 [M + H] + . TIFF2025523624000303.tif37128

[0499] Step 4: 7-(6-Amino-3-cyclopropylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine The deprotection of Boc and PMB was prepared in a manner similar to Example No. 71, Step 7. The residue was purified by reverse phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 1% - 35%, 8 min) to obtain 7-(6-amino-3-cyclopropylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, 98.06%, trifluoroacetate salt) as a yellow oil. LCMS Rt = 0.382 min, m / z = 536.3 [M + H] + . TIFF2025523624000304.tif45128

[0500] Step 5: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to that of Example No. 71, Step 11. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 35% - 55%, 8 minutes) to obtain (E)-1-[(3R)-3-[[7-(6-amino-3-cyclopropyl-2-pyridyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-methyl-amino]pyrrolidin-1-yl]-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (34.15 mg, 39.63%) as a yellow amorphous solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.19 (d, J = 1.6 Hz, 1H), 7.49 - 7.33 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 5.43 - 5.16 (m, 2H), 4.85 (s, 2H), 4.25 - 4.10 (m, 3H), 4.04 - 3.96 (m, 1H), 3.91 - 3.70 (m, 2H), 3.63 - 3.47 (m, 1H), 3.41 (s, 3H), 3.15 - 3.06 (m, 3H), 2.88 (quin, J = 7.6 Hz, 1H), 2.42 - 2.28 (m, 2H), 2.12 - 1.97 (m, 3H), 1.91 - 1.80 (m, 3H), 1.71 - 1.63 (m, 1H), 1.32 (dd, J = 7.0, 8.6 Hz, 6H), 0.70 - 0.60 (m, 2H), 0.52 - 0.42 (m, 2H). LCMS Rt = 2.707 min, m / z = 700.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.707 min, ESI+ measured value [M + H] = 700.3. TIFF2025523624000305.tif49128

[0501] Example 9: (E)-1-((R)-3-(((6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000306.tif41128

[0502] Step 1: (3R)-tert-Butyl 3-((7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a manner similar to Example No. 65, Step 14. The resulting residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to obtain (3R)-tert-butyl 3-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 50.85%) as a white solid. LCMS Rt = 0.674 min, m / z = 899.5 [M + H] + . TIFF2025523624000307.tif40132

[0503] Step 2: (R)-tert-Butyl 3-(((6S,7S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate and (R)-tert-butyl 3-(((6R,7R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate A mixture of diastereoisomers was separated by SFC to afford the following arbitrarily assigned ones. As a white solid, (R)-tert-butyl 3-(((6S,7S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (Peak 1, retention time = 1.948 min) (150 mg, 25.42%). LCMS Rt = 0.674 min, m / z = 899.5 [M + H] + . As a white solid, (R)-tert-butyl 3-(((6R,7R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (Peak 2, retention time = 2.865 min) (120 mg, 20.34%). LCMS Rt = 0.674 min, m / z = 899.5 [M + H] + . SFC (column: REGIS (S,S) WHELK-O1 (250 mm * 25 mm, 10 um); mobile phase: [0.1% NH3H2O IPA]; B%: 62% - 62%, 20 min). TIFF2025523624000308.tif36128

[0504] Step 3: (6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine The deprotection of Boc and PMB was carried out in a manner similar to Example No. 65, Step 15. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 1% - 30%, 8 minutes) to obtain (6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine (80 mg, 89.07%, trifluoroacetate salt) as a white solid. LCMS Rt = 0.578 min, m / z = 559.3 [M + H] + . TIFF2025523624000309.tif49128

[0505] Step 4: (E)-1-((R)-3-(((6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 65, Step 16. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 70%, 8 minutes) to obtain (E)-1-((R)-3-(((6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (12.77 mg, 24.73%) as a yellow solid. 1H NMR (400 MHz, acetonitrile-d3) δ 7.51 - 7.43 (m, 1H), 7.41 - 7.33 (m, 1H), 6.28 (s, 1H), 5.24 (s, 2H), 4.79 - 4.58 (m, 1H), 4.16 (dd, J = 8.0, 10.3 Hz, 1H), 4.03 - 3.89 (m, 3H), 3.87 - 3.74 (m, 1H), 3.68 (br d, J = 8.6 Hz, 1H), 3.52 - 3.36 (m, 1H), 3.17 (td, J = 5.3, 10.3 Hz, 1H), 3.07 - 2.94 (m, 3H), 2.93 (d, J = 3.1 Hz, 3H), 2.89 - 2.81 (m, 1H), 2.66 (s, 4H), 2.41 (s, 1H), 2.40 (s, 1H), 2.38 (d, J = 3.5 Hz, 2H), 2.30 - 2.23 (m, 1H), 2.21 - 2.14 (m, 1H), 2.13 - 2.03 (m, 2H), 1.91 (td, J = 6.1, 12.1 Hz, 2H), 1.86 - 1.71 (m, 4H), 1.66 - 1.54 (m, 2H), 0.77 (d, J = 6.3 Hz, 3H). LCMS Rt = 2.987 minutes, m / z = 695.4 [M + H]+. LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.987 minutes, ESI+ measured value [M + H] = 695.4. TIFF2025523624000310.tif62128

[0506] Example 10: (E)-1-(3-(((7-(6-amino-3,4-dimethylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000311.tif48128

[0507] Step 1: tert-butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-3,4-dimethylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to give tert-butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-3,4-dimethylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (1.09 g, 49.01%) as a brown oil. LCMS Rt = 2.282 minutes, m / z = 864.5 [M + H] + . TIFF2025523624000312.tif46128

[0508] Step 2: 7-(6-Amino-3,4-dimethylpyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the PMB group was prepared in a manner similar to Example No. 71, Step 7. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 1% - 20%, 8 minutes) to obtain 7-(6-amino-3,4-dimethylpyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (60 mg, 40.71%, trifluoroacetate salt) as a pale brown oil. LCMS Rt = 0.376 min, m / z = 524.3 [M + H] + . TIFF2025523624000313.tif62128

[0509] Step 3: (E)-1-(3-(((7-(6-Amino-3,4-dimethylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3) - acetonitrile]; B%: 30% - 60%, 8 minutes) to obtain (E)-1-(3-(((7-(6-amino-3,4-dimethylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (1.7 mg, 2.68%) as a yellow oil. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.27 - 9.19 (m, 1H), 7.34 - 7.26 (m, 1H), 7.17 - 7.08 (m, 1H), 6.52 - 6.45 (m, 1H), 5.37 - 5.17 (m, 1H), 4.82 - 4.59 (m, 2H), 4.46 (br t, J = 8.7 Hz, 1H), 4.29 - 4.21 (m, 2H), 4.21 - 4.10 (m, 4H), 3.95 - 3.88 (m, 1H), 3.56 (s, 3H), 3.28 - 3.17 (m, 3H), 3.15 - 3.07 (m, 2H), 2.97 (br s, 1H), 2.25 (s, 6H), 1.91 - 1.73 (m, 4H), 1.62 - 1.44 (m, 2H), 1.31 (d, J = 7.0 Hz, 6H). LCMS Rt = 1.901 min, m / z = 688.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.1% trifluoroacetic acid) retention time 1.901 minutes, ESI+ measured value [M+H] = 688.3. TIFF2025523624000314.tif45128

[0510] Example 11: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000315.tif45128

[0511] Step 1: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to that in Example No. 71, Step 11. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 35% - 65%, 8 minutes) to obtain (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (32.23 mg, 14.80%) as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.20 - 9.14 (m, 1H), 7.50 - 7.32 (m, 2H), 6.48 - 6.43 (m, 1H), 5.18 (br d, J = 2.6 Hz, 2H), 4.79 - 4.71 (m, 2H), 4.22 - 4.18 (m, 1H), 4.16 (s, 1H), 4.04 - 3.96 (m, 1H), 3.91 - 3.82 (m, 1H), 3.80 - 3.70 (m, 1H), 3.64 - 3.45 (m, 1H), 3.41 (s, 3H), 3.19 - 3.08 (m, 2H), 3.07 - 3.02 (m, 1H), 2.93 - 2.82 (m, 1H), 2.44 - 2.40 (m, 1H), 2.39 (s, 4H), 2.37 (s, 2H), 2.35 - 2.27 (m, 1H), 2.22 (br d, J = 4.4 Hz, 1H), 2.10 (br d, J = 2.8 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.91 - 1.78 (m, 3H), 1.74 - 1.64 (m, 1H), 0.57 - 0.48 (m, 2H), -0.01 (br d, J = 4.5 Hz, 2H). LCMS Rt = 2.723 min, m / z = 686.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.723 min, ESI+ observed value [M + H] = 686.3. TIFF2025523624000316.tif44128

[0512] Example 12: 1 - ((R)-3 - ((7-(3 - chloro - 2 - cyclopropyl - 5 - hydroxyphenyl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)prop - 2 - en - 1 - one TIFF2025523624000317.tif17128

[0513] Step 1: 1-Bromo-3-chloro-2-cyclopropyl-benzene To a solution of 1-bromo-3-chloro-2-iodo-benzene (20 g, 63.02 mmol) in dioxane (180 mL) and water (60 mL) were added cyclopropylboronic acid (7.04 g, 81.93 mmol), potassium phosphate (48.16 g, 226.88 mmol), and 5% palladium on barium sulfate (2.31 g, 3.15 mmol). The mixture was then heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Welch Xtimate C18 250*70mm #10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 70% - 96%, 20 min) to give 1-bromo-3-chloro-2-cyclopropyl-benzene (6 g, 41.12%) as a colorless oil. TIFF2025523624000318.tif26128

[0514] Step 2: 2-(3-Bromo-5-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-3-chloro-2-cyclopropyl-benzene (1 g, 4.32 mmol) in hexane (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 g, 12.96 mmol, 1.88 mL), (1Z,5Z)-cycloocta-1,5-diene;2,4-dimethyl-BLAH bicyclo[1.1.0]butane (143.16 mg, 215.97 umol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (69.56 mg, 259.16 umol). The mixture was then heated to 60 °C and stirred for 2 h under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 5% ethyl acetate in petroleum ether) to give 2-(3-bromo-5-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 64.76%) as a yellow oil. TIFF2025523624000319.tif17128

[0515] Step 3: 3-Bromo-5-chloro-4-cyclopropyl-phenol To a solution of 2-(3-bromo-5-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 2.80 mmol) in tetrahydrofuran (10 mL) and water (5 mL) were added acetic acid (10.78 g, 179.59 mmol) and hydrogen peroxide (1.8 g, 53.43 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h. The mixture was quenched at 0 °C with saturated sodium sulfite (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give 3-bromo-5-chloro-4-cyclopropyl-phenol (660 mg, 95.32%) as a colorless oil. TIFF2025523624000320.tif17128

[0516] Step 4: 1-Bromo-3-chloro-2-cyclopropyl-5-(methoxymethyl)benzene To a solution of 3-bromo-5-chloro-4-cyclopropyl-phenol (660 mg, 2.67 mmol) in dichloromethane (7 mL) were added N,N-diisopropylethylamine (1.03 g, 8.00 mmol) and chloromethyl methyl ether (429.38 mg, 5.33 mmol) at 0 °C, then the mixture was warmed to 20 °C and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 4% ethyl acetate in petroleum ether) to give 1-bromo-3-chloro-2-cyclopropyl-5-(methoxymethyl)benzene (600 mg, 77.17%) as a colorless oil. TIFF2025523624000321.tif26128

[0517] Step 5: 2-[3-Chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene (400 mg, 1.37 mmol) in dioxane (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (696.75 mg, 2.74 mmol), potassium acetate (403.92 mg, 4.12 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (100.38 mg, 137.19 μmol), and then the mixture was heated to 100 °C and stirred for 12 h under a nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were concentrated to dryness under vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 5% ethyl acetate in petroleum ether) to give 2-[3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260 mg, 51.49%) as a pale green oil. TIFF2025523624000322.tif41128

[0518] Step 6: (R)-tert-Butyl 3-((7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate A solution of (R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, 371.05 μmol) in dioxane (3 mL) and water (1.5 mL) was treated with 2-[3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (251.30 mg, 742.09 μmol), potassium phosphate (236.28 mg, 1.11 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (31.41 mg, 37.10 μmol). The mixture was then heated to 60 °C and stirred under a nitrogen atmosphere for 8 h. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-12% methanol in dichloromethane) to afford (R)-tert-butyl 3-((7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (250 mg, 65.00%) as a pale yellow oil. LCMS Rt = 0.738 min, m / z = 714.3 [M + H] + . TIFF2025523624000323.tif37128

[0519] Step 7: 7-(3-Chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the MOM group was prepared in a manner similar to Example No. 71, Step 7. The reaction mixture was concentrated under vacuum to obtain 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (85 mg, crude hydrochloride), which was used in the next step without further purification. LCMS Rt = 0.591 min, m / z = 614.3 [M + H] + . TIFF2025523624000324.tif44128

[0520] The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 60%, 8 min) to obtain 1-((R)-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (32.68 mg, 36.16%) as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.21 - 9.09 (m, 1H), 7.00 - 6.92 (m, 1H), 6.86 - 6.76 (m, 1H), 6.66 - 6.47 (m, 1H), 6.29 - 6.18 (m, 1H), 5.72 - 5.61 (m, 1H), 5.18 (br s, 2H), 4.22 - 4.16 (m, 1H), 4.15 - 4.09 (m, 1H), 4.08 - 3.90 (m, 1H), 3.89 - 3.76 (m, 1H), 3.69 - 3.59 (m, 1H), 3.57 - 3.42 (m, 1H), 3.38 (d, J = 2.3 Hz, 3H), 3.22 - 3.08 (m, 2H), 3.06 (s, 1H), 2.96 - 2.82 (m, 1H), 2.40 - 2.13 (m, 4H), 2.06 - 2.01 (m, 1H), 1.91 - 1.77 (m, 4H), 0.68 - 0.49 (m, 2H), 0.12 - -0.09 (m, 2H). LCMS Rt = 2.843 min, m / z = 624.2 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.1% ammonium bicarbonate) retention time 2.843 min, ESI+ found [M+H] = 624.2. TIFF2025523624000325.tif48128

[0521] Example 13: (S)-4-(7-(6 - Amino - 4 - methyl - 3-(trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorooctahydro - 1H - pyrrolidin - 7a - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)-2-(cyanomethyl)piperazine - 1 - carbonitrile TIFF2025523624000326.tif35128

[0522] Step 1: (S)-tert-Butyl 2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate The substitution reaction was prepared in a manner similar to Example No. 71, Step 3. The mixture was concentrated under vacuum to obtain (S)-tert-butyl 2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, crude product) as a brown solid, which was used in the next step without further purification. LCMS Rt = 0.681 min, m / z = 441.1 [M + H] + . TIFF2025523624000327.tif37128

[0523] Step 2: (S)-tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The substitution reaction was prepared in a manner similar to Example No. 71, Step 4. The mixture was purified by reverse-phase HPLC (column: Welch Xtimate C18 250*70mm #10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 40% - 70%, 20 min) to obtain (S)-tert-butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.1 g, 44.00%) as a white solid. LCMS Rt = 2.111 min, m / z = 563.2 [M + H] + . TIFF2025523624000328.tif36128

[0524] Step 3: (S)-tert-Butyl 2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate The tin reagent formation was prepared in a manner similar to Example No. 71, Step 5. The mixture was purified by column chromatography (silica gel, 100 - 200 mesh, 80 - 100% ethyl acetate in petroleum ether) to obtain (S)-tert-butyl 2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (480 mg, 52.16%) as a yellow oil. LCMS Rt = 0.673 min, m / z = 819.4 [M + H] + . TIFF2025523624000329.tif43128

[0525] Step 4: (S)-tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate The still reaction was prepared in a manner similar to Example No. 71, Step 6. The mixture was concentrated to dryness under vacuum to obtain (S)-tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (500 mg, crude) as a yellow oil and used in the next step without any further purification. LCMS Rt = 0.858 min, m / z = 943.4 [M + H] + . TIFF2025523624000330.tif41128

[0526] Step 5: 2-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile The deprotection of Boc and PMB was prepared in a manner similar to Example No. 71, Step 7. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 1%-30%, 8 min) to obtain 2-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (60 mg, 15.79%, trifluoroacetate salt) as a white solid. LCMS Rt = 0.547 min, m / z = 603.3 [M + H] + . TIFF2025523624000331.tif48128

[0527] Step 6: (S)-4-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carbonitrile To a solution of 2-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (30 mg, 41.81 μmol) in acetonitrile (2 mL) was added potassium carbonate (17.33 mg, 125.42 μmol) and cyanogen bromide (6.64 mg, 62.71 μmol), and then the mixture was stirred at 50 °C for 60 minutes. The reaction mixture was quenched with saturated sodium carbonate (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 55%, 8 minutes) to give (S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carbonitrile (1.70 mg, 6.20%) as a white solid. 11H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.07 (s, 1H), 6.81 (s, 2H), 6.51 (s, 1H), 5.43 - 5.15 (m, 1H), 4.24 - 4.10 (m, 3H), 4.09 - 4.03 (m, 1H), 3.98 (br d, J = 2.9 Hz, 1H), 3.90 - 3.78 (m, 2H), 3.76 - 3.68 (m, 1H), 3.59 - 3.51 (m, 1H), 3.22 - 3.06 (m, 4H), 3.02 (s, 1H), 2.87 - 2.78 (m, 1H), 2.37 (br d, J = 1.3 Hz, 3H), 2.16 - 1.98 (m, 3H), 1.89 - 1.74 (m, 3H). LCMS Rt = 2.769 min, m / z = 628.2 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.769 min, ESI+ measured value [M + H] = 628.2. TIFF2025523624000332.tif55128

[0528] Example 14: (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000333.tif55128

[0529] Step 1: (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The reaction mixture was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 50%, 8 minutes) to obtain (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (25.02 mg, 18.44%) as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.21 (s, 1H), 7.39 - 7.29 (m, 1H), 7.22 - 7.14 (m, 1H), 6.59 (s, 1H), 5.48 (s, 2H), 5.37 - 5.19 (m, 1H), 4.48 (t, J = 8.6 Hz, 1H), 4.27 (br dd, J = 5.4, 14.2 Hz, 2H), 4.22 - 4.13 (m, 4H), 3.95 (dd, J = 5.6, 10.6 Hz, 1H), 3.57 (s, 3H), 3.18 (br d, J = 13.0 Hz, 2H), 3.14 - 3.03 (m, 2H), 2.95 - 2.88 (m, 1H), 2.46 (br d, J = 1.6 Hz, 3H), 2.13 - 2.05 (m, 3H), 1.93 - 1.85 (m, 3H), 1.59 (s, 6H). LCMS Rt = 2.526 min, m / z = 758.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.526 minutes, ESI+ measured value [M + H] = 758.3. TIFF2025523624000334.tif51128

[0530] Example 15: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one TIFF2025523624000335.tif51128

[0531] Step 1: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)prop-2-en-1-one (18.38 mg, 37.03%) as a white solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.14 (s, 1H), 7.80 - 7.68 (m, 1H), 7.39 - 7.24 (m, 1H), 6.57 (s, 1H), 5.53 (br d, J = 6.4 Hz, 2H), 5.39 - 5.17 (m, 2H), 4.26 - 4.21 (m, 1H), 4.19 - 4.13 (m, 1H), 4.04 - 3.97 (m, 1H), 3.88 - 3.74 (m, 1H), 3.65 - 3.46 (m, 1H), 3.41 (s, 3H), 3.17 - 3.13 (m, 1H), 3.08 (br d, J = 6.3 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.66 (s, 1H), 2.63 (s, 1H), 2.45 (br d, J = 1.6 Hz, 3H), 2.34 - 2.29 (m, 1H), 2.26 - 2.16 (m, 4H), 2.15 - 2.10 (m, 1H), 2.10 - 2.02 (m, 1H), 1.95 - 1.77 (m, 4H). LCMS Rt = 2.810 min, m / z = 730.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.1% ammonium bicarbonate) retention time 2.810 min, ESI+ measured value [M + H]=730.3. TIFF2025523624000336.tif50128

[0532] Example 16: (E)-1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-en-1-one TIFF2025523624000337.tif50128

[0533] Step 1: (E)-1-(3-(((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-en-1-one The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain (E)-1-(3-(((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-en-1-one (5.1 mg, 6.03%) as a yellow amorphous solid. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.20 - 9.12 (m, 1H), 6.68 - 6.53 (m, 2H), 6.09 (br d, J = 15.0 Hz, 1H), 5.45 (br s, 2H), 5.35 - 5.16 (m, 1H), 4.29 (s, 1H), 4.18 - 4.05 (m, 6H), 3.83 - 3.78 (m, 1H), 3.63 - 3.58 (m, 4H), 3.53 (s, 3H), 3.18 - 3.12 (m, 3H), 3.07 (br d, J = 4.9 Hz, 3H), 2.92 - 2.87 (m, 1H), 2.43 (br s, 4H), 2.37 (br s, 3H), 2.04 (br s, 3H), 1.89 - 1.73 (m, 3H). LCMS Rt = 2.433 minutes, m / z = 731.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate), retention time 2.433 minutes, ESI+ measured value [M + H] = 731.3. TIFF2025523624000338.tif49128

[0534] Example 17: (E)-1-((R)-3-(((6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000339.tif37128

[0535] Step 1: (6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine Deprotection of Boc and PMB was prepared in a manner similar to Example No. 65, Step 15. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 1% - 30%, 8 minutes) to obtain (6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine (110 mg, 97.98%, trifluoroacetate salt) as a white solid. LCMS Rt = 0.571 minute, m / z = 559.3 [M + H] + . TIFF2025523624000340.tif49128

[0536] Step 2: (E)-1-((R)-3-(((6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amide coupling reaction was prepared in a manner similar to Example No. 65, Step 16. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 70%, 8 minutes) to obtain (E)-1-((R)-3-(((6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (15.6 mg, 29.93%) as a yellow solid. 1H NMR (400 MHz, acetonitrile-d3) δ 7.51 - 7.43 (m, 1H), 7.41 - 7.33 (m, 1H), 6.28 (s, 1H), 5.24 (s, 2H), 4.79 - 4.58 (m, 1H), 4.16 (dd, J = 8.0, 10.3 Hz, 1H), 4.03 - 3.89 (m, 3H), 3.87 - 3.74 (m, 1H), 3.68 (br d, J = 8.6 Hz, 1H), 3.52 - 3.36 (m, 1H), 3.17 (td, J = 5.3, 10.3 Hz, 1H), 3.07 - 2.94 (m, 3H), 2.93 (d, J = 3.1 Hz, 3H), 2.89 - 2.81 (m, 1H), 2.66 (s, 4H), 2.41 (s, 1H), 2.40 (s, 1H), 2.38 (d, J = 3.5 Hz, 2H), 2.30 - 2.23 (m, 1H), 2.21 - 2.14 (m, 1H), 2.13 - 2.03 (m, 2H), 1.91 (td, J = 6.1, 12.1 Hz, 2H), 1.86 - 1.71 (m, 4H), 1.66 - 1.54 (m, 2H), 0.77 (d, J = 6.3 Hz, 3H). LCMS Rt = 2.742 minutes, m / z = 695.4 [M + H]+. LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate), retention time 2.742 minutes, ESI+ measured value [M + H] = 695.4. TIFF2025523624000341.tif45128

[0537] Example 18: 1 - ((R)-3 - ((((6S,7S)-7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-2 - ((hexahydro - 1H - pyrrolidin - 7a - yl)methoxy)-6 - methyl - 5,6,7,8 - tetrahydroquinazolin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)prop - 2 - en - 1 - one TIFF2025523624000342.tif45128

[0538] Step 1: 1 - ((R)-3 - ((((6S,7S)-7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-2 - ((hexahydro - 1H - pyrrolidin - 7a - yl)methoxy)-6 - methyl - 5,6,7,8 - tetrahydroquinazolin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)prop - 2 - en - 1 - one The amide coupling reaction was prepared in a manner similar to Example No. 65, Step 16. The reaction mixture was concentrated under vacuum and purified by reverse - phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 35% - 70%, 8 minutes) to obtain 1 - ((R)-3 - ((((6S,7S)-7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-2 - ((hexahydro - 1H - pyrrolidin - 7a - yl)methoxy)-6 - methyl - 5,6,7,8 - tetrahydroquinazolin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)prop - 2 - en - 1 - one (13.43 mg, 28.73%) as a yellow oil. 11H NMR (400 MHz, acetonitrile-d3) δ 6.59 (dd, J = 10.3, 16.8 Hz, 1H), 6.34 - 6.16 (m, 2H), 5.67 (ddd, J = 2.4, 5.0, 10.4 Hz, 1H), 5.20 (br s, 2H), 4.79 - 4.49 (m, 1H), 4.10 - 3.89 (m, 3H), 3.84 - 3.70 (m, 1H), 3.63 - 3.50 (m, 1H), 3.44 - 3.30 (m, 1H), 3.17 (td, J = 5.2, 10.6 Hz, 1H), 2.96 (br dd, J = 4.9, 9.7 Hz, 3H), 2.92 (d, J = 4.6 Hz, 3H), 2.88 - 2.80 (m, 1H), 2.69 - 2.56 (m, 3H), 2.54 - 2.45 (m, 1H), 2.38 (q, J = 3.5 Hz, 3H), 2.15 - 2.02 (m, 3H), 1.94 - 1.87 (m, 2H), 1.86 - 1.70 (m, 4H), 1.65 - 1.54 (m, 2H), 0.77 (d, J = 6.4 Hz, 3H). LCMS Rt = 2.818 min, m / z = 613.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.818 min, ESI+ found [M+H]=613.3. TIFF2025523624000343.tif60128

[0539] Example 19: (E)-1-(3-(((7-(6-amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000344.tif48128

[0540] Step 1: tert-Butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to give tert-Butyl 3-(((7-(6-(bis(4-methoxybenzyl)amino)-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (270 mg, crude), obtained as a yellow gum, and used in the next step without any further purification. LCMS Rt = 0.962 min, m / z = 890.5 [M + H] + . TIFF2025523624000345.tif46128

[0541] Step 2: 7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the PMB group was prepared in a manner similar to Example No. 71, Step 7. The mixture was purified by reverse-phase HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 1% - 30%, 8 minutes) to obtain 7-(6-amino-3-cyclopropyl-4-methylpyridin-2-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (55 mg, 29.49%, trifluoroacetate salt) as a yellow oil. LCMS Rt = 1.147 min, m / z = 550.3 [M + H] + . TIFF2025523624000346.tif60128

[0542] Step 3: (E)-1-(3-(((7-(6-amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The crude product was purified by reverse-phase preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain (E)-1-(3-(((7-(6-amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (11.67 mg, 19.73%) as a white solid. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.24 (s, 1H), 7.37 - 7.30 (m, 1H), 7.21 - 7.13 (m, 1H), 6.52 (s, 1H), 5.40 - 5.15 (m, 1H), 4.54 - 4.47 (m, 1H), 4.34 - 4.10 (m, 6H), 4.01 - 3.93 (m, 1H), 3.62 - 3.57 (m, 3H), 3.33 - 3.17 (m, 1H), 3.17 - 3.06 (m, 4H), 2.93 - 2.86 (m, 1H), 2.49 - 2.36 (m, 3H), 2.26 - 2.01 (m, 3H), 1.93 - 1.69 (m, 4H), 1.37 - 1.22 (m, 6H), 0.55 (br d, J = 8.5 Hz, 2H), -0.01 (br d, J = 4.8 Hz, 2H). LCMS Rt = 1.948 minutes, m / z = 714.4 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 1.948 minutes, ESI+ measured value [M+H] = 714.4. TIFF2025523624000347.tif45128

[0543] Example 20: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000348.tif45128

[0544] Step 1: (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 65%, 8 minutes) to obtain (E)-1-((R)-3-((7-(6-Amino-3-cyclopropyl-4-methylpyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (13.64 mg, 27.82%) as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.21 (d, J = 2.1 Hz, 1H), 7.53 - 7.37 (m, 2H), 6.52 - 6.47 (m, 1H), 5.50 - 5.18 (m, 2H), 4.88 - 4.76 (m, 2H), 4.30 - 4.19 (m, 2H), 4.18 - 4.13 (m, 1H), 4.08 - 3.87 (m, 2H), 3.83 - 3.75 (m, 1H), 3.67 - 3.51 (m, 1H), 3.45 (s, 3H), 3.19 - 3.14 (m, 2H), 3.13 - 3.07 (m, 1H), 2.97 - 2.87 (m, 1H), 2.43 (s, 3H), 2.38 - 2.32 (m, 1H), 2.26 - 2.20 (m, 2H), 2.15 - 2.12 (m, 1H), 2.10 - 2.05 (m, 1H), 1.94 - 1.83 (m, 3H), 1.78 - 1.69 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H), 1.35 (d, J = 7.0 Hz, 3H), 0.59 - 0.52 (m, 2H), 0.06 - 0.00 (m, 2H). LCMS Rt = 2.918 min, m / z = 714.4 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.918 min, ESI+ found [M+H] = 714.4. TIFF2025523624000349.tif49128

[0545] Example 21: (E)-1-((3R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000350.tif37128

[0546] Step 1: 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine The deprotection of Boc and PMB was prepared in a manner similar to Example No. 65, Step 15. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 1% - 30%, 8 minutes) to obtain 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,6-dimethyl-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine (70 mg, 93.52%, trifluoroacetate salt) as a white solid. LCMS Rt = 0.453 min, m / z = 559.3 [M + H] + . TIFF2025523624000351.tif50128

[0547] Step 2: (E)-1-((3R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 65, Step 16. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3) - acetonitrile]; B%: 35% - 65%, 8 minutes) to obtain (E)-1-((3R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (8.23 mg, 19.92%) as a yellow solid. 1H NMR (400 MHz, acetonitrile-d3) δ 7.50 - 7.43 (m, 1H), 7.40 - 7.30 (m, 1H), 6.27 (s, 1H), 5.32 (br s, 2H), 4.80 - 4.55 (m, 1H), 4.23 - 4.09 (m, 1H), 4.07 - 3.91 (m, 3H), 3.89 - 3.76 (m, 1H), 3.76 - 3.58 (m, 1H), 3.52 - 3.39 (m, 1H), 3.22 - 3.13 (m, 1H), 3.08 - 2.96 (m, 3H), 2.94 - 2.90 (m, 2H), 2.89 - 2.80 (m, 1H), 2.69 - 2.56 (m, 4H), 2.46 (br dd, J = 4.9, 16.4 Hz, 3H), 2.41 (s, 1H), 2.37 - 2.33 (m, 2H), 2.20 - 2.03 (m, 3H), 1.95 - 1.87 (m, 2H), 1.86 - 1.71 (m, 4H), 1.67 - 1.52 (m, 2H), 0.75 (br d, J = 6.4 Hz, 3H). LCMS Rt = 2.748 minutes, m / z = 695.4 [M + H]+. LCMS (5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.748 minutes, ESI+ measured value [M+H] = 695.4. TIFF2025523624000352.tif55128

[0548] Example 22: (E)-1-(3-(((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000353.tif49128

[0549] Step 1: tert-Butyl 3-(((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate The Stille reaction was prepared in a manner similar to Example No. 71, Step 6. The mixture was purified by reverse-phase HPLC (column: Phenomenex Luna C18 250*50mm*10um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 45% - 75%, 10 minutes) to obtain tert-butyl 3-(((7-(3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidine-1-carboxylate (400 mg, 25.85%, trifluoroacetate salt) as a yellow solid. 11H NMR (400 MHz, chloroform-d) δ 9.28 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.24 - 7.19 (m, 2H), 7.10 (br d, J = 8.5 Hz, 4H), 6.76 (br d, J = 8.5 Hz, 4H), 6.61 (s, 1H), 5.59 - 5.31 (m, 1H), 4.89 - 4.82 (m, 2H), 4.55 - 4.49 (m, 2H), 4.02 (br d, J = 8.1 Hz, 2H), 3.75 - 3.68 (m, 6H), 3.57 - 3.38 (m, 4H), 3.28 - 3.17 (m, 1H), 3.04 - 2.94 (m, 1H), 2.79 - 2.63 (m, 2H), 2.54 - 2.37 (m, 3H), 2.30 - 2.15 (m, 3H), 1.57 (br d, J = 7.4 Hz, 3H), 1.37 (s, 9H), 1.30 (br d, J = 7.4 Hz, 3H). LCMS Rt = 0.887 min, m / z = 920.4 [M + H] + . TIFF2025523624000354.tif46128

[0550] Step 2: 7-(3-Amino-8-chloroisoquinolin-1-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine The deprotection of the Boc group and the PMB group was prepared in a manner similar to Example No. 71, Step 7. The mixture was concentrated under vacuum to obtain 7-(3-amino-8-chloroisoquinolin-1-yl)-N-(azetidin-3-ylmethyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetate salt) as a yellow oil. LCMS Rt = 0.509 min, m / z = 580.2 [M + H]+ . TIFF2025523624000355.tif55128

[0551] Step 3: (E)-1-(3-(((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The crude product was purified by reverse phase preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain (E)-1-(3-(((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (11.93 mg, 13.62%) as a yellow amorphous solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.26 - 9.20 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.23 (br d, J = 7.4 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.92 (s, 1H), 5.33 - 5.13 (m, 3H), 4.47 (t, J = 8.6 Hz, 1H), 4.31 - 4.06 (m, 7H), 3.93 (br dd, J = 5.6, 10.3 Hz, 1H), 3.57 (s, 3H), 3.27 - 3.20 (m, 1H), 3.17 - 3.10 (m, 2H), 3.08 - 3.04 (m, 1H), 2.89 (br s, 1H), 2.06 (br d, J = 17.8 Hz, 3H), 1.86 (br s, 3H), 1.57 (s, 6H). LCMS Rt = 2.666 min, m / z = 760.3 [M + H] + . LCMS (Over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.666 minutes, ESI+ measured value [M + H] = 760.3. TIFF2025523624000356.tif53128

[0552] Example 23: 1-(3-(((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-yn-1-one TIFF2025523624000357.tif53128

[0553] Step 1: 1-(3-(((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The crude product was purified by reverse-phase preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20% - 50%, 8 minutes) to obtain 1-(3-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-morpholinobut-2-en-1-one (18.39 mg, 23.27%) as a yellow amorphous solid. 1 1H NMR (400 MHz, acetonitrile-d3) δ 9.19 - 9.14 (m, 1H), 6.56 (s, 1H), 5.44 (s, 2H), 5.35 - 5.18 (m, 1H), 4.28 (t, J = 8.7 Hz, 1H), 4.22 - 4.00 (m, 6H), 3.82 (dd, J = 5.6, 9.9 Hz, 1H), 3.64 - 3.58 (m, 4H), 3.53 (s, 3H), 3.43 (s, 2H), 3.23 - 3.11 (m, 3H), 3.06 (s, 1H), 2.93 - 2.85 (m, 1H), 2.49 - 2.45 (m, 4H), 2.43 (br d, J = 1.4 Hz, 3H), 2.20 - 2.15 (m, 1H), 2.11 (br s, 2H), 1.91 - 1.79 (m, 3H). LCMS Rt = 2.612 minutes, m / z = 729.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.612 minutes, ESI+ measured value [M+H] = 729.3. TIFF2025523624000358.tif45128

[0554] Example 24: 1 - ((R)-3 - ((7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-4 - morpholinobut - 2 - yn - 1 - one TIFF2025523624000359.tif45128

[0555] Step 1: 1 - ((R)-3 - ((7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-4 - morpholinobut - 2 - yn - 1 - one The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The residue was purified by reverse - phase HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (formic acid) - acetonitrile]; B%: 1% - 30%, 8 minutes) to obtain 1 - ((R)-3 - ((7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-4 - morpholinobut - 2 - yn - 1 - one (1.3 mg, 1.75%, formate) as a yellow oil. 11H NMR (400 MHz, acetonitrile-d3) δ 9.20 (d, J = 3.4 Hz, 1H), 6.60 (s, 1H), 5.54 - 5.46 (m, 2H), 5.44 - 5.38 (m, 1H), 4.63 - 4.52 (m, 1H), 4.19 - 3.96 (m, 1H), 3.94 - 3.79 (m, 1H), 3.77 - 3.72 (m, 1H), 3.70 - 3.62 (m, 9H), 3.52 (s, 1H), 3.50 (s, 1H), 3.46 (s, 1H), 3.44 (s, 1H), 3.28 - 3.14 (m, 1H), 2.54 (td, J = 4.6, 15.1 Hz, 4H), 2.47 (br d, J = 1.4 Hz, 3H), 2.41 - 2.33 (m, 2H), 2.01 - 1.99 (m, 2H), 1.87 - 1.79 (m, 6H). LCMS Rt = 1.865 min, m / z = 729.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 1.865 min, ESI+ found [M+H] = 729.3. TIFF2025523624000360.tif60128

[0556] Example 25: (E)-1-(3-(((7-(3-Amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one TIFF2025523624000361.tif18128

[0557] Step 1: (E)-Ethyl 4-(((E)-(1-amino-2,2-difluoropropylidene)amino)oxy)-4-oxobut-2-enoate A solution of (E)-4-ethoxy-4-oxo-but-2-enoic acid (5 g, 34.69 mmol) and 1-hydroxypyrrolidine-2,5-dione (12 g, 104.27 mmol) in acetonitrile (100 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (13.30 g, 69.38 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (E)-ethyl 4-(((E)-(1-amino-2,2-difluoropropylidene)amino)oxy)-4-oxobut-2-enoate (16.8 g, crude) as a yellow oil and used in the next step without further purification. TIFF2025523624000362.tif19128

[0558] Step 2: (E)-ethyl 4-(((E)-(1-amino-2,2-difluoropropylidene)amino)oxy)-4-oxobut-2-enoate The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 8. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (E)-ethyl 4-(((E)-(1-amino-2,2-difluoropropylidene)amino)oxy)-4-oxobut-2-enoate (3.6 g, crude) as a brown oil and used in the next step without further purification. LCMS Rt = 0.510 min, m / z = 250.1 [M + H] + . TIFF2025523624000363.tif16128

[0559] Step 3: Ethyl (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoate The cyclization reaction was prepared in a manner similar to Example No. 71, Step 9. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to obtain ethyl (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoate (1.1 g, 32.04%) as a white solid. LCMS Rt = 0.633 min, m / z = 232.1 [M + H] + . TIFF2025523624000364.tif16128

[0560] Step 4: (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoic acid The hydrolysis reaction was prepared in a manner similar to Example No. 71, Step 10. The reaction mixture was concentrated under vacuum to obtain (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoic acid (1 g, crude) as a white solid and used in the next step without further purification. LCMS Rt = 0.545 min, m / z = 204.0 [M + H] + . TIFF2025523624000365.tif60128

[0561] Step 5: (E)-1-(3-(((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorhexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one The amid coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The crude product was purified by reverse phase preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 60%, 8 minutes) to obtain (E)-1-(3-(((7-(3-amino-8-chloroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-3-(3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl)prop-2-en-1-one (11.06 and 12.37%) as a yellow solid. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.27 - 9.20 (m, 1H), 7.63 (br d, J = 8.4 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.26 (br d, J = 16.0 Hz, 2H), 6.92 (s, 1H), 5.33 - 5.12 (m, 3H), 4.48 (br t, J = 8.8 Hz, 1H), 4.28 - 4.09 (m, 6H), 3.97 - 3.91 (m, 1H), 3.57 (s, 3H), 3.22 (br d, J = 6.9 Hz, 1H), 3.16 - 3.10 (m, 2H), 3.06 (br s, 1H), 2.91 - 2.86 (m, 1H), 2.08 (br s, 3H), 2.03 (br s, 3H), 1.89 - 1.74 (m, 3H). LCMS Rt = 2.701 minutes, m / z = 766.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.701 minutes, ESI+ measured value [M+H] = 766.3. TIFF2025523624000366.tif45128

[0562] Example 26: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000367.tif49128

[0563] Step 1: Diethyl (2-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate The amid coupling reaction was prepared in a manner similar to that of Example No. 2, Step 5. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 30% - 60%, 8 minutes) to obtain diethyl (2-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-oxoethyl)phosphonate (7.77 mg, 14.68%) as a yellow oil. LCMS Rt = 1.766 minutes, m / z = 756.3 [M + H] + . TIFF2025523624000368.tif42128

[0564] Step 2: (R)-tert-Butyl 2-((E)-3-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The reaction mixture was concentrated under vacuum to give (R)-tert-butyl 2-((E)-3-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (70 mg, crude) as a yellow oil and used in the next step without any further purification. LCMS Rt = 1.553 min, m / z = 787.4 [M + H] + . TIFF2025523624000369.tif45128

[0565] Step 3: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-azetidin-2-yl)prop-2-en-1-one The deprotection of the Boc group was prepared in a manner similar to Example No. 71, Step 7. The reaction mixture was concentrated to obtain (E)-1-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-azetidin-2-yl)prop-2-en-1-one (60 mg, crude, trifluoroacetate salt) as a yellow oil and used in the next step without any further purification. LCMS Rt = 0.598 min, m / z = 687.3 [M + H] + . TIFF2025523624000370.tif45128

[0566] Step 4: (E)-1-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one The reductive amination reaction was prepared in a manner similar to Example No. 2, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 45%, 8 min) to obtain (E)-1-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((R)-1-methylazetidin-2-yl)prop-2-en-1-one (7.77 mg, 14.68%) as a yellow oil. 11H NMR (400 MHz, acetonitrile-d3) δ 9.14 (d, J = 2.1 Hz, 1H), 6.78 (ddd, J = 1.8, 5.7, 15.1 Hz, 1H), 6.58 (s, 1H), 6.39 (t, J = 14.6 Hz, 1H), 5.50 (br s, 2H), 5.41 - 5.18 (m, 2H), 4.28 - 4.19 (m, 1H), 4.18 - 4.10 (m, 1H), 4.10 - 3.89 (m, 1H), 3.89 - 3.73 (m, 1H), 3.70 - 3.61 (m, 1H), 3.56 (br dd, J = 4.8, 12.0 Hz, 1H), 3.40 (d, J = 1.5 Hz, 3H), 3.34 - 3.27 (m, 1H), 3.16 (br d, J = 7.6 Hz, 2H), 3.09 (s, 1H), 2.97 - 2.87 (m, 1H), 2.87 - 2.77 (m, 1H), 2.46 (d, J = 1.5 Hz, 3H), 2.41 - 2.34 (m, 1H), 2.27 (s, 3H), 2.21 - 2.11 (m, 4H), 2.10 - 2.03 (m, 1H), 1.99 (br s, 1H), 1.95 - 1.80 (m, 4H). LCMS Rt = 2.686 min, m / z = 701.3 [M + H] + . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate) retention time 2.686 min, ESI+ found [M+H] = 701.3. TIFF2025523624000371.tif45128

[0567] Example 27: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one TIFF2025523624000372.tif45128

[0568] Step 1: (S)-tert-Butyl 2-((E)-3-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate The Horner-Wadsworth-Emmons reaction was prepared in a manner similar to Example No. 2, Step 6. The reaction mixture was concentrated under vacuum to obtain (S)-tert-butyl 2-((E)-3-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (80 mg, crude) as a yellow oil and used in the next step without any further purification. LCMS Rt = 0.572 min, m / z = 787.4 [M + H] + . TIFF2025523624000373.tif45128

[0569] Step 4: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one The deprotection of the Boc group was prepared in a manner similar to Example No. 2, Step 7, and the reaction mixture was concentrated under vacuum to obtain (E)-1-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-azetidin-2-yl)prop-2-en-1-one (80 mg, crude, trifluoroacetate salt) as a yellow oil and used in the next step without any further purification. LCMS Rt = 0.454 min, m / z = 687.3 [M + H] + . TIFF2025523624000374.tif45128

[0570] Step 5: (E)-1-((R)-3-((7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one The reductive amination reaction was prepared in a manner similar to Example No. 2, Step 8. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25% - 60%, 8 minutes) to obtain (E)-1-((R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-((S)-1-methylazetidin-2-yl)prop-2-en-1-one (19.85 mg, 27.79%) as a yellow oil. 1 1H NMR (400 MHz, acetonitrile-d3) δ 9.05 - 9.00 (m, 1H), 6.67 (td, J = 5.2, 15.1 Hz, 1H), 6.58 - 6.45 (m, 1H), 6.33 - 6.19 (m, 1H), 5.44 (br d, J = 6.6 Hz, 2H), 5.28 - 5.06 (m, 2H), 4.15 - 4.07 (m, 1H), 4.06 - 4.01 (m, 1H), 3.98 - 3.79 (m, 1H), 3.78 - 3.65 (m, 1H), 3.55 - 3.42 (m, 2H), 3.28 (br d, J = 4.6 Hz, 3H), 3.24 - 3.16 (m, 1H), 3.05 (br d, J = 5.8 Hz, 2H), 2.98 (br s, 1H), 2.83 - 2.77 (m, 1H), 2.76 - 2.67 (m, 1H), 2.34 (br s, 3H), 2.28 - 2.24 (m, 1H), 2.23 - 2.15 (m, 3H), 2.15 - 2.12 (m, 2H), 2.11 - 2.07 (m, 1H), 2.06 - 2.00 (m, 2H), 1.99 - 1.94 (m, 1H), 1.79 (br dd, J = 10.3, 19.0 Hz, 4H). LCMS Rt = 1.802 min, m / z = 701.3 [M + H]+ . LCMS (over 6 minutes, 5 - 95% acetonitrile in water + 0.03% ammonium bicarbonate), retention time 1.802 minutes, ESI+ measured value [M + H] = 701.3. TIFF2025523624000375.tif45128

[0571] Example 28: 1 - ((R)-3 - ((7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-4 - (dimethylamino)but - 2 - yn - 1 - one TIFF2025523624000376.tif45128

[0572] Step 1: 1 - ((R)-3 - ((7-(6 - amino - 4 - methyl - 3 - (trifluoromethyl)pyridin - 2 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidin - 1 - yl)-4 - (dimethylamino)but - 2 - yn - 1 - one The amide coupling reaction was prepared in a manner similar to Example No. 71, Step 11. The residue was purified by reverse - phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ac...

Claims

1. A compound of formula A, formula B, or formula C: or a salt thereof; and / or an isotopically substituted form thereof [wherein, ring A is a 6-membered aryl or a 5- to 10-membered heteroaryl; R Ｆ is selected from the group consisting of H, halo, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, and C １ -C ４ haloalkoxy; Each R Ｇ is independently selected from halo, -OH, -NH ２ , C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, C ３ -C ６ cycloalkyl, and C ２ -C ３ alkynyl; each GG is independently 0, 1, 2, or 3; R １ is a saturated carbocyclic group having 4 to 8 ring atoms or a heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the carbocyclic group or heterocyclic group is selected from halo, hydroxy, C １ -C ４ alkyl, spiro C ３ -C ４ cycloalkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, and C １ -C ４ haloalkoxy and is substituted by 0, 1, 2, or 3 substituents independently selected therefrom; R ２ is selected from the group consisting of R ２ｂ , R ２ｃ , and R ２ｅ ; R ２ｂ is -NR １０ R １１ and; R １０ is selected from the group consisting of H, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, and C １ -C ４ haloalkoxy; and R １１ is -(CH ２ ) ｗ -R １３ or; alternatively R １０ and R １１ together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom within the ring atoms, said second nitrogen of said 4- to 8-membered saturated heterocyclic group is substituted by cyano, and said 4- to 8-membered saturated heterocyclic group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; and may be further substituted by; R １３ is a 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, said nitrogen being substituted by cyano, and said heterocyclic group being further substitutable by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -cyanoalkyl, C １ -C ４ -haloalkoxy, and halo; or R １３ is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatoms within the ring atoms, one of said nitrogens being substituted by cyano, and said heterocyclic group being further optionally substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -cyanoalkyl, C １ -C ４ -haloalkoxy, and halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; or R １３ is a 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of said nitrogen ring atom(s) is substituted by cyano, and said heterocyclic group is further optionally substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; w is 0, 1, or 2; R ２ｃ is -NR １５ R １６ ; R １５ is H, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; and R １６ is -(CH ２ ) ｙ -R ２１ ; R ２１ is A 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R １９ )=C(R ２０ )R １８ substituted, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; said 4- to 5-membered saturated heterocyclic group; A 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom within the ring atoms, wherein one of said nitrogens of said heterocyclic group is -C(O)C(R １９ )=C(R ２０ )R １８ is substituted, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; or A 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms (s) of the heterocyclic group is -C(O)C(R １９ )=C(R ２０ )R １８ is substituted by, and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated heterocyclic group selected from; R １８ is selected from the group consisting of hydrogen, -COOH, -C(O)O-C 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)NR ２２ R ２３ , -(CH ２ ) ｚ -NR ２２ R ２３ , -(CH ２ ) ｕ -R ３４ , -(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, and R ３５ ; R １９ is selected from the group consisting of hydrogen, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, and C １ -C ４ -haloalkoxy; R ２０ is selected from the group consisting of hydrogen, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, and C １ -C ４ -haloalkoxy; R ２２ and R ２３ is independently selected from the group consisting of hydrogen, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, and C １ -C ４ -haloalkoxy; R ３４ is a 4- to 10-membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl; R ３５ is a 5- to 6-membered heteroaryl group optionally substituted with zero, one, or two substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ４ -hydroxyalkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and is optionally substituted with one or two substituents independently selected from halo and methyl; and C ３ -C ６ -heterocyclyl, and is optionally substituted with one or two substituents independently selected from halo and methyl; and is optionally substituted with zero, one, or two substituents independently selected from C ３ -C ６ -cycloalkyl; y is 0, 1, or 2; z is 1 or 2; q is 0 or 1; u is 0, 1, or 2; R ２ｅ is -NR ２８ R ２９ ; R ２８ is H, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; and R ２９ is -(CH ２ )t-R ３０ and; R ３０ is A 4- to 5-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C≡CR ３１ and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; the 4- to 5-membered saturated heterocyclic group A 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom within the ring atoms, wherein one of said nitrogens of said heterocyclic group is substituted by -C(O)C≡CR ３１ and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ cyanoalkyl, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; and A 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms (s) of the heterocyclic group is substituted by -C(O)C≡CR ３１ and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ cyanoalkyl, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, or halo, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated heterocyclic group selected from; R ３１ is selected from the group consisting of -(CH ２ ) ｖ -NR ３２ R ３３ and -(CH ２ ) ｐ -R ３６ ; R ３２ and R ３３ are independently selected from the group consisting of hydrogen, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, C １ -C ４ -haloalkyl, and C １ -C ４ -haloalkoxy; t is 0, 1, or 2; v is 1 or 2; p is 0, 1, or 2; R ３６ is a 4- to 10-membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl].

2. The compound according to claim 1, which is a compound of formula A or a salt thereof.

3. The compound according to claim 1, which is a compound of formula B or a salt thereof.

4. The compound according to claim 1, which is a compound of formula C or a salt thereof.

5. R Ｆ The compound according to claim 1 or 3, wherein R is methyl.

6. The compound according to any one of claims 1 to 5, wherein ring A is selected from phenyl, pyridinyl, and isoquinolinyl.

7. The compound according to any one of claims 1 to 5, wherein ring A is selected from phenyl, pyridin-2-yl, pyridin-4-yl, and isoquinolin-1-yl.

8. Each moiety represented by is independently selected from the group consisting of, the compound according to any one of claims 1 to 5.

9. Each moiety represented by is independently selected from the group consisting of, the compound according to any one of claims 1 to 5.

10. Each R Ｇ is independently selected from -F, -Cl, -Me, -CF ３ , and cyclopropyl, the compound according to any one of claims 1 to 9.

11. Each moiety represented by is independently selected from the group consisting of, the compound according to any one of claims 1 to 6.

12. R １ is a saturated monocyclic carbocyclic group of 4 to 8 members or a monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the carbocyclic group or heterocyclic group is selected from halo, hydroxy, C １ -C ４ alkyl, spiro C ３ -C ４ cycloalkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, and C １ -C ４ haloalkoxy, and is substituted by 0, 1, 2, or 3 substituents independently selected therefrom, the compound according to any one of claims 1 to 11.

13. R １ is a 4- to 8-membered saturated bicyclic carbocyclic group or a bicyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the carbocyclic group or heterocyclic group is selected from halo, hydroxy, C １ -C ４ alkyl, spiro C ３ -C ４ cycloalkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, and C １ -C ４ haloalkoxy, and is substituted by 0, 1, 2, or 3 substituents independently selected therefrom, the compound according to any one of claims 1 to 11.

14. R １ The compound according to any one of claims 1 to 13, wherein the carbocyclic group or heterocyclic group of R is unsubstituted or substituted by one fluoro.

15. R １ is The compound according to any one of claims 1 to 11, selected from the group consisting of.

16. R １ is The compound according to any one of claims 1 to 11, selected from the group consisting of.

17. R ２ wherein R ２ｂ is as defined in any one of claims 1 to 16, the compound according to any one of claims 1 to 16.

18. R １０ The compound according to any one of claims 1 to 17, wherein R is methyl.

19. R １１ is -(CH ２ ) ｗ -R １３ The compound according to any one of claims 1 to 18.

20. The compound according to any one of claims 1 to 19, wherein w is 0 or 1.

21. R １３ is a 4- to 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein said nitrogen is substituted by cyano, and said heterocyclic group is further optionally substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ cyanoalkyl, C １ -C ４ alkyl, C １ -C ４ alkoxy, or halo, the compound according to any one of claims 1 to 20.

22. R １３ The compound according to any one of claims 1 to 21, wherein the heterocyclic group of R is further unsubstituted.

23. R １３ The compound according to any one of claims 1 to 21, wherein the heterocyclic group of R is further substituted by methyl, methoxy, or fluoro.

24. R １１ is The compound according to any one of claims 1 to 21, selected from the group consisting of.

25. R １１ is The compound according to any one of claims 1 to 21, selected from the group consisting of.

26. R １０ and R １１ together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom within the ring atoms, said second nitrogen of said 4- to 8-membered saturated heterocyclic group being substituted by cyano, and said 4- to 8-membered saturated heterocyclic group being further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo, and may be further substituted by one substituent selected from the group consisting of hydroxy, CN, C

27. R １０ and R １１ together with the nitrogen to which R １０ and R １１ form the 4- to 8-membered saturated heterocyclic group formed by Selected from the group consisting of, wherein the second nitrogen atom is substituted by cyano, and the heterocyclic group is hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ The compound according to any one of claims 1 to 17, which may be further substituted by one substituent selected from the group consisting of haloalkoxy and halo.

28. R １０ and R １１ together with the nitrogen to which R １０ and R １１ forms the 4- to 8-membered saturated heterocyclic group formed by and a -CH of one example ２ The compound according to any one of claims 1 to 17, which may be further substituted by CN.

29. R ２ wherein R ２ｃ is as defined in any one of claims 1 to 16 and claims 18 to 28.

30. R １５ The compound according to any one of claims 1 to 16 and claims 18 to 29, wherein R is methyl.

31. The compound according to any one of claims 1 to 16 and claims 18 to 30, wherein y is 0 or 1.

32. R ２１ is A 4- to 5-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom is substituted by -C(O)C(R １９ )=C(R ２０ )R １８ , and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; said 4- to 5-membered saturated monocyclic heterocyclic group; A 6-membered saturated monocyclic heterocyclic group containing one or two nitrogens as the only heteroatom within the ring atoms, wherein one of said nitrogens is -C(O)C(R １９ )=C(R ２０ )R １８ ) and is substituted, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; and A 7-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of said nitrogen ring atom(s) is -C(O)C(R １９ )=C(R ２０ )R １８ is substituted, and said heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom, said 7-membered saturated monocyclic heterocyclic group The compound according to any one of claims 1 to 16 and claims 18 to 31, selected from

33. R ２１ is a 4- to 5-membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, and the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C(R １９ )=C(R ２０ )R １８ , and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; a compound according to any one of claims 1 to 16 and claims 18 to 31.

34. R ２１ The compound according to any one of claims 1 to 16 and claims 18 to 33, wherein the heterocyclic group of R is further unsubstituted.

35. R ２１ wherein the heterocyclic group is further substituted by one substituent selected from the group consisting of hydroxy, CN, Me, -CH ２ CN, and F, the compound according to any one of claims 1 to 16 and claims 18 to 33.

36. R ２１ wherein said heterocyclic group is selected from the group consisting of, wherein said ring nitrogen of said heterocyclic group is -C(O)C(R １９ )=C(R ２０ )R １８ substituted, and said heterocyclic group is either unsubstituted or substituted by one substituent selected from hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; a compound according to any one of claims 1 to 16 and claims 18 to 31.

37. R ２１ The compound according to claim 36, wherein the heterocyclic group of

38. R ２１ wherein the heterocyclic group is further substituted by one substituent selected from the group consisting of hydroxy, CN, Me, -CH ２ CN, and F, the compound according to claim 36.

39. R １６ is The compound according to any one of claims 1 to 16 and claims 18 to 31, selected from the group consisting of

40. R １６ is The compound according to any one of claims 1 to 16 and claims 18 to 31, selected from the group consisting of

41. R １９ The compound according to any one of claims 1 to 16 and claims 18 to 40, wherein R is hydrogen.

42. R ２０ The compound according to any one of claims 1 to 16 and claims 18 to 41, wherein R is hydrogen.

43. R １８ is hydrogen, -COOH, -C(O)O-C １ -C ４ alkyl, -C(O)-C １ -C ４ alkyl, -C(O)NR ２２ R ２３ -(CH ２ ) ｚ -NR ２２ R ２３ -(CH ２ ) ｕ -R ３４ -(C １ -C ２ alkyl)-(C1-C ２ alkoxy), -S(O) ２ -C １ -C ４ alkyl, and is selected from the group consisting of R ３５ and the compound according to any one of claims 1 to 16 and claims 18 to 42.

44. R ２２ and R ２３ wherein R and R are independently selected from methyl and ethyl, and the compound according to any one of claims 1 to 16 and claims 18 to 43.

45. R ３４ is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), said monocyclic heterocycle being selected from halo, hydroxy, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ alkynyl, and is substituted with 0, 1, 2, 3, or 4 substituents independently selected therefrom, a compound according to any one of claims 1 to 16 and claims 18 to 43.

46. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 45, wherein the monocyclic hetero ring of R is substituted with 0 or 1 example of methyl.

47. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 45, wherein R is selected from azetidinyl, pyrrolidinyl and morpholinyl, which are substituted by 0 or 1 example of methyl.

48. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 45, wherein R is azetidinyl substituted with 0 or 1 methyl group(s).

49. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 45, wherein R is pyrrolidinyl substituted with 0 or 1 methyl.

50. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 45, wherein R is morpholinyl substituted by 0 or 1 methyl group.

51. R ３４ The compound according to any one of claims 1 to 16 and claims 18 to 50, wherein the bonding point for R is a carbon atom.

52. R ３４ is The compound according to claim 51, selected from the group consisting of

53. R ３４ is The compound according to claim 51, selected from the group consisting of

54. R ３４ is a 4- to 10-membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms 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, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ alkynyl, and is a compound according to any one of claims 1 to 16 and claims 18 to 44.

55. R ３４ is selected from azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 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, 2-oxa-5-azabicyclo[2.2.2]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, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane, and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each of which is halo, hydroxy, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ The compound according to claim 54, which is substituted by 0, 1, 2, 3, or 4 substituents independently selected from alkynyl.

56. R ３４ is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl, the compound according to claim 54.

57. R ３４ The compound according to any one of claims 54 to 56, wherein the bonding point for

58. R ３４ is selected from the group consisting of, each being halo, hydroxy, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkynyl, the compound according to claim 57.

59. R ３４ is Selected from the group consisting of, each being halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl, and is substituted by 0, 1, 2, 3, or 4 substituents independently selected therefrom, the compound according to claim 57.

60. R ３４ is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl The compound according to claim 57, which is

61. R ３４ The compound according to any one of claims 54 to 60, wherein the 4- to 10-membered heterocyclic ring of R is substituted with 0, 1, or 2 substituents independently selected from fluoro and methyl.

62. R ３４ The compound according to any one of claims 54 to 60, wherein the 4- to 10-membered heterocyclic ring of R is unsubstituted.

63. R ３４ is The compound according to any one of claims 54 to 59, selected from the group consisting of

64. R ３４ is unsubstituted The compound according to any one of claims 54 to 59, which is

65. R ３４ is unsubstituted The compound according to any one of claims 54 to 59, which is

66. The compound according to any one of claims 54 to 65, wherein u is 1.

67. R ３５ is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom, wherein the heteroaryl is selected from halo, hydroxy, C １ -C ４ alkyl, C １ -C ４ hydroxyalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and is optionally substituted by one or two substituents independently selected from halo and methyl, C ３ -C ６ heterocyclyl, and is optionally substituted by one or two substituents independently selected from halo and methyl, C ３ -C ６ cycloalkyl, and is substituted by zero, one, or two substituents independently selected therefrom, the compound according to any one of claims 1 to 16 and claims 18 to 66.

68. R ３５ 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 being halo, hydroxy, C １ -C ４ alkyl, C １ -C ４ hydroxyalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, independently selected from one or two substituents selected from halo and methyl, and may be substituted by C ３ -C ６ heterocyclyl, and independently selected from one or two substituents selected from halo and methyl, and may be substituted by C ３ -C ６ cycloalkyl, and is substituted by 0, 1, or 2 substituents independently selected therefrom, the compound according to any one of claims 1 to 16 and claims 18 to 66.

69. R ３５ is Selected from the group consisting of, each being halo, hydroxy, C １ -C ４ alkyl, C １ -C ４ hydroxyalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, optionally substituted by one or two substituents independently selected from halo and methyl, C ３ -C ６ heterocyclyl, and optionally substituted by one or two substituents independently selected from halo and methyl, C ３ -C ６ cycloalkyl, and is substituted by 0, 1, or 2 substituents independently selected therefrom, the compound according to any one of claims 1 to 16 and claims 18 to 66.

70. R ３５ is The compound according to any one of claims 1 to 16 and claims 18 to 66, selected from the group consisting of

71. R ３５ The compound according to any one of claims 1 to 16 and claims 18 to 70, wherein the point of attachment for R is on a carbon atom.

72. R １８ is -CH ２ R ３４ and is a compound according to any one of claims 1 to 16 and claims 18 to 66.

73. R １８ wherein R ３４ is as defined in any one of claims 1 to 16, 18 to 43, and 45 to 66.

74. R １８ wherein R ３５ is as defined in any one of claims 1 to 16, 18 to 43, and 67 to 73.

75. R １８ is -CH ２ N(CH ３ ) and is a compound according to any one of claims 1 to 16 and claims 18 to 44.

76. R １８ The compound according to any one of claims 1 to 16 and claims 18 to 44, wherein R is H.

77. R １８ A compound according to any one of claims 1 to 16 and claims 18 to 75, wherein R is not H.

78. R １８ is hydrogen, -COOH, -C(O)OCH ３ , -C(O)OCH ２ CH ３ , -C(O)OCH(CH ３ ) ２ , -C(O)N(CH ３ ) ２ , -C(O)-cyclopropyl, -CH ２ OCH ３ , -CH ２ N(CH ３ ) ２ , -S(O) ２ CH ３ , -S(O) ２ CH ２ CH ３ , -S(O) ２ -cyclopropyl, The compound according to any one of claims 1 to 16 and claims 18 to 42, selected from the group consisting of

79. R １８ is hydrogen, -CH ２ N(CH ３ ) ２ , The compound according to any one of claims 1 to 16 and claims 18 to 42, selected from the group consisting of

80. The double bond in the -C(O)C(R １９ )=C(R ２０ )R １８ moiety is in the E configuration, a compound according to any one of claims 1 to 16 and claims 18 to 79.

81. R ２ wherein R ２ｅ is as defined in any one of claims 1 to 16, the compound according to any one of claims 1 to 16.

82. R ２８ The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 81, wherein R is methyl.

83. The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 82, wherein t is 0 or 1.

84. R ３０ is a 4- to 5-membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the nitrogen ring atom of the heterocyclic group is substituted by -C(O)C≡CR ３１ and the heterocyclic group is either unsubstituted or further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo; a compound according to any one of claims 1 to 16, 18 to 28, and 30 to 83.

85. R ３０ The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 84, wherein the heterocyclic group of

86. R ３０ wherein the heterocyclic group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo, the compound according to any one of claims 1 to 16, 18 to 28, and 30 to 84.

87. R ３０ wherein said heterocyclic group is selected from the group consisting of, wherein said ring nitrogen of said heterocyclic group is -C(O)C≡CR ３ 1 is substituted, and said heterocyclic group is either unsubstituted or substituted with hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and is substituted with one substituent selected from halo, according to any one of claims 1 to 16, 18 to 28, and 30 to 83 compound.

88. R ３０ The compound according to claim 87, wherein the heterocyclic group of

89. R ３０ wherein said heterocyclic group is further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ cyanoalkyl, and halo, the compound according to claim 87.

90. R ２９ is selected from the group consisting of, wherein the azetidine group and the pyrrolidine group are either unsubstituted or substituted with one substituent selected from hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ cyanoalkyl, C １ -C ４ haloalkoxy, and halo, and the compound according to any one of claims 1 to 16, 18 to 28, and 30 to 82.

91. The compound according to claim 90, wherein the azetidine group and the pyrrolidine group are further unsubstituted.

92. The azetidine group and the pyrrolidine group are further substituted by one substituent selected from the group consisting of hydroxy, CN, C １ -C ４ alkyl, C １ -C ４ cyanoalkyl, and halo, the compound according to claim 90.

93. R ３１ is -CH ２ -NR ３２ R ３３ and -CH ２ -R ３６ The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 92, which is selected from the group consisting of

94. R ３２ and R ３３ is independently selected from methyl and ethyl, the compound according to any one of claims 1 to 16, 18 to 28, and 30 to 93.

95. R ３６ is a 4- to 7-membered monocyclic heterocycle containing a nitrogen atom as the only heteroatom, and the monocyclic heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ alkynyl, the compound according to any one of claims 1 to 16, 18 to 28, and 30 to 93.

96. R ３６ The compound according to claim 95, wherein the monocyclic heterocycle of ３６ is substituted with 0 or 1 example of methyl.

97. R ３６ The compound according to claim 96, wherein R is selected from azetidinyl, pyrrolidinyl and morpholinyl, which are substituted by 0 or 1 methyl group.

98. R ３６ The compound according to claim 96, wherein R is azetidinyl substituted by 0 or 1 methyl group(s).

99. R ３６ The compound according to claim 96, wherein R is pyrrolidinyl substituted by 0 or 1 methyl group.

100. R ３６ The compound according to claim 96, wherein R is morpholinyl substituted by 0 or 1 methyl group.

101. R ３６ The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 100, wherein the bonding point for

102. R ３６ is The compound according to claim 101, which is selected from the group consisting of

103. The compound according to any one of claims 95 to 102, wherein p is 0.

104. R ３６ is a 4- to 10-membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms 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, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ alkynyl, a compound according to any one of claims 1 to 16, 18 to 28, and 30 to 94.

105. R ３６ is selected from azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 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, 2-oxa-5-azabicyclo[2.2.2]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, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane, and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each being halo, hydroxy, C １ -C ４ alkyl, C １ -C ６ aminoalkyl, C １ -C ６ alkoxy, C １ -C ４ haloalkyl, C １ -C ４ haloalkoxy, and C ２ -C ３ The compound according to claim 104, which is substituted by 0, 1, 2, 3, or 4 substituents independently selected from alkynyl.

106. R ３６ is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl, the compound according to claim 105.

107. R ３６ The compound according to any one of claims 104 to 106, wherein the bonding point for

108. R ３６ is Selected from the group consisting of, each being halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl, and is substituted with 0, 1, 2, 3, or 4 substituents independently selected therefrom, the compound according to claim 107.

109. R ３６ is substituted by 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C １ -C ４ -alkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -alkoxy, C １ -C ４ -haloalkyl, C １ -C ４ -haloalkoxy, and C ２ -C ３ -alkynyl The compound according to claim 108, wherein it is

110. R ３６ The compound according to any one of claims 104 to 109, wherein the 4- to 10-membered heterocyclic ring of R is unsubstituted.

111. R ３６ is The compound according to any one of claims 104 to 108, which is selected from the group consisting of

112. R ３６ is unsubstituted The compound according to any one of claims 104 to 110, wherein it is

113. R ３６ is unsubstituted The compound according to any one of claims 104 to 110, wherein it is

114. The compound according to any one of claims 104 to 113, wherein p is 1.

115. R ３１ is The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 92, which is selected from the group consisting of

116. R ３１ is The compound according to any one of claims 1 to 16, 18 to 28, and 30 to 92, which is selected from the group consisting of

117. The compound according to claim 1, and all its salts and isotope substituents, which are selected from the group consisting of

118. The compound according to any one of claims 1 to 117, which is not a salt.

119. The compound according to any one of claims 1 to 117, which is a salt.

120. The compound according to claim 119, wherein the salt is a formate.

121. The compound according to claim 119, wherein the salt is a trifluoroacetate.

122. The compound according to claim 119, wherein the salt is a pharmaceutically acceptable salt.

123. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 122, when the compound is a salt, the salt is a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

124. A compound according to any one of claims 1 to 122 or a pharmaceutical preparation according to claim 123 for use in a method of treating or suppressing cancer, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 122, or when the salt is a pharmaceutically acceptable salt when the compound is a salt, or the pharmaceutical preparation according to claim 123.

125. The compound or pharmaceutical preparation for use according to claim 124, wherein the cancer is selected from the group consisting of cancers of the lung, colorectal, pancreas, bile duct, thyroid, gallbladder, uterus, mesothelioma, cervix, and bladder.

126. The compound or pharmaceutical preparation for use according to claim 124, wherein the cancer is glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colorectal adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma of the liver, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine body, squamous cell carcinoma and adenocarcinoma of the cervix, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasmacytic myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal cell carcinoma, pheochromocytoma / paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, and melanoma, and is selected from the group consisting of.

127. The compound or pharmaceutical preparation for use according to any one of claims 124 to 126, wherein the cancer is KRAS G12C-mediated cancer.

128. The compound or pharmaceutical preparation for use according to any one of claims 124 to 127, wherein the subject is diagnosed with having KRAS G12C-mediated cancer.

129. The compound or pharmaceutical preparation for use according to any one of claims 124 to 128, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

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