TW202506692A - Pyridopyrimidine derivatives and uses thereof - Google Patents

Abstract

The present disclosure provides compounds and methods useful in the treatment and suppression of cancer, for example, useful for treating or suppressing cancers characterized byKRAS G12C. Also provided are pharmaceutical formulations containing such compounds and processes for preparing such compounds.

Description

Pyridopyrimidine derivatives and uses thereof

The present disclosure provides compounds useful for treating or inhibiting cancer, and in particular, useful for treating or inhibiting cancer characterized by a KRAS G12C mutant. Pharmaceutical formulations containing such compounds, methods for preparing such compounds, and methods of using such compounds to treat or inhibit cancer are also provided.

KRAS is a molecular switch. Under normal physiological conditions, the protein is bound to guanosine diphosphate (GDP) in the "off state." In response to signaling through 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 promote downstream signaling, which leads to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP in a process facilitated by GAPs (GTPase activating proteins), thereby returning to the off state.

KRAS mutations are found in approximately 30% of all human cancers and are extremely common in the three most lethal forms of cancer: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%). Together, these cancers occur in more than 200,000 patients each year in the United States alone. One specific mutation, a glycine to cysteine substitution at position 12 (G12C), occurs in more than 40,000 patients each year. The KRAS G12C mutation impairs the hydrolysis of GTP to GDP, thereby trapping KRAS in the on state and promoting cancer cell proliferation.

The cysteine residue of G12C provides an opportunity to develop targeted covalent drugs for this mutant KRAS. Early clinical trial results of the KRAS G12C inhibitors AMG 510 and MRTX849 have shown encouraging results in non-small cell lung cancer (NSCLC), but data in colorectal cancer (CRC) are less convincing. In addition, even in cases where patients respond to initial treatment, there are signs that the duration of response may be limited and resistance may develop rapidly.

Most inhibitors of KRAS mutants bind preferentially to the GDP-bound form of the protein. For example, Amgen KRAS inhibitor AMG 510 and Mirati 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 through RTKs, thereby increasing the amount of GTP-bound KRAS, which is less affected by current inhibitors. Therefore, generating molecules that can bind to and inhibit both the GDP-bound and GTP-bound forms of KRAS could have substantial utility.

There is a need for compounds useful for treating cancers, such as cancers characterized by KRAS G12C. There is a further need for compounds useful for treating cancers characterized by KRAS G12C, wherein the compounds bind to and inhibit both the inactive GDP-bound form and the activated GTP-bound form of KRAS. There is a further need for compounds useful for treating cancers characterized by KRAS G12C, wherein the compounds have improved inhibition of the GTP-bound form of KRAS G12C.

In one embodiment, the present invention provides a compound of formula (I): Formula (I), or a salt thereof and/or an isotopologue thereof; wherein: X is -N(CH ₃ )- or -O-; X ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ or cyclopropyl, each of which is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, -OH and -OCH ₃ ; q is 0 or 1; R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the heterocyclic group is substituted by 0, 1, 2 or 3 R ^1A ; R ^1A is independently selected from halogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C _4- halogen alkoxy and -C(O)(C ₁ -C ₄ alkyl); or two zygote R ^1A together with the carbon atom to which they are attached form a C ₃ -C ₄ cycloalkyl substituted with 0, 1 or 2 halogen groups; or two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ ; ^Ra is H or CH ₃ ; R ² is or ; R ³ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁴ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁵ is H or -OH; Y is CH or N; R ⁶ is independently selected from the group consisting of halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogen, C ₃ -C ₄ cycloalkyl and -NH ₂ ; and r is 0, 1, 2 or 3; provided that when q is 0, then R ¹ is not , , , , , or any mirror image thereof; when for or or any mirror image isomer thereof, then R ² is not ; and when for or any mirror image isomer thereof, then R ² is not or .

In some embodiments, including any of the embodiments in the preceding paragraphs, the compound is selected from the group consisting of the compounds of Table 1 and all salts and isotopologues thereof.

In another aspect, a pharmaceutical formulation is provided, comprising a compound as described herein, including but not limited to the compounds described in the preceding paragraphs, and a pharmaceutically acceptable carrier, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

In another aspect, a method for treating or inhibiting cancer is provided, the method comprising: administering to an individual in need thereof a therapeutically effective amount of a compound as described herein, including but not limited to the compound described in the preceding paragraph, or a pharmaceutical formulation, including but not limited to the pharmaceutical formulation 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 lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In some embodiments, the cancer is selected from the group consisting of: polymorphic neuroblastoma, low-grade neuroglioma, 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, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin melanoma, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms tumor (pediatric Wilms' tumor), pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In some embodiments, including any of the foregoing embodiments, the method is used to treat cancer. In some embodiments, including any of the foregoing embodiments, the method is used to inhibit cancer. In some embodiments, including any of the foregoing embodiments, the cancer is a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the individual is diagnosed with a KRAS G12C-mediated cancer. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of an additional chemotherapeutic agent.

In another aspect, there is provided a use of a compound as described herein (including but not limited to any of the foregoing embodiments) as a medicament. In another aspect, there is provided a use of a compound as described herein (including but not limited to any of the foregoing embodiments) for treating or inhibiting cancer. In another aspect, there is provided a use of a compound as described herein (including but not limited to any of the foregoing embodiments) for the manufacture of a medicament for treating or inhibiting 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 inhibiting cancer.

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

It is understood that descriptions of compounds, compositions, formulations, and methods of treatment described herein include "comprising," "consisting of," and "consisting essentially of." In some embodiments, for all compositions described herein and all methods of using the compositions described herein, the compositions may comprise, or may "consist essentially of," the listed components or steps. When a composition is described as "consisting essentially of the listed ingredients", the composition contains the listed ingredients and may contain other ingredients that do not substantially affect the disease to be treated in addition to those ingredients explicitly listed, but does not contain any other ingredients that substantially affect the disease to be treated; or, if the composition does contain additional ingredients that substantially affect the disease to be treated in addition to those listed, the composition does not contain the additional ingredients in a concentration or amount sufficient to substantially affect the disease to be 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 disease to be treated in addition to those steps explicitly listed, but the method does not contain any other steps that substantially affect the disease to be treated. As a non-limiting specific example, when a composition is described as "consisting essentially of a component," the composition may additionally contain any amount of a pharmaceutically acceptable carrier, vehicle or diluent and other such components that do not substantially affect the disease to be treated.

Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through practice of the present disclosure.

Provided herein are compounds useful for treating cancer, and methods of using such compounds for treating cancer. In some embodiments, the compounds are useful for treating cancer characterized by KRAS G12C. In some embodiments, the compounds advantageously inhibit both the inactive GDP-bound form and the activated GTP-bound form of KRAS G12C. In some embodiments, the compounds advantageously have improved inhibition of the GTP-bound form of KRAS G12C. Definitions

Unless otherwise indicated, abbreviations used herein have their commonly understood meanings in chemistry and biotechnology.

It is to be understood that the depictions of compound structures (including possible substitutions) are limited to those that are chemically possible.

Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as described. The "Example" row of Table 1 indicates the synthetic example number corresponding to the structure provided in the same column of Table 1. A group of compounds each having the absolute stereochemistry in Table 1 may have multiple example numbers specified in the "Example" row. In this case, each of the specified examples produces only one of those compounds. However, the absolute stereochemistry of that compound has not yet been determined. For example, compounds 7-2 and 7-3 in Table 1 have "22 or 23" indicated in the "Example" row, meaning that only one of compounds 7-2 and 7-3 was obtained from Example 22 and only the other compound was obtained from Example 23. As another example, compounds 15-3, 15-4, 15-5, and 15-6 in Table 1 have "36 or 37" indicated in the "Example" row, meaning that only one of the four compounds was obtained from Example 36, and only one of the other three compounds was obtained from Example 37.

Compounds with an (and) designation in the stereochemistry row of Table 1 are mixtures of mirror image isomers with relative stereochemistry as indicated. Compounds with a stereogenic center where the configuration is not indicated in the depicted structure and no designation in the stereochemistry row of Table 1 are mixtures of mirror image isomers at that center. Compounds with a stereogenic center where the configuration is indicated by a bold wedge or a hashed wedge in the structure and no designation or marked with (abs) in the stereochemistry row of Table 1 are single mirror image isomers with absolute stereochemistry as indicated.

For example, compound 7-2 are single mirror image isomers with stereochemistry as indicated.

Bold or hashed non-wedge-shaped (ie, rectangular) keys in a compound indicate that the compound is a mixture of different non-imaging isomers with a fixed cis or trans configuration.

For example, compound 7-1 Compound 7-2 and A mixture of 7-3.

In some cases, the stereochemistry row of Table 1 contains different designators selected from ( abs ) and ( and ) to refer to different stereocenters or pairs of stereocenters of the molecule.

For example, compound 27-1 The "amino-pyrrolidine- ( abs )" indicates that the amino-pyrrolidine head group of the compound has the depicted (R,R) configuration; and " ^R1- ( and )" indicates that the ^R1 group of the compound has (R) or (S) stereochemistry, so that the compound obtained from Example 55 is compound 27-2 Mixture with 27-3 .

Those skilled in the art will be able to separate racemic compounds into their individual mirror isomers using methods known in the art, such as chiral analysis, chiral recrystallization and the like. Reference to the compounds as a racemic mixture is intended to also include the individual mirror isomers contained in the mixture.

Reference herein to "about" a value or parameter includes (and describes) variations with respect to that value or parameter itself. For example, a description referring to "about X" includes a description of "X". As used herein, and unless otherwise specified, the terms "about" and "approximately" when used in conjunction with a temperature, dosage, amount, or weight percentage of an ingredient of a composition or dosage form, means a dosage, amount, or weight percentage that is generally considered by those skilled in the art to provide a pharmacological effect equivalent to that obtained from a specified dosage, amount, or weight percentage. Specifically, the terms "about" and "approximately" when used in this context are intended to be within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1% or 0.5% of a specified dosage, amount, or weight percentage.

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

The terms "subject," "individual," and "patient" refer to an individual organism, preferably a vertebrate, more preferably a mammal, and most preferably a human. Examples of patients include humans; livestock, such as cattle, goats, sheep, pigs, and rabbits; and companion animals, such as dogs, cats, and horses. In some embodiments, the individual has been identified or diagnosed as having a cancer or tumor with a KRAS G12C mutation (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay).

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

"Inhibition" of a disorder using the compounds and methods discussed herein is defined as the administration of one or more compounds discussed herein, with or without additional therapeutic agents, to inhibit the clinical manifestation of the disorder, or to inhibit the manifestation of adverse symptoms of the disorder. The distinction between treatment and inhibition is that treatment occurs after adverse symptoms of the disorder have manifested in an individual, whereas inhibition occurs before adverse symptoms of the disorder have manifested in an individual. Inhibition may be partial, substantially complete, or total. In some embodiments, genetic screening may be used to identify patients at risk for the disorder. Asymptomatic patients at risk for developing clinical symptoms of the disorder may then be administered the compounds and methods disclosed herein to inhibit the appearance of any adverse symptoms.

"Therapeutic use" of the compounds discussed herein is defined as the use of one or more compounds discussed herein to treat or inhibit 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 of the disorder, or to delay the progression of the disorder or one or more symptoms of the disorder, or to reduce the severity of the disorder or one or more symptoms of the disorder, or to inhibit the clinical manifestation of the disorder, or to inhibit the manifestation of adverse symptoms of the disorder. An effective amount can be given in one or more administrations.

"KRAS G12C-mediated cancer" is used interchangeably herein with "cancer characterized by KRAS G12C" and refers to a cancer that contains cells containing the KRAS G12C mutant.

Although the compounds described herein may exist and be used as neutral (non-salt) compounds, the description is intended to cover 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.

A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable to humans and/or animals and that retains at least some of the desired pharmacological activity of the parent compound after administration. Such salts include: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, apple 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, glucoheptanoic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfuric acid, gluconic acid, glutamine, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and similar acids; or (b) a salt formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkali earth metal ion or an aluminum ion); or a salt formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N -methylglucamine and similar bases. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences , 17th edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

When chemically relevant, all stereoisomers of a compound are included herein, including both non-mirror and mirror isomers. Mixtures of possible stereoisomers in any ratio are also included, including but not limited to racemic mixtures. Unless the stereochemistry is explicitly indicated in a structure, the structure is intended to encompass all possible stereoisomers of the depicted compound. If the stereochemistry of one or more parts of a molecule is explicitly indicated, but the stereochemistry of another part or parts of the molecule is not explicitly indicated, the structure is intended to encompass all possible stereoisomers of the part or parts where the stereochemistry is not explicitly indicated.

"Isotopologues" herein refer to compounds that have an isotopic composition that is different from their "natural" isotopic composition. "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds listed herein are intended to represent any stable isotope of that atom. For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position should be understood to be a hydrogen with its natural isotopic composition. Descriptions of compounds herein also include all isotopologues of all compounds herein, in some embodiments, partially deuterated or fully deuterated analogs. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" refers to the percentage of the natural isotopic abundance of a given atom in a molecule that is replaced by a certain amount of a specific isotope. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the natural distribution 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 isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

"Alkyl" means a saturated monovalent hydrocarbon group having a specified number of carbon atoms in a straight chain, branched chain, or combination thereof. For example, C1- _C4 alkyl includes groups such _as methyl, ethyl, propyl, 2-propyl, butyl, and the like.

"Alkylene" means a saturated divalent hydrocarbon group having a specified number of carbon atoms in a straight chain, branched chain, or combination thereof. For example, _C1 - _C4 alkylene includes groups such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and the like.

"Alkenyl" means a straight or branched monovalent hydrocarbon group containing one or more double bonds and having the specified _{number of carbons. For example, C2-C4 alkenyl} includes, for example, vinyl, prop-1-en-2-yl, prop-1-en-1-yl, allyl, and the like.

"Alkynyl" means a straight or branched monovalent hydrocarbon radical containing one or more bonds and having the specified _{number of carbon atoms. For example, C2-C4 alkynyl} includes ethynyl, propynyl, 2-propynyl, butynyl and the like.

"Alkoxy" means a ^-ORx radical, wherein ^Rx is an alkyl radical as defined above, or a ^-Rx'orx " radical, wherein ^Rx ' is an alkylene radical and ^Rx " is an alkyl radical as defined above, wherein the fixed number of alkyl carbons in the alkoxy radical is equal to the total number of carbons in ^Rx ' and ^Rx ". For example, ^C1 - _C4 alkoxy refers to radicals _such as methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, the alkoxy radical is a ^-ORx radical. In some embodiments, the alkoxy radical is a ^-Rx'ORx " radical. In some embodiments, when nitrogen is substituted with an alkoxy radical, the alkoxy radical is not attached to the nitrogen through the oxygen or the carbon immediately adjacent to ^the oxygen in the alkoxy radical. For example, an alkoxy-substituted nitrogen is not N-OR ^x or N-CH ₂ -OR ^x ".

"Alkoxyalkoxy" means a ^-ORy radical where ^Ry is an alkoxy radical as defined above, provided that the point of attachment of ^Ry is not an oxygen atom, or a -Ry'ORy" radical where ^Ry ' is an alkylene radical and ^{Ry "} is an alkoxy radical as defined above, provided that the point of attachment of ^Ry " is not an oxygen atom, wherein the specified number of alkyl carbons in the alkoxyalkoxy radical is equal to the total number of carbons in ^Ry ' and ^{Ry "} . For example, C ₁ -C ₆ alkoxyalkoxy refers to, for example, -OCH ₂ OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₂ OCH 3 , -CH 2 OCH ₂ CH ₂ OCH ₂ CH ₃ , -CH ₂ CH 2 OCH 2 CH ₂ OCH ₂ CH ₃ and the like. In some embodiments, the alkoxyalkoxy group is a -OR ^y group. In some embodiments, the alkoxyalkoxy group is a —R ^y 'OR ^y " group. In some embodiments, when the nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not attached to the nitrogen through the oxygen or the carbon adjacent to the oxygen in the alkoxyalkoxy group. For example, the nitrogen substituted with the alkoxyalkoxy group is not N—OR ^y or N—CH ₂ —OR ^y ".

"Aminoalkyl" means a ^-NHRz radical, wherein ^Rz is an alkyl radical as defined above, or a ^{-NRzRz '} radical, wherein ^Rz and ^Rz ' are alkyl radicals as defined above, or a ^-Rz " _NH2 radical, wherein ^Rz " is an alkylene radical as defined above, or a ^-Rz " ^NHRz radical, wherein ^Rz " is an alkylene radical as defined above and ^Rz ' is an alkyl radical as defined above, or ^{a -Rz} " ^{NRzRz '} radical, wherein ^Rz " is an alkylene radical as defined above and ^Rz and ^Rz ' are alkyl radicals as defined above, wherein the specified number of alkyl carbons in the aminoalkyl radical is equal to the total number of carbons in ^Rz , ^Rz ' and ^Rz " ( _as the case may be). For example, a _C1 - _C6aminoalkyl radical indicates, for example, _-NHCH3 , _{-NHCH2CH3 In some} embodiments _{, the} aminoalkyl group is a _{-NHR z group . In some embodiments} , the _aminoalkyl group is _a -NR z _R z 'group _{. In some} embodiments, _{the aminoalkyl group} is a -R _{z "} NH _{2 group} . In some embodiments, _the aminoalkyl group is a _-R z " _{NHR z} group. In some embodiments, the aminoalkyl group _{is a -R z "NHR z} ^{group . In} some embodiments, the aminoalkyl group is ^{a -R z " NR z} R ^{z '} group. In some embodiments, when the oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not linked to the oxygen via the nitrogen or the carbon immediately adjacent to the nitrogen in the aminoalkyl group. For example, the oxygen substituted with the aminoalkyl group is not O- ^NRz or ^O-CH2-NHRz _.

"Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group has six ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C ₁₄ aryl"; e.g., anthracenyl). In some embodiments, "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl and naphthyl, wherein the point of attachment can be on any carbon atom. Exemplary aryl groups also include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like, wherein the point of attachment is on the phenyl. In some embodiments, "aryl" does not include ring systems in which an aryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls.

"Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon group having the specified number of carbon atoms. For example, C ₃ -C ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Cycloalkylene" means a monocyclic saturated divalent hydrocarbon group having a specified number of carbon atoms. For example, C ₃ -C ₆ cycloalkylene includes cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.

"Cyanoalkyl" means an alkyl group as defined above, substituted with a cyano (-CN) group. Cyanoalkyl groups may also be referred to as alkylnitriles.

"Halogen" means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen group is fluorine or chlorine.

"Haloalkyl" means an alkyl group as defined above, which is substituted with one or more halogen atoms, for example, one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, for example, _-CH2Cl , _-CF3 , _-CHF2 , _-CH2CF3 , _-CF2CF3 , -CF( _CH3 ) ₂ , and _{the like} . When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.

"Haloalkoxy" means a -OR ^a' group, wherein Ra ^' is a haloalkyl group as defined above, or a -R ^{b'OR c'} group, wherein R ^b' and R ^c' are alkyl or haloalkyl groups as defined above, wherein the specified number of alkyl carbons in the haloalkoxy group is equal to the total number of carbons in R ^b' and R ^c' . The halogen atom may be present in R ^b' or R ^c' or both, provided that at least one of R ^b' and R ^c' comprises a halogen atom. For example, C ₁ -C ₄ haloalkoxy refers to groups such as -OCF ₃ , -OCHF ₂ , -CH ₂ OCF ₃ , -CH ₂ CH(F)CH ₂ OCH ₃ , -CH ₂ CH(F)CH ₂ OCHF ₂ and the like. In some embodiments, the haloalkoxy group is a -OR ^a' group. In some embodiments, the halogen alkoxy group is a -R ^{b'OR c'} group. When all halogen atoms in the halogen alkoxy group are fluorine, it may be referred to as a fluoroalkoxy group in the present application. In some embodiments, when nitrogen is substituted by a halogen alkoxy group, the halogen alkoxy group is not connected to the nitrogen via oxygen or the carbon adjacent to the oxygen in the halogen alkoxy group. For example, the nitrogen substituted by the halogen alkoxy group is not N-OR ^a' or NC(H) _n (X) _m -OR" (wherein X is a halogen and n and m are integers, provided that n+m=2).

"Hydroxyalkyl" means an alkyl group as defined above substituted with one or more hydroxy (-OH) groups, e.g., one to three hydroxy groups, e.g., _-CH2OH , _-CH2CH2OH , -C(OH)( _CH3 ) _{2 ,} -CH(OH) _CH3 , and the like.

Unless otherwise stated, "heterocyclic" or "heterocycle" means a saturated or partially unsaturated cyclic group containing 3-12 ring atoms, of which 1-4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and the remainder of the ring is C. A sulfhydryl group can exist as -S- or as -S(O) _2- . Unless otherwise stated, heterocyclic groups include monocyclic systems as well as polycyclic systems, including fused, bridged and spirocyclic systems. "Heterocyclic" or "heterocycle" also includes ring systems in which a heterocyclic group as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring or the heterocyclic ring. In some embodiments, "heterocyclyl" or "heterocycle" also includes ring systems in which a heterocyclyl as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members represents the number of ring members in the heterocyclyl ring system. In some embodiments, the heterocyclyl is a monocyclic ring. In some embodiments, the heterocyclyl comprises two fused rings. In some embodiments, the heterocyclyl comprises two spiro rings. In some embodiments, the heterocyclyl comprises a bridged ring system.

Unless otherwise specified, "carbocyclyl" or "carbocycle" means a saturated or partially unsaturated cyclic group containing 3-12 ring atoms, wherein the ring atoms are C. Unless otherwise specified, carbocyclyl includes monocyclic and polycyclic systems, including fused, bridged and spirocyclic systems. In some embodiments, the carbocyclyl is a monocyclic ring. In some embodiments, the carbocyclyl contains two fused rings. In some embodiments, the carbocyclyl contains two spirocyclic rings. In some embodiments, the carbocyclyl contains a bridged ring system.

Unless otherwise indicated, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms, wherein one or more (in some embodiments, one, two or three) of the ring atoms are heteroatoms independently selected from N, O or S, and the remaining ring atoms are carbon. In some embodiments, "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls, wherein the point of attachment is on the heteroaryl ring. In such cases, unless otherwise indicated, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. In some embodiments, "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl/heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl). In some embodiments, "heteroaryl" does not include a ring system in which a 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, quinolyl, isoquinolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

"Spiro"cycloalkyl indicates that the cycloalkyl is attached to the rest of the compound via a spiro bond. "Spiro"cycloalkyl substituents have two points of attachment to the same carbon of the substituted moiety, thereby forming a spiro connection. For example, a cyclohexyl substituted with a "spiro C ₃ -C ₄ cycloalkyl" indicates: or .

As used herein, "in need of treatment" means that a patient is treated by a physician or other caregiver after a disease is diagnosed or the patient is determined to be at risk of developing a disease. In some embodiments, the patient is diagnosed with a KRAS G12C-mediated cancer. In some embodiments, the patient is determined to be at risk of developing a KRAS G12C-mediated cancer.

"Administration", "administering" and similar terms, when applied to, for example, a patient, a cell, a tissue, an organ or a biological fluid, refer to the contact of, for example, a compound of Formula (I), Formula (I') or Formula (I") or a pharmaceutically acceptable salt and/or isotopologue thereof, a pharmaceutical composition comprising the same, or a diagnostic agent with a subject, a cell, a tissue, an organ or a biological fluid. In the case of cells, administration includes contact of an agent with a cell (e.g., in vitro or ex vivo), as well as contact of an agent with a fluid, wherein the fluid is in contact with a cell.

“Contingent” or “subject to” means that the subsequently described event or circumstance may but may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.

"Pharmaceutically acceptable carriers or excipients" means carriers or excipients that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise desirable, and include carriers or excipients that are acceptable for veterinary use as well as human medical use. As used in the specification and patent application, "pharmaceutically acceptable carriers/excipients" include one or more such excipients.

As used herein, the term "disease" is intended to be generally synonymous and used interchangeably with the terms "symptom," "syndrome," and "disease" (as in medical disorders) because they all reflect an abnormal condition of the human or animal body or one of its parts that impairs the normal functioning, typically manifests itself as distinctive signs and symptoms, and results in a decrease in the life span or quality of life of a human or animal.

The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or conditions described in this disclosure. Such administration encompasses co-administration of such 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. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the diseases or conditions described herein. Compounds

Compounds of formula (I) are provided herein. Unless the context requires otherwise, references throughout this specification to "a compound of formula (I)" or "compound of formula (I)" refer to all embodiments of formula (I), including, for example, formula (I'), (I''), (I-a), (I-b), (I-c), (I-d), (IA), (IB), (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (IA-a), (IA- In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In some embodiments, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) is provided in the form of the corresponding free base (i.e., not a salt).

In one embodiment, a compound of formula (I) is provided: Formula (I), or a salt thereof and/or an isotopologue thereof; wherein: X is -N(CH ₃ )- or -O-; X ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ or cyclopropyl, each of which is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, -OH and -OCH ₃ ; q is 0 or 1; R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the heterocyclic group is substituted by 0, 1, 2 or 3 R ^1A ; R ^1A is independently selected from halogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C _4- halogen alkoxy and -C(O)(C ₁ -C ₄ alkyl); or two zygote R ^1A together with the carbon atom to which they are attached form a C ₃ -C ₄ cycloalkyl substituted with 0, 1 or 2 halogen groups; or two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ ; ^Ra is H or CH ₃ ; R ² is or ; R ³ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁴ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁵ is H or -OH; Y is CH or N; R ⁶ is independently selected from the group consisting of halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogen, C ₃ -C ₄ -cycloalkyl and -NH ₂ ; and r is 0, 1, 2 or 3.

In some embodiments, when q is 0, ^R1 is not , , , , , or any mirror image isomer thereof. In some embodiments, when for or any mirror image isomer thereof, then R ² is not In some embodiments, when for or any mirror image isomer thereof, then R ² is not In some embodiments, when for or any mirror image isomer thereof, then R ² is not In some embodiments, when R ¹ is or any mirror image isomer thereof, then R ² is not or In some embodiments, when for or any mirror image isomer thereof, then R ² is not or .

In some embodiments, ^R2 is In some embodiments, ^R3 is selected from the group consisting of halogen, C1 _{- C4} alkyl and _C2 - _C3 alkynyl. In some embodiments, ^R3 is selected from the group consisting of -F, -Cl, -Et, -C≡CH and -C≡C- _CH3 . In some embodiments, ^R4 is hydrogen or halogen. In some embodiments, ^R4 is hydrogen or -F. In some embodiments, ^R5 is -OH. In some embodiments, ^R5 is H.

In some embodiments, ^R2 is , , , , , or In some embodiments, ^R2 is .

In some embodiments, ^R2 is In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R ⁶ is independently selected from the group consisting of -Cl, -OH, -CH ₃ , -CF ₃ , cyclopropyl, and -NH ₂ at each occurrence. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

In some embodiments, ^R2 is In some embodiments, ^R2 is In some embodiments, R ^6A is cyclopropyl or -CF ₃ . In some embodiments, R ^6B is -Cl or -CH ₃ . In some embodiments, R ^6C is -OH or -NH ₂ .

In some embodiments, ^R2 is , or .

In some embodiments, X is -N(CH ₃ )-. In some embodiments, X is -O-.

In some embodiments, X ¹ is -CH ₃ , -CH ₂ F, -CH ₂ OCH ₃ , -CH ₂ CH ₃ , -CH(OH)CH ₃ , -CH=CH ₂ or cyclopropyl. In some embodiments, X ¹ is -CH ₃ .

In some embodiments, the compound Part of , , , , , , , , , or In some embodiments, the compound Part of , , , , , , , , , , , , , , , , , , , , or In some embodiments, the compound Part of or In some embodiments, the compound Part of .

In some embodiments, R ¹ is substituted with 0, 1, 2 or 3 R ^1A or In some embodiments, R ^1A is independently -F, -OH, -CH ₃ , -OCH ₃ , -OCF ₃ , -OCHF ₂ or -C(O)CH ₃ at each occurrence. In some embodiments, two zygote R ^1A together with the carbon atom to which they are attached form a cyclopropyl substituted with 0, 1 or 2 fluorines. In some embodiments, two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ .

In some embodiments, ^R1 is , , , , , , , , , , , , , , , , , , , or In some embodiments, R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some embodiments, R ¹ is In some embodiments, R ¹ is .

In some embodiments, ^R1 is , , , , , , , , , , , , , , , , , , or In some embodiments, R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^Ra is H. In some embodiments, ^Ra is CH ₃ .

In some embodiments, a compound of formula (I') is provided Formula (I') or a salt thereof; and/or an isotopologue thereof; wherein: ^R1 is a 4-8 membered saturated carbocyclic group or heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the carbocyclic group or the heterocyclic group is substituted by 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, _C1 - _C4 alkyl, spiro _C3 - _C4 cycloalkyl, _C1 - _C4 alkoxy, _C1 - _C4 haloalkyl and _C1 - _C4 haloalkoxy; ^R3 is selected from hydrogen, halogen, _C1 - _C4 alkyl, _C3 - _C4 cycloalkyl, _C1 - _C4 alkoxy, _C1 - _C4 haloalkyl, _C1 - _C4 haloalkoxy and _C2 -C R ₄ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogenalkyl ^, C ₁ -C ₄ halogenalkoxy and C ₂ -C ₃ alkynyl; and q is 0 or 1; provided that when q is 0, R ¹ is not , , , , , or any mirror image isomer thereof.

In one embodiment, the compound has formula (IA) or formula (IB) Formula (IA) Formula (IB); or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA).

In one embodiment, the compound has formula (1B).

In one embodiment, the compound has Formula (Ia), Formula (Ib) or Formula (Ic): Formula (Ia) Formula (Ib) Formula (Ic) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (I-a).

In one embodiment, the compound has formula (I-b).

In one embodiment, the compound has formula (I-c).

In one embodiment, the compound has Formula (Ia-1) or Formula (Ia-2): Formula (Ia-1) Formula (Ia-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (I-a-1).

In one embodiment, the compound has formula (I-a-2).

In one embodiment, the compound has Formula (IA-a) or Formula (IB-a): Formula (IA-a) Formula (IB-a) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-a).

In one embodiment, the compound has formula (IB-a).

In one embodiment, the compound has Formula (IA-a-1), Formula (IA-a-2), Formula (IB-a-1), or Formula (IB-a-2): Formula (IA-a-1) Formula (IA-a-2) Formula (IB-a-1) Formula (IB-a-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-a-1).

In one embodiment, the compound has formula (IA-a-2).

In one embodiment, the compound has formula (IB-a-1).

In one embodiment, the compound has formula (IB-a-2).

In one embodiment, the compound has Formula (Ib-1) or Formula (Ib-2): Formula (Ib-1) Formula (Ib-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (I-b-1).

In one embodiment, the compound has formula (I-b-2).

In one embodiment, the compound has Formula (IA-b) or Formula (IB-b): Formula (IA-b) Formula (IB-b) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-b).

In one embodiment, the compound has formula (IB-b).

In one embodiment, the compound has Formula (IA-b-1), Formula (IA-b-2), Formula (IB-b-1), or Formula (IB-b-2): Formula (IA-b-1) Formula (IA-b-2) Formula (IB-b-1) Formula (IB-b-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-b-1).

In one embodiment, the compound has formula (IA-b-2).

In one embodiment, the compound has formula (IB-b-1).

In one embodiment, the compound has formula (IB-b-2).

In one embodiment, the compound has Formula (Ic-1) or Formula (Ic-2): Formula (Ic-1) Formula (Ic-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (I-c-1).

In one embodiment, the compound has formula (I-c-2).

In one embodiment, the compound has Formula (IA-c) or Formula (IB-c): Formula (IA-c) Formula (IB-c) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-c).

In one embodiment, the compound has formula (IB-c).

In one embodiment, the compound has Formula (IA-c-1), Formula (IA-c-2), Formula (IB-c-1), or Formula (IB-c-2): Formula (IA-c-1) Formula (IA-c-2) Formula (IB-c-1) Formula (IB-c-2) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-c-1).

In one embodiment, the compound has formula (IA-c-2).

In one embodiment, the compound has formula (IB-c-1).

In one embodiment, the compound has formula (IB-c-2).

In one embodiment, the compound has formula (Id): Formula (Id) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has Formula (IA-d) or Formula (IB-d): Formula (IA-d) Formula (IB-d) or a salt thereof; and/or an isotopologue thereof, wherein R ¹ , R ³ and R ⁴ are as defined in any of the embodiments described herein.

In one embodiment, the compound has formula (IA-d).

In one embodiment, the compound has formula (IA-d).

As generally defined herein, each ^R3 is independently selected from the group consisting of hydrogen, halogen, _C1 - _C4 alkyl, _C3 - _C4 cycloalkyl, _C1 - _C4 alkoxy, _C1 - _{C4 halogen, C1-C4 halogen ,} and _C2 - _C3 alkynyl. In one embodiment, each ^R3 is independently selected from the group consisting of hydrogen, halogen, _C1 - _C4 alkyl, _C3 - _C4 cycloalkyl, C1- _C4 halogen, and _C2 - _C3 alkynyl. In one embodiment, each ^R3 is independently selected from the group consisting of hydrogen, halogen, and _{C1 - C4} alkyl. In one embodiment, each R ³ is independently selected from the group consisting of hydrogen, halogen and C ₃ -C ₄ cycloalkyl. In one embodiment, each R ³ is independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₄ halogen alkyl. In one embodiment, each R ³ is independently selected from the group consisting of hydrogen, halogen and C ₂ -C ₃ alkynyl. In one embodiment, R ³ is selected from halogen and C ₁ -C ₄ alkyl. In one embodiment, R ³ is selected from halogen and C ₂ -C ₃ alkynyl. In one embodiment, each R ³ is independently selected from the group consisting of hydrogen and halogen. In one embodiment, each R ³ is independently halogen. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF ₃ and -C≡CH. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F, -Cl, -Me and -Et. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F, -Cl and -cyclopropyl. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F, -Cl and -CF _3. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F, -Cl and -C≡CH. In one embodiment, each R ³ is independently selected from the group consisting of -H, -F and -Cl. In one embodiment, ^R is selected from -F, -Cl, -Et and -C≡CH. In one embodiment, ^R is selected from -F, -Cl and -Et. In one embodiment, ^R is selected from -F, -Cl and -C≡CH. In one embodiment, each ^R is independently selected from the group consisting of -F and -Cl. In one embodiment, R is ^-F . In one embodiment, ^R is -Cl. In one embodiment, ^R is -Et. In one embodiment, ^R is -C≡CH.

As generally defined herein, each R ⁴ is independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogen alkoxy, and C ₂ -C ₃ alkynyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ halogen, and C ₂ -C ₃ alkynyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₄ alkyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen, halogen and C ₃ -C ₄ cycloalkyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₄ halogen alkyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen, halogen and C ₂ -C ₃ alkynyl. In one embodiment, each R ⁴ is independently selected from the group consisting of hydrogen and halogen. In one embodiment, each R ⁴ is independently halogen. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF ₃ and -C≡CH. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F, -Cl, -Me and -Et. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F, -Cl and -cyclopropyl. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F, -Cl and -CF _3. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F, -Cl and -C≡CH. In one embodiment, each R ⁴ is independently selected from the group consisting of -H, -F and -Cl. In one embodiment, each R ⁴ is independently selected from the group consisting of -F and -Cl. In one embodiment, R ⁴ is selected from -H and -F. In one embodiment, R ⁴ is -H. In one embodiment, R ⁴ is -F.

As generally defined herein, R ¹ is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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, with the proviso that in formula (I), when q is 0, R ¹ is not , , , , , or any mirror image isomer thereof.

In one embodiment, R ¹ is a 4-8 membered saturated bicyclic carbocyclic group or a bicyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the carbocyclic group or the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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. In one embodiment, R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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. In one embodiment, R ¹ is a 4-8 membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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. In one embodiment, R ¹ is a 4-8 membered saturated bicyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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.

In one embodiment, the carbocyclic or heterocyclic group of R ¹ is unsubstituted or substituted with a substituent selected from halogen, hydroxyl or spiro C ₃ -C ₄ cycloalkyl. In one embodiment, the carbocyclic or heterocyclic group of R ¹ is unsubstituted or substituted with a fluoro or spiro C ₃ -C ₄ cycloalkyl. In one embodiment, R ¹ is selected from the group consisting of: , and , wherein R ^d is as defined in any of the embodiments described herein. In one embodiment, R ¹ is or , wherein R ^d is as defined herein. In one embodiment, R ¹ is selected from , and In one embodiment, ^R1 is selected from , and Group of people.

In one embodiment, ^R1 is , wherein R ^d is as defined in any of the embodiments described herein. In one embodiment, R ¹ is In one embodiment, ^R1 is selected from and In one embodiment, R ¹ is .

In one embodiment, ^R1 is In one embodiment, R ¹ is .

As generally defined herein, q is 0 or 1. In one embodiment, q is 0, provided that in Formula (I), when q is 0, R ¹ is not , , , , , Or any mirror image isomer thereof. In one embodiment, q is 1.

As generally defined herein, ^Rd is H or F. In one embodiment, ^Rd is H. In one embodiment, ^Rd is F.

In one embodiment, the compound is selected from the compounds in Table 1 or salts thereof; and/or isotopologues thereof. In one embodiment, the compound is not a salt.

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

In one embodiment, provided herein are compounds of Table 1 or salts thereof and/or isotopologues thereof. In some embodiments, the salt is a pharmaceutically acceptable salt. Table 1. Compound No. Examples Structure Stereochemistry 1-1 1-1 R ¹ - ( abs ) amino-pyrrolidine- ( and ) 1-2 1-2 1-3 1-3 1-4 27 1-5 28 2-1 2 2-2 6 2-3 3 2-4 8 3-1 4 3-2 10 3-3 5 3-4 9 5 7 6 12 R ¹ - ( abs ) amino-pyrrolidine- ( and ) 7-1 twenty one R ¹ - ( abs ) amino-pyrrolidine- ( and ) 7-2 22 or 23 7-3 22 or 23 8-1 twenty four R ¹ - ( abs ) amino-pyrrolidine- ( and ) 8-2 25 or 26 8-3 25 or 26 9 17 10 18 11 19 12 20 13-1 29 or 30 13-2 29 or 30 14-1 31 R ¹ - ( and ) amino-pyrrolidine- ( abs ) 14-2 32 or 33 14-3 32 or 33 15-1 34 or 35 15-2 34 or 35 15-3 36 or 37 15-4 36 or 37 15-5 36 or 37 15-6 36 or 37 16 38 17-1 39 or 40 17-2 39 or 40 17-3 41 R ¹ - ( and ) amino-pyrrolidine- ( abs ) 17-4 42 or 43 17-5 42 or 43 18 44 19 45 20 46 21-1 47 R ¹ - ( and ) amino-pyrrolidine- ( abs ) 21-2 48 or 49 21-3 48 or 49 twenty two 50 twenty three 51 twenty four 52 25 53 26 54 27-1 55 R ¹ - ( and ) amino-pyrrolidine- ( abs ) 27-2 27-3 28 56 29-1 57 R ¹ - ( and ) amino-pyrrolidine- ( abs ) 29-2 29-3 29-4 29-5 30-1 58 or 59 30-2 58 or 59 31 60 32 61 33 62 34 63 35 64 36-1 65 or 66 36-2 65 or 66 37 67 38-1 68 38-2

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

Any formula given herein, such as formula (I), is intended to represent compounds having the structure depicted by the structural formula, as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different mirror or non-mirror isomeric forms. All optical isomers and stereoisomers of the compounds of the general formula and mixtures thereof in any ratio are considered to be within the scope of the formula. Therefore, any formula given herein is intended to represent a racemate, one or more mirror isomeric forms, one or more non-mirror isomeric forms, one or more atropisomer forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any formula given herein is intended to also refer to hydrates, solvates, and any of amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

Representative examples of the compounds (including intermediates and final compounds) described in detail herein are described in the tables and elsewhere herein. It should be understood that in one aspect, any of the compounds can be used in the methods described in detail herein, including (when appropriate) intermediate compounds that can be isolated and administered to a subject.

The compounds described herein may exist in salt form, even if no salt is described, and it is understood that the compositions and methods provided herein encompass all salts and solvents of the compounds described herein, as well as non-salt and non-solvent forms of the compounds, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

In one variation, the compounds herein are synthetic compounds prepared for administration to a subject. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier are provided. In another variation, methods of administering the compounds are provided. The purified forms of the compounds, pharmaceutical compositions, and methods of administration are suitable for any of the compounds or forms thereof detailed herein.

Any variation or embodiment provided herein can be combined with every ^other variation or embodiment of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , Ra, ^X , ^X1 , ^q , r, ^R1A , ^R6A , ^R6B , ^R6C , ^Rx , ^{Rx '} , ^Rx ", Ry ^{, Ry '} , ^{Ry "} , ^{Rz , Rz ' , Rz ' '} , ^{Ra ' , Rb ' or Rc ' .} Every other variation or combination of embodiments of ^{R y} ', R ^y ", R ^z , R ^z ', R ^z '', Ra ^' , R ^{b '} or R ^{c '} is as if each combination had been individually and specifically described.

As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. Methods for treating cancer

The compounds of formula (I) and their pharmaceutically acceptable salts and/or isotopologues (including the embodiments disclosed herein) can be used to treat cancer, including but not limited to various types of cancer, including, for example, lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. More specifically, the cancers that can be treated by the compounds of formula (I) and their pharmaceutically acceptable salts and/or isotopologues (including the embodiments disclosed herein) include but are not limited to the following cancers: such as polymorphic neuroblastoma, low-grade neuroglioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung cancer, adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic leukemia B cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, Uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In some embodiments, including any of the foregoing embodiments, the cancer is a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the individual is diagnosed with a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the individual is determined to be at risk for developing a KRAS G12C-mediated cancer.

In one aspect, provided is a compound of formula (I) as described in any of the Examples described herein or a pharmaceutical formulation as described in any of the Examples described herein for use as a medicament.

In one embodiment, a compound of formula (I) as described in any embodiment described herein or a pharmaceutical formulation as described in any embodiment described herein is provided for treating or inhibiting cancer. 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 lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. In one embodiment, the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, 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, colon adenocarcinoma , rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia Leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the individual is diagnosed with a 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 in a therapeutically effective amount.

In one embodiment, a compound of formula (I) as described in any embodiment described herein or a pharmaceutical formulation as described in any embodiment described herein is provided for use in the manufacture of a medicament for treating or inhibiting 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 lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. In one embodiment, the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, 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, colon adenocarcinoma , rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia Leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the individual is diagnosed with a 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.

In one embodiment, the use of a compound of formula (I) as described in any embodiment described herein or a pharmaceutical formulation as described in any embodiment described herein is provided for the manufacture of a medicament for treating or inhibiting 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 lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. In one embodiment, the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, 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, colon adenocarcinoma , rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia Leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the individual is diagnosed with a 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.

In one aspect, there is provided a use of a compound of formula (I) as described in any embodiment described herein or a pharmaceutical formulation as described in any embodiment described herein for treating or inhibiting 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 lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In one embodiment, the cancer is selected from the group consisting of multiforme neuroblastoma, low-grade neuroglioma, 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, colon adenocarcinoma , rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia Leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the individual is diagnosed with a 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 involves a therapeutically effective amount of a compound or composition.

In some embodiments, including any of the foregoing embodiments, the individual and/or the cancer is resistant or refractory to treatment with certain KRAS inhibitors (e.g., a G12C KRAS inhibitor).

The compounds of formula (I) and their pharmaceutically acceptable salts and/or isotopologues (including the embodiments disclosed herein) can be used in a method of inhibiting KRAS G12C in a cell by contacting a cell in need of inhibition of KRAS G12C activity with an amount of the compound effective to inhibit KRAS G12C activity. Inhibition can be partial or complete. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. Testing

The compounds of formula (I) and their pharmaceutically acceptable salts and/or isotopologues (including the embodiments disclosed herein) can be tested by, for example, the methods described in the Examples below or by known and generally accepted cell and/or animal models.

The ability of the compounds of Formula (I) and their pharmaceutically acceptable salts and/or isotopologues to inhibit the activity of the GTP-bound form of KRAS G12C can be tested using in vitro assays such as those described in Examples 69 and 70 below. Example 69 describes the determination of the half-maximal inhibition (IC ₅₀ ) of various compounds on the binding of KRAS G12C loaded with the GTP analog GMPPNP to cRaf as the Ras binding domain (RBD). Example 70 describes the determination of the half-maximal inhibition (IC ₅₀ ) of various compounds on the binding of KRAS G12C loaded with the GTP analog GMPPNP to PI3Kα as the Ras binding domain (RBD). Example 71 describes the ability of test compounds to inhibit cell viability in the MCF10A G12C/A59G mutant, which abolishes GTPase activity, thereby preventing the hydrolysis of GTP to GDP. Pharmaceutical Compositions

The terms pharmaceutical composition and pharmaceutical formulation are used interchangeably throughout.

In general, the compounds of formula (I) of the present disclosure and their pharmaceutically acceptable salts and/or isotopologues (also referred to herein as "compounds" or "compounds of the present disclosure") will be administered in a therapeutically effective amount by any of the modes of administration accepted for agents with similar utilities. The therapeutically effective amount of the compounds of the present disclosure may be in the range of about 0.01 to about 500 mg per kilogram of patient body weight per day, which may be administered in a single or multiple doses. In some embodiments, a suitable dosage level may be about 0.1 to about 250 mg/kg per day; or about 0.5 to about 100 mg/kg per day. A suitable dosage level may 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 may 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 compositions may be provided in the form of tablets containing about 1.0 to about 1000 mg of active ingredient, specifically about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of active ingredient. The actual amount of the compound (i.e., active ingredient) of the present disclosure will depend on many factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

In general, the compounds of the present disclosure will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred route of administration is oral with a convenient daily dosage regimen that can be adjusted according to the severity of the affliction. The composition may take the form of a tablet, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other appropriate composition.

The choice of 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, including enteric-coated or delayed-release tablets, pills, or capsules, are preferred) and the bioavailability of the drug substance.

The composition generally comprises a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. An acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic benefits of the compound of the present disclosure. Such excipients may be any solid, liquid, semisolid, or, in the case of aerosol compositions, gaseous excipients generally available to those skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skimmed milk powder and the like. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextrose solutions and glycols.

The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be in unit dose form, for example in ampoules or in multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents, such as suspending agents, stabilizers and/or dispersants. The formulations may be in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be in powder form or stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

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

In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., sparingly soluble salts.

For buccal or sublingual administration, the composition may take the form of tablets, troches, soft tablets or gels formulated in a known manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and gum arabic or tragacanth.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds of the present disclosure may be administered topically, that is, by non-systemic administration. This includes external application of the compound to the epidermis or buccal cavity and instillation of such compounds into the ears, eyes, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for percutaneous penetration into the inflamed area, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise 2% w/w to 5% w/w. In other embodiments, it may comprise 0.1% to 1% w/w of the formulation.

For administration by inhalation, the compounds may be conveniently delivered from an insufflator, nebulizer pressurized pack or other convenient means of delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the present disclosure may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dose form, for example, in capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhaler or insufflator. Other suitable pharmaceutical formulations and their formulations are described in Remington's Pharmaceutical Sciences, ed. E. W. Martin (Mack Publishing Company, 20th ed., 2000).

The level of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain about 0.01-99.99 wt % of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical formulations. For example, the compound is present at a level of about 1-80 wt %. Combinations and Combination Therapies

The compounds of the present disclosure may be used in combination with one or more other drugs to treat diseases or conditions for which the compounds of the present disclosure or other drugs may be effective. Such one or more other drugs may 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 may also include therapy in which the compounds of the present disclosure and one or more other drugs are administered at 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 other active ingredients may be used in lower doses than when each is used alone.

Therefore, 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.

The above combination includes not only the combination of the compound of the present disclosure with one other drug, but also the combination with two or more other active drugs. Similarly, the compound of the present disclosure can be used in combination with other drugs used to prevent, treat, control, improve the disease or illness for which the compound of the present disclosure can be used, or reduce the risk of such diseases or illnesses. Such other drugs can be administered simultaneously or sequentially with the compound of the present disclosure. When the compound of the present disclosure is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present disclosure can be used. Therefore, the pharmaceutical composition of the present disclosure also includes those containing one or more other active ingredients in addition to the compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient can vary and will depend on the effective dose of each component. In general, the therapeutically effective dose of each will be used.

Where a subject in need thereof suffers from or is at risk of developing cancer, the subject may be treated with a compound of the disclosure in any combination with one or more other anti-cancer agents.

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 use in the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-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), while 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 late-stage clinical trials. Another CDK 4/6 inhibitor that can be used in the methods herein is the CDK 2/4/6 inhibitor PF-06873600 (6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one).

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 use in the provided compositions and methods include, but are not limited to, encorafenib. (LGX818): (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonylamino)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'-oxolinyl-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridyl]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-oxolinylpyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide; L Y 3009120: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea; Lifirafenib (BGB-283); 5-(((1R,1aS,6bS)-1-(6-(trifluoro-methyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropen[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-dimethoxyquinazoline-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-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methylsulfonamide.

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 use in the provided compositions and methods include, but are not limited to, 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-oxolinylethoxy)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-morpholinylethoxy)phenyl)pyridin-2-yl)acetamide). In one embodiment, the Src inhibitor is dasatinib. In one embodiment, the Src inhibitor is sacatinib. 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.

In another embodiment, the compounds of the present disclosure are used in combination with a SHP-2 inhibitor, including but not limited to SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 (3(3S,4S)-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(2,3-dichlorophenyl)pyrazin-2-yl)methanol), RMC-4360 (Revolution Medicines), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

In another embodiment, the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for use in the provided compositions and methods include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (Deforolimus; MK-8669), sapanisertib (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 (INK128; 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine), (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)propionitrile; buparlisib (5-(2,6-dioxolin-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]oxoline); GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholinyl)-7-(oxacyclobutan-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-yl-purin-6-yl)pyrimidin-2-amine); and vistusertib (AZD-2014; 3-(2,4-bis((S)-3-methylmorpholinyl)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide).

In another embodiment, the compounds of the present disclosure are used in combination with a pan-ErbB family inhibitor. In one embodiment, KRAS and a 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 use in the provided compositions and methods include, but are not limited to, afatinib; dacomitinib; canertinib; poziotinib, AV 412 (N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazine-1-butyn-1-yl]-6-quinazolinyl]-2-acrylamide); PF 6274484 N-4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-acrylamide) and HKI 357 N-(2(E)-N-[[4-[[3-chloro-4-[(fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenamide). In another embodiment, the pan-ErbB family inhibitor is a reversible inhibitor. Examples of reversible pan-ErbB family inhibitors suitable for use in the provided compositions and methods include, but are not limited to, erlotinib, gefitinib, sapitinib; varlitinib; TAK-285 (N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutyramide); 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]aminocarbonyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propylene-1-amine bromide); BMS 599626 ((3S)-3-oxolinylmethyl[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[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).

In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of the following two: AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazoline-4-amine hydrochloride); AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-acrylamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-acrylamide; AG 825 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 (N ⁸ -(3-chloro-4-fluorophenyl)-N ² -(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-fluoroquinoline)ethyl]oxime hydrochloride); PD 153035 (4-(3-bromophenylamino)-6,7-dimethoxyquinazoline hydrochloride); and PD 158780 (N ⁴ -(3-bromophenyl)-N ⁶ -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine).

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 targeting 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 compositions and methods provided include necitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for the compositions and methods provided include pertuzumab, trastuzumab, and trastuzumab emtansine.

In some embodiments, the compounds of the disclosure are used in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors suitable for use with the provided compositions and methods include, but are not limited to, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors, such as Pembrolizumab (Keytruda®), Nivolumab (Opdivo®), Cemiplimab (Libtayo®), Atezolizumab (Tecentriq®), Avelumab (Bavencio®), Durvalumab (Imfinzi™), Ipilimumab (Yervoy®), Relatlimab, Opdualag, and Dostarlimab (Jemperli).

The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (e.g., radiation or surgical intervention) as preoperative or postoperative adjuvants .

The following examples represent some aspects of the present invention. Group A.

Example 1. A compound of formula (I'), Formula (I') or a salt thereof; and/or an isotopologue thereof; wherein: ^R1 is a 4-8 membered saturated carbocyclic group or heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the carbocyclic group or the heterocyclic group is substituted by 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, _C1 - _C4 alkyl, spiro _C3 - _C4 cycloalkyl, _C1 - _C4 alkoxy, _C1 - _C4 haloalkyl and _C1 - _C4 haloalkoxy; ^R3 is selected from hydrogen, halogen, _C1 - _C4 alkyl, _C3 - _C4 cycloalkyl, _C1 - _C4 alkoxy, _C1 - _C4 haloalkyl, _C1 - _C4 haloalkoxy and _C2 -C R ₄ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogenalkyl ^, C ₁ -C ₄ halogenalkoxy and C ₂ -C ₃ alkynyl; and q is 0 or 1; provided that when q is 0, R ¹ is not , , , , , or any mirror image isomer thereof.

Example 2. The compound of Example 1, wherein the compound has formula (IA) or formula (IB) Formula (IA) Formula (IB); or a salt thereof; and/or an isotopologue thereof.

Embodiment 3. The compound of Embodiment 2, wherein the compound has formula (IA).

Embodiment 4. The compound of Embodiment 2, wherein the compound has formula (1B).

Embodiment 5. The compound of Embodiment 1, wherein the compound has Formula (Ia), Formula (Ib) or Formula (Ic): Formula (Ia) Formula (Ib) Formula (Ic) or a salt thereof; and/or an isotopologue thereof.

Embodiment 6. The compound of Embodiment 5, wherein the compound has formula (I-a).

Embodiment 7. The compound of Embodiment 5, wherein the compound has formula (I-b).

Embodiment 8. The compound of Embodiment 5, wherein the compound has formula (I-c).

Embodiment 9. The compound of Embodiment 1, wherein the compound has Formula (Ia-1) or Formula (Ia-2): Formula (Ia-1) Formula (Ia-2) or a salt thereof; and/or an isotope thereof.

Example 10. A compound as in Example 9, wherein the compound has formula (I-a-1).

Example 11. A compound as in Example 9, wherein the compound has formula (I-a-2).

Example 12. The compound of Example 1, wherein the compound has Formula (IA-a) or Formula (IB-a): Formula (IA-a) Formula (IB-a) or a salt thereof; and/or an isotopologue thereof.

Example 13. A compound as in Example 12, wherein the compound has formula (IA-a).

Example 14. A compound as in Example 12, wherein the compound has formula (IB-a).

Embodiment 15. The compound of Embodiment 1, wherein the compound has Formula (IA-a-1), Formula (IA-a-2), Formula (IB-a-1) or Formula (IB-a-2): Formula (IA-a-1) Formula (IA-a-2) Formula (IB-a-1) Formula (IB-a-2) or a salt thereof; and/or an isotopologue thereof.

Example 16. The compound of Example 15, wherein the compound has formula (IA-a-1).

Example 17. A compound as in Example 15, wherein the compound has formula (IA-a-2).

Example 18. A compound as in Example 15, wherein the compound has formula (IB-a-1).

Example 19. A compound as in Example 15, wherein the compound has formula (IB-a-2).

Embodiment 20. The compound of Embodiment 1, wherein the compound has Formula (Ib-1) or Formula (Ib-2): Formula (Ib-1) Formula (Ib-2) or a salt thereof; and/or an isotope thereof.

Example 21. A compound as in Example 20, wherein the compound has formula (I-b-1).

Example 22. A compound as in Example 20, wherein the compound has formula (I-b-2).

Embodiment 23. The compound of Embodiment 1, wherein the compound has Formula (IA-b) or Formula (IB-b): Formula (IA-b) Formula (IB-b) or a salt thereof; and/or an isotopologue thereof.

Example 24. A compound as in Example 23, wherein the compound has formula (IA-b).

Example 25. A compound as in Example 23, wherein the compound has formula (IB-b).

Embodiment 26. The compound of Embodiment 1, wherein the compound has Formula (IA-b-1), Formula (IA-b-2), Formula (IB-b-1) or Formula (IB-b-2): Formula (IA-b-1) Formula (IA-b-2) Formula (IB-b-1) Formula (IB-b-2) or a salt thereof; and/or an isotopologue thereof.

Example 27. A compound as in Example 26, wherein the compound has formula (IA-b-1).

Example 28. A compound as in Example 26, wherein the compound has formula (IA-b-2).

Example 29. A compound as in Example 26, wherein the compound has formula (IB-b-1).

Example 30. A compound as in Example 26, wherein the compound has formula (IB-b-2).

Embodiment 31. The compound of Embodiment 1, wherein the compound has formula (Ic-1) or formula (Ic-2): Formula (Ic-1) Formula (Ic-2) or a salt thereof; and/or an isotope thereof.

Example 32. A compound as in Example 31, wherein the compound has formula (I-c-1).

Example 33. A compound as in Example 31, wherein the compound has formula (I-c-2).

Embodiment 34. The compound of Embodiment 1, wherein the compound has Formula (IA-c) or Formula (IB-c): Formula (IA-c) Formula (IB-c) or a salt thereof; and/or an isotopologue thereof.

Example 35. A compound as in Example 34, wherein the compound has formula (IA-c).

Example 36. A compound as in Example 34, wherein the compound has formula (IB-c).

Embodiment 37. The compound of Embodiment 1, wherein the compound has Formula (IA-c-1), Formula (IA-c-2), Formula (IB-c-1) or Formula (IB-c-2): Formula (IA-c-1) Formula (IA-c-2) Formula (IB-c-1) Formula (IB-c-2) or a salt thereof; and/or an isotopologue thereof.

Example 38. A compound as in Example 37, wherein the compound has formula (IA-c-1).

Example 39. A compound as in Example 37, wherein the compound has formula (IA-c-2).

Example 40. A compound as in Example 37, wherein the compound has formula (IB-c-1).

Example 41. A compound as in Example 37, wherein the compound has formula (IB-c-2).

Embodiment 42. The compound of Embodiment 1, wherein the compound has formula (Id). Formula (Id) or a salt thereof; and/or an isotopologue thereof.

Embodiment 43. The compound of Embodiment 1, wherein the compound has Formula (IA-d) or Formula (IB-d): Formula (IA-d) Formula (IB-d) or a salt thereof; and/or an isotopologue thereof.

Example 44. A compound as in Example 43, wherein the compound has formula (IA-d).

Example 45. A compound as in Example 43, wherein the compound has formula (IA-d).

Embodiment 46. The compound according to any one of embodiments 1 to 45, wherein R ³ is selected from halogen, C ₁ -C ₄ alkyl and C ₂ -C ₃ alkynyl.

Embodiment 47. The compound according to any one of embodiments 1 to 45, wherein R ³ is selected from halogen and C ₁ -C ₄ alkyl.

Embodiment 48. The compound according to any one of embodiments 1 to 45, wherein R ³ is selected from halogen and C ₂ -C ₃ alkynyl.

Embodiment 49. The compound according to any one of Embodiments 1 to 45, wherein R ³ is halogen.

Embodiment 50. The compound according to any one of embodiments 1 to 45, wherein R ³ is selected from -F, -Cl, -Et and -C≡CH.

Embodiment 51. The compound of any one of Embodiments 1 to 45, wherein R ³ is selected from -F, -Cl and -Et.

Embodiment 52. The compound according to any one of embodiments 1 to 45, wherein R ³ is selected from -F, -Cl and -C≡CH.

Embodiment 53. The compound according to any one of Embodiments 1 to 45, wherein R ³ is selected from -F and -Cl.

Embodiment 54. The compound according to any one of Embodiments 1 to 45, wherein R ³ is -F.

Embodiment 55. The compound according to any one of Embodiments 1 to 45, wherein R ³ is -Cl.

Embodiment 56. The compound according to any one of Embodiments 1 to 45, wherein R ³ is -Et.

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

Embodiment 58. The compound according to any one of embodiments 1 to 57, wherein R ⁴ is selected from hydrogen and halogen.

Embodiment 59. The compound according to any one of Embodiments 1 to 57, wherein R ⁴ is selected from -H and -F.

Embodiment 60. The compound according to any one of Embodiments 1 to 57, wherein R ⁴ is -H.

Embodiment 61. The compound according to any one of Embodiments 1 to 57, wherein R ⁴ is -F.

Embodiment 62. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is a 4-8 membered saturated bicyclic carbocyclic group or a bicyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atoms, wherein the carbocyclic group or the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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.

Embodiment 63. The compound of any one of embodiments 1 to 41 and 46 to 61, wherein R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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.

Embodiment 64. The compound of any one of embodiments 1 to 41 and 46 to 61, wherein R ¹ is a 4-8 membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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.

Embodiment 65. The compound of any one of embodiments 1 to 41 and 46 to 61, wherein R ¹ is a 4-8 membered saturated bicyclic heterocyclic group containing one nitrogen as the only heteroatom within the ring atom, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxyl, 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.

Embodiment 66. The compound according to any one of embodiments 62 to 65, wherein the carbocyclyl or the heterocyclyl of R ¹ is unsubstituted or substituted with a substituent selected from halogen, hydroxyl or spiro C ₃ -C ₄ cycloalkyl.

Embodiment 67. The compound according to any one of embodiments 62 to 65, wherein the carbocyclyl or the heterocyclyl of R ¹ is unsubstituted or substituted with one fluoro or spiro C ₃ -C ₄ cycloalkyl.

Embodiment 68A. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is selected from the group consisting of: , or , wherein R ^d is H or F.

Embodiment 68B. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is , , , , , , , , , , , , , , , , , , or .

Example 68C. The compound of any one of Examples 1 to 41 and 46 to 61, wherein R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

Embodiment 69. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is or , where R ^d is H or F.

Embodiment 70. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is , wherein R ^d is H or F.

Embodiment 71. The compound according to any one of embodiments 68 to 70, wherein ^Rd is H.

Embodiment 72. The compound according to any one of Embodiments 68 to 70, wherein ^Rd is F.

Embodiment 73. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is selected from and .

Embodiment 74. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is .

Embodiment 75. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is .

Embodiment 76. The compound of any one of Embodiments 1 to 61, wherein R ¹ is .

Embodiment 77. The compound of any one of Embodiments 1 to 41 and 46 to 61, wherein R ¹ is selected from , and Group of people.

Embodiment 78. The compound of any one of Embodiments 1 to 61, wherein R ¹ is .

Embodiment 79. The compound of any one of Embodiments 1 to 78, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , and or its salts; and/or its isotopologues.

Embodiment 80. A compound as in any one of Embodiments 1 to 79, wherein the compound is not a salt.

Embodiment 81. A compound as in any one of Embodiments 1 to 79, wherein the compound is a salt.

Example 82. A compound as in Example 81, wherein the salt is a formate salt.

Example 83. A compound as in Example 81, wherein the salt is trifluoroacetic acid salt.

Example 84. The compound of Example 81, wherein the salt is a pharmaceutically acceptable salt.

Embodiment 85. A pharmaceutical formulation comprising a compound as described in any one of Embodiments 1 to 84 and a pharmaceutically acceptable carrier, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

Embodiment 86. A method for treating or inhibiting cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1 to 84 or a pharmaceutical formulation of Embodiment 85, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

Embodiment 88. The method of embodiment 86, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative 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, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia Leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, Uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

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

Embodiment 90. The method of any one of Embodiments 86 to 88, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

Embodiment 91.      The method of any one of Embodiments 86 to 88, wherein the method further comprises administering to the individual a therapeutically effective amount of an additional chemotherapeutic agent.

Example 92. A compound as in any one of Examples 1 to 84 or a pharmaceutical formulation as in Example 77 for use as a medicament.

Embodiment 93. A compound as in any one of Embodiments 1 to 84 or a pharmaceutical formulation as in Embodiment 77, which is used to treat or inhibit cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

Embodiment 94. A compound or pharmaceutical formulation for use as in Embodiment 93, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

Embodiment 95. A compound or pharmaceutical formulation for use as in Embodiment 93, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal carcinoma, Cancer of the intestine, stomach, small intestine, colon, rectum, hepatocellular carcinoma, bile duct, gallbladder, pancreatic, kidney, clear cell, bladder, prostate, ovarian, uterine, endometrial, cervical squamous, and cervical glands, skin, melanoma, acute lymphoblastic leukemia disease, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, breast Adenoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

Embodiment 96. A compound or pharmaceutical formulation for use as in any one of Embodiments 93 to 95, wherein the cancer is a KRAS G12C-mediated cancer.

Embodiment 97. A compound or pharmaceutical formulation for use as in any one of Embodiments 93 to 95, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

Embodiment 98. A compound or pharmaceutical formulation for use as in any one of Embodiments 93 to 97, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

Embodiment 99. A compound or pharmaceutical formulation for use as in any one of Embodiments 93 to 98, wherein the compound or the pharmaceutical formulation is configured for administration in a therapeutically effective amount.

Embodiment 100. A compound as in any one of Embodiments 1 to 84 or a pharmaceutical formulation as in Embodiment 77, which is used for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

Embodiment 102. A compound or pharmaceutical formulation for use according to embodiment 100, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, food poisoning Cancer of the intestine, stomach, small intestine, colon, rectum, hepatocellular carcinoma, bile duct, gallbladder, pancreatic, kidney, clear cell, bladder, prostate, ovarian, uterine, endometrial, cervical squamous, and cervical glands, skin, melanoma, acute lymphoblastic leukemia disease, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, breast Adenoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

Embodiment 103. A compound or pharmaceutical formulation for use as in any one of Embodiments 100 to 102, wherein the cancer is a KRAS G12C-mediated cancer.

Embodiment 104. A compound or pharmaceutical formulation for use according to any one of Embodiments 100 to 102, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

Embodiment 105. A compound or pharmaceutical formulation for use as in any one of Embodiments 100 to 104, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

Embodiment 106. A compound or pharmaceutical formulation for use as in any one of Embodiments 100 to 105, wherein the medicament comprises a therapeutically effective amount of the compound or the composition.

Embodiment 107. A use of a compound as in any one of Embodiments 1 to 84 or a pharmaceutical formulation as in Embodiment 77 for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

Embodiment 109. The use of embodiment 107, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small Colon cancer, colon cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic leukemia, acute bone marrow cancer Myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma , uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

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

Embodiment 111. The use of any one of Embodiments 107 to 109, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

Embodiment 112. The use of any one of Embodiments 107 to 111, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

Embodiment 113. The use of any one of Embodiments 107 to 112, wherein the medicament comprises a therapeutically effective amount of the compound or the pharmaceutical formulation.

Embodiment 114. A use of a compound as in any one of Embodiments 1 to 84 or a pharmaceutical formulation as in Embodiment 77 for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

Embodiment 116. The use of embodiment 114, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small Colon cancer, colon cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic leukemia, acute bone marrow cancer Myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma , uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

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

Embodiment 118. The use of any one of Embodiments 114 to 116, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

Embodiment 119. The use of any one of Embodiments 114 to 118, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

Embodiment 120. The use of any one of embodiments 114 to 119, wherein the use involves a therapeutically effective amount of the compound or the composition. Group B.

1. A compound of formula (I''): Formula (I''), or a salt thereof and/or an isotopologue thereof; wherein: X is -N(CH ₃ )- or -O-; X ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ or cyclopropyl, each of which is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, -OH and -OCH ₃ ; q is 0 or 1; R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the heterocyclic group is substituted by 0, 1, 2 or 3 R ^1A ; R ^1A is independently selected from halogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogenalkyl, C ₁ -C _4- halogen alkoxy and -C(O)(C ₁ -C ₄ alkyl); or two zygote R ^1A together with the carbon atom to which they are attached form a C ₃ -C ₄ cycloalkyl substituted with 0, 1 or 2 halogen groups; or two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ ; ^Ra is H or CH ₃ ; R ² is or ; R ³ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁴ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁵ is H or -OH; Y is CH or N; R ⁶ is independently selected from the group consisting of halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogen, C ₃ -C ₄ cycloalkyl and -NH ₂ ; and r is 0, 1, 2 or 3; provided that when q is 0, then R ¹ is not , , , , , or any mirror image thereof; when for or any mirror image isomer thereof, then R ² is not ; and when for or any mirror image isomer thereof, then R ² is not or .

2. The compound or its salt and/or its isotope according to Example 1, wherein R ² is .

3. The compound or its salt and/or its isotopologue according to Example 2, wherein R ³ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₂ -C ₃ alkynyl.

4. The compound or its salt and/or its isotopologue according to Example 2, wherein R ³ is selected from the group consisting of -F, -Cl, -Et, -C≡CH and -C≡C-CH ₃ .

5. The compound according to any one of Embodiments 2 to 4, or a salt thereof and/or an isotopologue thereof, wherein R ⁴ is hydrogen or a halogen group.

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

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

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

9. The compound or its salt and/or its isotope according to Example 2, wherein R ² is , , , , , or .

10. The compound or its salt and/or its isotope according to Example 1, wherein R ² is .

11.    The compound or its salt and/or its isotope according to Example 10, wherein Y is CH.

12.    The compound or its salt and/or its isotope according to Example 10, wherein Y is N.

13. The compound according to any one of embodiments 10 to 12, or a salt thereof and/or an isotopologue thereof, wherein R ⁶ in each instance is independently selected from the group consisting of -Cl, -OH, -CH ₃ , -CF ₃ , cyclopropyl and -NH ₂ .

14.    A compound or a salt thereof and/or an isotope thereof according to any one of Examples 10 to 13, wherein r is 3.

15. The compound according to any one of Examples 10 to 13, or a salt thereof and/or an isotope thereof, wherein R ² is .

16. The compound according to any one of Examples 10 to 13, or a salt thereof and/or an isotope thereof, wherein R ² is , wherein R ^6A is cyclopropyl or -CF ₃ ; R ^6B is -Cl or -CH ₃ ; and R ^6C is -OH or -NH ₂ .

17. The compound or its salt and/or its isotope according to Example 10, wherein R ² is , or .

18. The compound according to any one of Embodiments 1 to 17, or a salt thereof and/or an isotopologue thereof, wherein X is -N(CH ₃ )-.

19.    A compound or a salt thereof and/or an isotope thereof according to any one of Examples 1 to 17, wherein X is -O-.

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

20. The compound according to any one of Examples 1 to 19, or a salt thereof, and/or an isotopologue thereof, wherein X ¹ is -CH ₃ , -CH ₂ F, -CH ₂ OCH ₃ , -CH ₂ CH ₃ , -CH(OH)CH ₃ , -CH=CH ₂ or cyclopropyl.

22. The compound or salt thereof and/or isotopologue according to any one of Examples 1 to 17, wherein the Part of , , , , , , , , , or .

23. The compound or salt thereof and/or isotopologue according to any one of Examples 1 to 17, wherein Part of , , , , , , , , , , , , , , , , , , , , or .

24. The compound or salt thereof and/or isotopologue according to any one of Examples 1 to 23, wherein R ¹ is substituted with 0, 1, 2 or 3 R ^1A or .

25. The compound or salt thereof and/or isotopologue according to any one of Embodiments 1 to 24, wherein R ^1A is independently -F, -OH, -CH ₃ , -OCH ₃ , -OCF ₃ , -OCHF ₂ or -C(O)CH ₃ in each case; or two zygote R ^1A together with the carbon atom to which they are attached form a cyclopropyl substituted with 0, 1 or 2 fluorine atoms; or two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ .

26. The compound according to any one of Examples 1 to 25, or a salt thereof and/or an isotope thereof, wherein R ¹ is , , , , , , , , , , , , , , , , , , or .

27. The compound according to any one of Examples 1 to 25, or a salt thereof and/or an isotope thereof, wherein R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

28. The compound according to any one of embodiments 1 to 27, wherein ^Ra is H.

29. The compound according to any one of embodiments 1 to 27, wherein ^Ra is _CH3 .

30.    A compound or a salt thereof and/or an isotopomer thereof as in Example 1, wherein the compound is selected from the group consisting of compounds in Table 1.

31.    A compound or a salt and/or an isotopologue according to any one of Examples 1 to 30, wherein the salt is a pharmaceutically acceptable salt.

32. A pharmaceutical formulation comprising a compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopomer thereof and a pharmaceutically acceptable carrier.

33. A method for treating or inhibiting cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotope thereof or a pharmaceutical formulation of Example 32.

34. The method of embodiment 33, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

35. The method of embodiment 33, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative 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, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia Leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, Uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

36.    The method of any one of Examples 33 to 35, wherein the cancer is a KRAS G12C-mediated cancer.

37. The method of any one of Examples 33 to 35, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

38.    The method of any one of Examples 33 to 35, wherein the method further comprises administering to the individual a therapeutically effective amount of an additional chemotherapeutic agent.

39.    A compound as described in any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation as described in Example 32, for use as a medicament.

40.    A compound as described in any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation as described in Example 32, which is used to treat or inhibit cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

41.    A compound for use as described in Example 40 or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

42.    The compound for use according to Example 40 or its pharmaceutically acceptable salt and/or its isotopomer or pharmaceutical formulation, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, Squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute Lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

43. A compound for use according to any one of Examples 38 to 40, or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the cancer is a KRAS G12C-mediated cancer.

44. A compound for use according to any one of Examples 40 to 42, or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

45.    A compound for use according to any one of Examples 40 to 44, or a pharmaceutically acceptable salt thereof and/or an isotopomer thereof, or a pharmaceutical formulation thereof, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

46. A compound for use according to any one of Examples 40 to 45, or a pharmaceutically acceptable salt thereof and/or an isotopomer thereof or a pharmaceutical formulation, wherein the compound or the pharmaceutical formulation is configured for administration in a therapeutically effective amount.

47.    A compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation according to Example 30, which is used for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

48.    A compound for use as described in Example 47 or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

49.    The compound for use according to Example 47 or its pharmaceutically acceptable salt and/or its isotopomer or pharmaceutical formulation, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, Squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute Lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

50. A compound for use according to any one of Examples 47 to 49, or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the cancer is a KRAS G12C-mediated cancer.

51. A compound for use according to any one of Examples 47 to 49, or a pharmaceutically acceptable salt thereof and/or an isotopomer or a pharmaceutical formulation thereof, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

52. A compound for use according to any one of Examples 47 to 51, or a pharmaceutically acceptable salt thereof and/or an isotopomer thereof, or a pharmaceutical formulation thereof, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

53. A compound for use according to any one of Examples 47 to 52, or a pharmaceutically acceptable salt and/or an isotopomer or a pharmaceutical formulation thereof, wherein the medicament comprises a therapeutically effective amount of the compound or the composition.

54. A use of a compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation according to Example 32 for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

56. The use of embodiment 54, wherein the cancer is selected from the group consisting of: multiforme neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative 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, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia Leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, Uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

57.    The use of any one of embodiments 54 to 56, wherein the cancer is a KRAS G12C-mediated cancer.

58. The use of any one of embodiments 54 to 56, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

59. The use of any one of embodiments 54 to 58, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

60.    The use of any one of embodiments 54 to 59, wherein the medicament comprises a therapeutically effective amount of the compound or the pharmaceutical formulation.

61. A use of a compound as described in any one of Examples 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation as described in Example 30 for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

62.    The use of embodiment 61, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

63. The use of Example 61, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative 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, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical gland carcinoma, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia Leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, Uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma and melanoma.

64.    The use of any one of embodiments 61 to 63, wherein the cancer is a KRAS G12C-mediated cancer.

65.    The use of any one of Examples 61 to 63, wherein the individual is diagnosed with KRAS G12C-mediated cancer.

66. The use of any one of embodiments 61 to 65, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent.

67. The use according to any one of embodiments 61 to 66, wherein the use involves a therapeutically effective amount of the compound or the composition. General Synthesis Methods

The compounds in Table 1 of the present disclosure are or can be prepared according to the methods described in the Examples section or variations thereof, which variations will be within the knowledge of those skilled in the art.

Starting materials and reagents used to prepare these compounds can be obtained from commercial suppliers (such as MilliporeSigma., Bachem., etc.), or prepared by methods known to those skilled in the art following the procedures described in the following references: 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 Supplements (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). These schemes illustrate only some of the methods by which the compounds of the present disclosure may be synthesized, and various modifications to these schemes may be made and will occur to those skilled in the art who read this disclosure. If necessary, the starting materials and intermediates and final products of the reactions may be isolated and purified using known techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using known means, including physical constants and spectral data.

Unless otherwise indicated, the reactions described herein are conducted at atmospheric pressure at a temperature range of about -78°C to about 150°C, such as about 0°C to about 125°C and further such as at about room temperature (or ambient temperature), e.g., about 20°C.

In some embodiments, the compounds provided herein can be synthesized according to Method 1. Method 1 . , wherein X', q, R ¹ and R ³ are as defined for Formula (I) or any variation thereof as described in detail herein.

An exemplary embodiment of method 1 is shown in method 1a. Method 1a. , wherein X', q, R ¹ and R ³ are as defined for Formula (I) or any variation thereof as described in detail herein.

An exemplary embodiment of Method 1 is further shown in the following steps. Step 1: 3-(Benzyl(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester

To a solution of tert-butyl 3-amino-(X') _q -pyrrolidine-1-carboxylate (1.0 equiv) in methanol [0.5 M], sodium cyanoborohydride (2.0 equiv), acetic acid (1.0 equiv) and benzaldehyde (1.1 equiv) were added at 0°C for 1 hour. Then, formaldehyde (3.0 equiv) was added to the mixture and the reaction was stirred at 0°C for 2 hours. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography to give tert-butyl 3-[benzyl(methyl)amino]-(X') _q -pyrrolidine-1-carboxylate. Step 2: (X') _q -3-(Methylamino)pyrrolidine-1-carboxylic acid tributyl ester

To a solution of palladium on carbon in methanol [0.16 M] was added cis-3-[benzyl(methyl)amino]-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester (1.0 equivalent), and the mixture was stirred under hydrogen atmosphere at 40° C. for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated to dryness in vacuo to give (X') _q -3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester. Step 3 : 3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-(X') _q - pyrrolidine -1- carboxylic acid tributyl ester

To a solution of (X') _q -3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester (1.0 equiv) and 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.18 equiv) in 1,4-dioxane [0.24 M] was added N , N -diisopropylethylamine (3.0 equiv) and the mixture was stirred at 0°C for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester. Step 4 : 3-((7- chloro -8- fluoro -2-((R ¹ -methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-(X ') _q -pyrrolidine -1- carboxylic acid tributyl ester

To a solution of R ¹ -methanol (1.5 eq.) and 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid (1.0 eq.) in dioxane [0.14 M] was added N , N -diisopropylethylamine (3.1 eq.), and the mixture was stirred at 80° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to obtain tert-butyl 3-((7-chloro-8-fluoro-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X′) _q -pyrrolidine-1-carboxylate. Step 5 : 3-((8- fluoro -7-(7-R ³ -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-((R ¹ -methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-(X') _q - pyrrolidine -1- carboxylic acid tributyl ester

To a mixture of ((7-R ³ -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv.) and 3-((7-chloro-8-fluoro-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester (1.0 equiv.) in 1,4-dioxane/water [2:1 v/v, 0.1 To the solution in 4% 4-nitropropene was added potassium phosphate (3.0 equivalents) and palladium (II) chloride (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] (0.2 equivalents), and the mixture was stirred at 80° C. for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 3-((8-fluoro-7-(7-R ³ -8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -Pyrrolidine-1-carboxylic acid tributyl ester. Step 6 : 3-((7-(8- ethynyl -7-R ³ -naphthyl ) -8 - fluoro -2-((R ¹ -methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-(X') _q -pyrrolidine -1- carboxylic acid tributyl ester

To a solution of 3-((8-fluoro-7-(7-R ³ -8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester (1.0 equiv) in N , N -dimethylformamide [0.07 M] was added cesium fluoride (10.0 equiv) and the mixture was stirred at 20° C. for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 3-((7-(8-ethynyl-7-R ³ -naphthyl)-8-fluoro-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylic acid tributyl ester. Step 7 : 7-(8- ethynyl- 7-R ³ -naphthyl -1- yl )-8- fluoro -2-((R ¹ -methoxy )-N- methyl -N-(X') _q -pyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

To a solution of tributyl 3-((7-(8-ethynyl-7-R ³ -naphthol-1-yl)-8-fluoro-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') _q -pyrrolidine-1-carboxylate (1.0 equiv) in dichloromethane [0.063 M] was added trifluoroacetic acid (3.0 equiv) and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated to dryness in vacuo to give 7-(8-ethynyl-7-R ³ -naphthol-1-yl)-8-fluoro-2-((R ¹ -methoxy)-N-methyl-N-(X') _q -pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine as the trifluoroacetate salt. Step 8 : ((7-(8- ethynyl -7-R ³ -naphth -1- yl )-8 -fluoro -2-((R ¹ -methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-(X′) _q -pyrrolidin -1- yl ) prop -2- en -1 -one

To a solution of 7-(8-ethynyl-7-R ³ -naphth-1-yl)-8-fluoro-2-((R ¹ -methoxy)-N-methyl-N-(X′) _q -pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (trifluoroacetate) (1.0 equiv.) in a mixture of tetrahydrofuran and water [3:1 v/v, 0.07 M] were added sodium bicarbonate (3.0 equiv.), prop-2-enoyl chloride (0.9 equiv.), and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was then concentrated to dryness in vacuo and purified by reverse phase HPLC to give ((7-(8-ethynyl-7-R ³ -naphth-1-yl)-8-fluoro-2-((R ¹ -methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X′) _q -pyrrolidin-1-yl)prop-2-en-1-one. Example

The following preparations of the compound of formula (I) and its pharmaceutically acceptable salt are given to enable those skilled in the art to more clearly understand and practice the present disclosure. Such preparations should not be considered to limit the scope of the present disclosure, but are merely illustrative and representative thereof.

The following abbreviations are used in this section: Boc Tertiary Butoxycarbonyl PMB p-Methoxybenzyl ACN Acetonitrile TFA Trifluoroacetic acid FA Formic acid mmol Millimole g Grams mg mg h Hours mL ml NMR Nuclear Magnetic Resonance MHz Million Hertz Hz Hertz LCMS LC-MS R Detention time m/z Mass/charge min minute um Micrometer mm Millimeters M Mohr concentration mM Millimolar concentration umol Micromolar HPLC HPLC BEH Ethylene bridged hybrid ESI Electrospray ionization Bn Benzyl OBD Optimum bed density TIPS Triisopropylsilane Å Egypt SFC Supercritical fluid stratification Psi Pounds per square inch MOM Methoxymethyl THF Tetrahydrofuran DMF N,N -Dimethylformamide DCM Dichloromethane EtOAc Ethyl acetate TIC Total Ion Chromatography UV Ultraviolet FCC Rapid Column Analysis DIBAL Diisobutyl Aluminum Hydrogenate TBDPS Tertiary butyl diphenylsilyl

Unless otherwise stated, all reagents were obtained from commercial suppliers and used without further purification . Example 1-1 : Synthesis of Compound 1-1 ; cis -1-(-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 1) Step 1: cis-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester

To a solution of cis-3-amino-2-methyl-pyrrolidine-1-carboxylic acid tributyl ester (1 g, 4.99 mmol) in methanol (10 mL) were added sodium cyanoborohydride (627.55 mg, 9.99 mmol), acetic acid (299.84 mg, 4.99 mmol) and benzaldehyde (582.86 mg, 5.49 mmol) at 0°C for 1 hour, then formaldehyde (1.22 g, 14.98 mmol) was added to the mixture and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate/petroleum ether) to give cis-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (1 g, crude) as a colorless oil, which was used in the next step without any further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.32 - 7.28 (m, 1H), 7.27 - 7.24 (m, 3H), 7.20 - 7.16 (m, 1H), 4.08(s, 1H), 3.99 (br s, 1H), 3.63 - 3.50 (m, 1H), 3.47 - 3.31 (m, 1H), 3.29 - 3.16 (m, 1H), 2.77 - 2.59 (m, 1H), 2.03 -1.99 (m, 3H), 1.97 (s, 1H), 1.88 - 1.74 (m, 1H), 1.40 (d, J = 2.0 Hz, 9H), 1.14 - 1.06 (m, 3H). LCMS Rt = 0.338 min, m/z = 304.2 [M + H] ⁺ . Step 2: cis-2-methyl-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

To a solution of palladium on carbon (200 mg, purity 10%) in methanol (10 mL) was added cis-3-[benzyl(methyl)amino]-2-methyl-pyrrolidine-1-carboxylic acid tributyl ester (500 mg, 1.6 mmol), and the mixture was stirred at 40° C. under hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give tri-butyl cis-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (300 mg, crude) as a colorless oil, which was used in the next step without any further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.02 - 3.76 (m, 1H), 3.25 - 2.98 (m, 2H), 2.90 - 2.72 (m, 1H), 2.34 (s, 3H), 1.79 (br s, 2H), 1.36 (s, 9H), 1.02 - 0.88 (m, 3H). LCMS Rt = 0.295 min, m/z = 214.2 [M + H] ⁺ . Step 3: cis-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester

To a solution of cis-2-methyl-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester (252.54 mg, 1.18 mmol) and 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (350 mg, 1.39 mmol) in dioxane (5 mL) was added N,N-diisopropylethylamine (537.53 mg, 4.16 mmol) and the mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 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, 65-70% ethyl acetate/petroleum ether) to give cis-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (350 mg, 58.67%) as a yellow solid. LCMS Rt = 0.651 min, m/z = 429.1 [M + H] ⁺ . Step 4 : cis -3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (66.60 mg, 418.31 μmol) and cis-3-[(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-methyl-amino]-2-methyl-pyrrolidine-1-carboxylic acid tributyl ester (120 mg, 278.87 μmol) in dioxane (2 mL) was added N,N-diisopropylethylamine (108.13 mg, 836.62 μmol) and the mixture was stirred at 80 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 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, 80-100% ethyl acetate/petroleum ether) to give cis-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (150 mg, 97.26%) as a yellow solid. LCMS Rt = 1.491 min, m/z = 552.2 [M + H] ⁺ . Step 5 : cis -3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (306.81 mg, 678.07 μmol) and cis-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (150 mg, 271.23 μmol) in dioxane (2 mL) and water (1 mL) was added potassium phosphate (172.72 mg, 813.68 μmol). μmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42.68 mg, 54.25 μmol) were added and the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 85-100% ethyl acetate/petroleum ether) to give cis-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (180 mg, crude) as a yellow solid, which was used in the next step without any further purification. LCMS Rt = 0.624 min, m/z = 842.5 [M + H] ⁺ . Step 6 : cis -3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1-carboxylic acid tributyl ester

To a solution of cis-tributyl 3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (180 mg, 213.50 μmol) in N,N-dimethylformamide (3 mL) was added cesium fluoride (324.31 mg, 2.13 mmol) and the mixture was stirred at 20 °C for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 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, 10-25% methanol/dichloromethane) to give cis-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (130 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.478 min, m/z = 686.3 [M + H] ⁺ . Step 7 : cis -7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-( cis -2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

To a solution of tributyl cis-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (65 mg, 94.65 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (32.38 mg, 283.94 μmol), and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness in vacuo to give cis-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (65 mg, crude, trifluoroacetic acid salt) as a brown oil, which was used in the next step without any further purification. LCMS Rt = 0.365 min, m/z = 586.3 [M + H] ⁺ . Step 8 : cis -1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H - pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en -1- one

To a solution of cis-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (65 mg, 92.77 μmol, trifluoroacetate) in tetrahydrofuran (1 mL) and water (0.3 mL) were added sodium bicarbonate (23.38 mg, 278.30 μmol) and prop-2-enoyl chloride (7.56 mg, 83.49 μmol), and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give cis-1-((2RS,3RS)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (10.11 g) as a yellow solid. mg, 15.63%): 1H NMR (400 MHz, chloroform-d) δ 9.18 (br s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 3H). δ 5.14 - 5.12 (m, 1H), 2.62 - 2.71 (m, 1H), 2.47 - 2.69 (m, 2H), 2.11 - 2.80 (m, 3H), 1.54 - 1.63 (m, 3H). LCMS Rt = 2.226 min, m/z = 641.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.226 min, ESI+ found [M+H] ⁺ = 641.3. Examples 1-2 and 1-3 : Isolation of Compounds 1-2 and 1-3 ; 1-((2S,3S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one and 1-((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin-7a(5H)-yl ) methoxy ) pyrido[4,3-d] pyrimidin - 4 - yl ) ( methyl ) amino ) -2 - methylpyrrolidin - 1 - yl ) prop- 2-en-1-one 3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en -1- one ( SFC separation from Example 1-1 )

1-(cis-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro- ₂ -(((2R, _7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (100 mg) was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 4 OH)]; B%: 50%, isocratic elution mode) to give the following substances as arbitrarily designated: Example 1-2: 1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 1.467 minutes) (33.02 mg): ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 9.21 - 9.16 (m, 1H), 8.02 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.31 (m, 1H), 6.57 - 6.36 (m, 2H), 5.77 - 5.68 (m, 1H), 5.45 - 5.20 (m, 1H), 5.10 - 4.89 (m, 2H), 4.45 - 4.15 (m, 2H), 3.94 - 3.81 (m, 1H), 3.68 (s, 1H), 3.63 (s, 3H), 3.48 - 3.14 (m, 3H), 3.01 (s, 1H), 2.86 (s, 1H), 2.59 - 2.28 (m, 3H), 2.27 - 2.09 (m, 2H), 2.04 - 1.86 (m, 3H), 1.13 (d, J = 4.9 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.226 minutes, ESI+ experimental value [M+H] ⁺ = 641.3; and Example 1-3: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 2, retention time = 1.617 minutes) (30.58 mg): ¹ H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 2.97 (m, 1H), 2.91 - δ 5.14 - 5.12 (m, 1H), 1.22 - 1.42 (m, 3H), 4.62 - 4.71 (m, 1H), 2.47 - 2.30 (m, 2H), 2.22 - 2.14 (m, 2H), 2.04 - 1.89 (m, 3H), 1.74 - 1.59 (m, 3H), 1.20 - 1.07 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.226 min, ESI+ found [M+H] ⁺ = 641.3. Example 2 : Synthesis of Compound 2-1 ; 1-((3R,4R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1: (3R,4R)-3-(Benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester

The reductive amination reaction was carried out in a similar manner to Method #1 Step 1 . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give tributyl (3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate (5.25 g, 70.49%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.30 - 7.20 (m, 5H), 3.60 - 3.50 (m, 2H), 3.38 - 3.31 (m, 1H), 3.29 - 3.05 (m, 3H), 2.79 - 2.66 (m, 1H), 2.38 - 2.24 (m, 1H), 1.97 (s, 3H), 1.39 (s, 9H), 0.99-0.97 (dd, J = 1.6, 6.9 Hz, 3H). LCMS Rt = 0.323 min, m/z = 304.2 [M + H] ⁺ . Step 2: (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of the Bn group was performed in a similar manner to Method #1 Step 2. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to afford (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (3.54 g, crude) as a white solid, which was used in the next step without any further purification. LCMS Rt = 0.282 min, m/z = 214.2 [M + H] ⁺ . Step 3 : (3R,4R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 3. The crude residue was diluted with a (10:1) mixture of petroleum ether:ethyl acetate (10 mL) and the resulting precipitate was filtered to afford tributyl (3R,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (9.25 g, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.578 min, m/z = 429.1 [M + H]+. Step 4 : (3R,4R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to method #1 step 4. The mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Phenomenex luna C18 250×150 mm×15 um; mobile phase:

[H ₂ O (0.1% TFA) - ACN]; gradient: 30%-60% B in 20.0 min) to give (3R,4R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester (7.77 g, 54.24%, trifluoroacetate) as a yellow solid. LCMS Rt = 2.194 min, m/z = 552.2 [M + H] ⁺ . Step 5 : (3R,4R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner to Method #1 Step 5 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 85%-95% B in 8.0 min) to give (3R,4R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester (285 mg, 75.16%) as a white solid. LCMS Rt = 0.639 min, m/z = 842.5 [M + H] ⁺ . Step 6 : (3R,4R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to afford (3R,4R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (110 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.454 min, m/z = 686.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((3R,4R)-4- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4R)-4-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.335 min, m/z = 586.3 [M + H] ⁺ . Step 8 : 1-((3R,4R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop -2- en -1 -one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 8.0 min) to give 1-((3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one (43.90 mg, 39.87%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.30 - 9.17 (m, 1H), 8.21 - 8.07 (m, 2H), 7.74 - 7.64 (m, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.27 (dd, J = 2.1, 16.7 Hz, 1H), 5.71 (dd, J = 1.9, 10.4 Hz, 1H), 5.66 - 5.44 (m, 1H), 5.39 - 5.16 (m, 1H), 4.27 - 4.19 (m, 1H), 4.16 - 4.10 (m, 1H), 4.08 - 3.91 (m, 2H), 3.56 - 3.48 (m, 1H), 3.47 - 3.30 (m, 3H), 3.30 - 3.24 (m, 1H), 3.16 (br d, J = 4.6 Hz, 2H), 3.08 (s, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.86 (m, 1H), 2.24 - 2.14 (m, 3H), 2.12 (br d, J = 2.6 Hz, 1H), 2.10 - 2.02 (m, 1H), 1.90 - 1.81 (m, 2H), 1.21 - 1.07 (m, 3H). LCMS Rt = 2.997 min, m/z = 640.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.997 min, ESI+ found [M+H] = 640.3. Example 3 : Synthesis of Compound 2-3 ; 1-((3R,4S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1: (3R,4S)-3-(Benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester

The reductive amination reaction was performed in a similar manner to Method #1 Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 10%-20% ethyl acetate/petroleum ether) to afford (3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 67.13%) as a yellow oil. LCMS Rt = 0.298 min, m/z = 304.2 [M + H]+. Step 2: (3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of the Bn group was performed in a similar manner to Method #1 Step 2. The reaction mixture was concentrated in vacuo to afford (3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester (3.2 g, crude) as a white oil, which was used in the next step without any further purification. LCMS Rt = 0.508 min, m/z = 214.2 [M + H]+. Step 3 : (3R,4S)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 3. The mixture was filtered and concentrated in vacuo to afford tributyl (3R,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (5.7 g, 66.88%) as a yellow solid and used in the next step without further purification. LCMS Rt = 0.572 min, m/z = 429.1 [M + H] ⁺ . Step 4 : (3R,4S)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Welch Xtimate C18 250×100 mm #10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 20.0 min) to give (3R,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester (2.5 g, 34.74%) as a yellow solid. LCMS Rt = 0.406 min, m/z = 552.2 [M + H] ⁺ . Step 5 : (3R,4S)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 30-100% ethyl acetate/petroleum ether) to give (3R,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester (400 mg, 52.48%) as a yellow solid and used in the next step without further purification. LCMS Rt = 0.616 min, m/z = 842.5 [M + H] ⁺ . Step 6 : (3R,4S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The mixture was filtered and concentrated to dryness in vacuo to afford (3R,4S)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (400 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.451 min, m/z = 686.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((3R,4S)-4 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7 . The mixture was concentrated in vacuo and purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [water (0.1% TFA)-ACN]; gradient: 10%-40% B in 8.0 min) to give 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4S)-4-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (300 mg, 73.51%, trifluoroacetate) as a yellow oil. LCMS Rt = 0.358 min, m/z = 586.3 [M + H] ⁺ . Step 8 : 1-((3R,4S)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop -2- en -1 -one

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

The substitution reaction was carried out in a similar manner to Method #1 Step 3 . The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give tributyl (2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (800 mg, 93.87%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.93 (s, 1H), 5.21 - 5.11 (m, 1H), 3.96 - 3.84 (m, 2H), 3.36 (s, 3H), 3.30 (t, J = 10.3 Hz, 1H), 2.53 - 2.45 (m, 1H), 1.78 - 1.69 (m, 1H), 1.42 (s, 9H), 1.33 (d, J = 6.0 Hz, 3H). LCMS Rt = 0.568 min, m/z = 429.1 [M + H] ⁺ . Step 2 : (2S,4R)-4-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4 . The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give (2S,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (300 mg, 31.12%) as a yellow solid: ^1H NMR 1H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (s, 1H), 5.32 - 5.14 (m, 1H), 5.11 - 5.01 (m, 1H), 4.22 (br s, 2H), 3.95 - 3.81 (m, 2H), 3.29 (s, 3H), 3.27 - 3.23 (m, 1H), 3.22 - 3.09 (m, 2H), 2.93 (br s, 1H), 2.49 - 2.41 (m, 1H), 2.28 -2.13 (m, 2H), 2.09 (br d, J = 3.0 Hz, 1H), 1.96 - 1.69 (m, 5H), 1.42 (s, 9H), 1.32 (br d, J = 5.9 Hz, 3H). LCMS Rt = 1.605 min, m/z = 552.2 [M + H] ⁺ . Step 3 : (2S,4R)-4-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 step 5. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2S,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate as a yellow solid (300 mg, 65.60%). LCMS Rt = 0.639 min, m/z = 842.5 [M + H] ⁺ . Step 4 : (2S,4R)-4-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner as in Method #1, Step 6 . The mixture was filtered and purified by reverse phase HPLC (column: 3-Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [water (0.1% TFA)-ACN]; gradient: 30%-60% B in 8.0 min) to give (2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (120 mg, 84.23%, trifluoroacetate) as a yellow solid. LCMS Rt = 1.839 min, m/z = 686.3 [M + H] ⁺ . Step 5 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methyl -N-((3R,5S)-5 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (80 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.341 min, m/z = 586.3 [M + H] ⁺ . Step 6 : 1-((2S,4R)-4-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

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

The reductive amination reaction was carried out in a similar manner to Method # 1, Step 1 . The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give tributyl (2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (720 mg, 47.37%) as a colorless oil: ¹ H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.23 (m, 5H), 4.00 (quintet, J = 6.6 Hz, 1H), 3.65 - 3.60 (m, 1H), 3.58 - 3.47 (m, 2H), 3.29 - 3.15 (m, 2H), 2.12 (s, 3H), 2.08 - 1.86 (m, 2H), 1.47 (s, 9H), 1.19 (br d, J = 6.4 Hz, 3H). Step 2: (2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of the Bn group was performed in a similar manner to Method #1 Step 2. The reaction mixture was concentrated in vacuo to afford tributyl (2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1-carboxylate (510 mg, crude) as a yellow oil and used as such in the next step: ¹ H NMR (400 MHz, Methanol-d4) δ 3.95 (br s, 1H), 3.55 (br s, 1H), 3.31 - 3.09 (m, 2H), 2.35 (s, 3H), 1.94 -1.80 (m, 2H), 1.46 (s, 9H), 1.20 (br d, J = 6.3 Hz, 3H). Step 3 : (2R,4R)-4-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 3. The mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (700 mg, 85.03%) as a yellow solid. LCMS Rt = 0.572 min, m/z = 429.1 [M + H] ⁺ . Step 4 : (2R,4R)-4-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,4R)-tert-butyl 4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (580 mg, 70.51%) as a yellow solid. LCMS Rt = 0.657 min, m/z = 552.2 [M + H] ⁺ . Step 5 : (2R,4R)-4-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner as Method #1 step 5. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2R,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate as a brown solid (790 mg, 95.96%). LCMS Rt = 1.041 m/z = 842.5 [M + H] ⁺ . Step 6 : (2R,4R)-4-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The mixture was concentrated to dryness in vacuo to afford (2R,4R)-tert-butyl 4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (590 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS Rt = 1.838 min, m/z = 686.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methyl -N-((3R,5R)-5 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5R)-5-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, crude, hydrochloride) as a yellow solid which was used in the next step without further purification. LCMS Rt = 0.347 min, m/z = 586.3 [M + H] ⁺ . Step 8 : 1-((2R,4R)-4-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was concentrated in vacuo and purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 8.0 min) to give 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (75.66 mg, 39.76%) as a pale yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.17 - 9.11 (m, 1H), 8.16 - 8.07 (m, 2H), 7.71 - 7.61 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.25 (dt, J = 1.8, 16.9 Hz, 1H), 5.67 (ddd, J = 2.3, 10.4, 12.7 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.36 - 5.17 (m, 1H), 4.42 (br d, J = 3.3 Hz, 1H), 4.22 - 4.11 (m, 2H), 4.11 - 3.83 (m, 1H), 3.79 - 3.61 (m, 1H), 3.39 (s, 3H), 3.28 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.04 (m, 1H), 2.93 - 2.85 (m, 1H), 2.63 - 2.36 (m, 1H), 2.23 - 2.12 (m, 3H), 2.09 - 1.98 (m, 2H), 1.89 - 1.83 (m, 2H), 1.34 - 1.24 (m, 3H). LCMS Rt = 2.976 min, m/z = 640.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.976 min, ESI+ experimental value [M+H] = 640.3. Example 6 : Synthesis of Compound 2-2 ; 1-((3S,4S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1: (3S,4S)-3-[Benzyl(methyl)amino]-4-methyl-pyrrolidine-1-carboxylic acid tributyl ester

The reductive amination reaction was carried out in a similar manner to Method #1 Step 1 . The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 10-20% ethyl acetate/petroleum ether) to give (3S,4S)-3-[benzyl(methyl)amino]-4-methyl-pyrrolidine-1-carboxylic acid tributyl ester (850 mg, 55.92%) as a colorless oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.36 - 7.24 (m, 5H), 3.75 (br t, J = 6.2 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.55 (dd, J = 7.6, 9.8 Hz, 1H), 3.44 (br dd, J = 5.3, 9.7 Hz, 1H), 3.36 - 3.30 (m, 1H), 3.29 - 3.17 (m, 1H), 2.84 - 2.75 (m, 1H), 2.44 - 2.37 (m, 1H), 2.05 (s, 3H), 1.48 (s, 9H), 1.07 (br d, J = 6.5 Hz, 3H). Step 2: (3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of the Bn group was performed in a similar manner to Method #1 Step 2. The reaction mixture was concentrated in vacuo to afford tributyl (3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate (580 mg, crude) as a colorless oil which was used in the next step without further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 3.50 - 3.38 (m, 2H), 3.28 - 3.03 (m, 3H), 2.42 (s, 3H), 2.37 - 2.28 (m, 1H), 1.45 (s, 9H), 1.00 - 0.95 (m, 3H). Step 3 : (3S,4S)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (3S,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (930 mg, 87.39%) as a yellow solid. LCMS Rt = 2.354 min, m/z = 429.11 [M + H] ⁺ . Step 4 : (3S,4S)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 50-100% ethyl acetate/petroleum ether) to afford (3S,4S)-tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (1.02 g, 95.62%) as a yellow solid. LCMS Rt = 0.427 min, m/z = 552.2 [M + H] ⁺ . Step 5 : (3S,4S)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (3S,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tributyl ester (490 mg, 80.36%) as a brown solid. LCMS Rt = 1.122 min, m/z = 842.5 [M + H] ⁺ . Step 6 : (3S,4S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The filtrate was concentrated to dryness in vacuo to afford (3S,4S)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate (450 mg, crude) as a brown solid which was used in the next step without further purification. LCMS Rt = 0.451 min, m/z = 686.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((3S,4S)-4 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((3S,4S)-4-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (220 mg, crude, trifluoroacetic acid salt) as a yellow solid which was used in the next step without further purification. LCMS Rt = 0.358 min, m/z = 586.3 [M + H] ⁺ . Step 8 : 1-((3S,4S)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-4- methylpyrrolidin -1- yl ) prop -2- en -1 -one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-65% B in 8.0 min) to obtain 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one (24.23 mg, 21.42%) as a yellow amorphous solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.23 - 9.18 (m, 1H), 8.15 - 8.08 (m, 2H), 7.70 - 7.63 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.25 (dd, J = 2.0, 16.8 Hz, 1H), 5.69 (br d, J = 10.4 Hz, 1H), 5.63 - 5.43 (m, 1H), 5.36 - 5.15 (m, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 3.97 (m, 2H), 3.96 - 3.82 (m, 2H), 3.51 - 3.46 (m, 1H), 3.44 (t, J = 4.4 Hz, 3H), 3.36 - 3.28 (m, 1H), 3.27 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.09 - 3.03 (m, 1H), 3.01 - 2.86 (m, 2H), 2.19 - 2.16 (m, 1H), 2.10 (br d, J = 2.6 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.92 - 1.81 (m, 2H), 1.11 (t, J = 7.7 Hz, 3H). LCMS Rt = 2.992 min, m/z = 640.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.992 min, ESI+ experimental value [M+H] = 640.3. Example 7 : Synthesis of Compound 5 ; 1-((R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-5- methyl -5- azaspiro [2.4] hept -6- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -1- yl ) prop -2- en -1- one ( Method 1) Step 1 : (S)-(5- methyl -5- azaspiro [2.4] hept -6- yl ) methanol

To a solution of (6S)-5-methyl-5-azaspiro[2.4]heptane-6-carboxylic acid (300 mg, 1.93 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydroxide (2.5 M, 1.16 mL) in tetrahydrofuran at 0°C. The mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with sodium sulfate decahydrate (100 mg) at 0°C and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give (S)-(5-methyl-5-azaspiro[2.4]hept-6-yl)methanol (260 mg, crude) as a white solid and used in the next step without further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 -2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4,12.5 Hz, 1H), 0.54 - 0.40 (m, 4H). Step 2 : (R)-3-((7- chloro -8- fluoro -2-(((S)-5- methyl -5- azaspiro [2.4] hept -6- yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane/methanol) to afford (R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]hept-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 31.96%) as a white solid. LCMS Rt = 0.633 min, m/z = 520.24 [M + H] ⁺ . Step 3 : (R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((S)-5- methyl -5- azaspiro [2.4] hept -6- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidine -1- carboxylic acid tributyl ester

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

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The mixture was concentrated to dryness in vacuo to afford (R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]hept-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (100 mg, crude) as a brown oil, which was used in the next step without any further purification. LCMS Rt = 0.468 min, m/z = 654.3 [M + H] ⁺ . Step 5 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N- methyl -2-(((S)-5- methyl -5- azaspiro [2.4] hept -6- yl ) methoxy )-N-((R) -pyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-2-(((S)-5-methyl-5-azaspiro[2.4]hept-6-yl)methoxy)-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (90 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS Rt = 0.353 min, m/z = 554.3 [M + H] ⁺ . Step 6 : 1-((R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1 -yl )-8- fluoro -2-(((S)-5- methyl -5 -azaspiro [2.4] hept - 6- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin - 1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-75% B in 8.0 min) to give 1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]hept-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (23.41 mg, 24.53%) as a yellow amorphous solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.17 (br s, 1H), 8.16 - 8.08 (m, 2H), 7.71 - 7.65 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H), 6.66 - 6.52 (m, 1H), 6.25 (br d, J = 16.8 Hz, 1H), 5.73 - 5.64 (m, 1H), 5.45 - 5.29 (m, 1H), 4.57 - 4.51 (m, 1H), 4.40 - 4.34 (m, 1H), 4.14 - 3.93 (m, 1H), 3.92 - 3.79 (m, 1H), 3.74 - 3.62 (m, 1H), 3.61 - 3.45 (m, 1H), 3.43 (s, 3H), 3.32 - 3.25 (m, 1H), 2.93 - 2.85 (m, 1H), 2.66 (br d, J = 8.9 Hz, 1H), 2.52 (br d, J = 8.8 Hz, 1H), 2.41 (d, J = 1.9 Hz, 3H), 2.33 - 2.24 (m, 2H), 2.05 (br dd, J = 8.0, 12.4 Hz, 1H), 1.69 (br dd, J = 7.5, 12.5 Hz, 1H), 0.62 - 0.48 (m, 4H). LCMS Rt = 2.928 min, m/z = 608.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.928 min, ESI+ found [M+H] = 608.3. Example 8 : Synthesis of Compound 2-4 ; 1-((3S,4R)-3-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-4 -methylpyrrolidin -1- yl ) prop -2- en -1 - one

¹ H NMR (400 MHz, acetonitrile-d3) δ 9.22 - 9.15 (m, 1H), 8.15 - 8.09 (m, 2H), 7.70 - 7.62 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.57 (ddd, J = 10.4, 13.3, 16.8 Hz, 1H), 6.27 - 6.20 (m, 1H), 5.67 (ddd, J = 2.2, 4.2, 10.4 Hz, 1H), 5.37 - 5.16 (m, 1H), 5.08 - 4.86 (m, 1H), 4.21 - 4.16 (m, 1H), 4.15 - 4.01 (m, 2H), 4.01 - 3.93 (m, 1H), 3.70 - 3.46 (m, 1H), 3.45 - 3.42 (m, 3H), 3.30 - 3.23 (m, 1H), 3.20 - 3.11 (m, 2H), 3.05 (s, 1H), 2.93 - 2.84 (m, 1H), 2.81 - 2.61 (m, 1H), 2.23 - 2.15 (m, 2H), 2.11 - 2.03 (m, 2H), 1.91 - 1.81 (m, 3H), 1.17 - 1.11 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.998 min, ESI+ found [M+H] ⁺ = 641.3. Example 9 : Synthesis of Compound 3-4 ; 1-((2S,4S)-4-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one

¹ H NMR (400 MHz, acetonitrile-d3) δ 9.14 (s, 1H), 8.16 - 8.07 (m, 2H), 7.66 (d, J = 5.4 Hz, 2H), 7.44 (t, J = 9.1 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.33 - 6.18 (m, 1H), 5.74 - 5.62 (m, 1H), 5.60 - 5.46 (m, 1H), 5.35 - 5.17 (m, 1H), 4.49 - 4.34 (m, 1H), 4.24 - 4.18 (m, 1H), 4.15 - 4.11 (m, 1H), 3.94 - 3.66 (m, 1H), 3.39 (s, 3H), 3.30 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.06 (s, 1H), 2.93 - 2.85 (m, 1H), 2.64 - 2.36 (m, 1H), 2.24 - 2.16 (m, 2H), 2.10 (br d, J = 3.1 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.90 - 1.76 (m, 3H), 1.34 - 1.25 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.985 min, ESI+ found [M+H] ⁺ = 641.3. Example 10 : Synthesis of Compound 3-2 ; 1-((2R,4S)-4-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one

¹ H NMR (400 MHz, acetonitrile-d3) δ 9.16 - 9.12 (m, 1H), 8.14 - 8.08 (m, 2H), 7.66 (d, J = 5.6 Hz, 2H), 7.44 (t, J = 9.1 Hz, 1H), 6.68 - 6.47 (m, 1H), 6.21 (d, J = 16.9 Hz, 1H), 5.65 (d, J = 7.8 Hz, 1H), 5.34 - 5.06 (m, 2H), 4.33 - 4.16 (m, 2H), 4.12 - 4.08 (m, 1H), 3.71 - 3.46 (m, 1H), 3.44 (s, 3H), 3.28 - 3.22 (m, 1H), 3.17 - 3.10 (m, 2H), 3.08 - 3.03 (m, 1H), 2.92 - 2.84 (m, 1H), 2.77 - 2.45 (m, 1H), 2.21 - 2.13 (m, 3H), 2.10 - 2.07 (m, 1H), 2.04 (s, 1H), 1.91 - 1.81 (m, 3H), 1.41 (d, J = 6.3 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.003 min, ESI+ found [M+H] ⁺ = 641.3. Example 12 : Synthesis of Compound 6 ; 1- cis- 1-(3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-5- methyl -5- azaspiro [2.4] hept -6- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en -1- one

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.30 - 9.10 (m, 1H), 8.01 - 7.93 (m, 2H), 7.66 - 7.58 (m, 2H), 7.35 (t, J = 8.8 Hz, 1H), 6.52 - 6.39 (m, 2H), 5.77 - 5.68 (m, 1H), 5.11 - 4.91 (m, 2H), 4.75 - 4.58 (m, 1H), 4.50 - 4.36 (m, 1H), 3.92 - 3.83 (m, 1H), 3.64 - 3.60 (m, 3H), 3.10 - 2.97 (m, 1H), 2.90 - 3H), 2.82 (m, 1H), 2.79 - 2.69 (m, 1H), 2.65 - 2.59 (m, 1H), 2.56 - 2.50 (m, 3H), 2.43 - 2.34 (m, 1H), 2.20 - 2.11 (m, 1H), 1.86 - 1.56 (m, 3H), 1.20 - 1.10 (m, 3H), 0.69 - 0.63 (m, 1H), 0.59 - 0.48 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.982 minutes, ESI+ found [M+H] ⁺ = 623.3. Example 17 : Synthesis of Compound 9 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- hydroxytetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1 : (2R,3R)-3-((2-(((2R,7aS)-2-(( tributyldiphenylsilyl ) oxy ) tetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy )-7- chloro -8- fluoropyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1.0 g, 2.324 mmol), ((2R,7aS)-2-((tributyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.839 g, 4.64 mmol) and 4Å molecular sieve (160 mg) in 1,4-dioxane (40 mL) was added N,N -diisopropylethylamine (901 mg, 6.96 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 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 Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 60%-90% B in 8.0 min) to give (2R,3R)-3-((2-(((2R,7aS)-2-((tributyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (600 mg, 32.70%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.82 (s, 1H), 7.58 - 7.50 (m, 4H), 7.41 - 7.25 (m, 6H), 4.95 - 4.78 (m, 1H), 4.51 - 4.32 (m, 2H), 4.13 - 3.93 (m, 1H), 3.70 - 3.46 (m, 2H), 3.45 - 3.25 (m, 5H), 3.06 - 2.93 (m, 1H), 2.85 - 2.57 (m, 1H), 2.54 - 2.33 (m, 1H), 2.31 - 2.20 (m, 2H), 2.17 - 2.07 (m, 2H), 2.06 - 1.95 (m, 2H), 1.94 - 1.73 (m, 2H), 1.40 (s, 9H), 1.03 - 0.95 (m, 12H). LCMS Rt = 2.396 min, m/z = 789.2/790.2 [M + H] ⁺ . Step 2 : (2R,3R)-3-((2-(((2R,7aS)-2-(( tributyldiphenylsilyl ) oxy ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin- 4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

(2R,3R)-3-((2-(((2R,7aS)-2-((tributyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (500 mg, 633.35 μmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (429.87 mg, 950.03 μmol), potassium phosphate (403.32 mg, 1.90 A mixture of 2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (45.64 mg, 63.34 μmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 60%-90% B in 8.0 min) to obtain (2R,3R)-3-((2-(((2R,7aS)-2-((tributyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (420 μM) as a yellow solid. ^7.54 (d, J = 10.7 Hz, 1H), 3.70 (d, J = 5.1 Hz, 1H), 3.87 (d, J = 11.7 Hz, 1H), 3.54 (d, J = 4.2 Hz, 1H), 3.53 (d, J = 3.1 Hz, 1H), 3.61 (d, J = 11.7 Hz, 1H), 3.57 (d, J = 4.2 Hz, 1H), 3.61 (d, J = 11.7 Hz, 1H), 3.63 (d, J = 11.7 Hz, 1H), 3.61 (d, J = 11.7 Hz, 1H), 3.63 (d, J = 11.7 Hz, 1H), 9.7 Hz, 1H), 3.54 (s, 1H), 3.38 - 3.33 (m, 1H), 2.52 - 2.50 (m, 3H), 2.36 (dd, J = 5.6, 13.7 Hz, 3H), 2.21 (s, 2H), 2.15 (d, J = 11.8 Hz, 2H), 1.79 (s, 4H), 1.46 (s, 9H), 1.39 (d, J = 3.9 Hz, 1H), 1.20 - 1.16 (m, 2H), 1.08 (s, 9H), 1.02 - 1.00 (m, 1H), 0.85 (d, J = 6.4 Hz, 18H), 0.61 (dt, J = 7.0, 14.2 Hz, 3H). LCMS Rt = 2.706 min, m/z = 1079.5 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- hydroxytetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

To a solution of (2R,3R)-3-((2-(((2R,7aS)-2-((tributyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (200 mg, 185.27 μmol, trifluoroacetate) in N,N -dimethylformaldehyde (1 mL) was added csium fluoride (562.86 mg, 3.71 mmol). The mixture was stirred at 50 °C under nitrogen atmosphere for 12 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated lithium chloride (3 x 5 mL), dried over sodium sulfate and concentrated in vacuo to afford tributyl (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (126 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.432 min, m/z = 685.2 [M + H] ⁺ . Step 4 : (2R,7aS)-7a-(((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoro -4-( methyl ((2R,3R)-2 -methylpyrrolidin -3- yl ) amino ) pyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) hexahydro -1H -pyrrolizin -2- ol

A solution of tributyl (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (126 mg, 184.00 μmol) in HCl/ethyl acetate (2M, 2 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to dryness in vacuo to give (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (106 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.339 min, m/z = 585.2 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- hydroxytetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

To a solution of (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (106 mg, 170.66 μmol, hydrochloride) in tetrahydrofuran (1 mL) and water (0.3 mL) were added sodium bicarbonate (43.01 mg, 511.98 μmol) and prop-2-enoyl chloride (10.81 mg, 119.46 μmol), and the mixture was stirred at 0° C. under nitrogen atmosphere for 10 minutes. The reaction mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-hydroxytetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (8.48 g) as a yellow solid. mg, 7.08%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.24 (d, J = 4.8 Hz, 1H), 8.18 - 8.11 (m, 2H), 7.69 (d, J = 4.8 Hz, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.74 - 5.66 (m, 1H), 5.04 - 4.79 (m, 2H), 4.55 - 4.38 (m, 1H), 4.31 - 4.06 (m, 2H), 3.94 - 3.72 (m, 1H), 3.72 - 3.65 (m, 1H), 3.62 (d, J = 4.9 Hz, 3H), 3.61 - 3.50 (m, 1H), 3.29 (s, 1H), 3.19 - 3.08 (m, 1H), 2.95 (td, J = 5.2, 16.5 Hz, 1H), 2.89 - 2.77 (m, 1H), 2.61 - 2.48 (m, 2H), 2.47 - 2.32 (m, 2H), 1.88 - 1.78 (m, 3H), 1.71 - 1.63 (m, 1H), 1.17 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.705 min, ESI+ found [M+H] ⁺ = 639.3. Example 18 : Synthesis of Compound 10 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((6'R,7a'S)-6' - fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1 : 1-( tert-butyl) -2 -methyl (2S,4S)-4-(( tert-butyldimethylsilyl ) oxy ) pyrrolidine - 1,2 - dicarboxylate

To a solution of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (20 g, 81.54 mmol) in dichloromethane (100 mL) was added tert-butyl-chloro-dimethyl-silane (13.52 g, 89.70 mmol), N,N -dimethylpyridin-4-amine (996.18 mg, 8.15 mmol) and imidazole (11.10 g, 163.08 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (500 mL) at 0 °C and extracted with dichloromethane (3 x 200 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/petroleum ether) to give 1-(tert-butyl)-2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate) as a white solid (25 g, 85.27%): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.47 - 4.27 (m, 2H), 3.73 (s, 3H), 3.70 - 3.54 (m, 1H), 3.41 - 3.27 (m, 1H), 2.39 - 2.23 (m, 1H), 2.17 - 2.06 (m, 1H), 1.54 - 1.41 (m, 9H), 0.91 - 0.85 (m, 9H), 0.11 - 0.00 (m, 6H). LCMS Rt = 0.642 min, m/z = 360.1 [M + H] ⁺ . Step 2 : (2S,4S)-4-(( tributyldimethylsilyl ) oxy )-2-(2-( chloromethyl ) allyl ) pyrrolidine -1,2- dicarboxylic acid 1-( tributyl ) 2- methyl ester

To a solution of 1-(tributyl)-2-methyl (2S,4S)-4-((tributyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (20 g, 55.63 mmol) in tetrahydrofuran (300 mL) was added lithium hexamethyldisilazane (83.44 mL, 83.44 mmol, 1 M in tetrahydrofuran). The mixture was stirred at -78°C under nitrogen atmosphere for 2 hours. Then 3-chloro-2-(chloromethyl)prop-1-ene (10.43 g, 83.44 mmol) was added to the above solution at -78°C. The mixture was stirred at 20°C under nitrogen atmosphere for 10 hours. The reaction mixture was quenched with saturated ammonium chloride (500 mL) at 0 °C and extracted with ethyl acetate (3 x 100 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/petroleum ether) to give 1-(tert-butyl)-2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (15 g, 60.18%) as a white solid. LCMS Rt = 0.716 min, m/z = 448.2/450.1 [M + H] ⁺ . Step 3 : (2S,4S)-2-(2-( chloromethyl ) allyl )-4- hydroxypyrrolidine -1,2 -dicarboxylic acid 1-( tert-butyl ) 2- methyl ester

To a solution of 1-(tert-butyl)-2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (11 g, 24.55 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (29.46 mL, 29.46 mmol, 1M in tetrahydrofuran). The mixture was stirred at 20 °C for 1 hour. The mixture was diluted with saturated sodium chloride (300 mL) and water (200 mL) and extracted with ethyl acetate (3 x 200 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/petroleum ether) to give 1-(tert-butyl)-2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (6 g, 73.22%) as a white solid. LCMS Rt = 0.458 min, m/z = 334.0/336.0 [M + H] ⁺ . Step 4 : (2S,4R)-2-(2-( chloromethyl ) allyl )-4- fluoropyrrolidine -1,2- dicarboxylic acid 1-( tert-butyl ) 2- methyl ester

To a solution of 1-(tert-butyl)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 2-methyl ester (7 g, 20.97 mmol) in dichloromethane (100 mL) was added (bis(2-methoxyethyl)amino)sulfur trifluoride (9.28 g, 41.94 mmol) at -78 °C. The mixture was stirred at 20 °C under nitrogen atmosphere for 12 hours. The mixture was diluted with saturated sodium bicarbonate (500 mL) and water (150 mL) and extracted with dichloromethane (3 x 200 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/petroleum ether) to give 1-(tert-butyl)-2-methyl-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (3.7 g, 52.54%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 5.47 - 5.33 (m, 1H), 5.29 - 5.04 (m, 2H), 4.22 - 4.09 (m, 2H), 3.94 - 3.68 (m, 5H), 3.33 - 3.16 (m, 1H), 2.86 (d, J = 14.4 Hz, 1H), 2.65 - 2.28 (m, 2H), 1.50 - 1.45 (m, 9H). LCMS Rt = 0.549 min, m/z = 336.0/338.0 [M + H] ⁺ . Step 5: Methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate (2.6 g, crude, trifluoroacetic acid salt) as a white solid which was used in the next step without any further purification. LCMS Rt = 0.174 min, m/z = 236.0/238.0 [M + H] ⁺ . Step 6 : (2R,7aS)-2- fluoro -6- methylenetetrahydro -1H -pyrrolazine -7a(5H) -carboxylic acid methyl ester

To a solution of methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate (2.6 g, 11.03 mmol, trifluoroacetate) in methanol (5 mL) was added ammonia (20 mL, 140.00 mmol, 7M in methanol). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.7 g, 77.35%) as a white solid. LCMS Rt = 0.146 min, m/z = 200.1 [M + H] ⁺ . Step 7 : (6'R,7a'S)-6'- fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -carboxylic acid methyl ester

To a solution of (2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (1.6 g, 8.03 mmol) in dichloromethane (50 mL) at 0 °C under nitrogen was added diethylzinc (40.16 mL, 40.16 mmol, 1M in toluene) and diiodomethane (21.51 g, 80.31 mmol). The mixture was stirred at 20 °C under nitrogen atmosphere for 12 hours. The reaction mixture was quenched with saturated ammonium chloride (300 mL) at 0 °C and extracted with dichloromethane (3 x 200 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/petroleum ether) to give (6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (300 mg, 30%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 5.29 - 5.12 (m, 1H), 3.67 (s, 3H), 3.25 - 3.21 (m, 1H), 3.17 - 3.09 (m, 2H), 2.84 (dd, J = 1.2, 8.8 Hz, 1H), 2.35 - 2.23 (m, 2H), 2.23 - 2.17 (m, 1H), 2.14 - 2.08 (m, 1H), 0.55 - 0.42 (m, 4H). LCMS Rt = 0.520 min, m/z = 214.1 [M + H] ⁺ . Step 8 : ((6'R,7a'S)-6'- fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methanol

To a solution of (6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (250 mg, 1.17 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum tetrahydride (1.41 mL, 3.52 mmol, 2.5M in tetrahydrofuran). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (200 mg) at 0°C. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give ((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (200 mg, crude) as a colorless oil which was used in the next step without any further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 5.35 - 5.14 (m, 1H), 3.51 (d, J = 10.3 Hz, 1H), 3.29 (d, J = 10.5 Hz, 1H), 3.20 - 3.15 (m, 2H), 3.14 - 3.02 (m, 1H), 2.79 (dd, J = 1.1, 9.3 Hz, 1H), 2.28 - 2.21 (m, 1H), 2.21 - 2.13 (m, 1H), 2.11 - 2.06 (m, 1H), 1.45 - 1.41 (m, 1H), 0.59 - 0.47 (m, 4H). Step 9 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((6'R,7a'S)-6' -fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (120 mg, 47.98%) as a yellow solid. LCMS Rt = 0.422 min, m/z = 579.2/581.2 [M + H] ⁺ . Step 10 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((6'R,7a'S)-6'- fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner as in Method #1, Step 5. The residues were purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 65%-95% in 8.0 min. B) The crude product was purified to give tributyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (20 mg, 13.33%) as a brown solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.28 - 9.23 (m, 1H), 7.98 - 7.89 (m, 2H), 7.62 - 7.52 (m, 2H), 7.34 (dt, J = 1.9, 8.7 Hz, 1H), 5.47 - 5.26 (m, 1H), 5.23 - 4.94 (m, 1H), 4.59 - 4.44 (m, 2H), 3.69 - 3.57 (m, 3H), 3.54 (s, 2H), 3.43 (ddd, J = 3.4, 6.8, 10.3 Hz, 1H), 3.34 - 3.23 (m, 2H), 2.47 - 2.30 (m, 4H), 2.29 - 2.18 (m, 2H), 1.83 (d, J = 8.6 Hz, 2H), 1.50 (d, J = 0.8 Hz, 9H), 1.33 - 1.24 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.91 - 0.86 (m, 18H), 0.62 - 0.56 (m, 4H). LCMS Rt = 2.906 min, m/z = 869.3 [M + H] ⁺ . Step 11 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((6'R,7a'S)-6' -fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to afford (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (8 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.494 min, m/z = 713.4 [M + H] ⁺ . Step 12 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((6'R,7a'S)-6'- fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (7.3 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.376 min, m/z = 613.4 [M + H] ⁺ . Step 13 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((6'R,7a'S)-6'- fluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1, Step 8. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-80% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6' 1H, 8H-dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (1.11 mg, 13.77%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.09 (m, 2H), 7.70 - 7.64 (m, 2H), 7.45 (t, J = 9.1 Hz, 1H), 6.64 - 6.53 (m, 1H), 6.32 - 6.19 (m, 1H), 5.68 (dd, J = 2.3, 10.3 Hz, 1H), 5.41 - 5.22 (m, 1H), 4.97 - 4.81 (m, 2H), 4.46 - 4.24 (m, 2H), 3.90 - 3.66 (m, 1H), 3.61 (d, J = 5.4 Hz, 3H), 3.59 - 3.45 (m, 1H), 3.26 (d, J = 8.5 Hz, 1H), 3.16 (d, J = 8.8 Hz, 2H), 3.13 - 3.08 (m, 1H), 2.75 (d, J = 8.0 Hz, 1H), 2.65 - 2.47 (m, 1H), 2.44 - 2.27 (m, 2H), 2.24 (s, 3H), 1.15 - 1.05 (m, 3H), 0.53 (s, 4H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 4.113 min, ESI+ found [M+H] ⁺ = 667.3. Example 19 : Synthesis of Compound 11 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin - 1- yl ) prop -2- en -1- one ( Method 1 ) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((S)-1 -methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (340 mg, 57.48%) as a yellow solid. LCMS Rt = 0.391 min, m/z = 509.2/510.2 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((S)-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 40%-70% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (260 mg, 55.21%, trifluoroacetic acid salt) as a yellow solid. LCMS Rt = 0.602 min, m/z = 799.5 [M + H] ⁺ . Step 3 : 8- Fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -2-(((S)-1- methylpyrrolidin -2- yl ) methoxy )-N-((2R,3R)-2- methylpyrrolidin- 3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.507 min, m/z = 699.5 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 -fluoro -N- methyl -2-(((S)-1 -methylpyrrolidin -2- yl ) methoxy )-N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (81 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.315 min, m/z = 543.2 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoro -2-(((S)-1- methylpyrrolidin- 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1 - yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (28.48 mg, 31.90%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.07 (m, 2H), 7.69 - 7.63 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.58 (dd, J = 10.3, 16.8 Hz, 1H), 6.32 - 6.20 (m, 1H), 5.68 (dd, J = 2.2, 10.3 Hz, 1H), 4.99 - 4.79 (m, 2H), 4.53 - 4.41 (m, 1H), 4.37 - 4.25 (m, 1H), 3.88 - 3.65 (m, 1H), 3.62 - 3.46 (m, 4H), 3.28 (s, 1H), 3.07 - δ 5.14 (m, 1H), 1.22 (m, 3H), 1.17 (m, 3H), 1.22 (m, 3H), 1.44 (m, 3H), 1.23 (m, 3H). 3.39 (m, 1H), 2.97 (m, 1H), 2.68 (d, J = 4.8 Hz, 1H), 2.60 - 2.46 (m, 1H), 2.41 (s, 3H), 2.37 (d, J = 6.3 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.07 - 1.97 (m, 1H), 1.83 - 1.66 (m, 3H), 1.15 - 1.03 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.814 min, ESI+ found [M+H] ⁺ = 597.3. Example 20 : Synthesis of Compound 12 ; 1-((2R,3R)-3-((7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 1) Step 1 : (2R,3R)-3-((7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (220 mg, 88.06%) as a yellow solid. LCMS Rt = 0.471 min, m/z = 691.4 [M + H] ⁺ . Step 2 : 7-(8- ethyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (181 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.566 min, m/z = 591.3 [M + H] ⁺ . Step 3 : 1-((2R,3R)-3-((7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (27.03 mg, 14.28%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.30 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.96 (dd, J = 6.1, 8.9 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.41 (t, J = 9.4 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.29 (dd, J = 10.3, 15.9 Hz, 1H), 5.70 (d, J = 10.0 Hz, 1H), 5.38 - 5.17 (m, 1H), 5.01 - 4.86 (m, 2H), 4.29 - 4.11 (m, 2H), 3.91 - 3.67 (m, 1H), 3.63 (d, J = 6.1 Hz, 3H), 3.60 - 3.48 (m, 1H), 3.20 - 3.05 (m, 3H), 2.96 - 2.85 (m, 1H), 2.68 - 2.46 (m, 2H), 2.43 - 2.20 (m, 3H), 2.12 (s, 1H), 2.07 - 2.00 (m, 1H), 1.93 - 1.80 (m, 3H), 1.17 - 1.06 (m, 3H), 0.88 - 0.79 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.261 min, ESI+ found [M+H] ⁺ = 645.3. Example 21 : Synthesis of Compound 7-1 ; 1-( cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 1) Step 1 : cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-55% B in 8.0 min) to give (2R,3R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (25 mg, 33.05%, trifluoroacetic acid salt) as a yellow solid. LCMS Rt = 1.615 min, m/z = 697.3/698.3 [M + H] ⁺ . Step 2 : 7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-( cis- 2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (25 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.352 min, m/z = 597.3/598.4 [M + H] ⁺ . Step 3 : 1-( cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1 - yl ) prop -2- en -1 -one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×25 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (10.75 mg, 46.88%) as a yellow solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.28 (d, J = 4.2 Hz, 1H), 8.19 - 8.14 (m, 1H), 8.13 - 8.07 (m, 1H), 7.72 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.34 - 6.21 (m, 1H), 5.70 (d, J = 10.4 Hz, 1H), 5.39 - 5.17 (m, 1H), 5.00 - 4.83 (m, 2H), 4.31 - 3.79 (m, 3H), 3.77 - 3.50 (m, 5H), 3.21 - 3.05 (m, 3H), 2.97 - 2.85 (m, 1H), 2.68 - 2.33 (m, 2H), 2.14 - 2.11 (m, 1H), 2.10 - 2.03 (m, 1H), 1.92 - 1.80 (m, 3H), 1.16 - 1.08 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.007 min, ESI+ found [M+H] ⁺ = 651.0/652.0. Examples 22 and 23 : Synthesis of compounds 7-2 and 7-3 ; 1-((2S,3S)-3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin- 1 - yl ) prop-2-en - 1 - one and 1-( cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2 - en -1- one ( Method 1) Step 1 : cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-55% B in 8.0 min) to give cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (110 mg, 39.66%, trifluoroacetate) as a yellow solid. LCMS Rt = 1.624 min, m/z = 697.3/698.3 [M + H] ⁺ . Step 2 : 7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-( cis- 2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (80 mg, crude, trifluoroacetic acid salt) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.350 min, m/z = 597.3/598.3 [M + H] ⁺ . Step 3 : 1-((2S,3S)-3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop-2-en -1 - one and 1-( cis -3-((7-(8- chloro -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop-2-en - 1 - one

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

A mixture of cis-anisomeric _isomers of 1-(cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8- _fluoro -2-(((2R, _7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (30 mg) was further purified by SFC [SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 50%, isocratic elution mode)] to give the following substances arbitrarily designated: Example 22: 1-((2R,3R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 1.508 min) (10.22 mg, 11.69%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 - 3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.957 minutes, ESI+ experimental value [M+H] ⁺ = 651.4/652.4; and Example 23: 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 2, retention time = 1.787 minutes) (10.22 mg, 11.69%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.29 (d, J = 4.2 Hz, 1H), 8.21 - 8.15 (m, 1H), 8.10 (dd, J = 5.9, 8.9 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.55 (t, J = 9.0 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.35 - 6.19 (m, 1H), 5.70 (d, J = 10.0 Hz, 1H), 5.40 - 5.17 (m, 1H), 5.06 - 4.82 (m, 2H), 4.26 - 4.18 (m, 1H), 3.89 (t, J = 9.5 Hz, 1H), 3.74 - 3.50 (m, 5H), 3.24 - 3.06 (m, 3H), 2.97 - 2.85 (m, 1H), 2.70 - 2.48 (m, 1H), 2.45 - 2.32 (m, 1H), 2.14 - 2.06 (m, 3H), 1.94 - 1.82 (m, 3H), 1.16 - 1.06 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.956 min, ESI+ found [M+H] ⁺ = 651.4/652.4. Example 24 : Synthesis of Compound 8-1 ; 1-( cis -3-((7-(7,8 -difluoronaphthalen -1 -yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin - 1- yl ) prop -2- en -1- one ( Method 1) Step 1 : cis -3-((7-(7,8 -difluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 30%-60% B in 8.0 min) to give cis-3-((7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (280 mg, 97.42%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.461 min, m/z = 681.6 [M + H] ⁺ . Step 2 : 7-(7,8 -difluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-( cis- 2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (120 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.332 min, m/z = 581.3 [M + H] ⁺ . Step 3 : 1-( cis- 3-((7-(7,8 -difluoronaphthalen -1 -yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 minutes) to obtain 1-(cis-3-((7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (54.77 mg, 49.95%) as a pale yellow amorphous solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.31 (d, J = 3.8 Hz, 1H), 8.18 - 8.09 (m, 1H), 7.92 (ddd, J = 1.7, 5.0, 9.2 Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.60 - 7.52 (m, 1H), 6.61 (dd, J = 10.2, 16.7 Hz, 1H), 6.28 (dd, J = 9.3, 16.5 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.37 - 5.19 (m, 1H), 4.93 (d, J = 9.0 Hz, 2H), 4.29 - 4.06 (m, 2H), 3.92 - 3.67 (m, 1H), 3.63 (d, J = 6.8 Hz, 3H), 3.59 - 3.42 (m, 1H), 3.20 - 3.11 (m, 2H), 3.08 (s, 1H), 2.95 - 2.87 (m, 1H), 2.64 - 2.35 (m, 2H), 2.14 - 2.03 (m, 3H), 1.94 - 1.88 (m, 2H), 1.87 - 1.79 (m, 1H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.981 min, ESI+ found [M+H] ⁺ = 635.1. Examples 25 and 26 : Synthesis of compounds 8-2 and 8-3 ; 1-((2R,3R)-3-((7-(7,8 -difluoronaphthalen -1 -yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop- 2 - en - 1- one and 1-((2S,3S)-3-((7-(7,8- difluoronaphthalen -1 -yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one ( Method 1)

A mixture of cis-anisomeric isomers of 1-(cis-3-((7-(7,8-difluoronaphthalen- ₁ -yl)-8-fluoro- ₂ -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[ _4,3 -d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (100 mg) was further purified by SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 50%, isocratic elution mode) to give the following substances arbitrarily designated: Example 25: 1-((2R,3R)-3-((7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 2, retention time = 1.639 min) (31.69 mg, 14.63%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.22 - 8.04 (m, 1H), 7.91 (ddd, J = 1.5, 5.1, 9.1Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.56 (dt, J = 7.7, 9.6 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.28 (dd, J = 8.5, 16.3 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.39 - 5.15 (m, 1H), 4.92 (d, J = 7.3 Hz, 2H), 4.30 - 4.06 (m, 2H), 3.95 - 3.47 (m, 5H), 3.22 - 3.04 (m, 3H), 2.99 - 2.83 (m, 1H), 2.70 - 2.46 (m, 1H), 2.43 - 2.21 (m, 2H), 2.12 (d, J = 3.5 Hz, 2H), 1.94 - 1.82 (m, 3H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.910 minutes, ESI+ experimental value [M+H] ⁺ = 635.3; and Example 26: 1-((2S,3S)-3-((7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 1.446 minutes) (29.88 mg, 13.93%): ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.13 (dt, J = 2.2, 4.7 Hz, 1H), 7.92 (ddd, J = 1.5, 5.1, 9.2 Hz, 1H), 7.71 (d, J = 5.4 Hz, 2H), 7.56 (dt, J = 7.6, 9.6 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.28 (dd, J = 9.8, 16.4 Hz, 1H), 5.70 (d, J = 10.1Hz, 1H), 5.41 - 5.16 (m, 1H), 4.92 (s, 2H), 4.32 - 4.03 (m, 2H), 3.94 - 3.50 (m, 5H), 3.21 - 3.04 (m, 3H), 2.99 - 2.86 (m, 1H), 2.72 - 2.47 (m, 1H), 2.46 - 2.20 (m, 2H), 2.14 - 2.05 (m, 2H), 1.94 - 1.79 (m, 3H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.908 min, ESI+ found [M+H] ⁺ = 635.4. Example 27 : Synthesis of Compound 1-4 ; 1-((2R,3S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 2) Step 1 : (2R,3S)-3-( Benzyl ( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2R,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (400 mg, 2.00 mmol), benzaldehyde (233.14 mg, 2.20 mmol) and acetic acid (119.94 mg, 2.00 mmol) in methanol (5 mL) was added sodium cyanoborohydride (251.02 mg, 3.99 mmol) at 0°C and the mixture was stirred at 0°C for 1 hour. Then formaldehyde (486.23 mg, 5.99 mmol, 37% purity in water) was added to the above solution at 0°C and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) at 0°C and extracted with ethyl acetate (3 x 20 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/petroleum ether) to give (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 74.01%) as a colorless oil. LCMS Rt = 0.344 min, m/z = 305.2 [M + H] ⁺ . Step 2 : (2R,3S)-2- methyl -3-( methylamino ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 1.97 mmol) in methanol (6 mL) was added Pd/C (300 mg, 281.9 μmol, purity 10%). The mixture was stirred at 45 °C under hydrogen (50 Psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give tributyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (470 mg, crude) as a yellow oil which was used in the next step without further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 3.77 - 3.61 (m, 1H), 3.44 - 3.34 (m, 1H), 2.86 - 2.79 (m, 1H), 2.45 - 2.41 (m, 3H), 2.13 - 1.96 (m, 1H), 1.76 - 1.65 (m, 2H), 1.47 - 1.44 (m, 9H), 1.22 (s, 3H). LCMS Rt = 0.280 min, m/z = 215.3 [M + H] ⁺ . Step 3 : (2R,3S)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (550 mg, 2.18 mmol) in 1,4-dioxane (8 mL) was added N,N -diisopropylethylamine (844.69 mg, 6.54 mmol) and tributyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (443.53 mg, 2.07 mmol) at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 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/petroleum ether) to give (2R,3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (780 mg, 82.37%) as a yellow solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.09 - 8.91 (m, 1H), 5.21 - 5.05 (m, 1H), 4.08 - 3.89 (m, 1H), 3.88 - 3.70 (m, 1H), 3.54 - 3.47 (m, 1H), 3.47 - 3.44 (m, 3H), 2.52 - 2.38 (m, 1H), 2.17 - 2.07 (m, 1H), 1.52 - 1.47 (m, 9H), 1.43 - 1.35 (m, 3H). LCMS Rt = 0.585 min, m/z = 430.1/431.0 [M + H] ⁺ . Step 4 : (2R,3S)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4 . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give (2R,3S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (794 mg, 79.11%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.87 (s, 1H), 5.39 - 5.19 (m, 1H), 5.10 - 4.94 (m, 1H), 4.37 - 4.17 (m, 2H), 4.08 - 3.90 (m, 1H), 3.86 - 3.65 (m, 1H), 3.51 - 3.41 (m, 1H), 3.38 - 3.35 (m, 3H), 3.30 - 3.20 (s, 3H), 3.05 - 2.94 (m, 1H), 2.47 - 2.35 (m, 1H), 2.32 - 2.17 (m, 2H), 2.17 - 2.05 (m, 2H), 2.02 - 1.87 (m, 3H), 1.51 - 1.47 (m, 9H), 1.36 - 1.31 (m, 3H). LCMS Rt = 0.421 min, m/z = 553.3/555.2 [M + H] ⁺ . Step 5 : (2R,3S)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give (2R,3S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (500 mg, 65.60%) as an orange solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.30 - 9.11 (m, 1H), 7.97 - 7.89 (m, 2H), 7.62 - 7.52 (m, 2H), 7.34 (t, J = 8.8 Hz, 1H), 5.27 - 5.04 (m, 1H), 4.10 - 3.71 (m, 4H), 3.58 - 3.43 (m, 3H), 3.43 - 3.38 (m, 2H), 3.31 - 3.22 (m, 2H), 3.18 - 2.87 (m, 2H), 2.55 - 2.34 (m, 3H), 2.11 (s, 4H), 2.02 - 1.96 (m, 1H), 1.54 - 1.52 (m, 3H), 1.51 - 1.50 (m,9H), 1.20 (s, 3H), 0.92 - 0.84 (m, 18H). LCMS Rt = 0.628 min, m/z = 843.4 [M + H] ⁺ . Step 6 : (2R,3S)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner as in Method #1, Step 6 . The reaction mixture was concentrated in vacuo to give (2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (366 mg, crude) as a yellow solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.14 - 9.09 (m, 1H), 8.00 - 7.92 (m, 2H), 7.65 - 7.56 (m, 2H), 7.37 - 7.32 (m, 1H), 5.40 - 5.21 (m, 1H), 5.11 - 5.00 (m, 1H), 4.29 - 4.18 (m, 1H), 4.07 - 3.71 (m, 3H), 3.44 - 3.40 (m, 3H), 3.25 (s, 3H), 3.19 (s, 2H), 3.00 (d, J = 5.4 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.32 - 2.26 (m, 1H), 2.23 - 2.13 (m, 3H), 1.99 - 1.90 (m, 3H), 1.50 (s, 9H), 1.21 (d, J = 6.8 Hz, 3H). LCMS Rt = 0.474 min, m/z = 687.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3S)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3S)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (90 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.356 min, m/z = 587.3 [M + H] ⁺ . Step 8 : 1-((2R,3S)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) to give 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (34.94 mg, 34.26%) as a yellow amorphous solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.14 - 9.09 (m, 1H), 8.03 - 7.90 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.30 (m, 1H), 6.55 - 6.39 (m, 2H), 5.81 - 5.72 (m, 1H), 5.44 - 5.20 (m, 1H), 5.18 - 5.08 (m, 1H), 4.51 - 4.27 (m, 3H), 4.15 - 3.80 (m, 2H), 3.79 - 3.58 (m, 1H), 3.42 (s, 3H), 3.34 - 3.16 (m, 2H), 3.09 - 2.80 (m, 2H), 2.67 - 2.51 (m, 1H), 2.36 - 2.11 (m, 4H), 2.06 - 2.88 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.055 minutes, ESI+ found [M+H] ⁺ = 641.3. Example 28 : Synthesis of Compound 1-5 ; 1-((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 2) Step 1: (2S,3R)-3-(Benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester

Reductive amination was performed in a similar manner to Method #2 Step 1. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (400 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.339 min, m/z = 305.3 [M + H] ⁺ . Step 2: (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

The debenzylation reaction was performed in a similar manner to Method #2 Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, crude) as a yellow oil which was used in the next step without any further purification. Step 3 : (2S,3R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2 Step 3. The reaction mixture was concentrated to dryness in vacuo to afford tributyl (2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.583 min, m/z = 430.1/432.0 [M + H] ⁺ . Step 4 : (2S,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2S,3R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (200 mg, 62.25%) as a yellow solid. LCMS Rt = 0.421 min, m/z = 553.3/555.2 [M + H] ⁺ . Step 5 : (2S,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 step 5. The reaction mixture was concentrated to dryness in vacuo to afford (2S,3R)-tert-butyl 3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (280 mg, crude) as a brown oil which was used in the next step without any further purification. LCMS Rt = 0.646 min, m/z = 843.5 [M + H] ⁺ . Step 6 : (2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine - 1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #2 Step 6. The reaction mixture was concentrated in vacuo to afford (2S,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (230 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.649 min, m/z = 687.3 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2S,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Boc deprotection was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2S,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (90 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.342 min, m/z = 587.2 [M + H] ⁺ . Step 8 : 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-65% B in 8.0 minutes) to obtain 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (12.41 mg, 97.15%) as a yellow amorphous solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.15 (s, 1H), 8.01 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.35 (t, J = 8.8 Hz, 1H), 6.55 - 6.38 (m, 2H), 5.80 - 5.72 (m, 1H), 5.45 - 5.23 (m, 1H), 5.19 - 5.09 (m, 1H), 4.55 - 4.21 (m, 3H), 4.20 - 3.88 (m, 2H), 3.82 - 3.65 (m, 1H), 3.47 - 3.41 (m, 3H), 3.38 - 3.14 (m, 2H), 3.11 - 2.96 (m, 1H), 2.95 - 2.82 (m, 1H), 2.58 (d, J = 9.8 Hz, 1H), 2.44 - 2.17 (m, 4H), 2.11 - 1.89 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.056 min, ESI+ found [M+H] ⁺ = 641.3. Example 29 : Synthesis of Compound 13-1 or 13-2 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,E)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one ( Method 1) Step 1: (R)-4-(Fluoromethylene)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester

To a solution of potassium tert-butoxide (22.14 g, 197.32 mmol) in N,N -dimethylformamide (210 mL) was added 2-((fluoromethyl)sulfonyl)pyridine (20.74 g, 118.39 mmol) and 1-(tert-butyl)-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate (24 g, 98.66 mmol) at -78 °C. The mixture was stirred at 30 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (300 mL) at 0 °C and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 (250×70 mm, 15 um); mobile phase: [H ₂ O (0.1% TFA); gradient: 30%-65% B in 20.0 min) to give 1-(tert-butyl)-2-methyl 4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate (3.4 g, 13.29%) as a yellow oil. LCMS Rt = 1.694 min, m/z = 260.1 [M + H] ⁺ . Step 2: (R)-(4-(Fluoromethylene)-1-methylpyrrolidin-2-yl)methanol

To a solution of (R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (3.4 g, 13.11 mmol) in tetrahydrofuran (80 mL) was added lithium aluminum hydroxide (20.98 mL, 2.5 M in tetrahydrofuran, 52.45 mmol) at 0°C. The mixture was stirred at 70°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (50 mL) at 0°C and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (R)-(4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methanol (1.3 g, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.137 min, m/z = 146.2 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester and (2R,3R)-3-((7- chloro -8- fluoro -2-(((R,E)-4-( fluoromethylene )-1 -methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 15%-45% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((R)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (550 mg, 35.25%) as a yellow solid. LCMS Rt = 1.397 min, m/z = 539.2/541.2 [M + H] ⁺ .

The non-mirror isomeric mixture of Z-olefin and E-olefin (550 mg) was separated by SFC to give the following arbitrarily designated substances: (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (peak 2, retention time = 1.618 min) as a yellow solid (200 mg, 11.83%). LCMS Rt = 1.397 min, m/z = 539.2/541.2 [M + H] ⁺ ; and (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester as a yellow solid (peak 1, retention time = 1.411 min) (360 mg, 21.29%). LCMS Rt = 1.397 min, m/z = 539.2/541.2 [M + H] ⁺ .

SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 50%, isocratic elution mode). Step 4 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((R,E)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (380 mg, 79.69%) as a yellow solid. LCMS Rt = 0.594 min, m/z = 829.4 [M + H] ⁺ . Step 5 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,E)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (120 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.439 min, m/z = 673.3 [M + H] ⁺ . Step 6 : 7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,E)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, crude, hydrochloride) as a white solid which was used in the next step without any further purification. LCMS Rt = 0.339 min, m/z = 573.3 [M + H] ⁺ . Step 7 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((R,E)-4-( fluoromethylene )-1- methylpyrrolidin - 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (19.05 mg, 16.83%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.09 (m, 2H), 7.69 (d, J = 4.5 Hz, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.83 - 6.53 (m, 2H), 6.36 - 6.21 (m, 1H), 5.77 - 5.63 (m, 1H), 5.08 - 4.82 (m, 2H), 4.62 - 4.33 (m, 2H), 3.94 - 3.67 (m, 1H), 3.63 (d, J = 4.3 Hz, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.28 (s, 1H), δ 5.14 - 5.12 (m, 3H). 3.32 (m, 1H). 4.15 (s, 3H). 3.04 (m, 1H). 4.16 (s, 3H). 3.02 (m, 1H). 4.17 (m, 1H). 3.03 (m, 1H). 3.05 (m, 3H) ^. 4.13 (s, 3H). Example 30 : Synthesis of Compound 13-1 or 13-2 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one ( Method 1) Step 1 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 45%-85% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (200 mg, 72.24%, trifluoroacetate) as a yellow solid. LCMS Rt = 2.324 min, m/z = 829.4 [M + H] ⁺ . Step 2 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to afford tributyl (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (180 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.461 min, m/z = 673.2 [M + H] ⁺ . Step 3 : 7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin -2- yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.355 min, m/z = 573.2 [M + H] ⁺ . Step 4 : 1-((2R,3R)-3-((7-(8- ethynyl- 7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((R,Z)-4-( fluoromethylene )-1- methylpyrrolidin - 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (15.70 mg, 8.94%) as a yellow solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.06 (m, 2H), 7.70 (d, J = 4.8 Hz, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.73 - 6.42 (m, 2H), 6.34 - 6.22 (m, 1H), 5.77 - 5.61 (m, 1H), 5.01 - 4.81 (m, 2H), 4.65 - 4.36 (m, 2H), 3.93 - 3.68 (m, 2H), 3.63 (s, 4H), 3.36 - 3.20 (m, 1H), 2.98 (d, J = 14.3 Hz, 1H), 2.87 δ 5.14 (m, 1H), 1.25 (m, 4H), 1.12 (m, 5H), 1.2 (m, 4H). δ 5.15 (m, 1H), 1.2 (m, 4H), 1.4 (m, 5H). δ 5.13 (m, 1H), 1.2 (m, 4H), 1.2 (m, 5H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.997 min, ESI+ found [M+H] ⁺ = 627.3. Example 31 : Synthesis of Compound 14-1 ; 1-((2R,3R)-3-((2-((2-( difluoromethylene ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one ( Method 1) Step 1 : 2-( Difluoromethylene )-5 -oxo-tetrahydro -1H -pyrrolizine -7a(5H) -carboxylic acid ethyl ester

To a solution of potassium tert-butoxide (10.63 g, 94.69 mmol) in N,N -dimethylformamide (400 mL) was added ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (10 g, 47.35 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (10.97 g, 56.81 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at 30 °C under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and diluted with hydrochloric acid (10 mL, 12 M in water) and extracted with ethyl acetate (3 x 60 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/petroleum ether) to give ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (5.45 g, 46.94%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.29 (d, J = 14.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 14.1 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.73 (td, J = 9.7, 16.9 Hz, 1H), 2.55 (ddd, J = 1.8, 9.3, 13.1 Hz, 1H), 2.48 - 2.27 (m, 2H), 2.07 (td, J = 10.1, 13.2 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). LCMS Rt = 0.394 min, m/z = 246.4 [M + H] ⁺ . Step 2: (2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

To a solution of ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (5 g, 20.39 mmol) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (203.90 mL, 20.39 mmol, 1 M in toluene) at 0°C, and the reaction solution was stirred at 25°C under a nitrogen atmosphere for 1 hour. The solution was quenched with sodium sulfate decahydrate (500 mg) at 0°C. The mixture was then filtered, and the filtrate was concentrated to dryness in vacuo to give (2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (3.3 g, crude) as a yellow oil. LCMS Rt = 0.091 min, m/z = 190.3 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7- chloro -2-((2-( difluoromethylene ) tetrahydro - 1H -pyrrolizin -7a(5H) -yl ) methoxy )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-tert-butyl 3-((7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (310 mg, 45.76%) as a yellow oil. LCMS Rt = 0.419 min, m/z = 583.2/585.1 [M + H] ⁺ . Step 4 : (2R,3R)-3-((2-((2-( difluoromethylene ) tetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((2-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (310 mg, 69.00%) as a yellow solid. LCMS Rt = 1.890 min, m/z = 873.6 [M + H] ⁺ . Step 5 : 2-((2-( difluoromethylene ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 2-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (50 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.495 min, m/z = 773.4 [M + H] ⁺ . Step 6 : 2-((2-( difluoromethylene ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to afford 2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.360 min, m/z = 617.3 [M + H] ⁺ . Step 7 : 1-((2R,3R)-3-((2-((2-( difluoromethylene ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin-1 - yl ) prop - 2- en - 1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 8.0 min) to give 1-((2R,3R)-3-((2-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (10.57 mg, 23.91%) as a yellow solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (s, 1H), 8.24 - 8.08 (m, 2H), 7.77 - 7.58 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.66 - 6.55 (m, 1H), 6.42 - 6.17 (m, 1H), 5.83 - 5.62 (m, 1H), 5.03 - 4.80 (m, 2H), 4.33 - 4.10 (m, 2H), 3.70 (d, J = 14.1 Hz, 2H), 3.63 (d, J = 7.1 Hz, 3H), 3.41 - 3.26 (m, 2H), 3.10 - 3.03 (m, 3H), 1.77 - 1.76 (m, 4H), 1.19 - 1.03 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 min) retention time 2.494 min, ESI+ found [M+H] ⁺ = 671.2. Examples 32 and 33 : Synthesis of Compounds 14-2 and 14-3 ; 1-((2R,3R)-3-((2-(((S)-2-( difluoromethylene ) tetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) -7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one and 1- ((2R,3R)-3-((2-(((R)-2-( difluoromethylene ) tetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one ( Method 1 )

A mixture of non-mirror isomers of 1-((2R,3R)-3-((2-((2-(difluoromethylene) _tetrahydro- 1H-pyrrolazin-7a _{(5H )} -yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (50 mg) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 40%, isocratic elution mode) to obtain the following substances arbitrarily designated: Example 32: 1-((2R,3R)-3-((2-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 0.626 min) (20.16 mg, 48.89%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.14 (s, 1H), 8.12 - 7.92 (m, 2H), 7.70 - 7.49 (m, 2H), 7.37 (t, J = 9.1 Hz, 1H), 6.67 - 6.38 (m, 1H), 6.22 - 6.10 (m, 1H), 5.68 - 5.43 (m, 1H), 4.90 - 4.71 (m, 2H), 4.20 - 4.06 (m, 2H), 3.66 - 3.54 (m, 2H), 3.52 (d, J = 5.4 Hz, 3H), 3.33 - 3.14 (m, 2H), 3.00 - 2.89 (m, 1H), 2.64 - 2.48 (m, 2H), 2.37 - 2.22 (m, 2H), 2.03 (d, J = 2.5 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.85 - 1.67 (m, 4H), 1.08 - 0.95 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.111 minutes, ESI+ experimental value [M+H] ⁺ = 671.3; and Example 33: 1-((2R,3R)-3-((2-(((R)-2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 2, retention time = 0.733 minutes) (19.62 mg, 47.44%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.25 (s, 1H), 8.19 - 8.08 (m, 2H), 7.73 - 7.64 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.70 - 6.53 (m, 1H), 6.36 - 6.22 (m, 1H), 5.76 - 5.64 (m, 1H), 5.03 - 4.82 (m, 2H), 4.34 - 4.15 (m, 2H), 3.79 - 3.67 (m, 2H), 3.63 (d, J = 6.4 Hz, 3H), 3.41 - 3.25 (m, 2H), 3.14 - 3.02 (m, 1H), 2.74 - 2.62 (m, 2H), 2.48 - 2.34 (m, 2H), 2.14 (d, J = 2.6 Hz, 1H), 2.06 (d, J = 10.1 Hz, 1H), 1.96 - 1.76 (m, 4H), 1.22 - 1.04 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.112 min, ESI+ found [M+H] ⁺ = 671.3. Example 34 : Synthesis of Compound 15-1 or 15-2 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 1) Step 1 : (E)-2-( Fluoromethylene )-5 -oxotetrahydro -1H -pyrrolizine -7a(5H) -carboxylic acid ethyl ester and (Z)-2-( Fluoromethylene )-5 -oxotetrahydro -1H- pyrrolizine -7a(5H) -carboxylic acid ethyl ester

To a solution of (fluoromethyl)triphenylphosphonium tetrafluoroborate (62.42 g, 163.34 mmol) in tetrahydrofuran (500 mL) was added sodium bis(trimethylsilyl)amide (163.34 mL, 163.34 mmol, 1M in tetrahydrofuran) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1.5 hours. Ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (23 g, 108.89 mmol) was then added to the above solution at -78°C. The mixture was stirred at -78°C under nitrogen atmosphere for 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride (100 mL) at 0° C. and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×150mm×15um; mobile phase: [H ₂ O (0.1%TFA)-ACN]; gradient: 20%-50% B in 20.0 minutes) to give (E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (700 mg, 2.83%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 6.70 - 6.45 (m, 1H), 4.40 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.90 (d, J = 16.0 Hz, 1H), 3.05 (d, J = 15.0 Hz, 1H), 2.84 (td, J = 9.8, 16.9 Hz, 1H), 2.65 - 2.47 (m, 2H), 2.44 - 2.35 (m, 1H), 2.17 (td, J = 10.2, 13.1Hz, 1H), 1.30 (t, J = 7.1Hz, 3H). LCMS Rt = 1.390 min, m/z = 228.2 [M + H] ⁺ .

(Z)-2-(Fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (700 mg, 2.83%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 6.74 - 6.49 (m, 1H), 4.35 (d, J = 14.5 Hz, 1H), 4.23 (dq, J = 1.9, 7.1Hz, 2H), 3.73 (d, J = 14.6 Hz, 1H), 3.32 (d, J = 16.4 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.72 - 2.64 (m, 1H), 2.54 - 2.40 (m, 2H), 2.21 - 2.09 (m, 1H), 1.30 (dt, J = 1.9, 7.1 Hz, 3H). LCMS Rt = 1.436 min, m/z = 228.2 [M + H] ⁺ . Step 2 : (E)-(2-( Fluoromethylene ) tetrahydro -1H -pyrrolizine- 7a(5H) -yl ) methanol

To a solution of ethyl (E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (650 mg, 2.86 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydroxide (1.72 mL, 4.29 mmol, 2.5 M in tetrahydrofuran) at 0°C under nitrogen atmosphere. The mixture was stirred at 70°C under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (14.20 g) at 0°C and dried over sodium sulfate. The resulting precipitate was filtered and the filtrate was concentrated in vacuo to give (E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (550 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt = 0.284 min, m/z = 172.3 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 15%-45% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (250 mg, 18.91%, trifluoroacetic acid salt) as a yellow solid. LCMS Rt = 0.409 min, m/z = 565.3/567.3 [M + H] ⁺ . Step 4 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 65%-95% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (100 mg, 33.04%) as a yellow solid. LCMS Rt = 0.620 min, m/z = 855.4 [M + H] ⁺ . Step 5 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of TIPS was performed in a similar manner to Method #1 Step 6. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (12 mg, crude) as a yellow oil which was used in the next step without further purification. LCMS Rt = 0.458 min, m/z = 699.3 [M + H] ⁺ . Step 6 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (10 mg, crude, hydrochloride) as a yellow oil which was used in the next step without further purification. LCMS Rt = 0.336 min, m/z = 599.2 [M + H] ⁺ . Step 7 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((E)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-70% B in 8.0 min) to obtain 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (3.31 mg, 9.34%) as a yellow solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.22 (s, 1H), 8.15 - 8.08 (m, 2H), 7.69 - 7.65 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.72 - 6.45 (m, 2H), 6.31 - 6.21 (m, 1H), 5.70 - 5.63 (m, 1H), 4.95 - 4.84 (m, 2H), 4.26 - 4.10 (m, 2H), 3.92 - 3.71 (m, 2H), 3.67 (d, J = 10.9 Hz, 1H), 3.60 (d, J = 5.4 Hz, 3H), 3.58 - 3.41 (m, 1H), 3.37 (d, J = 14.1 Hz, 1H), 3.29 - 3.24 (m, 1H), 3.11 - 3.00 (m, 1H), 2.63 - 2.58 (m, 2H), 2.36 (d, J = 15.5 Hz, 2H), 2.03 (dt, J = 3.9, 8.0 Hz, 1H), 1.91 - 1.82 (m, 2H), 1.80 - 1.72 (m, 1H), 1.15 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.042 min, ESI+ found [M+H] ⁺ = 653.3. Example 35 : Synthesis of Compound 15-1 or 15-2 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 1) Step 1 : (Z)-(2-( Fluoromethylene ) tetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methanol

To a solution of (Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (740 mg, 3.26 mmol) in tetrahydrofuran (6 mL) was added lithium aluminum hydroxide (1.95 mL, 4.88 mmol, 2.5 M in tetrahydrofuran) at 0°C under nitrogen atmosphere. The mixture was stirred at 70°C under nitrogen atmosphere for 2 hours. The reaction mixture was quenched with sodium sulfate decahydrate (1 g) at 0°C and dried over sodium sulfate. The resulting precipitate was filtered and concentrated in vacuo to give (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (600 mg, crude) as a yellow oil which was used in the next step without further purification: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 6.63 - 6.31 (m, 1H), 3.24 (d, J = 5.3 Hz, 1H), 3.17 - 2.95 (m, 2H), 2.57 - 2.43 (m, 2H), 2.36 - 2.23 (m, 2H), 2.00 - 1.85 (m, 2H), 1.76 - 1.50 (m, 4H). LCMS Rt = 0.154 min, m/z = 172.3 [M + H] ⁺ . Step 2 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 20%-50% B in 10.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (350 mg, 36.96%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.401 min, m/z = 565.3/567.3 [M + H] ⁺ . Step 3 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 45%-75% B in 8.0 minutes) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (110 mg, 18.32%, trifluoroacetate) as a yellow solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.79 - 9.40 (m, 1H), 8.01 - 7.78 (m, 2H), 7.66 - 7.45 (m, 2H), 7.30 (dt, J = 4.0, 8.7 Hz, 1H), 6.91 - 6.44 (m, 1H), 5.14 - 4.88 (m, 1H), 4.82 - 4.63 (m, 1H), 4.56 - 4.40 (m, 2H), 4.04 - 3.83 (m, 2H), 3.58 - 3.48 (m, 3H), 3.45 - 3.32 (m, 1H), 3.17 - 2.67 (m, 3H), 2.50 - δ 1.14 - 1.16 (m, 1H), 1.54 - 1.71 (m, 1H), 1.20 - 1.43 (m, 9H), 1.11 - 1.00 (m, 3H), 0.92 - 0.69 (m, 18H), 0.62 - 0.37 (m, 3H). LCMS Rt = 0.622 min, m/z = 855.4 [M + H] ⁺ . Step 4 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of TIPS was performed in a similar manner to Method #1 Step 6. The reaction mixture was filtered and concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (16 mg, crude) as a white solid which was used in the next step without further purification. LCMS Rt = 0.475 min, m/z = 699.3 [M + H] ⁺ . Step 5 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (15 mg, crude, hydrochloride) as a white solid which was used in the next step without further purification. LCMS Rt = 0.342 min, m/z = 599.2 [M + H] ⁺ . Step 6 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((Z)-2-( fluoromethylene ) tetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (2.87 mg, 18.62%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (s, 1H), 8.21 - 8.07 (m, 2H), 7.76 - 7.63 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.83 - 6.53 (m, 2H), 6.39 - 6.19 (m, 1H), 5.70 (dd, J = 2.3, 10.3 Hz, 1H), 5.02 - 4.84 (m, 2H), 4.29 - 4.13 (m, 2H), 3.63 (d, J = 6.9 Hz, 3H), 3.31 - 3.21 (m, 2H), 3.14 - 3.07 (m, 2H), 2.77 (td, J = 2.7, 16.3 Hz, 1H), 2.62 - 2.58 (m, 1H), 2.47 (d, J = 16.9 Hz, 1H), 2.10 - 2.03 (m, 1H), 1.91 - 1.86 (m, 1H), 1.82 - 1.76 (m, 1H), 1.66 - 1.58 (m, 2H), 1.41 - 1.34 (m, 2H), 1.16 (s, 1H), 0.99 (t, J = 7.3 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.036 min, ESI+ found [M+H] ⁺ = 653.3. Examples 36 and 37: Synthesis of two of compounds 15-3 to 15-6 (Method 1)

A mixture of non-mirror isomers of 1-((2R,3R)-3-((7-(8 _- ethynyl-7-fluoronaphthalen- _{1- yl} )-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (30 mg) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 35%, isocratic elution mode) to obtain the following substances arbitrarily designated: Example 36: (Peak 1, retention time = 1.244 min) (8.85 mg, 29.13%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.14 (d, J = 2.9 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.58 (d, J = 5.0 Hz, 2H), 7.36 (t, J = 9.1 Hz, 1H), 6.63 - 6.36 (m, 2H), 6.24 - 6.11 (m, 1H), 5.63 - 5.54 (m, 1H), 4.89 - 4.72 (m, 2H), 4.13 - 4.01 (m, 2H), 3.80 - 3.58 (m, 2H), 3.54 - 3.38 (m, 4H), 3.31 - 3.16 (m, 2H), 2.95 (d, J = 4.1 Hz, 1H), 2.56 - 2.50 (m, 2H), 2.26 (d, J = 15.0 Hz, 2H), 2.11 (s, 1H), 1.97 - 1.89 (m, 1H), 1.84 - 1.71 (m, 2H), 1.71 - 1.61 (m, 1H), 1.05 - 0.96 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.054 minutes, ESI+ experimental value [M+H] ⁺ = 653.3; and Example 37: (peak 2, retention time = 1.339 minutes) (8.85 mg, 29.13%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.25 (d, J = 2.4 Hz, 1H), 8.19 - 8.10 (m, 2H), 7.69 (d, J = 4.4 Hz, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.73 - 6.47 (m, 2H), 6.35 - 6.22 (m, 1H), 5.70 (dd, J = 2.3, 10.3 Hz, 1H), 4.99 - 4.80 (m, 2H), 4.32 - 4.08 (m, 2H), 3.94 - 3.78 (m, 1H), 3.77 - 3.68 (m, 1H), 3.62 (d, J = 6.1 Hz, 4H), 3.38 (d, J = 15.0 Hz, 1H), 3.31 - 3.25 (m, 1H), 3.10 - 3.03 (m, 1H), 2.69 - 2.51 (m, 3H), 2.37 (d, J = 15.0 Hz, 2H), 2.08 - 1.99 (m, 1H), 1.94 - 1.83 (m, 2H), 1.82 - 1.72 (m, 1H), 1.17 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.052 minutes, ESI+ found [M+H] ⁺ = 653.3. Example 38 : Synthesis of Compound 16 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-2- methylenetetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((S)-2- methylenetetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% tetrahydrofuran/ethyl acetate) to afford (2R,3R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (550 mg, 86.52%) as a yellow oil. LCMS Rt = 0.413 min, m/z = 547.3/549.3 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((S)-2- methylenetetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (730 mg, 88.34%) as a yellow solid. LCMS Rt = 2.470 min, m/z = 837.4 [M + H] ⁺ . Step 3 : 8- Fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -2-(((S)-2- methylenetetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N-((2R,3R)-2- methylpyrrolidin- 3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-2-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (300 mg, crude, hydrochloride) as a yellow oil which was used in the next step without further purification. LCMS Rt = 0.479 min, m/z = 737.4 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N- methyl -2-(((S)-2 -methylenetetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of TIPS was performed in a similar manner to Method #1 Step 6. The reaction mixture was filtered and concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (200 mg, crude) as a white solid which was used in the next step without further purification. LCMS Rt = 0.347 min, m/z = 581.4 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-2- methylenetetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 100×30 mm×3 um; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 20%-55% B in 8.0 minutes) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (22.32 mg, 68.27%, formate) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.25 (s, 1H), 8.20 - 8.05 (m, 2H), 7.69 (d, J = 5.4 Hz, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.34 - 6.22 (m, 1H), 5.70 (dd, J = 2.3, 10.3 Hz, 1H), 4.98 - 4.84 (m, 4H), 4.26 - 4.14 (m, 2H), 3.74 - 3.65 (m, 2H), 3.62 (s, 3H), 3.34 - 3.25 (m, 2H), 3.15 - 3.06 (m, 3H), 1.76 - 1.54 (m, 1H), 2.5 - 2.63 (m, 4H), 2.42 - 2.89 (m, 2H), 2.05 (dd, J = 3.2, 7.5 Hz, 1H), 1.95 - 1.85 (m, 2H), 1.82 - 1.71 (m, 1H), 1.22 - 1.03 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.931 min, ESI+ found [M+H] ⁺ = 635.3. Examples 39 and 40 : Synthesis of Compounds 17-1 and 17-2 ; 1-((2R,3R)-3-((2-(((3aS,5S)-2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H)-yl ) methoxy ) -7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin - 4 - yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop-2-en -1 - one and 1- ((2R,3R)-3-((2-(((3aR,5R)-2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin - 1 - yl ) prop -2- en - 1- one ( Method 1) Step 1: 3-allyl-1-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester

To a solution of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (125 g, 535.88 mmol) in N,N -dimethylformamide (1500 mL) at 0°C under nitrogen atmosphere was added 3-bromoprop-1-ene (324.14 g, 2.68 mol) followed by sodium hydride (64.30 g, 1.61 mol, 60% purity). The mixture was stirred at 20°C under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (3000 mL) and water (100 mL) at 0°C and extracted with ethyl acetate (3 x 500 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/petroleum ether) to give methyl 3-allyl-1-benzyl-5-oxopyrrolidine-3-carboxylate (120 g, 81.93%) as a white solid. LCMS Rt = 0.411/0.430 min, m/z = 274.1 [M + H] ⁺ . Step 2: 1-Benzyl-3-(oxiran-2-ylmethyl)-5-oxopyrrolidine-3-carboxylic acid methyl ester

To a solution of methyl 3-allyl-1-benzyl-5-oxopyrrolidine-3-carboxylate (120 g, 439.04 mmol) in dichloromethane (3000 mL) at 0°C under nitrogen atmosphere was added methyl 3-chloroperoxybenzoate (118.04 g, 581.38 mol, purity 85%). The mixture was stirred at 40°C under nitrogen atmosphere for 3 hours. The reaction mixture was quenched with saturated sodium sulfite (3000 mL) and water (1000 mL) at 0°C and extracted with dichloromethane (3 x 500 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/petroleum ether) to give methyl 1-benzyl-3-(oxiran-2-ylmethyl)-5-oxopyrrolidine-3-carboxylate (120 g, 94.47%) as a white solid. LCMS Rt = 0.380 min, m/z = 290.1 [M + H] ⁺ . Step 3: 2-Benzyl-5-hydroxy-1-oxocyclopenta[c]pyrrole-3a(1H)-carboxylic acid methyl ester

To a solution of methyl 1-benzyl-3-(oxiran-2-ylmethyl)-5-oxopyrrolidine-3-carboxylate (75 g, 259.23 mmol) in tetrahydrofuran (900 mL) was added lithium bis(trimethylsilyl)amide (518.46 mL, 518.46 mol, 1 M in tetrahydrofuran) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 hours and then at 20 °C for 10 hours under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride (2500 mL) and water (1000 mL) at 0 °C and extracted with dichloromethane (3 x 500 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/petroleum ether) to give methyl 2-benzyl-5-hydroxy-1-oxohexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylate (4 g, 5.33%) as a white solid. LCMS Rt = 0.342 min, m/z = 290.1 [M + H] ⁺ . Step 4 : cis -2- benzyl -5- fluoro - 1-oxocyclopenta [c] pyrrole -3a(1H) -carboxylic acid methyl ester and trans -2- benzyl -5- fluoro - 1-oxocyclopenta [c] pyrrole -3a(1H) -carboxylic acid methyl ester

To a solution of methyl 2-benzyl-5-hydroxy-1-oxohexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylate (3.9 g, 13.48 mmol) in dichloromethane (10 mL) at 0°C was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethanamine (3.58 g, 16.18 mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (300 mL) and water (100 mL) at 0°C and extracted with dichloromethane (3 x 100 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, 0-50% ethyl acetate/petroleum ether) to give cis-2-benzyl-5-fluoro-1-oxocyclopenta[c]pyrrole-3a(1H)-carboxylic acid methyl ester (1 g, 25.47%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.31 - 7.08 (m, 5H), 5.17 - 4.91 (m, 1H), 4.46 (d, J = 14.6 Hz, 1H), 4.27 (d, J = 14.6 Hz, 1H), 3.65 (s, 3H), 3.54 (dd, J = 4.7, 9.7 Hz, 1H), 3.39 (d, J = 10.4 Hz, 1H), 3.09 (d, J = 10.4 Hz, 1H), 2.81 - 2.63 (m, 1H), 2.45 - 2.19 (m, 2H), 1.72 - 1.52 (m, 1H). LCMS Rt = 0.414 min, m/z = 292.1 [M + H] ⁺ .

Trans-2-Benzyl-5-fluoro-1-oxocyclopenta[c]pyrrole-3a(1H)-carboxylic acid methyl ester (980 mg, 24.96%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.37 - 7.23 (m, 5H), 5.37 - 5.08 (m, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.35 (d, J = 14.8 Hz, 1H), 3.85 (d, J = 10.4 Hz, 1H), 3.74 (s, 3H), 3.37 - 3.22 (m, 2H), 2.71 - 2.39 (m, 2H), 2.28 - 2.08 (m, 2H). LCMS Rt = 0.414 min, m/z = 292.1 [M + H] ⁺ . Step 5 : ( cis -2- benzyl- 5 - fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methanol

To a solution of cis-2-benzyl-5-fluoro-1-oxohexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylic acid methyl ester (1 g, 3.43 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydroxide (4.12 mL, 10.30 mmol, 2.5 M in tetrahydrofuran) at 0°C under nitrogen atmosphere. The mixture was stirred at 50°C under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (1000 mg) at 0°C and dried over sodium sulfate. The resulting precipitate was filtered and concentrated in vacuo to give (cis-2-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (850 mg, crude) as a white solid, which was used in the next step without further purification. LCMS Rt = 0.262 min, m/z = 250.1 [M + H] ⁺ . Step 6 : ( cis - 5-fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methanol

To a solution of (cis-2-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (500 mg, 2.01 mmol) in ethyl acetate (10 mL) was added Pd/C (1.07 g, purity 10%). The mixture was then degassed and purged with hydrogen three times and stirred at 25 °C under hydrogen atmosphere (15 psi) for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give (cis-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (300 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt = 0.185 min, m/z = 160.3 [M + H] ⁺ . Step 7: 1-(cis-5-fluoro-3a-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one

To a solution of (cis-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (300 mg, 1.88 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added sodium carbonate (599.18 mg, 5.65 mmol) and acetyl chloride (221.88 mg, 2.83 mmol) at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated in vacuo to give 1-(cis-5-fluoro-3a-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (300 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt = 0.171 min, m/z = 202.2 [M + H] ⁺ . Step 8 : (2R,3R)-3-((2-(( cis -2- acetyl - 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7- chloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1, Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-65% B in 8.0 min) to give (2R,3R)-3-((2-((cis-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (20 mg, 5.59%, trifluoroacetate) as a white solid. LCMS Rt = 2.281 min, m/z = 595.3/597.2 [M + H] ⁺ . Step 9: (2R,3R)-3-((2-((cis-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 65%-95% B in 8.0 min) to give (2R,3R)-3-((2-((cis-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (17 mg, 50.62%, trifluoroacetate) as a white solid. LCMS Rt = 0.692 min, m/z = 885.5 [M + H] ⁺ . Step 10 : (2R,3R)-3-((2-(( cis -2- acetyl -5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of TIPS was performed in a similar manner to Method #1 step 6. The reaction mixture was filtered and concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((2-((cis-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (7 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS Rt = 0.516 min, m/z = 729.1 [M + H] ⁺ . Step 11 : 1-( cis- 3a-(((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -4-( methyl ((2R,3R)-2 -methylpyrrolidin -3 - yl ) amino ) pyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl )-5- fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ) ethan -1- one

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 1-(cis-3a-(((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (7 mg, crude, hydrochloride) as a white solid which was used in the next step without further purification. LCMS Rt = 0.491 min, m/z = 629.2 [M + H] ⁺ . Step 12 : 1-((2R,3R)-3-((2-(((3aS,5S)-2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H)-yl ) methoxy ) -7-(8- ethynyl- 7 - fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one and 1-((2R,3R)-3-((2-(((3aR,5R)-2- acetyl -5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1, Step 8. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) to give the following substances arbitrarily designated: Example 39: 1-((2R,3R)-3-((2-(((3aS,5S)-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (1.18 mg, 17.34%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.26 (s, 1H), 8.27 - 8.07 (m, 2H), 7.77 - 7.63 (m, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.71 - 6.53 (m, 1H), 6.36 - 6.16 (m, 1H), 5.74 - 5.65 (m, 1H), 5.36 - 5.18 (m, 1H), 4.99 - 4.84 (m, 2H), 4.57 - 4.38 (m, 2H), 3.94 - 3.84 (m, 1H), 3.82 - 3.66 (m, 3H), 3.64 (d, J = 4.3 Hz, 3H), 3.60 - 3.51 (m, 1H), 3.46 - 3.39 (m, 1H), 3.37 - 3.27 (m, 1H), 2.99 - 2.40 (m, 2H), 2.26 (d, J = 1.0 Hz, 2H), 2.15 - 2.14 (m, 3H), 2.12 (d, J = 2.0 Hz, 2H), 1.91 (s, 1H), 1.30 (s, 3H). LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 minutes) retention time 2.383 minutes, ESI+ experimental value [M+H] ⁺ = 683.3; and Example 40: 1-((2R,3R)-3-((2-(((3aR,5R)-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (1.11 mg, 16.74%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.26 (d, J = 2.1 Hz, 1H), 8.34 - 8.07 (m, 2H), 7.79 - 7.61 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.72 - 6.53 (m, 1H), 6.40 - 6.18 (m, 1H), 5.70 (dd, J = 2.1, 10.3 Hz, 1H), 5.21 (s, 1H), 5.01 - 4.82 (m, 2H), 4.56 - 4.38 (m, 2H), 3.94 - 3.84 (m, 1H), 3.83 - 3.66 (m, 3H), 3.64 (d, J = 4.3 Hz, 3H), 3.61 - 3.54 (m, 1H), 3.46 - 3.40 (m, 1H), 3.35 - 3.26 (m, 1H), 2.97 - 2.47 (m, 2H), 2.44 - 2.23 (m, 2H), 2.14 - 2.10 (m, 3H), 2.09 - 2.02 (m, 2H), 1.92 (d, J = 5.5 Hz, 1H), 1.30 (s, 3H). LCMS (5% to 95% ACN/H2O + 0.1% TFA over 6 min) retention time 2.384 min, ESI+ found [M+H] ⁺ = 683.3 Example 41 : Synthesis of Compound 17-3 ; 1-((2R,3R)-3-((2-(( trans -2- acetyl -5 - fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one ( Method 1) Step 1 : ( trans -2- benzyl -5 - fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methanol

To a solution of trans-2-benzyl-5-fluoro-1-oxocyclopenta[c]pyrrole-3a(1H)-carboxylic acid methyl ester (980 mg, 3.36 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydroxide (4.04 mL, 10.09 mmol, 2.5 M in tetrahydrofuran) at 0°C under nitrogen atmosphere. The mixture was stirred at 50°C under nitrogen atmosphere for 1 hour. The reaction mixture was then quenched with sodium sulfate decahydrate (1000 mg) at 0°C and dried over sodium sulfate. The resulting precipitate was filtered and concentrated in vacuo to give (trans-2-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (830 mg, crude) as a white solid, which was used in the next step without further purification. LCMS Rt = 0.270 min, m/z = 250.1 [M + H] ⁺ . Step 2 : ( trans -5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methanol

To a solution of (trans-2-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (350 mg, 1.40 mmol) in ethyl acetate (5 mL) was added Pd/C (400 mg, purity 10%). The mixture was then degassed and purged with hydrogen three times and stirred at 25 °C under hydrogen atmosphere (15 psi) for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give (trans-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (210 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt = 0.185 min, m/z = 160.3 [M + H] ⁺ . Step 3 : 1-( trans- 5- fluoro -3a-( hydroxymethyl ) hexahydrocyclopenta [c] pyrrol -2(1H) -yl ) ethan -1- one

To a solution of (trans-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (200 mg, 1.26 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added sodium carbonate (399.45 mg, 3.77 mmol) and acetyl chloride (147.92 mg, 1.88 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give 1-(trans-5-fluoro-3a-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (230 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt = 0.134 min, m/z = 202.2 [M + H] ⁺ . Step 4 : (2R,3R)-3-((2-(( trans -2- acetyl - 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7- chloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-65% B in 8.0 min) to give (2R,3R)-3-((2-((trans-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (45 mg, 13.26%, trifluoroacetate) as a white solid. LCMS Rt = 1.700 min, m/z = 595.3/597.2 [M + H] ⁺ . Step 5 : (2R,3R)-3-((2-(( trans- 2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-CAN]; gradient: 65%-95% B in 8.0 min) to give (2R,3R)-3-((2-((trans-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (50 mg, 74.45%, trifluoroacetate) as a white solid. LCMS Rt = 0.722 min, m/z = 885.5 [M + H] ⁺ . Step 6 : 1-( trans- 5- fluoro -3a-(((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-4-( methyl ((2R,3R)-2 -methylpyrrolidin -3- yl ) amino ) pyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) hexahydrocyclopenta [c] pyrrol -2(1H) -yl ) ethan -1- one

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 1-(trans-5-fluoro-3a-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (37 mg, crude, hydrochloride) as a yellow oil which was used in the next step without further purification. LCMS Rt = 0.557 min, m/z = 785.4 [M + H] ⁺ . Step 7 : 1-( trans- 3a-(((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -4-( methyl ((2R,3R)-2 -methylpyrrolidin -3 - yl ) amino ) pyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl )-5- fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ) ethan -1- one

Deprotection of TIPS was performed in a similar manner to Method #1 Step 6. The reaction mixture was filtered and concentrated in vacuo to afford 1-(trans-3a-(((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (28 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS Rt = 0.400 min, m/z = 629.2 [M + H] ⁺ . Step 8 : 1-((2R,3R)-3-((2-(( trans- 2- acetyl - 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen - 1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 min) to give 1-((2R,3R)-3-((2-((trans-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (1.18 mg, 17.34%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.26 (s, 1H), 8.18 - 8.11 (m, 2H), 7.69 (d, J = 5.3 Hz, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.35 - 6.23 (m, 1H), 5.70 (dd, J = 2.0, 10.3 Hz, 1H), 5.37 - 5.17 (m, 1H), 4.98 - 4.81 (m, 2H), 4.51 - 4.27 (m, 2H), 3.93 - 3.79 (m, 1H), 3.78 - 3.65 (m, 3H), 3.63 (s, 3H), 3.59 - 3.51 (m, 1H), 3.50 - 3.40 (m, 1H), 3.38 - 3.26 (m, 1H), 2.78 - 2.47 (m, 2H), 2.38 (d, J = 5.3 Hz, 2H), 2.20 (s, 3H), 2.18 - 2.04 (m, 2H), 1.90 (s, 1H), 1.18 - 1.07 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.889 min, ESI+ found [M+H] ⁺ = 683.3. Examples 42 and 43 : Synthesis of Compounds 17-4 and 17-5 ; 1-((2R,3R)-3-((2-(((3aS,5R)-2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H)-yl ) methoxy ) -7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin - 4 - yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop-2-en -1 - one and 1- ((2R,3R)-3-((2-(((3aR,5S)-2- acetyl- 5- fluorohexahydrocyclopenta [c] pyrrol -3a(1H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin - 1 - yl ) prop -2- en - 1- one ( Method 1)

A mixture of non-mirror isomers of 1-((2R,3R)-3-((2-((trans- ₂ -acetyl _- 5-fluorohexahydrocyclopenta[c]pyrrol-3a( _1H )-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (30 mg) was separated by SFC (column: DAICEL CHIRALCEL OX (250 mm×30 mm, 10 um); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2 O)]; B%: 60%, isocratic elution mode) to obtain the following substances arbitrarily designated as follows: Example 42: 1-((2R,3R)-3-((2-(((3aS,5R)-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow solid (peak 1, retention time = 1.852 minutes) (9.36 mg, 29.12%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.15 (s, 1H), 8.08 - 7.99 (m, 2H), 7.58 (d, J = 5.3 Hz, 2H), 7.37 (t, J = 9.0 Hz, 1H), 6.58 - 6.44 (m, 1H), 6.25 - 6.11 (m, 1H), 5.60 (dd, J = 2.1, 10.4 Hz, 1H), 5.27 - 5.07 (m, 1H), 4.89 - 4.70 (m, 2H), 4.36 - 4.18 (m, 2H), 3.81 - 3.71 (m, 1H), 3.68 - 3.54 (m, 3H), 3.53 (d, J = 3.9 Hz, 3H), 3.49 - 3.42 (m, 1H), 3.39 - 3.30 (m, 1H), 3.29 - 3.17 (m, 1H), 2.70 - 2.47 (m, 2H), 2.31 - 2.24 (m, 2H), 2.12 - 2.09 (m, 1H), 2.08 - 1.95 (m, 2H), 1.85 - 1.73 (m, 3H), 1.07 - 0.96 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.416 minutes, ESI+ experimental value [M+H] ⁺ = 683.3; and Example 43: 1-((2R,3R)-3-((2-(((3aR,5S)-2-acetyl-5-fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow solid (Peak 2, retention time = 1.493 minutes) (10.12 mg, 33.53%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.15 (s, 1H), 8.07 - 7.99 (m, 2H), 7.58 (d, J = 5.3 Hz, 2H), 7.36 (t, J = 9.1 Hz, 1H), 6.50 (dd, J = 10.4, 16.7 Hz, 1H), 6.24 - 6.12 (m, 1H), 5.64 - 5.55 (m, 1H), 5.26 - 5.08 (m, 1H), 4.88 - 4.70 (m, 2H), 4.36 - 4.16 (m, 2H), 3.81 - 3.70 (m, 1H), 3.65 - 3.54 (m, 3H), 3.52 (d, J = 2.6 Hz, 3H), 3.45 (d, J = 12.3 Hz, 1H), 3.39 - 3.29 (m, 1H), 3.27 - 3.15 (m, 1H), 2.66 - 2.41 (m, 2H), 2.32 - 2.21 (m, 2H), 2.10 - 1.99 (m, 2H), 1.85 (s, 3H), 1.84 - 1.67 (m, 1H), 1.07 - 0.95 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.815 min, ESI+ found [M+H] ⁺ = 683.3. Example 44 : Synthesis of Compound 18 ; 1-((2R,3R)-3-((7-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8 - fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2 - en - 1- one ( Method 1) Step 1 : (2R,3R)-3-((7-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 50%-80% B in 8.0 min) to give tributyl (2R,3R)-3-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (110 mg, 27.94%) as a yellow oil. LCMS Rt = 0.501 min, m/z = 751.3 [M + H] ⁺ . Step 2 : 5- ethyl -6- fluoro -4-(8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-4-( methyl ((2R,3R)-2 -methylpyrrolidin -3- yl ) amino ) pyrido [4,3-d] pyrimidin -7- yl ) naphthalen -2- ol

Deprotection of Boc and MOM groups was performed in a similar manner to Method #1 step 7. The reaction mixture was concentrated to dryness in vacuo to afford 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (85 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.328 min, m/z = 607.5 [M + H] ⁺ . Step 3 : 1-((2R,3R)-3-((7-(8- ethyl- 7 - fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl ) ( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (19.29 mg, 32.95%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.30 - 9.19 (m, 1H), 7.70 (dd, J = 5.9, 8.9 Hz, 1H), 7.35 - 7.22 (m, 2H), 7.08 - 6.84 (m, 1H), 6.67 - 6.47 (m, 1H), 6.29 (dd, J = 9.2, 16.1 Hz, 1H), 5.75 - 5.65 (m, 1H), 5.38 - 5.16 (m, 1H), 4.97 - 4.71 (m, 2H), 4.30 - 4.10 (m, 2H), 3.89 - 3.47 (m, 5H), 3.26 - 3.05 (m, 3H), 2.92 (s, 1H), 2.62 - 2.32 (m, 3H), 2.32 - 2.10 (m, 5H), 1.94 - 1.75 (m, 3H), 1.11 - 0.93 (m, 2H), 0.91 (d, J = 5.5 Hz, 1H), 0.79 (q, J = 7.4 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.983 min, ESI+ found [M+H] ⁺ = 661.3. Example 45 : Synthesis of Compound 19 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-1-((S)-1- methylpyrrolidin -2- yl ) ethoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 1) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-((S)-1-((S)-1- methylpyrrolidin -2- yl ) ethoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4 . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (640 mg, 58.50%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.90 (s, 1H), 5.44 - 5.35 (m, 1H), 5.10 - 4.99 (m, 1H), 4.47 (s, 1H), 3.76 - 3.73 (m, 1H), 3.62 (t, J=9.38 Hz, 1H), 3.49 (s, 3H), 3.41 - 3.33 (m, 1H), 3.10 (s, 1H), 2.72 (d, J=4.88 Hz, 1H), 2.50 (s, 3H), 1.91 - 1.83 (m, 4H), 1.78 - 1.72 (m, 2H), 1.48 (s, 9H), 1.38 (d, J=6.38 Hz, 3H), 1.09 (d, J=6.50 Hz, 3H). LCMS Rt = 0.414 min, m/z = 523.3/525.3 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-((S)-1-((S)-1- methylpyrrolidin- 2- yl ) ethoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% tetrahydrofuran/petroleum ether) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (800 mg, 98.96%) as a brown solid. LCMS Rt = 0.628 min, m/z = 813.6 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-1-((S)-1- methylpyrrolidin- 2- yl ) ethoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (700 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.464 min, m/z = 657.5 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N- methyl -2-((S)-1-((S)-1- methylpyrrolidin -2- yl ) ethoxy )-N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.340 min, m/z = 557.4 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoro -2-((S)-1-((S)-1- methylpyrrolidin- 2- yl ) ethoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (35.59 mg, 19.05%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.21 (d, J = 2.38 Hz, 1 H) 8.15 - 8.08 (m, 2 H) 7.69 - 7.63 (m, 2 H) 7.45 (t, J = 9.07 Hz, 1 H) 6.58 (dd, J = 16.70, 10.19 Hz, 1 H) 6.32 - 6.18 (m, 1 H) 5.67 (dd, J =10.32, 2.31 Hz, 1 H) 5.40 - 5.25 (m, 1 H) 5.05 - 4.79 (m, 2 H) 3.89 - 3.65 (m, 1 H) 3.62 - 3.58 (m, 3 H) 3.57 - 3.40 (m, 1H) 3.30 - 3.26 (m, 1 H) 3.03 - 2.93 (m, 1 H) 2.68 - 2.46 (m, 2 H) 2.38 (s, 3 H) 2.31 - 2.20 (m, 2 H) 1.87 - 1.67 (m, 4 H) 1.31 (d, J = 6.25 Hz, 3 H) 1.17 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.750 min, ESI+ found [M+H] ⁺ = 611.3. Example 46 : Synthesis of Compound 20 ; 1-((2R,3R)-3-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl ) oxy )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one ( Method 3) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl ) oxy )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.6 g, 3.65 mmol), (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylic acid tributyl ester (1.47 g, 7.29 mmol) and cesium carbonate (2.49 g, 7.66 mmol) in tetrahydrofuran (20 mL) was stirred under nitrogen atmosphere at 25° C. for 0.5 h. The reaction mixture was quenched with saturated ammonium chloride (20 mL) at 0° C. and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (2.89 g, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.434 min, m/z = 540.2/542.1 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl ) oxy )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% tetrahydrofuran/petroleum ether) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (490 mg, 63.75%) as a yellow oil. LCMS Rt = 0.618 min, m/z = 830.6 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl ) oxy )-2- methylpyrrolidine -1-carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner as in Method #1, Step 6 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 70%-95% B in 8.0 min) to give tributyl (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (90 mg, 48.21%) as a yellow solid. LCMS Rt = 0.485 min, m/z = 674.3 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-4-(((2R,3R)-2- methylpyrrolidin- 3- yl ) oxy ) pyrido [4,3-d] pyrimidine

Deprotection of the Boc group was performed in a similar manner to Method #1 step 7. The reaction mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(((2R,3R)-2-methylpyrrolidin-3-yl)oxy)pyrido[4,3-d]pyrimidine (86.75 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.337 min, m/z = 574.3 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl ) oxy )-2- methylpyrrolidin - 1 - yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (34.4 mg, 50.17%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.23 (s, 1H), 8.19 - 8.12 (m, 2H), 7.73 - 7.66 (m, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.70 - 6.55 (m, 1H), 6.34 - 6.23 (m, 1H), 5.86 (q, J = 6.3 Hz, 1H), 5.71 (dd, J = 2.1, 10.4 Hz, 1H), 5.40 - 5.19 (m, 1H), 4.70 - 4.56 (m, 1H), 4.33 - 4.20 (m, 2H), 3.90 - 3.65 (m, 2H), 3.25 - 3.13 (m, 3H), 3.11 (s, 1H), 2.97 - 2.88 (m, 1H), 2.57 - 2.31 (m, 2H), 2.25 - 2.17 (m, 2H), 2.15 - 2.03 (m, 2H), 1.95 - 1.87 (m, 2H), 1.38 - 1.27 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.117 minutes, ESI+ experimental value [M+H] ⁺ = 628.3. Example 47 : Synthesis of Compound 21-1 ; 1-( cis -3-((7-(3- chloro -2- cyclopropyl -5- hydroxyphenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one ( Method 1) Step 1 : cis -3-((7-(3- chloro -2- cyclopropyl -5- hydroxyphenyl )-8 -fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1-carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give cis-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (330 mg, crude) as a white solid and used in the next step without any further purification. LCMS Rt = 0.447 min, m/z = 685.3/686.3 [M + H] ⁺ . Step 2 : 3- chloro -4- cyclopropyl -5-(8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-4-( methyl ( cis -2 -methylpyrrolidin- 3- yl ) amino ) pyrido [4,3-d] pyrimidin -7- yl ) phenol

Deprotection of the Boc group was performed in a similar manner to Method #1 step 7. The reaction mixture was concentrated in vacuo to afford 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(methyl(cis-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)phenol (300 mg, crude, trifluoroacetic acid salt) as a brown oil and used in the next step without any further purification. LCMS Rt = 0.352 min, m/z = 585.3/587.2 [M + H] ⁺ . Step 3 : 1-( cis- 3-((7-(3- chloro -2- cyclopropyl - 5- hydroxyphenyl )-8 -fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1 - yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-65% B in 8.0 min) to give 1-(cis-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (4.62 mg, 1.66%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.20 (d, J = 5.6 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.80 (s, 1H), 6.63 - 6.43 (m, 1H), 6.22 (dd, J = 9.8, 16.2 Hz, 1H), 5.64 (d, J = 10.3 Hz, 1H), 5.38 - 5.09 (m, 1H), 5.03 - 4.62 (m, 2H), 4.23 - 3.97 (m, 2H), 3.88 - 3.59 (m, 1H), 3.55 (d, J = 7.7 Hz, 4H), 3.18 - 2.97 (m, 3H), 2.85 (q, J = 7.0 Hz, 1H), 2.62 - 2.42 (m, 1H), 2.37 - 2.19 (m, 2H), 2.06 (d, J = 3.7 Hz, 2H), 1.86 - 1.76 (m, 4H), 1.04 (d, J = 5.6 Hz, 3H), 0.58 (d, J = 7.0 Hz, 2H), 0.01 (d, J = 4.3 Hz, 2H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.846 min, ESI+ found [M+H] ⁺ = 639.5/640.5. Examples 48 and 49 : Synthesis of Compounds 21-2 and 21-3 ; 1-((2R,3R)-3-((7-(3- chloro -2- cyclopropyl -5- hydroxyphenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2 - en - 1- one and 1- ((2S,3S)-3-((7-(3- chloro -2- cyclopropyl -5- hydroxyphenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1 - yl ) prop -2- en -1- one ( Method 1 )

A mixture of non-mirror isomers of 1-(cis-3-((7-(3-chloro- ₂ -cyclopropyl-5-hydroxyphenyl)-8-fluoro- ₂ -(((2R, _7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (50 mg) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 50%, isocratic elution mode) to obtain the following substances arbitrarily designated as follows: Example 48: 1-((2R,3R)-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 1.787 min) (18.51 mg, 6.65%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.19 (d, J = 6.1 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 6.62 - 6.42 (m, 1H), 6.21 (dd, J = 7.9, 16.7 Hz, 1H), 5.70 - 5.53 (m, 1H), 5.33 - 5.09 (m, 1H), 4.93 - 4.73 (m, 2H), 4.24 - 4.02 (m, 2H), 3.88 - 3.57 (m, 1H), 3.54 (d, J = 8.4 Hz, 4H), 3.13 - 2.97 (m, 3H), 2.89 - 2.76 (m, 1H), 2.65 - 2.39 (m, 1H), 2.17 (s, 2H), 2.05 (d, J = 3.3 Hz, 2H), 1.86 - 1.75 (m, 4H), 1.06 - 0.98 (m, 3H), 0.57 (d, J = 8.1 Hz, 2H), -0.01 (d, J = 4.5 Hz, 2H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 2.838 minutes, ESI+ experimental value [M+H] ⁺ = 639.4/640.5; and Example 49: 1-((2S,3S)-3-((7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 2, retention time = 1.425 minutes) (21.63 mg, 7.89%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.19 (d, J = 5.8 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.79 (s, 1H), 6.54 (ddd, J = 5.6, 10.5, 16.5 Hz, 1H), 6.21 (dd, J = 8.9, 16.5 Hz, 1H), 5.77 - 5.55 (m, 1H), 5.37 - 5.09 (m, 1H), 4.97 - 4.75 (m, 2H), 4.28 - 3.97 (m, 2H), 3.90 - 3.59 (m, 1H), 3.54 (d, J = 8.5 Hz, 4H), 3.22 - 2.94 (m, 3H), 2.84 (d, J = 5.6 Hz, 1H), 2.66 - 2.39 (m, 1H), 2.37 - 2.17 (m, 2H), 2.05 - 1.99 (m, 2H), 1.86 - 1.75 (m, 4H), 1.03 (d, J = 4.0 Hz, 3H), 0.57 (d, J = 8.0 Hz, 2H), -0.01 (d, J = 3.9 Hz, 2H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.843 min, ESI+ found [M+H] ⁺ = 639.4/641.4. Example 50 : Synthesis of Compound 22 ; 1-((2R,3R)-3-((7-(3- chloro -5- hydroxy -2-( trifluoromethyl ) phenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop - 2 - en - 1- one ( Method 1) Step 1 : (2R,3R)-3-((7-(3- chloro -5- hydroxy -2-( trifluoromethyl ) phenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol/dichloromethane) to afford tributyl (2R,3R)-3-((7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (170 mg, 25.35%) as a yellow oil. LCMS Rt = 0.452 min, m/z = 713.3/714.3 [M + H] ⁺ . Step 2 : 3- Chloro -5-(8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-4-( methyl ((2R,3R)-2- methylpyrrolidin- 3- yl ) amino ) pyrido [4,3-d] pyrimidin -7- yl )-4-( trifluoromethyl ) phenol

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 3-chloro-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol (68 mg, crude, hydrochloride) as a yellow solid and used in the next step without any further purification. LCMS Rt = 0.359 min, m/z = 613.4/615.4 [M + H] ⁺ . Step 3 : 1-((2R,3R)-3-((7-(3- chloro -5- hydroxy -2-( trifluoromethyl ) phenyl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H - pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 20%-60% B in 8.0 min) to give 1-((2R,3R)-3-((7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (4.55 mg, 6.51%, formate) as a yellow amorphous solid: ¹ H NMR (400 MHz, chloroform-d) δ 9.12 - 8.99 (m, 1H), 7.04 - 6.92 (m, 1H), 6.63 - 6.36 (m, 3H), 5.76 (d, J = 8.8 Hz, 1H), 5.48 - 5.26 (m, 1H), 5.04 - 4.79 (m, 2H), 4.60 - 4.43 (m, 1H), 4.28 (d, J = 10.0 Hz, 1H), 3.88 - 3.77 (m, 1H), 3.69 - 3.55 (m, 3H), 3.54 (d, J = 8.6 Hz, 3H), 3.34 - 3.25 (m, 1H), 3.15 - 3.03 (m, 1H), 2.57 - 2.27 (m, 8H), 1.16 - 1.00 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 min) retention time 2.217 min, ESI+ experimental value [M+H] ⁺ = 667.3/669.3. Example 51 : Synthesis of Compound 23 ; 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2S,4R)-4 - methoxy -1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2S,4R)-4- methoxy -1 -methylpyrrolidin- 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The resulting residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 10%-45% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (240 mg, 31.63%, trifluoroacetate) as a yellow oil. LCMS Rt = 0.398 min, m/z = 539.2/541.2 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2S,4R)-4- methoxy -1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The resulting residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 50%-85% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (270 mg, 98.40%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.610 min, m/z = 829.7 [M + H] ⁺ . Step 3 : 8- Fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2S,4R)-4- methoxy -1- methylpyrrolidin- 2- yl ) methoxy )-N- methyl -N-((2R,3R)-2 -methylpyrrolidin- 3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.442 min, m/z = 729.4 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2S,4R)-4- methoxy -1- methylpyrrolidin -2- yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (82 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.330 min, m/z = 573.2 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8 -fluoro -2-(((2S,4R)-4- methoxy -1 -methylpyrrolidin - 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-methylpyrrolidin - 1- yl ) prop - 2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-75% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (18.31 mg, 20.08%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (s, 1H), 8.19 - 8.08 (m, 2H), 7.69 (d, J = 5.3 Hz, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.60 (dd, J = 10.4, 16.8 Hz, 1H), 6.36 - 6.22 (m, 1H), 5.74 - 5.64 (m, 1H), 5.03 - 4.80 (m, 2H), 4.55 - 4.30 (m, 2H), 3.95 - 3.68 (m, 2H), 3.61 (s, 3H), 3.60 - 3.28 (m, 3H), 3.25 (s, 3H), 2.83 (d, J = 3.8 Hz, 1H), 2.63 - 2.48 (m, 1H), 2.40 (s, 3H), 2.37 - 2.28 (m, 1H), 2.23 - 2.18 (m, 1H), 1.96 - 1.87 (m, 2H), 1.18 - 1.06 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.838 min, ESI+ found [M+H] ⁺ = 627.3. Example 52 : Synthesis of Compound 24 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2S,4R)-4 - fluoro -1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop - 2- en -1- one ( Method 1) Step 1 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2S,4R)-4 -fluoro -1- methylpyrrolidin -2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1, Step 4. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-75% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (200 mg, 26.85%) as a white solid. LCMS Rt = 0.388 min, m/z = 527.3/529.3 [M + H] ⁺ . Step 2 : (2R,3R)-3-((8- fluoro -2-(((2S,4R)-4- fluoro -1 -methylpyrrolidin -2- yl ) methoxy )-7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The resulting residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 20%-50% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (220 mg, 84.15%, trifluoroacetate) as a white solid. LCMS Rt = 0.870 min, m/z = 817.3 [M + H] ⁺ . Step 3 : 8- Fluoro -2-(((2S,4R)-4- fluoro -1- methylpyrrolidin -2- yl ) methoxy )-7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (200 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.439 min, m/z = 717.4 [M + H] ⁺ . Step 4 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2S,4R)-4 -fluoro -1- methylpyrrolidin -2- yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (150 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.340 min, m/z = 561.3 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoro -2-(((2S,4R)-4 -fluoro -1- methylpyrrolidin - 2- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 - methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (39.73 mg, 23.75%) as a yellow amorphous solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (s, 1H), 8.18 - 8.10 (m, 2H), 7.72 - 7.67 (m, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.66 - 6.55 (m, 1H), 6.34 - 6.23 (m, 1H), 5.70 (dd, J = 2.3, 10.3 Hz, 1H), 5.29 - 5.06 (m, 1H), 4.92 (d, J = 5.1 Hz, 2H), 4.59 - 4.34 (m, 2H), 3.92 - 3.69 (m, 1H), 3.63 (d, J = 5.4 Hz, 3H), 3.54 - 3.44 (m, 1H), 3.29 (s, 1H), 3.06 - 2.96 (m, 1H), 2.66 - 2.56 (m, 1H), 2.50 (d, J = 11.6 Hz, 1H), 2.45 (s, 3H), 2.43 - 2.21 (m, 2H), 2.17 - 1.98 (m, 2H), 1.19 - 1.06 (m, 3H). LCMS Rt = 2.914 min, m/z = 615.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.914 min, ESI+ found [M+H] ⁺ = 615.3. Example 53 : Synthesis of Compound 25 ; 1-((2R,3R)-3-((8- fluoro -7-(8- fluoronaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 1) Step 1 : (2R,3R)-3-((8- fluoro -7-(8- fluoronaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (590 mg, 98.47%) as a yellow solid. LCMS Rt = 0.467 min, m/z = 663.3 [M + H] ⁺ . Step 2 : 8- Fluoro -7-(8- fluoronaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (204 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.327 min, m/z = 563.4 [M + H] ⁺ . Step 3 : 1-((2R,3R)-3-((8- fluoro -7-(8- fluoronaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give 1-((2R,3R)-3-((8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (74.57 mg, 40.05%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.68 - 7.63 (m, 1H), 7.57 (dt, J = 5.0, 7.9 Hz, 1H), 7.25 (dd, J = 7.8, 13.1 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.36 - 6.22 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.38 - 5.16 (m, 1H), 4.99 - 4.85 (m, 2H), 4.29 - 4.12 (m, 2H), 3.92 - 3.68 (m, 1H), 3.63 (d, J = 7.3 Hz, 3H), 3.62 - 3.42 (m, 1H), 3.20 - 3.07 (m, 3H), 2.96 - 2.87 (m, 1H), 2.67 - 2.49 (m, 1H), 2.43 - 2.33 (m, 1H), 2.27 - 2.20 (m, 1H), 2.14 - 2.12 (m, 1H), 2.09 - 2.03 (m, 1H), 1.94 - 1.84 (m, 3H), 1.13 (s, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.958 min, ESI+ found [M+ H] ⁺ = 617.3. Example 54 : Synthesis of Compound 26 ; 1-((2R,3R)-3-((7-(8- chloronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 1) Step 1 : (2R,3R)-3-((7-(8- chloronaphthalen -1- yl )-8 -fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-tert-butyl 3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 81.43%) as a brown oil. LCMS Rt = 0.476 min, m/z = 679.4/681.4 [M + H] ⁺ . Step 3 : 7-(8- Chloronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The resulting residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 5%-50% B in 8.0 min) to give 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (170 mg, 41.65%, trifluoroacetate) as a yellow oil. LCMS Rt = 0.321 min, m/z = 579.4/581.4 [M + H] ⁺ . Step 4 : 1-((2R,3R)-3-((7-(8- chloronaphthalen -1 - yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 10.0 min) to give 1-((2R,3R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (60 mg, 38.64%) as a white solid. The product (60 mg) was further purified by SFC: (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm, 5 um); mobile phase: [CO ₂ -MeOH (0.1% NH ₃ H ₂ O)]; B%: 50%, isocratic elution mode).

1-((2R,3R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (peak 1, retention time = 1.344 min) (44.01 mg, 71.55%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.15 (dd, J = 5.2, 9.4 Hz, 1H), 8.04 - 7.86 (m, 2H), 7.61 - 7.35 (m, 4H), 6.47 (dd, J = 10.4, 16.6 Hz, 1H), 6.24 - 6.09 (m, 1H), 5.58 (dd, J = 2.3, 10.3 Hz, 1H), 5.26 - 5.04 (m, 1H), 4.85 - 4.65 (m, 2H), 4.17 - 3.96 (m, 2H), 3.78 - 3.52 (m, 1H), 3.46 (s, 3H), 3.44 - 3.28 (m, 1H), 3.08 - 2.92 (m, 3H), 2.83 - 2.73 (m, 1H), 2.48 - 2.28 (m, 1H), 2.19 - 2.11 (m, 1H), δ 5.14 - 5.12 (m, 1H), 1.22 - 1.48 (m, 3H), 4.61 - 4.77 (m, 3H), 2.11 - 2.01 (m, 1H), 2.01 - 1.96 (m, 1H), 1.96 - 1.88 (m, 1H), 1.83 - 1.66 (m, 3H), 0.95 (dd, J = 6.5, 11.4 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.969 min, ESI+ found [M+H] ⁺ = 633.3/635.3. Example 55 : Synthesis of Compound 27-1 ; 1-((2R,3R)-3-((2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 -fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 1) Step 1 : (2R,3R)-3-((7- chloro -2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 15%-50% B in 8.0 min) to give (2R,3R)-3-((7-chloro-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (650 mg, 51.79%, trifluoroacetic acid salt) as a yellow oil. LCMS Rt = 0.422 min, m/z = 561.2/563.2 [M + H] ⁺ . Step 2 : (2R,3R)-3-((2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3R)-3-((8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (590 mg, 98.47%) as a yellow solid. LCMS Rt = 0.467 min, m/z = 851.4 [M + H] ⁺ . Step 3 : 2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -N-((2R,3R)-2- methylpyrrolidin- 3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (55 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.491 min, m/z = 751.4 [M + H]+. Step 4 : 2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H)-yl ) methoxy ) -7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N- methyl -N-((2R,3R)-2 -methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin - 4- amine

Deprotection of the TIPS group was performed in a similar manner as in Method #1, Step 6 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-75% B in 8.0 min) to give 2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 96.31%) as a yellow solid. LCMS Rt = 1.227 min, m/z = 595.3 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1 - one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-70% B in 8.0 minutes) to give 1-((2R,3R)-3-((2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (2.5 mg, 10.30%) as a white solid: ¹ H NMR (400 MHz, chloroform-d) δ 9.25 (s, 1H), 8.17 - 8.12 (m, 2H), 7.72 - 7.67 (m, 2H), 7.51 - 7.44 (m, 1H), 6.62 (dd, J = 10.3, 16.7 Hz, 1H), 6.36 - 6.19 (m, 1H), 5.76 - 5.61 (m, 1H), 5.08 - 4.77 (m, 2H), 4.42 - 4.22 (m, 2H), 3.93 - 3.69 (m, 1H), 3.63 (d, J = 4.6 Hz, 3H), 3.62 - 3.43 (m, 1H), 3.33 3H), 1.76 - 1.54 (m, 4H). 3.22 (m, 1H), 3.15 - 3.04 (m, 1H), 2.88 - 2.73 (m, 3H), 2.60 - 2.36 (m, 2H), 2.07 - 2.01 (m, 2H), 1.89 (d, J = 7.9 Hz, 1H), 1.86 - 1.82 (m, 2H), 1.81 - 1.75 (m, 1H), 1.19 - 1.07 (m, 3H), 0.58 - 0.50 (m, 4H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.862 min, ESI+ found [M+H] ⁺ = 649.3. Example 56 : Synthesis of Compound 28 ; 1-((2R,3R)-3-((8- fluoro -7-(7- fluoro -8-( prop -1- yn- 1- yl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorohexahydro -1H -pyrrolazin- 7a- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop-2 - en -1 - one ( Method 1) Step 1: 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanecyclopentane

To a solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (4.0 g, 8.84 mmol) in N,N-dimethylformamide (50 mL) was added cesium fluoride (6.71 g, 44.20 mmol). The mixture was stirred at 25 °C under nitrogen atmosphere for 12 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated lithium chloride (3 x 5 mL), and dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanecyclopentane (2.1 g, 80.22%) as a red solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.81 - 7.64 (m, 3H), 7.37 (dd, J = 7.0, 8.1 Hz, 1H), 7.26 - 7.16 (m, 1H), 3.65 (s, 1H), 1.37 (s, 12H). LCMS Rt = 0.572 min, m/z = 297.0 [M + H] ⁺ . Step 2: 2-(7-fluoro-8-(prop-1-yn-1-yl)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanecyclopentane

To a solution of 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane cyclopentane (1.0 g, 3.376 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (5.06 mL, 5.06 mmol, 1M in tetrahydrofuran). The mixture was stirred at -78 °C under nitrogen atmosphere for 0.5 h. Then iodomethane (623.1 mg, 4.39 mmol) was added to the above solution at -78 °C. The mixture was stirred at 20 °C under nitrogen atmosphere for 0.5 h. The mixture was quenched with saturated ammonium chloride (20 mL) at 0 °C and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 2-(7-fluoro-8-(prop-1-yn-1-yl)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, crude), which was used in the next step without any further purification. LCMS Rt = 0.619 min, m/z = 311.0 [M + H] ⁺ . Step 3 : (2R,3R)-3-((8- fluoro -7-(7 -fluoro -8-( prop -1- yn -1- yl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorohexahydro -1H -pyrrolazin -7a- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-60% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-(prop-1-yn-1-yl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (410 mg, 37.10%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.465 min, m/z = 701.4 [M + H] ⁺ . Step 4 : 8- Fluoro -7-(7- fluoro - 8-( prop -1- yn -1- yl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorohexahydro -1H -pyrrolizin -7a - yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 8-fluoro-7-(7-fluoro-8-(prop-1-yn-1-yl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (200 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.335 min, m/z = 601.4 [M + H] ⁺ . Step 5 : 1-((2R,3R)-3-((8- fluoro -7-(7- fluoro -8-( prop -1- yn -1- yl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorohexahydro -1H -pyrrolazin- 7a- yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 100×30 mm×3 um; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to give 1-((2R,3R)-3-((8-fluoro-7-(7-fluoro-8-(prop-1-yn-1-yl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (26.31 mg, 13.20%, formate) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.34 (s, 1H), 8.18 - 8.00 (m, 2H), 7.69 - 7.57 (m, 2H), 7.44 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.28 (dd, J = 9.5, 16.0 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.16 (m, 1H), 4.93 (dd, J = 5.9, 11.5 Hz, 2H), 4.34 - 4.11 (m, 2H), 3.95 - 3.71 (m, 1H), 3.64 (d, J = 5.4 Hz, 3H), 3.53 (dd, J = 7.9, 9.5 Hz, 1H), 3.22 - 3.07 (m, 3H), 2.97 - 2.87 (m, 1H), 2.67 - 2.48 (m, 1H), 2.45 - 2.32 (m, 1H), 2.16 - 2.02 (m, 3H), 1.95 - 1.85 (m, 3H), 1.35 (d, J = 3.3 Hz, 3H), 1.14 - 1.03 (m, 3H). LCMS Rt = 2.964 min, m/z = 655.3 [M + H] ⁺ . LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.964 min, ESI+ found [M+H] ⁺ = 655.3. Example 57 : Synthesis of Compound 29-1 ; 1-((2R,3R)-3-((2-((2,2- difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 -fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2 - en -1- one ( Method 3) Step 1: 2,2-Difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester

To a solution of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (7 g, 33.45 mmol) and sodium iodide (2.51 g, 16.73 mmol) in tetrahydrofuran (80 mL) was added (trifluoromethyl)trimethylsilane (23.79 g, 167.27 mmol). The mixture was stirred at 70 °C under nitrogen atmosphere for 12 hours. The reaction mixture was quenched with saturated sodium carbonate (30 mL) at 0 °C and extracted with ethyl acetate (3 x 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/petroleum ether) to give ethyl 2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (8.5 g, 98.01%) as a yellow oil. LCMS Rt = 0.370 min, m/z = 260.1 [M + H] ⁺ . Step 2: (2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol

To a solution of ethyl 2,2-difluoro-5'-oxadihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (7.3 g, 28.16 mmol) in tetrahydrofuran (150 mL) was added lithium aluminum hydroxide (33.79 mL, 84.47 mmol, 2.5 M in tetrahydrofuran) at 0°C. The mixture was stirred at 70°C for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (30 g) at 0°C. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give (2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (3.8 g, crude), which was used in the next step without any further purification. LCMS Rt = 0.167 min, m/z = 204.0 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7- chloro -8- fluoro -2-( methylthio ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (3.15 g, 94.12%) as a white solid. LCMS Rt = 0.575 min, m/z = 442.2/444.2 [M + H] ⁺ . Step 4 : (2R,3R)-3-((7- chloro -8- fluoro -2-( methylsulfonyl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (3.15 g, 7.13 mmol) in dichloromethane (50 mL) was added methyl 3-chloroperoxybenzoate (4.34 g, 21.38 mmol). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated sodium carbonate (30 mL) at 0 °C and extracted with dichloromethane (3 x 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/petroleum ether) to give tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (2.84 g, 84.07%) as a white solid. LCMS Rt = 0.488 min, m/z = 474.1/476.0 [M + H] ⁺ . Step 5 : (2R,3R)-3-((7- chloro -2-((2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

To a mixture of (2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (3.65 g, 17.98 mmol) in THF (50 mL) was added t-BuONa (1.73 g, 17.98 mmol) at 0°C and the mixture was stirred at 0°C for 0.5 h, followed by THF (50 mL) containing (2R,3R)-3-[(7-chloro-8-fluoro-2-methylsulfonylpyrido[4,3-d]pyrimidin-4-yl)-methyl-amino]-2-methyl-pyrrolidine-1-carboxylic acid tributyl ester (2.84 g, 5.99 mmol) dropwise added to the previous mixture at 0°C. The mixture was stirred at 0°C for another 0.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 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/tetrahydrofuran) to give (2R,3R)-3-((7-chloro-2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g, 47.52%) as a yellow oil. LCMS Rt = 1.635 min, m/z = 597.3/598.3 [M + H] ⁺ . Step 6 : (2R,3R)-3-((2-((2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8 -fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/tetrahydrofuran) to afford tributyl (2R,3R)-3-((2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1.7 g, 67.30%) as a brown oil. LCMS Rt = 0.634 min, m/z = 887.4 [M + H] ⁺ . Step 7 : (2R,3R)-3-((2-((2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8 -fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1.17 g, crude) as a brown oil, which was used in the next step without any further purification. LCMS Rt = 0.485 min, m/z = 731.4 [M + H] ⁺ . Step 8 : 2-((2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 -fluoro -N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (1.07 g, crude, hydrochloride) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.345 min, m/z = 631.3 [M + H] ⁺ . Step 9 : 1-((2R,3R)-3-((2-((2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7 - fluoronaphthalen -1- yl )-8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-65% B in 10.0 min) to obtain 1-((2R,3R)-3-((2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (10.79 mg, 9.83e-1%): ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.25 (s, 1H), 8.19 - 8.09 (m, 2H), 7.69 (d, J = 5.1 Hz, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.8 Hz, 1H), 6.36 - 6.21 (m, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.03 - 4.81 (m, 2H), 4.37 - 4.22 (m, 1H), 4.16 - 3.85 (m, 1H), 3.79 - 3.43 (m, 5H), 3.29 (d, J = 2.7 Hz, 1H), 3.20 - 3.12 (m, 1H), 3.11 - 3.00 (m, 1H), 2.83 (dd, J = 5.8, 10.4 Hz, 1H), 2.76 - 2.59 (m, 1H), 2.38 (d, J = 6.9 Hz, 2H), 2.01 (s, 3H), 1.93 - 1.65 (m, 3H), 1.48 - 1.37 (m, 2H), 1.19 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.374 min, ESI+ experimental value [M+H] ⁺ = 685.2 Examples 58 and 59 : Synthesis of Compounds 30-1 and 30-2 ; 1-((2R,3R)-3-((7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((1S,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1 - yl ) prop -2- en -1- one and 1- ((2R,3R)-3-((7-(8- ethynyl - 7- fluoronaphthalen -1 -yl )-8 -fluoro -2-(((1R,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4 - yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop - 2- en - 1- one ( Method 4) Step 1 : (6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -carboxylic acid methyl ester

To a solution of (2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (500 mg, 2.51 mmol) in toluene (20 mL) were added tetrabutylammonium bromide (404.53 mg, 1.25 mmol) and (bromodifluoromethyl)trimethylsilane (7.65 g, 37.65 mmol). The mixture was stirred at 80° C. under nitrogen atmosphere for 1 hour. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate/petroleum ether) to give (6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (200 mg, 31.97%) as a yellow oil. LCMS Rt = 1.666 min, m/z = 250.0 [M + H] ⁺ . Step 2 : ((6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methanol

To a solution of (6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (200 mg, 802.47 μmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydroxide (962.97 μL, 2.41 mmol, 2.5M in tetrahydrofuran) at 0°C. The mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (1 g) at 0°C. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give ((6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (130 mg, crude) as a yellow oil which was used in the next step without further purification. LCMS Rt = 0.946 min, m/z = 222.1 [M + H] ⁺ . Step 3 : (2R,3R)-3-((7- chloro -2,8 -difluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

A mixture of tributyl (2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1 g, 2.32 mmol), silver fluoride (2.95 g, 23.24 mmol), 4 Å molecular sieve (1 g) in acetonitrile (30 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 70 °C under nitrogen atmosphere for 3 hours. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 1-100% ethyl acetate/petroleum ether) to give tributyl (2R,3R)-3-((7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (280 mg, 29.11%) as a yellow oil. LCMS Rt = 0.531 min, m/z = 414.1/416.1 [M + H] ⁺ . Step 4 : (2R,3R)-3-((2,8 -difluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 75%-95% B in 8.0 min) to give (2R,3R)-3-((2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (70 mg, 18.71%) as a yellow oil. LCMS Rt = 0.793 min, m/z = 704.4 [M + H] ⁺ . Step 5 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner as Method #1 Step 4. The mixture was diluted with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (25 mg, crude) as a brown oil which was used in the next step without any further purification. LCMS Rt = 0.632 min, m/z = 905.5 [M + H] ⁺ . Step 6 : 8- Fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl )-2-(((1S,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)-2-(((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (25 mg, crude, hydrochloride) as a brown oil which was used in the next step without any further purification. LCMS Rt = 0.469 min, m/z = 805.4 [M + H] ⁺ . Step 7 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 -fluoro -N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl )-2-(((1S,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- amine and 7-(8- ethynyl- 7- fluoronaphthalen -1 - yl )-8- fluoro -N- methyl -N-((2R,3R)-2- methylpyrrolidin -3 - yl )-2-(((1R,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1, Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. The crude material was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-60% B in 8.0 min) to give the following materials arbitrarily designated: Example 58: 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)-2-(((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (15 mg, 66.16%) as a yellow solid. LCMS Rt = 0.363 min, m/z = 649.3 [M + H] ⁺ ; and Example 59: 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)-2-(((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (12 mg, 59.15%) as a yellow solid. LCMS Rt = 0.376 min, m/z = 649.3 [M + H] ⁺ . Step 8 : 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((1S,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en - 1- one

The acylation reaction was carried out in a similar manner to method #1 step 8. The acylation reaction was carried out by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% in 8.0 min. B) The crude product was purified to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (2.26 mg, 13.85%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d ₃ ) δ 9.25 (s, 1H), 8.18 - 8.11 (m, 2H), 7.72 - 7.67 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.68 - 6.54 (m, 1H), 6.36 - 6.20 (m, 1H), 5.70 (dd, J = 2.2, 10.2 Hz, 1H), 5.43 - 5.19 (m, 1H), 5.00 - 4.84 (m, 2H), 4.45 - 4.25 (m, 1H), 4.24 - 3.86 (m, 2H), 3.81 - 3.67 (m, 1H), 3.63 (d, J = 7.1 Hz, 3H), 3.31 - 3.09 (m, 5H), 2.68 - 2.42 (m, 2H), 2.40 - 2.29 (m, 2H), 2.28 - 2.23 (m, 2H), 1.48 - 1.40 (m, 2H), 1.20 - 1.07 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.073 minutes, ESI+ found [M+H] ⁺ = 703.3. Step 9 : 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((1R,6'R,7a'S)-2,2,6'- trifluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2' -pyrrolizine ]-7a'(5'H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop -2- en - 1- one

The acylation reaction was carried out in a similar manner to method #1 step 8. The acylation reaction was carried out by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% in 8.0 min. B) The resulting residue was purified to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (1.07 mg, 7.85%) as a yellow solid: ¹ H NMR (400 MHz, acetonitrile-d ₃ ) δ 9.30 - 9.21 (m, 1H), 8.20 - 8.10 (m, 2H), 7.74 - 7.66 (m, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.69 - 6.52 (m, 1H), 6.37 - 6.21 (m, 1H), 5.71 (dd, J = 2.3, 10.3 Hz, 1H), 5.41 - 5.15 (m, 1H), 5.00 - 4.81 (m, 2H), 4.47 - 4.23 (m, 2H), 3.90 - 3.69 (m, 1H), 3.64 (d, J = 6.1 Hz, 3H), 3.62 - 3.47 (m, 1H), 3.37 - 3.18 (m, 3H), 3.16 - 3.00 (m, 2H), 2.70 - 2.45 (m, 2H), 2.44 - 2.34 (m, 2H), 2.29 (d, J = 7.9 Hz, 2H), 1.50 - 1.38 (m, 2H), 1.19 - 1.08 (m, 3H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.140 min, ESI+ found [M+H] ⁺ = 703.3. Example 60 : Synthesis of Compound 31 ; 1-((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidin -1- yl ) prop - 2 - en - 1- one ( Method 5) Step 1 : 1- ( tert-butyl) -2 -methyl (2S,3S)-3-(( tert-butyldiphenylsilyl ) oxy ) pyrrolidine - 1,2 -dicarboxylate

To a solution of 1-(tert-butyl)-2-methyl (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (5 g, 20.39 mmol) and imidazole (2.08 g, 30.58 mmol) in dichloromethane (120 mL) at 0°C was added tributylchlorodiphenylsilane (6.16 g, 22.42 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (90 mL) and extracted with dichloromethane (3 x 90 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/petroleum ether) to give 1-(tert-butyl)-2-methyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (8.5 g, 86.21%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.69 - 7.64 (m, 4H), 7.51 - 7.37 (m, 6H), 4.43 - 4.18 (m, 2H), 3.73 - 3.53 (m, 5H), 1.90 - 1.79 (m, 2H), 1.51 (s, 3H), 1.46 - 1.41 (m, 6H), 1.10 (s, 9H). LCMS Rt = 0.704 min, m/z = 484.2 [M + H] ⁺ . Step 2 : (2R,3S)-3-(( tributyldiphenylsilyl ) oxy )-2-( hydroxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of 1-(tert-butyl)-2-methyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (8.1 g, 16.75 mmol) in tetrahydrofuran (200 mL) at 0°C was added lithium borohydride (25.12 mL, 50.25 mmol, 2 M in tetrahydrofuran). The mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with saturated ammonium chloride (300 mL) at 0°C and extracted with ethyl acetate (3 x 300 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/petroleum ether) to give tributyl (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (7.6 g, 99.59%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 - 7.55 (m, 4H), 7.40 - 7.28 (m, 6H), 4.08 - 3.98 (m, 1H), 3.72 (s, 1H), 3.59 - 3.50 (m, 1H), 3.37 - 3.17 (m, 3H), 1.79 - 1.66 (m, 2H), 1.41 (s, 9H), 0.99 (s, 9H). LCMS Rt = 0.697 min, m/z = 456.2 [M + H] ⁺ . Step 3 : (2S,3S)-3-(( tributyldiphenylsilyl ) oxy )-2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2 g, 4.39 mmol) in dichloromethane (20 mL) was added (diethylamino)sulfur trifluoride (778.24 mg, 4.83 mmol) at -10 °C. The mixture was stirred at -10 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) at 0 °C and extracted with dichloromethane (3 x 20 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/petroleum ether) to give tributyl (2S,3S)-3-((tributyldiphenylsilyl)oxy)-2-(fluoromethyl)pyrrolidine-1-carboxylate (1.69 g, 84.13%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.61 - 7.54 (m, 4H), 7.40 - 7.35 (m, 2H), 7.33 (s, 2H), 7.29 (d, J = 1.3 Hz, 1H), 7.19 (s, 1H), 4.36 - 4.05 (m, 1H), 3.89 - 3.80 (m, 1H), 3.64 (dd, J = 1.6, 4.5 Hz, 1H), 3.59 - 3.48 (m, 1H), 3.44 - 3.22 (m, 2H), 1.75 - 1.59 (m, 1H), 1.49 (s, 1H), 1.37 (s, 9H), 1.02 - 0.98 (m, 9H). LCMS Rt = 0.758 min, m/z = 458.2 [M + H] ⁺ . Step 4 : (2S,3S)-2-( Fluoromethyl )-3- hydroxypyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3S)-3-((tributyldiphenylsilyl)oxy)-2-(fluoromethyl)pyrrolidine-1-carboxylate (1.60 g, 3.50 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (3.85 mL, 3.85 mmol, 1 M in tetrahydrofuran). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to give (2S,3S)-2-(fluoromethyl)-3-hydroxypyrrolidine-1-carboxylic acid tributyl ester (720 mg, 93.93%) as a colorless oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.62 - 4.24 (m, 1H), 4.20 - 4.03 (m, 1H), 3.83 (d, J = 13.2 Hz, 1H), 3.78 - 3.72 (m, 1H), 3.66 (s, 1H), 2.99 - 2.81 (m, 2H), 1.56 (d, J = 8.6 Hz, 1H), 1.52 - 1.43 (m, 1H), 1.42 - 1.36 (m, 9H). LCMS Rt = 0.355 min, m/z = 220.2 [M + H] ⁺ . Step 5 : (2S,3S)-2-( Fluoromethyl )-3-(( methylsulfonyl ) oxy ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3S)-2-(fluoromethyl)-3-hydroxypyrrolidine-1-carboxylate (720 mg, 3.28 mmol) and triethylamine (498.44 mg, 4.93 mmol) in dichloromethane (8 mL) was added methanesulfonyl chloride (740 mg, 6.46 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) at 0° C. and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2S,3S)-2-(fluoromethyl)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (900 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.439 min, m/z = 298.1 [M + H] ⁺ . Step 6 : (2S,3R)-3 -azido -2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3S)-2-(fluoromethyl)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (900 mg, 3.03 mmol) in N , N -dimethylformamide (5 mL) was added sodium azide (530 mg, 8.15 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with saturated sodium carbonate (5 mL) at 0 °C and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2S,3R)-3-azido-2-(fluoromethyl)pyrrolidine-1-carboxylate (623 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.503 min, m/z = 245.1 [M + H] ⁺ . Step 7 : (2S,3R)-3- amino -2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3R)-3-azido-2-(fluoromethyl)pyrrolidine-1-carboxylate (623 mg, 2.55 mmol) in ethyl acetate (5 mL) was added Pd/C (500 mg, purity 10%). The mixture was then degassed and purged with hydrogen three times and stirred at 25 °C under hydrogen atmosphere (15 psi) for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give tributyl (2S,3R)-3-amino-2-(fluoromethyl)pyrrolidine-1-carboxylate (550 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.185 min, m/z = 219.1 [M + H] ⁺ . Step 8: (2S,3R)-3-(Benzyl(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylic acid tributyl ester

Reductive amination was performed in a similar manner to Method #2 Step 1 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 8.0 minutes) to give tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylate (170 mg, 20.92%) as a white solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.34 (d, J = 4.9 Hz, 4H), 7.28 - 7.24 (m, 1H), 5.12 - 4.87 (m, 1H), 4.58 - 4.16 (m, 2H), 3.79 - 3.67 (m, 2H), 2.94 - 2.54 (m, 3H), 2.36 (s, 3H), 2.08 (dd, J = 4.4, 12.6 Hz, 1H), 1.71 (d, J = 12.5 Hz, 1H), 1.49 (s, 9H). LCMS Rt = 2.218 min, m/z = 323.2 [M + H] ⁺ . Step 9: (2S,3R)-2-(Fluoromethyl)-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of Bn was performed in a similar manner as Method #2 Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford tributyl (2S,3R)-2-(fluoromethyl)-3-(methylamino)pyrrolidine-1-carboxylate (110 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.239 min, m/z = 233.2 [M + H] ⁺ . Step 10 : (2S,3R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylate (100 mg, 51.20%) as a yellow solid. LCMS Rt = 0.574 min, m/z = 448.1/450.1 [M + H] ⁺ . Step 11 : (2S,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1, Step 4. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 50%-75% B in 8.0 min) to give (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylic acid tributyl ester (25 mg, 28.04%) as a white solid. LCMS Rt = 2.238 min, m/z = 571.3/573.3 [M + H] ⁺ . Step 12 : (2S,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 48%-78% B in 8.0 min) to give (2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylic acid tributyl ester (35 mg, 81.98%, trifluoroacetate) as a white solid. LCMS Rt = 0.660 min, m/z = 861.6 [M + H] ⁺ . Step 13 : (2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to afford (2S,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(fluoromethyl)pyrrolidine-1-carboxylate (25 mg, crude) as a white solid which was used in the next step without any further purification. LCMS Rt = 0.458 min, m/z = 705.2 [M + H] ⁺ . Step 14 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -N-((2S,3R)-2-( fluoromethyl ) pyrrolidin -3- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-((2S,3R)-2-(fluoromethyl)pyrrolidin-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (25 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.328 min, m/z = 605.3 [M + H] ⁺ . Step 15 : 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( fluoromethyl ) pyrrolidin -1- yl ) prop -2- en -1 -one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-60% B in 8.0 min) to give 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(fluoromethyl)pyrrolidin-1-yl)prop-2-en-1-one (6.08 mg, 25.20%) as a white solid: ¹ H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (d, J = 9.4 Hz, 1H), 8.23 - 8.09 (m, 2H), 7.81 - 7.60 (m, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.86 - 6.67 (m, 1H), 6.29 - 6.15 (m, 1H), 5.84 - 5.66 (m, 1H), 5.48 - 5.23 (m, 2H), 5.22 - 4.78 (m, 2H), 4.49 - 4.30 (m, 1H), 4.28 - 4.13 (m, 2H), 3.65 - 3.49 (m, 4H), 3.46 - 3.32 (m, 3H), 3.29 - 3.15 (m, 3H), 3.03 - 2.88 (m, 2H), 2.13 - 2.04 (m, 4H), 1.93 (dd, J = 2.2, 4.9 Hz, 4H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 2.938 min, ESI+ found [M+H] ⁺ = 659.3. Example 61 : Synthesis of Compound 32 ; 1-((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidin -1- yl ) prop - 2- en - 1- one ( Method 5) Step 1 : (2S,3S)-3- hydroxypyrrolidine -1,2- dicarboxylic acid 1-( tert-butyl ) 2- methyl ester

(2S,3S)-1-tert-butyloxycarbonyl-3-hydroxy-pyrrolidine-2-carboxylic acid (1.00 eq., 3.00 g, 12.97 mmol) was dissolved in DMF (25 mL). The solution was cooled to 0 °C and potassium carbonate (3.00 eq., 5.378 mg, 38.91 mmol) was added. The solution was stirred at this temperature for 5 min and iodomethane (1.00 eq., 0.81 mL, 12.97 mmol) was introduced. The solution was warmed to room temperature and the reaction was stirred at this temperature for 16 h. The reaction was then diluted with EtOAc and the organic phase was washed three times with brine. The organic extract was dried _{over Na2SO4} , filtered and concentrated in vacuo. The product, 1-(tert-butyl)-2-methyl (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (3.09 g, 97.08% crude) was isolated as a _{yellow oil} and used in the next step without further purification. LCMS [5-95% MeCN/ _H2O + 0.1% FA] calcd for _C11H19NO5Na [M+Na] ⁺ 268.1, found 268.1, retention time = 1.272 min. Step 2 : 1- ( tert-butyl ) -2 -methyl (2S,3S)-3-(( methylsulfonyl ) oxy ) pyrrolidine -1,2- dicarboxylate

1-(tert-butyl)-2-methyl (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.00 eq., 3.00 g, 12.2 mmol) was dissolved in DCM (15 mL) and the solution was cooled to 0°C. At this temperature, N , N -diisopropylethylamine (1.50 eq., 3.2 mL, 18.3 mmol) and 4-dimethylaminopyridine (0.200 eq., 299 mg, 2.45 mmol) were added, followed by methanesulfonyl chloride (1.20 eq., 1.1 mL, 14.7 mmol). The reaction mixture was then allowed to warm to room temperature and stirring was continued for 16 hours. Afterwards, the reaction was quenched by the addition of saturated _{NH4Cl ( aq.)} solution. The layers were partitioned and the aqueous phase was extracted three times with DCM. The combined extracts were dried _{over Na2SO4} , filtered, and concentrated in vacuo. The crude residue was purified by column chromatography [0-100% EtOAc/heptane; silica gel] to give 1-(tert-butyl)-2-methyl (2S,3S)-3-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (3.90 g, 12.1 mmol, 98.61% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 5.22 (d, J = 4.0 Hz, 1H), 4.62 - 4.39 (m, 1H), 3.78 (s, 3H), 3.75 - 3.63 (m, 1H), 3.63 - 3.50 (m, 1H), 3.11 - 3.07 (s, 3H), 2.31 - 2.19 (m, 2H), 1.51 - 1.37 (m, 9H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd for C ₁₂ H ₂₁ NO ₇ SNa [M+Na] ⁺ 346.1, found 346.1, retention time = 1.564 min. Step 3 : (2S,3R)-3 -azidopyrrolidine -1,2- dicarboxylic acid 1-( tert-butyl ) 2- methyl ester

1-(tert-butyl)-2-methyl (2S,3S)-3-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (1.00 equiv., 1.00 g, 3.08 mmol) was dissolved in DMF (6.5 mL). Sodium azide (1.62 equiv., 326 mg, 5.01 mmol) was then added at room temperature and the mixture was heated at 70 °C under nitrogen for 16 h. The reaction was then cooled to room temperature and the solution was diluted with 10 mL of EtOAc. The organic phase was then washed with water (50 mL) and the aqueous phase was further extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), _dried over _Na2SO4 , filtered, and concentrated in vacuo to give 1-(tert-butyl)-2-methyl (2S,3R)-3-azidopyrrolidine-1,2-dicarboxylate (712 mg, 2.63 mmol, 85.36% crude). The crude product was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl3) δ 4.57 - 4.38 (m, 1H), 4.37 - 4.26 (m, 1H), 3.79 (s, 3H), 3.72 - 3.58 (m, 1H), 3.51 - 3.37 (m, 1H), 2.22 - 1.99 (m, 2H), 1.48 - 1.37 (m, 9H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd for C ₁₁ H ₁₈ N ₄ O ₄ Na [M+Na] ⁺ 293.1, found 293.1 [ TIC only , no chromophore ] Step 4 : (2S,3R)-3- aminopyrrolidine -1,2- dicarboxylic acid 1-( tert-butyl ) 2- methyl ester

1-(tert-butyl)-2-methyl (2S,3R)-3-azidopyrrolidine-1,2-dicarboxylate (1.00 equiv., 711 mg, 2.63 mmol) was dissolved in methanol (50 mL). The solution was circulated through an H-Cube® Mini Plus flow reactor [10% Pd/C CatCart; 3 ml/min flow rate; 4 bar _H2 pressure, 30 °C] three times and the system was flushed with methanol (20 mL). The collected solution was concentrated in vacuo to give 1-(tert-butyl)-2-methyl (2S,3R)-3-aminopyrrolidine-1,2-dicarboxylate (575 mg, 2.35 mmol, 89.48% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 4.35 - 4.18 (m, 1H), 3.75 (s, 3H), 3.71 (s, 2H), 3.68 - 3.44 (m, 1H), 3.42 - 3.29 (m, 1H), 2.25 - 2.05 (m, 1H), 2.00 - 1.76 (m, 2H), 1.50 - 1.38 (m, 9H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd for C ₁₁ H ₂₀ N ₂ O ₄ Na [M+Na] ⁺ 267.1, found 267.1, retention time = 0.983 min [ TIC only , no UV absorption ] Step 5: (2S,3R)-3-(Benzyl(methyl)amino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester

Reductive amination was performed in a similar manner as Method #2 Step 1. After the reaction was confirmed to be complete by LCMS, the mixture was then concentrated to dryness and purified by FCC column chromatography [0-100% EtOAc/heptane; silica gel] to give the product as a colorless solid. ¹ H NMR (400 MHz, CDCl3) δ 7.43 - 7.18 (m, 5H), 4.70 (d, J = 5.9 Hz, 1H), 4.63 - 4.16 (m, 1H), 3.90 - 3.75 (m, 1H), 3.74 - 3.66 (m, 3H), 3.62 - 2.99 (m, 3H), 2.29 - 2.14 (m, 1H), 2.13 - 2.02 (m, 3H), 2.01 - 1.79 (m, 1H), 1.50 - 1.37 (m, 9H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd. for C ₁₉ H ₂₉ N ₂ O ₄ [M+H] ⁺ 349.2, found 349.3, retention time = 1.562 min Step 6 : (2S,3R)-3-( Benzyl ( methyl ) amino )-2-( hydroxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

1-(tert-butyl)-2-methyl (2S,3R)-3-(benzyl(methyl)amino)pyrrolidine-1,2-dicarboxylate (1.00 equiv., 1.18 g, 3.39 mmol) was dissolved in THF (28.7 mL) and the solution was cooled to 0°C under nitrogen atmosphere. At this temperature, DIBAL solution (4.00 equiv., 11 mL, 13.5 mmol) [1.2 M in hexanes] was added and the solution was stirred at 0°C for 2 hours. After confirming complete consumption of the starting material, the reaction was quenched by adding 150 uL of water. After stirring for 5 minutes, 150 uL of 15% NaOH _{( aq.)} (w/w) was added and stirring was continued for 5 minutes. Then another 450 uL of water was added, followed by the addition of MgSO ₄ . The resulting slurry was then allowed to warm to room temperature and stirred for 30 minutes. The slurry was filtered through a pad of celite, washing with EtOAc. The crude residue was concentrated in vacuo to afford tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (766 mg, 2.39 mmol, 70.59% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.36 - 7.26 (m, 5H), 4.84 - 4.72 (m, 1H), 4.35 - 4.17 (m, 1H), 4.10 - 3.94 (m, 1H), 3.93 - 3.85 (m, 1H), 3.77 - 3.53 (m, 2H), 3.52 - 3.42 (m, 1H), 3.37 - 3.29 (m, 2H), 3.15 - 2.95 (m, 1H), 2.22 - 1.96 (m, 2H), 1.90 - 1.75 (m, 2H), 1.49 (s, 9H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd for C ₁₈ H ₂₉ N ₂ O ₃ [M+H] ⁺ 321.4, found 321.2, retention time = 0.994 min. Step 7 : (2S,3R)-3-( Benzyl ( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

A solution of tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 eq., 60 mg, 0.187 mmol) in anhydrous THF (2.2 mL) was cooled to 0 °C under positive pressure of nitrogen. At this temperature, sodium hydride (60% w/w in mineral oil, 1.20 eq., 9.0 mg, 0.225 mmol) was added. After stirring for 30 min, iodomethane (1.50 eq., 0.018 mL, 0.281 mmol) was added. The reaction was allowed to slowly warm to room temperature and stirring was continued for another 12 h. Afterwards, the reaction was quenched by the addition of NH ₄ Cl _{( saturated)} . The mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted three times with EtOAc and the combined extracts were dried _{over Na2SO4} , filtered and concentrated in vacuo to give tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (54 mg, 0.161 mmol, 86.22% yield, crude) as a colorless oil. No further purification was performed. ¹ H NMR (400 MHz, CDCl3) δ 7.46 - 7.31 (m, 5H), 4.31 - 4.02 (m, 1H), 3.88 - 3.73 (m, 2H), 3.66 - 3.50 (m, 2H), 3.47 - 3.35 (m, 3H), 2.99 - 2.83 (m, 1H), 2.18 (s, 3H), 2.13 - 1.80 (m, 2H), 1.55 (s, 9H), 1.38 - 1.25 (m, 2H). LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd for C ₁₉ H ₃₁ N ₂ O ₃ [M+H] ⁺ 335.2, found 335.3, retention time = 1.391 min. Step 8: (2S,3R)-2-(methoxymethyl)-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Benzyl deprotection was performed in a similar manner to Method #2 Step 2. The reaction mixture was concentrated in vacuo to afford tri-butyl (2S,3R)-2-(methoxymethyl)-3-(methylamino)pyrrolidine-1-carboxylate (36.4 mg, 71.18% crude) as a colorless oil which was used in the next step without any further purification. ¹ H NMR (400 MHz, MeOD) δ 4.77 (s, 3H), 3.94 - 3.74 (m, 1H), 3.71 - 3.49 (m, 1H), 3.48 - 3.30 (m, 1H), 3.27 - 3.22 (m, 3H), 3.20 - 3.14 (m, 1H), 2.39 (s, 2H), 2.22 - 1.92 (m, 2H), 1.89 - 1.67 (m, 1H), 1.39 (s, 9H). LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 0.937 min, ESI+ found [M+H] ⁺ = 245.2. Step 9 : (2S,3R)-3-((7- chloro -8- fluoro -2-( methylthio ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #3, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2S,3R)-3-((7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (43 mg, 61.15%) as a yellow solid. LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 1.977 min, ESI+ Found [M+H] ⁺ = 472.2. Step 10 : (2S,3R)-3-((7- chloro -8- fluoro -2-( methylsulfonyl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

A 2 dram vial was charged with tributyl (2S,3R)-3-((7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.00 equiv, 43 mg, 0.0911 mmol) and dichloromethane (0.911 mL). The resulting solution was cooled to -10 °C in a brine bath and 3-chloroperbenzoic acid (77% w/w, 3.00 equiv, 61 mg, 0.273 mmol) was introduced. The reaction was stirred at -10 °C for 1 hour, followed by an additional 2 hours at room temperature to ensure complete oxidation to the aryl sulfone. The reaction was quenched by addition _{of Na2S2O3} (saturated) _solution at room temperature and the layers were separated. The aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with _Na2CO3 (saturated) solution, dried over _Na2SO4 , filtered and concentrated in vacuo to give tributyl ( _2S ,3R ₎ -3-((7-chloro-8-fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (43 mg, 93.65%) as a yellow residue. No further purification was performed. LCMS [5-95% MeCN/H ₂ O + 0.1% FA] calcd. for C ₂₀ H ₂₇ N ₅ O ₅ ClFS [M+Na]+ 480.1, found 480.2, retention time = 1.423 min Step 11 : (2S,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #3, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/tetrahydrofuran) to afford tributyl (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (43 mg, 80.95%) as a yellow oil. LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 1.742 min, ESI+ experimental value [M+H] ⁺ = 583.3. Step 12 : (2S,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/tetrahydrofuran) to give (2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tributyl ester (28 mg, 74.79%) as a brown oil. LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 minutes) retention time 1.699 minutes, ESI+ experimental value [M+H] ⁺ = 873.5. Step 13 : (2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford tributyl (2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidine-1-carboxylate (18 mg, 78% crude) as a brown oil which was used in the next step without any further purification. LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 1.730 min, ESI+ assay [M+H] ⁺ = 717.4 Step 14 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N-((2S,3R)-2-( methoxymethyl ) pyrrolidin- 3- yl )-N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-((2S,3R)-2-(methoxymethyl)pyrrolidin-3-yl)-N-methylpyrido[4,3-d]pyrimidin-4-amine (13.0 mg, 94.4% crude) as a brown solid which was used in the next step without any further purification. LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 1.197 min, ESI+ assay [M+H] ⁺ = 617.3 Step 15 : 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-( methoxymethyl ) pyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Agilent Prep 100 Å C18, 21.2 × 50 mm; mobile phase: [H ₂ O (0.1% formic acid)-ACN (0.1% formic acid)]; gradient: 5%-95% B in 15.0 min) to give 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one (5.1 mg, 34.3%) as a white solid: ¹ H NMR (400 MHz, CD ₃ CN) δ 9.43 (d, J = 8.2 Hz, 1H), 8.30 - 8.17 (m, 2H), 7.79 (d, J = 5.4 Hz, 2H), 7.57 (t, J = 9.2 Hz, 1H), 6.83 (d, J = 43.2 Hz, 1H), 6.38 (d, J = 16.4 Hz, 1H), 5.81 (d, J = 14.3 Hz, 1H), 5.60 (d, J = 51.7 Hz, 1H), 5.20 - 4.87 (m, 2H), 4.85 - 4.55 (m, 2H), 4.06 - 3.80 (m, 2H), 3.81 - 3.74 (m, 4H), 3.48 - 3.22 (m, 7H), 2.88 - 2.14 (m, 10H). LCMS (5% to 95% acetonitrile/water + 0.1% formic acid over 3 min) retention time 1.624 min, ESI+ experimental value [M+H] ⁺ = 671.3 Example 62 : Synthesis of Compound 33 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 5) Step 1 : (2S,3S)-3-(( tert-butyldiphenylsilyl ) oxy )-2- formylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of oxalyl chloride (2.92 g, 23.04 mmol) in dichloromethane (200 mL) was added dimethyl sulfoxide (3.00 g, 38.41 mmol) at -60 °C under nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at -60 °C for about 10 minutes, followed by the dropwise addition of a solution of (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tributyl ester (7 g, 15.36 mmol) in dichloromethane (100 mL) over a period of five minutes. After the addition was complete, the reaction mixture was stirred for 15 minutes, followed by the addition of triethylamine (7.77 g, 76.81 mmol) while maintaining the temperature of the reaction mixture at -60 °C. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred under nitrogen atmosphere for 15 minutes. The reaction mixture was quenched with saturated sodium bicarbonate (100 mL) at 0 °C and extracted with dichloromethane (3 x 100 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/petroleum ether) to give (2S,3S)-3-((tributyldiphenylsilyl)oxy)-2-formylpyrrolidine-1-carboxylic acid tributyl ester (5.5 g, 78.92%) as a colorless oil. LCMS Rt = 0.712 min, m/z = 454.2 [M + H] ⁺ . Step 2 : (2R,3S)-3-(( tert-butyldiphenylsilyl ) oxy )-2- vinylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of methyl(triphenyl)phosphonium bromide (6.50 g, 18.19 mmol) in tetrahydrofuran (200 mL) was added potassium tri-butoxide (15.76 mL, 1M in tetrahydrofuran) at 0°C and stirred at 25°C for 0.5 h, followed by the addition of tri-butyl (2S,3S)-3-((tri-butyldiphenylsilyl)oxy)-2-formylpyrrolidine-1-carboxylate (5.5 g, 12.12 mmol) to the above solution at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 0.5 h. The reaction mixture was quenched with saturated ammonium chloride (30 mL) at 0°C and extracted with dichloromethane (3 x 100 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/petroleum ether) to give (2R,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 91.31%) as a light yellow oil. LCMS Rt = 0.783 min, m/z = 452.3 [M + H] ⁺ . Step 3: (2R,3S)-3-Hydroxy-2-vinylpyrrolidine-1-carboxylic acid tributyl ester

Deprotection of TBDPS was performed in a similar manner as Method #5, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3S)-3-hydroxy-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (2.33 g, 98.69%) as a colorless oil. LCMS Rt = 0.380 min, m/z = 214.1 [M + H] ⁺ . Step 4 : (2R,3R)-3-(1,3- dioxoisoindolin- 2- yl )-2- vinylpyrrolidine -1- carboxylic acid tributyl ester

A mixture of tributyl (2R,3S)-3-hydroxy-2-vinylpyrrolidine-1-carboxylate (1.9 g, 8.91 mmol), isoindoline-1,3-dione (1.97 g, 13.36 mmol), triphenylphosphine (3.50 g, 13.36 mmol) in tetrahydrofuran (50 mL) was degassed and purged with nitrogen three times. Diisopropyl azodicarboxylate (3.60 g, 17.82 mmol) was then added at 0°C. The mixture was stirred at 25°C under nitrogen atmosphere for 3 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to obtain (2R,3R)-3-(1,3-dioxoisoindolin-2-yl)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 26.23%) as a light yellow oil. LCMS Rt = 0.523 min, m/z = 343.2 [M + H] ⁺ . Step 5: (2R,3R)-3-amino-2-vinylpyrrolidine-1-carboxylic acid tributyl ester

To a solution of tributyl (2R,3R)-3-(1,3-dioxoisoindolin-2-yl)-2-vinylpyrrolidine-1-carboxylate (800 mg, 2.34 mmol) in isopropanol (15 mL) and water (3 mL) was added sodium borohydride (420 mg, 11.10 mmol) at 0°C for 2 hours. Acetic acid (1.05 g, 17.47 mmol) was then added at 0°C. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated to dryness in vacuo. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-55% B in 10.0 min) to give (2R,3R)-3-amino-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 26.21%) as a light yellow oil. LCMS Rt = 0.296 min, m/z = 213.2 [M + H] ⁺ . Step 6: (2R,3R)-3-(Methylamino)-2-vinylpyrrolidine-1-carboxylic acid tributyl ester

To a solution of (2R,3R)-3-amino-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 565.27 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (3 mL) was added methyl trifluoromethanesulfonate (92.76 mg, 565.27 μmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated to dryness in vacuo to give (2R,3R)-3-(methylamino)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, crude) as a brown oil, which was used in the next step without any further purification. LCMS Rt = 0.917 min, m/z = 227.1 [M + H] ⁺ . Step 7 : (2R,3R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 3. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 55%-75% B in 8.0 min) to give (2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-vinylpyrrolidine-1-carboxylic acid tributyl ester (25 mg, 28.54%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.571 min, m/z = 442.2/444.1 [M + H] ⁺ . Step 8 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/tetrahydrofuran) to afford (2R,3R)-tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-vinylpyrrolidine-1-carboxylate (20 mg, 78.28%) as a brown oil. LCMS Rt = 0.406 min, m/z = 565.4/566.4 [M + H] ⁺ . Step 9 : (2R,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 47%-77% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-vinylpyrrolidine-1-carboxylic acid tributyl ester (10 mg, 29.15%, trifluoroacetate) as a white solid. LCMS Rt = 0.630 min, m/z = 855.4 [M + H] ⁺ . Step 10 : (2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidine - 1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-vinylpyrrolidine-1-carboxylate (7 mg, crude) as a brown oil which was used in the next step without any further purification. LCMS Rt = 0.482 min, m/z = 699.5 [M + H] ⁺ . Step 11 : 7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- vinylpyrrolidin- 3- yl ) pyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-vinylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (5 mg, crude, hydrochloride) as a colorless oil which was used in the next step without any further purification. LCMS Rt = 0.361 min, m/z = 599.2 [M + H] ⁺ . Step 12 : 1-((2R,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- vinylpyrrolidin- 1- yl ) prop -2- en -1- one

The amide coupling reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 38%-65% B in 8.0 minutes) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-vinylpyrrolidin-1-yl)prop-2-en-1-one (1.04 mg, 21.13%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.15 (dd, J = 3.3, 6.3 Hz, 2H), 7.72 - 7.67 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H), 6.54 - 6.38 (m, 1H), 6.32 - 6.24 (m, 1H), 5.78 - 5.59 (m, 1H), 5.44 - 5.16 (m, 3H), 5.14 - 5.01 (m, 1H), 4.46 - 4.26 (m, 2H), 3.78 (d, J = 7.6 Hz, 1H), 3.55 (d, J = 3.8 Hz, 5H), 3.41 - 2.86 (m, 6H), 2.08 - 2.07 (m, 4H), 1.83 - 1.77 (m, 4H). LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 minutes) retention time 3.306 minutes, ESI+ found [M+H] ⁺ = 653.2. Example 63 : Synthesis of Compound 34 ; 1-((2R,3R)-2- ethyl- 3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -1- yl ) prop -2- en - 1- one ( Method 5) Step 1 : (2R,3S)-3-(( tert-butyldiphenylsilyl ) oxy )-2- ethylpyrrolidine -1- carboxylic acid tributyl ester

The hydrogenation reaction was carried out in a similar manner to Method #5 Step 7. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford tert-butyl (2R,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-ethylpyrrolidine-1-carboxylate (2 g, crude) as a colorless oil which was used in the next step without any further purification. LCMS Rt = 0.788 min, m/z = 454.4 [M + H] ⁺ . Step 2: (2R,3S)-2-ethyl-3-hydroxypyrrolidine-1-carboxylic acid tributyl ester

The deprotection reaction of TBDPS was carried out in a similar manner as method #5 step 4 . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/dichloromethane) to give tributyl (2R,3S)-2-ethyl-3-hydroxypyrrolidine-1-carboxylate (940 mg, 99.05%) as a colorless oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.10 - 4.05 (m, 1H), 3.70 - 3.64 (m, 1H), 3.58 - 3.41 (m, 2H), 3.34 (s, 1H), 2.02 - 1.76 (m, 4H), 1.39 (s, 9H), 0.86 (t, J = 7.4 Hz, 3H). LCMS Rt = 0.386 min, m/z = 216.0 [M + H] ⁺ . Step 3: (2R,3S)-2-ethyl-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tributyl ester

The mesylation reaction was performed in a similar manner as Method #5, Step 5. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford tributyl (2R,3S)-2-ethyl-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1.3 g, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.447 min, m/z = 294.0 [M + H] ⁺ . Step 4: (2R,3R)-3-azido-2-ethylpyrrolidine-1-carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #5 Step 6. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (2R,3R)-3-azido-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester (1 g, crude) as a red oil, which was used in the next step without any further purification. LCMS Rt = 0.584 min, m/z = 241.0 [M + H] ⁺ . Step 5: (2R,3R)-3-amino-2-ethylpyrrolidine-1-carboxylic acid tributyl ester

The reduction was carried out in a similar manner to Method #5 Step 7. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (2R,3R)-tert-butyl 3-amino-2-ethylpyrrolidine-1-carboxylate (1 g, crude) as a red oil which was used in the next step without any further purification. LCMS Rt = 0.281 min, m/z = 215.0 [M + H] ⁺ . Step 6: (2R,3R)-3-(Benzyl(methyl)amino)-2-ethylpyrrolidine-1-carboxylic acid tributyl ester

Reductive amination was performed in a similar manner to Method #2 Step 1 . The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50mm×10um; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 70%-90% B in 10.0 minutes) to give (2R,3R)-3-(benzyl(methyl)amino)-2-ethylpyrrolidine-1-carboxylic acid tributyl ester (250 mg, crude) as a yellow solid: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.27 - 7.17 (m, 5H), 4.09 - 3.78 (m, 1H), 3.54 (d, J = 12.9 Hz, 1H), 3.44 - 3.24 (m, 3H), δ 5.24 (m, 2H) , 1.54 (s, 9H), 0.91 (q, J = 7.2 Hz, 3H). LCMS Rt = 0.354 min, m/z = 319.3 [M + H] ⁺ . Step 7: (2R,3R)-2-ethyl-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of Bn was performed in a similar manner as Method #2 Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (2R,3R)-tert-butyl 2-ethyl-3-(methylamino)pyrrolidine-1-carboxylate (180 mg, crude) as a colorless oil, which was used in the next step without any further purification. LCMS Rt = 0.299 min, m/z = 229.1 [M + H] ⁺ . Step 8 : (2R,3R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- ethylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/dichloromethane) to afford tert-butyl (2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-ethylpyrrolidine-1-carboxylate (240 mg, 68.18%) as a yellow solid. LCMS Rt = 0.604 min, m/z = 444.2/446.1 [M + H] ⁺ . Step 9 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- ethylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-ethylpyrrolidine-1-carboxylic acid tributyl ester (110 mg, 43.10%) as a white solid. LCMS Rt = 0.495 min, m/z = 567.5/568.4 [M + H] ⁺ . Step 10 : (2R,3R)-2- ethyl- 3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The resulting residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 50%-90% B in 8.0 min) to give (2R,3R)-2-ethyl-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylic acid tributyl ester (120 mg, 63.70%, trifluoroacetate) as a yellow solid. LCMS Rt = 0.634 min, m/z = 857.4 [M + H] ⁺ . Step 11 : N-((2R,3R)-2- ethylpyrrolidin- 3- yl )-8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of the Boc group was performed in a similar manner to Method #1 step 7. The reaction mixture was concentrated to dryness in vacuo to afford N-((2R,3R)-2-ethylpyrrolidin-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (100 mg, crude, hydrochloride) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.448 min, m/z = 757.4 [M + H] ⁺ . Step 12 : N-((2R,3R)-2- ethylpyrrolidin -3- yl )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy )-N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner to Method #1, Step 6. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-65% B in 8.0 min) to give N-((2R,3R)-2-ethylpyrrolidin-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (50 mg, 66.05%) as a white solid. LCMS Rt = 0.386 min, m/z = 601.3 [M + H] ⁺ . Step 13 : 1-((2R,3R)-2- ethyl -3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro - 1H -pyrrolazin- 7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -1- yl ) prop -2- en -1 -one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to obtain 1-((2R,3R)-2-ethyl-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (13.87 mg, 25.43%) as a yellow amorphous solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.25 (s, 1H), 8.18 - 8.10 (m, 2H), 7.69 (d, J = 4.9 Hz, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.73 - 6.58 (m, 1H), 6.37 - 6.21 (m, 1H), 5.70 (d, J = 9.8 Hz, 1H), 5.41 - 5.21 (m, 1H), 4.99 - 4.77 (m, 2H), 4.36 - 4.14 (m, 2H), 3.90 - 3.64 (m, 2H), 3.63 - 3.54 (m, 3H), 3.31 - 3.12 (m, 4H), 2.95 (s, 1H), 2.64 - 2.45 (m, 2H), 2.31 - 2.14 (m, 3H), 2.12 - 2.04 (m, 1H), 1.91 (d, J = 9.5 Hz, 2H), 1.69 - 1.42 (m, 2H), 0.91 - 0.80 (m, 3H). LCMS Rt = 3.043 min, m/z = 655.3 [M + H] ⁺ .

LCMS (5% to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 6 min) retention time 3.043 min, ESI+ found [M+H] ⁺ = 655.3. Example 64 : Synthesis of Compound 35 ; 1-((2R,3R)-2 -cyclopropyl -3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -1- yl ) prop -2- en -1- one Step 1 : (2R,3S)-3-(( tert-butyldiphenylsilyl ) oxy )-2 -cyclopropylpyrrolidine

To a solution of diiodomethane (11.86 g, 44.28 mmol), trifluoroacetic acid (1.52 g, 13.28 mmol) in dichloromethane (40 mL) was added diethylzinc (17.72 mL, 17.72 mmol, 1.0 M in toluene) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C under nitrogen atmosphere for 0.5 h. Then tributyl (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-vinylpyrrolidine-1-carboxylate (4 g, 8.86 mmol) was added at 0°C under nitrogen atmosphere and stirred at 25°C for 11.5 h. The mixture was quenched with saturated sodium bicarbonate (10 mL) at 0°C and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-cyclopropylpyrrolidine (3.2 g, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.488 min, m/z = 366.3 [M + H] ⁺ . Step 2 : (2R,3S)-3-(( tert-butyldiphenylsilyl ) oxy )-2 -cyclopropylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-cyclopropylpyrrolidine (3.2 g, 8.76 mmol) in dichloromethane (10 mL), tetrahydrofuran (4 mL) and water (4 mL) was added di-tributyl dicarbonate (1.91 g, 8.76 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2R,3S)-3-((tributyldiphenylsilyl)oxy)-2-cyclopropylpyrrolidine-1-carboxylate (1.5 g, 37.50%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.56 (d, J = 6.9 Hz, 4H), 7.40 - 7.27 (m, 6H), 4.12 (d, J = 2.5 Hz, 1H), 3.67 - 3.43 (m, 1H), 3.35 (s, 1H), 3.26 - 2.89 (m, 1H), 2.00 - 1.75 (m, 2H), 1.40 (s, 9H), 0.96 (s, 9H), 0.33 - 0.05 (m, 4H), -0.39 - -0.69 (m, 1H). LCMS Rt = 2.844 min, m/z = 466.3 [M + H] ⁺ . Step 3: (2R,3S)-2-cyclopropyl-3-hydroxypyrrolidine-1-carboxylic acid tributyl ester

Deprotection of the TBDPS group was performed in a similar manner to Method #5, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford (2R,3S)-2-cyclopropyl-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (488 mg, 99.98%) as a yellow oil. LCMS Rt = 0.395 min, m/z = 228.0 [M + H] ⁺ . Step 4 : (2R,3S)-2 -cyclopropyl -3-(( methylsulfonyl ) oxy ) pyrrolidine -1- carboxylic acid tributyl ester

The mesylation reaction was performed in a similar manner to Method #5 Step 5. The reaction mixture was concentrated in vacuo to afford tributyl (2R,3S)-2-cyclopropyl-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (655 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.537 min, m/z = 306.2 [M + H] ⁺ . Step 5: (2R,3R)-3-azido-2-cyclopropylpyrrolidine-1-carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #5 Step 6. The reaction mixture was concentrated in vacuo to afford (2R,3R)-3-azido-2-cyclopropylpyrrolidine-1-carboxylic acid tributyl ester (500 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.595 min, m/z = 253.0 [M + H] ⁺ . Step 6: (2R,3R)-3-amino-2-cyclopropylpyrrolidine-1-carboxylic acid tributyl ester

The hydrogenation reaction was carried out in a similar manner to Method #5 Step 7. The reaction mixture was concentrated in vacuo to afford (2R,3R)-3-amino-2-cyclopropylpyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.287 min, m/z = 227.2 [M + H] ⁺ . Step 7: (2R,3R)-3-(Benzyl(methyl)amino)-2-cyclopropylpyrrolidine-1-carboxylic acid tributyl ester

The reductive amination reaction was carried out in a similar manner to Method #2, Step 1. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 55%-85% B in 10.0 min) to give (2R,3R)-3-(benzyl(methyl)amino)-2-cyclopropylpyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 17.12%) as a yellow oil. LCMS Rt = 1.250 min, m/z = 331.2 [M + H] ⁺ . Step 8: (2R,3R)-2-cyclopropyl-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of Bn was performed in a similar manner to Method #2 Step 2. The reaction mixture was concentrated in vacuo to afford (2R,3R)-2-cyclopropyl-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.285 min, m/z = 241.2 [M + H] ⁺ . Step 9: (2R,3R)-2-cyclopropyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1, Step 3. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give (2R,3R)-2-cyclopropyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylic acid tributyl ester (70 mg, 50.03%) as a yellow solid. LCMS Rt = 2.092 min, m/z = 456.1/458.1 [M + H] ⁺ . Step 10 : (2R,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -cyclopropylpyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #1 Step 4. The resulting residue was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 20%-50% B in 8.0 min) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-cyclopropylpyrrolidine-1-carboxylic acid tributyl ester (40 mg, 40.52%, trifluoroacetate) as a white solid. LCMS Rt = 1.496 min, m/z = 579.3/581.3 [M + H] ⁺ . Step 11 : (2R,3R)-2 -cyclopropyl -3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate/petroleum ether) to afford tributyl (2R,3R)-2-cyclopropyl-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (40 mg, 88.84%) as a yellow solid. LCMS Rt = 0.472 min, m/z = 869.6 [M + H] ⁺ . Step 12 : N-((2R,3R)-2 -cyclopropylpyrrolidin- 3- yl )-8- fluoro -7-(7 -fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy )-N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to afford N-((2R,3R)-2-cyclopropylpyrrolidin-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (32 mg, crude, hydrochloride) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.486 min, m/z = 769.4 [M + H] ⁺ . Step 13 : N-((2R,3R)-2 -cyclopropylpyrrolidin -3- yl )-7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) -N- methylpyrido [4,3-d] pyrimidin -4- amine

Deprotection of the TIPS group was performed in a similar manner as in Method #1, Step 6 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-65% B in 8.0 min) to give N-((2R,3R)-2-cyclopropylpyrrolidin-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (24 mg, 98.60%) as a white solid. LCMS Rt = 1.188 min, m/z = 613.4 [M + H] ⁺ . Step 14 : 1-((2R,3R)-2 -cyclopropyl -3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro - 1H -pyrrolazin- 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 carried out in a similar manner to Method #1 Step 8 . The crude material was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to give 1-((2R,3R)-2-cyclopropyl-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (6.7 mg, 25.09%) as a pale white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.30 (s, 1H), 8.24 - 8.09 (m, 2H), 7.77 - 7.67 (m, 2H), 7.50 (t, J = 9.1 Hz, 1H), 6.71 - 6.58 (m, 1H), 6.30 (d, J = 16.5 Hz, 1H), 5.74 (d, J = 8.8 Hz, 1H), 5.40 - 5.19 (m, 1H), 5.09 - 4.88 (m, 1H), 4.58 - 4.38 (m, 1H), 4.29 - 4.16 (m, 1H), 4.15 - 3.86 (m, 1H), 3.74 (s, 3H), 3.70 - 3.65 (m, 1H), 3.32 - 3.21 (m, 1H), 3.20 - 3.07 (m, 3H), 2.97 - 2.88 (m, 1H), 2.83 - 2.63 (m, 1H), 2.40 (s, 1H), 2.22 - 2.17 (m, 2H), 2.16 - 2.12 (m, 1H), 2.09 - 2.01 (m, 1H), 1.97 - 1.84 (m, 3H), 1.07 - 0.87 (m, 1H), 0.69 - 0.28 (m, 3H), 0.14 - -0.14 (m, 1H). LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 min) retention time 2.256 min, ESI+ found [M+H] ⁺ = 667.1. Examples 65 and 66 : Synthesis of Compounds 36-1 and 36-2 ; 1-((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidin -1 - yl ) prop -2- en -1- one and 1- ((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((S)-1- hydroxyethyl ) pyrrolidin -1- yl ) prop -2 - en - 1- one ( Method 5) Step 1 : (2S,3S)-3- hydroxy -2-( methoxy ( methyl ) aminoformyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of (2S,3S)-1-(tributyloxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (44 g, 190.27 mmol) and N -methoxymethylamine; hydrochloride (27.84 g, 285.41 mmol) in dichloromethane (500 mL) was added N , N -dimethylpyridin-4-amine (58.11 g, 475.69 mmol) and 3-(((ethylimino)methylene)amino) -N , N -dimethylpropan-1-amine (44.31 g, 285.41 mmol) at 0°C. The mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with hydrochloric acid (150 mL, 1 M in water) at 0°C and extracted with dichloromethane (3 x 150 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/petroleum ether) to give tributyl (2S,3S)-3-hydroxy-2-(methoxy(methyl)aminoformyl)pyrrolidine-1-carboxylate (47.5 g, 91.01%) as a yellow oil: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.65 - 4.45 (m, 1H), 4.28 (s, 1H), 3.77 - 3.67 (m, 3H), 3.67 - 3.49 (m, 2H), 3.14 (s, 3H), 2.14 - 2.00 (m, 1H), 1.85 - 1.76 (m, 1H), 1.40 - 1.33 (m, 9H). LCMS Rt = 0.305 min, m/z = 275.2 [M + H] ⁺ . Step 2 : (2S,3R)-3 -azido -2-( methoxy ( methyl ) aminoformyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3S)-3-hydroxy-2-(methoxy(methyl)aminocarbonyl)pyrrolidine-1-carboxylate (20.25 g, 73.82 mmol), triphenylphosphine (23.23 g, 88.59 mmol) in tetrahydrofuran (500 mL) was added ( E )-diazene-1,2-dicarboxylate (22.39 g, 110.73 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 10 minutes. Then diphenylphosphinoylazide (30.47 g, 110.73 mmol) was added to the above solution at 0°C under nitrogen atmosphere. The mixture was stirred at 25°C for 1.8 hours. Tributyl (2S,3R)-3-azido-2-(methoxy(methyl)aminocarbonyl)pyrrolidine-1-carboxylate (22 g, crude) in tetrahydrofuran (500 mL) was used in the next step without any further workup and purification. LCMS Rt = 0.404 min, m/z = 300.2 [M + H] ⁺ . Step 3 : (2S,3R)-3- amino- 2-( methoxy ( methyl ) aminoformyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3R)-3-azido-2-(methoxy(methyl)aminocarbonyl)pyrrolidine-1-carboxylate (22 g, 73.50 mmol) in tetrahydrofuran (500 mL) was added triphenylphosphine (38.56 g, 147.00 mmol) and water (8 mL). The mixture was stirred at 70 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 200 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/petroleum ether) to obtain (2S,3R)-3-amino-2-(methoxy(methyl)aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (15.9 g, 79.15%) as a yellow oil. LCMS Rt = 0.262 min, m/z = 274.2 [M + H] ⁺ . Step 4 : (2S,3R)-3-( Benzyl ( methyl ) amino )-2-( methoxy ( methyl ) aminoformyl ) pyrrolidine -1- carboxylic acid tributyl ester

Reductive amination was performed in a similar manner to Method #2, Step 1. The crude product was purified by reverse phase HPLC (column: Agela DuraShell C18 250×70 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 17.0 min) to give (2S,3R)-3-(benzyl(methyl)amino)-2-(methoxy(methyl)aminomethyl)pyrrolidine-1-carboxylic acid tributyl ester (10.5 g, 52.43%) as a white solid. LCMS Rt = 2.257 min, m/z = 378.2 [M + H] ⁺ . Step 5 : (2S,3R)-3-( Benzyl ( methyl ) amino )-2- formylpyrrolidine -1- carboxylic acid tributyl ester

To a solution of (2S,3R)-3-[benzyl(methyl)amino]-2-[methoxy(methyl)aminocarbonyl]pyrrolidine-1-carboxylic acid tributyl ester (5.8 g, 15.37 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydroxide (18.44 mL, 2.5M in tetrahydrofuran, 46.11 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with sodium sulfate decahydrate (5 g) at 0°C and dried over sodium sulfate. The resulting precipitate was filtered and the filtrate was concentrated in vacuo to give tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-formylpyrrolidine-1-carboxylate (4.8 g, crude) as a brown oil, which was used in the next step without any further purification. LCMS Rt = 0.326 min, m/z = 319.1 [M + H] ⁺ . Step 6 : (2S,3R)-3-( Benzyl ( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of (2S,3R)-3-(benzyl(methyl)amino)-2-formylpyrrolidine-1-carboxylic acid tributyl ester (4.8 g, 15.07 mmol) in tetrahydrofuran (150 mL) was added methylmagnesium bromide (15.07 mL, 3M in diethyl ether, 45.21 mmol) under nitrogen atmosphere. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with hydrochloric acid (50 mL, 1M in water) at 0 °C and extracted with ethyl acetate (3 x 150 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 Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 50%-80% B in 8.0 min) to obtain tributyl (2S,3R)-3-(benzyl(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate (0.8 g, 15.87%) as a yellow solid. LCMS Rt = 1.087 min, m/z = 335.3 [M + H] ⁺ . Step 7: (2S,3R)-2-((R)-1-hydroxyethyl)-3-(methylamino)pyrrolidine-1-carboxylic acid tributyl ester

Deprotection of Bn was performed in a similar manner as Method #2 Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford tributyl (2S,3R)-2-((R)-1-hydroxyethyl)-3-(methylamino)pyrrolidine-1-carboxylate (800 mg, crude) as a white solid, which was used in the next step without any further purification. LCMS Rt = 0.109 min, m/z = 245.3 [M + H] ⁺ . Step 8 : (2S,3R)-3-((2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 3. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-70% B in 8.0 min) to give (2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (0.5 g, 36.56%) as a white solid. LCMS Rt = 1.791 min, m/z = 460.2/462.0 [M + H] ⁺ . Step 9 : (2S,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidine -1-carboxylic acid tributyl ester

The substitution reaction was carried out in a similar manner to Method #2, Step 4. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-70% B in 10.0 min) to give (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (460 mg, 72.63%) as a white solid. LCMS Rt = 0.364 min, m/z = 583.4/585.4 [M + H] ⁺ . Step 10 : (2S,3R)-2- acetyl- 3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin - 4- yl )( methyl ) amino ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of oxalyl chloride (65.32 mg, 514.52 μmol) in dichloromethane (8 mL) was added dimethyl sulfoxide (53.60 mg, 686.04 μmol) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 10 minutes. Then, tributyl (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate (200 mg, 343.00 μmol) was added at -78°C. The mixture was stirred at -78°C for 10 minutes. Then trimethylamine (138.84 mg, 1372.04 μmol) was added at -78 °C. The mixture was stirred at 25 °C for 40 min. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (3 x 12 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give tributyl (2S,3R)-2-acetyl-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.379 min, m/z = 581.2/583.2 [M + H] ⁺ . Step 11 : (2S,3R)-3-((7- chloro -8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-(1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

To a solution of tributyl (2S,3R)-2-acetyl-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (100 mg, 172.10 μmol) in methanol (2 mL) was added sodium borohydride (13.02 mg, 344.20 μmol) at -78 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with hydrochloric acid (1 mL, 1 M in water) at 0 °C and extracted with ethyl acetate (3 x 1 mL). The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 25%-45% B in 8.0 min) to give (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (40 mg, 39.86%, trifluoroacetate) as a white solid. LCMS Rt = 0.381 min, m/z = 583.1/585.1 [M + H] ⁺ . Step 12 : (2S,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester and (2S,3R)-3-((8- fluoro -7-(7- fluoro -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 - yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2-((S)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

The Suzuki reaction was performed in a similar manner to Method #1, Step 5 . The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA )-ACN]; gradient: 40%-80% B in 8.0 min) to give the following substances as arbitrarily designated: Example 65: (2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (15 LCMS Rt = 2.149 min, m/z = 873.4 [M + H] ⁺ ; and Example 66: (2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((S)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (10 mg, 29.53%, trifluoroacetic acid salt) as a white solid. LCMS Rt = 2.105 min, m/z = 873.5 [M + H] ⁺ . Step 13 : (2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford (2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (12 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.429 min, m/z = 717.3 [M + H] ⁺ . Step 14 : (R)-1-((2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -2- yl ) ethan -1- ol

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 10%-40% B in 8.0 min) to give (R)-1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-2-yl)ethan-1-ol (8 mg, 65.40%, trifluoroacetate) as a yellow oil. LCMS Rt = 0.340 min, m/z = 617.1 [M + H] ⁺ . Step 15 : 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((R)-1- hydroxyethyl ) pyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-60% B in 8.0 min) to give 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((R)-1-hydroxyethyl)pyrrolidin-1-yl)prop-2-en-1-one (1.95 mg, 41.72%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ9.40 - 9.32 (m, 1H), 8.19 - 8.09 (m, 2H), 7.76 - 7.63 (m, 2H), 7.53 - 7.42 (m, 1H), 6.90 - 6.75 (m, 1H), 6.24 (dd, J = 2.2, 16.8 Hz, 1H), 5.74 (dd, J = 2.1, 10.5 Hz, 1H), 5.49 - 5.16 (m, 2H), 4.79 - 4.43 (m, 2H), 4.27 - 4.18 (m, 1H), 4.11 (d, J = 10.4 Hz, 1H), 4.06 - 3.94 (m, 2H), 3.36 (s, 1H), 3.25 (d, J = 11.8 Hz, 3H), 3.18 (d, J = 4.8 Hz, 2H), 3.11 (s, 1H), 3.01 - 2.85 (m, 2H), 2.15 - 2.06 (m, 4H), 1.96 - 1.79 (m, 4H), 1.25 (d, J = 6.1 Hz, 3H). LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 min) retention time 2.340 min, ESI+ found [M+H] ⁺ = 671.2. Example 66 : Synthesis of Compound 36-2 ; 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((S)-1- hydroxyethyl ) pyrrolidin -1- yl)prop-2 - en - 1 - one Step 1 : (2S,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((S)-1- hydroxyethyl ) pyrrolidine -1- carboxylic acid tributyl ester

Deprotection of the TIPS group was performed in a similar manner to Method #1 step 6. The reaction mixture was concentrated in vacuo to afford (2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((S)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tributyl ester (8 mg, crude) as a yellow oil, which was used in the next step without any further purification. LCMS Rt = 0.433 min, m/z = 717.3 [M + H] ⁺ . Step 2 : (S)-1-((2S,3R)-3-((7-(8- ethynyl - 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin- 7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino ) pyrrolidin -2- yl ) ethan -1- ol

Deprotection of Boc was performed in a similar manner to Method #1 Step 7. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [H ₂ O (0.1% TFA)-ACN]; gradient: 5%-40% B in 8.0 min) to give (S)-1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-2-yl)ethan-1-ol (5 mg, 61.31%, trifluoroacetate) as a yellow oil. LCMS Rt = 1.902 min, m/z = 617.3 [M + H] ⁺ . Step 3 : 1-((2S,3R)-3-((7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin - 7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2-((S)-1- hydroxyethyl ) pyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 40%-60% B in 8.0 min) to give 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-((S)-1-hydroxyethyl)pyrrolidin-1-yl)prop-2-en-1-one (1.07 mg, 96.28%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.43 - 9.29 (m, 1H), 8.20 - 8.10 (m, 2H), 7.79 - 7.60 (m, 2H), 7.52 - 7.42 (m, 1H), 6.87 - 6.74 (m, 1H), 6.24 (dd, J = 2.2, 16.8 Hz, 1H), 5.74 (dd, J = 2.2, 10.6 Hz, 1H), 5.53 - 5.21 (m, 2H), 4.76 (s, 2H), 4.38 - 4.16 (m, 2H), 4.09 - 3.94 (m, 2H), 3.37 (br d, J = 4.0 Hz, 1H), 3.33 - 3.15 (m, 6H), 3.07 - 2.86 (m, 2H), 2.15 - 2.12 (m, 4H), 1.94 - 1.78 (m, 4H), 1.34 - 1.29 (m, 3H). LCMS Rt = 2.340 min, m/z = 671.2 [M + H] ⁺ . Example 67 : Synthesis of Compound 37 ; 1-((2R,3R)-3-((7-(6- amino -4- methyl -3-( trifluoromethyl ) pyridin -2- yl )-8 -fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2 -methylpyrrolidin -1- yl ) prop-2-en -1 - one ( Method 6 ) Step 1 : (2R,3R)-3-((8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin- 7a(5H) -yl ) methoxy )-7-( trimethyltinyl ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

A mixture of tributyl (2R,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 904.09 μmol), trimethyl(trimethyltinyl)tinane (888.61 mg, 2.71 mmol) and di-tributyl(cyclopentyl)phosphane; dichloropalladium; iron (58.92 mg, 90.41 μmol) in toluene (5 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 110 °C under nitrogen atmosphere for 12 hours. The reaction mixture was filtered and concentrated to dryness in vacuo to give tributyl (2R,3R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(trimethyltinyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (620 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 1.285 min, m/z = 683.3 [M + H] ⁺ . Step 2 : (2R,3R)-3-((7-(6-( bis (4- methoxybenzyl ) amino )-4- methyl -3-( trifluoromethyl ) pyridin -2- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolazin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidine -1- carboxylic acid tributyl ester

(2R,3R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(trimethyltinyl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (580 mg, 851.18 μmol), 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (632.43 mg, 1.28 mmol) and palladium; tri-tributylphosphane (43.50 mg, 85.12 μmol) were dissolved in toluene (5 mL) and dioxane (2 The mixture in 10 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 110 °C under nitrogen atmosphere for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 65%-95% B in 8.0 min) to give (2R,3R)-3-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tributyl ester (30 mg, 7.50%) as a yellow solid. LCMS Rt = 2.809 min, m/z = 933.4 [M + H] ⁺ . Step 3 : 7-(6- amino -4- methyl -3-( trifluoromethyl ) pyridin -2- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H -pyrrolizin -7a(5H) -yl ) methoxy )-N- methyl -N-((2R,3R)-2- methylpyrrolidin -3- yl ) pyrido [4,3-d] pyrimidin -4- amine

A solution of tributyl (2R,3R)-3-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (30 mg, 32.15 μmol) in trifluoroacetic acid (1 mL) was stirred at 45 °C for 12 h. The reaction mixture was concentrated to dryness in vacuo to give 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (20 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.300 min, m/z = 593.3 [M + H] ⁺ . Step 4 : 1-((2R,3R)-3-((7-(6- amino - 4- methyl -3-( trifluoromethyl ) pyridin - 2- yl )-8 -fluoro -2-(((2R,7aS)-2 - fluorotetrahydro -1H -pyrrolazin -7a(5H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en -1- one

The acylation reaction was carried out in a similar manner to Method #1 Step 8 . The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to give 1-((2R,3R)-3-((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (13.86 mg, 69.27%) as a white solid: ¹ H NMR (400 MHz, acetonitrile-d3) δ 9.26 - 9.14 (m, 1H), 6.68 - 6.21 (m, 3H), 5.69 (dd, J = 3.0, 9.6 Hz, 1H), 5.53 (s, 2H), 5.37 - 5.17 (m, 1H), 4.98 - 4.78 (m, 2H), 4.29 - 4.09 (m, 2H), 3.93 - 3.65 (m, 1H), 3.58 (d, J = 6.6 Hz, 3H), 3.55 (s, 1H), 3.21 - 3.04 (m, 3H), 2.98 - 2.82 (m, 1H), 2.66 - 2.48 (m, 1H), 2.46 (d, J = 1.5 Hz, 3H), 2.40 - 2.28 (m, 1H), 2.19 (d, J = 7.5 Hz, 1H), 2.12 (d, J = 3.3 Hz, 1H), 2.08 - 2.01 (m, 1H), 1.94 - 1.80 (m, 3H), 1.15 - 1.03 (m, 3H).

LCMS (5% to 95% acetonitrile/water + 0.1% trifluoroacetic acid over 6 minutes) retention time 2.025 minutes, ESI+ experimental value [M+H] = 647.3. Example 68 : Synthesis of compound 38-1 ; 1-((2R,3R)-3-((7-(8- ethynyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2-( trifluoromethoxy ) tetrahydro -1H -pyrrolazin- 7a(5H)-yl ) methoxy )pyrido [ 4,3 -d] pyrimidin -4- yl )( methyl ) amino )-2- methylpyrrolidin -1- yl ) prop -2- en - 1- one

This compound was prepared in a manner similar to Example 1: ¹ H NMR (400 MHz, CD ₃ CN) δ 9.25 (s, 1H), 8.22 - 8.10 (m, 2H), 7.75 - 7.66 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.68 - 6.54 (m, 1H), 6.35 - 6.21 (m, 1H), 5.74 - 5.65 (m, 1H), 5.08 - 4.87 (m, 3H), 4.34 - 4.18 (m, 2H), 3.95 - 3.66 (m, 2H), 3.63 (d, J = 7.3 Hz, 3H), 3.60 - 3.43 (m, 1H), 3.30 - 3.17 (m, 2H), 3.09 - 3.00 (m, 2H), 2.69 - 2.57 (m, 2H), 2.46 - 2.35 (m, 2H), 1.91 - 1.85 (m, 2H), 1.84 - 1.67 (m, 2H), 1.18 - 1.07 (m, 3H). LCMS Rt = 3.147 min, m/z = 707.3 [M + H] ⁺ . Biological Examples Example 69 : Inhibition of KRAS ^G12C and cRAF Binding

AlphaScreen technology was used to determine the _IC50 of compound inhibition of KRAS G12C (which exists as a truncated form of Cys-light (C51S, C80L and C118S), containing amino acids 1-169) and cRAF. Compounds were diluted in 100% DMSO and each compound concentration was spotted onto a low volume white 384-well plate at 200 nl/well. KRAS G12C contains biotin-AviTag and cRaf is GST-tagged as the Ras binding domain (amino acids 50-131, RBD). KRAS G12C is preloaded with the GTP analog guanosine 5'-[β,γ-imino]triphosphate (GMPPNP). KRAS G12C was diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 0.01% TritonX-100, and 10 µM GMPPNP and added to the compound spotting plate at 10 ul/well to give a DMSO concentration of 2%. Plates were incubated for 2 hours. Then add a mixture of RBD and AlphaScreen streptavidin donor and glutathione acceptor beads diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 0.01% TritonX-100 and 2% DMSO at 10 ul/well and incubate for 60-90 minutes, then excite the donor beads at 680 nm and read the sample at 570 Emission at nm. All incubations were performed at room temperature. For the 10-point dose-response curve, the final maximum compound concentration was 50 µM at a 1:3 titration. Final assay conditions were 0.5 nM KRAS G12C, 0.75 nM RBD, and 5 ug/ml each of AlphaScreen donor and acceptor beads. _IC50s were determined using nonlinear regression fit of the [inhibitor] versus response (4 parameters).

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

The results for the compounds are shown in Table 1A. Table 1A. Inhibition of KRAS G12C and cRAF Binding (IC ₅₀ ) Compound No. Examples IC50 1-1 1-1 ++++ 1-2 1-2 + 1-3 1-3 ++++ 1-4 27 + 1-5 28 ++ 2-1 2 + 2-2 6 + 2-3 3 +++ 2-4 8 + 3-1 4 ++ 3-2 10 + 3-3 5 +++ 3-4 9 + 5 7 +++ 6 12 +++ 7-1 twenty one +++ 7-2 22 or 23 +++ or + 7-3 8-1 twenty four +++ 8-2 25 or 26 +++ or + 8-3 9 17 ++++ 10 18 +++ 11 19 +++ 12 20 +++ 13-1 29 or 30 ++ or + 13-2 14-1 31 ++++ 14-2 32 or 33 ++++ or + 14-3 15-1 34 or 35 ++++ 15-2 15-3 36 or 37 ++++ 15-4 15-5 15-6 16 38 ++++ 17-1 39 or 40 + 17-2 17-3 41 + 17-4 42 or 43 + 17-5 18 44 ++++ 19 45 + 20 46 ++ 21-1 47 ++++ 21-2 48 or 49 ++++ or + 21-3 twenty two 50 ++++ twenty three 51 +++ twenty four 52 +++ 25 53 +++ 26 54 +++ 27-1 55 ++++ 28 56 +++ 29-1 57 ++++ 30-1 58 or 59 ++ 30-2 31 60 + 32 61 ++++ 33 62 +++ 34 63 +++ 35 64 ++ 36-1 65 or 66 + 36-2 37 67 +++ 38-1 68 +++ _IC50 ++++ is less than 10 nM, +++ is 10 to less than 100 nM, ++ is 100 to less than 500 nM, + is greater than or equal to 500 nM. Example 70 : Inhibition of KRAS ^G12C and PI3Ka binding

AlphaScreen technology was used to determine the _IC50 of compound inhibition of KRAS G12C (which exists as a truncated form of Cys-light (C51S, C80L and C118S), containing amino acids 1-169) and PI3Ka. Certain compounds described herein were diluted in 100% DMSO and each compound concentration was spotted onto a low volume white 384-well plate at 200 nl/well. KRAS G12C contains biotin-AviTag and PI3Ka as the Ras binding domain (amino acids 157-300, RBD) is His-tagged. KRAS G12C is preloaded with the GTP analog guanosine 5'-[β,γ-imino]triphosphate (GMPPNP). KRAS G12C was diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 0.01% TritonX-100, and 10 µM GMPPNP and added to the compound spotting plate at 10 ul/well to give a DMSO concentration of 2%. Plates were incubated for 2 hours. Next, a mixture of RBD and AlphaScreen streptavidin donor and nickel chelate acceptor beads diluted in 25 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 0.01% TritonX-100, and 2% DMSO was added at 10 ul/well and incubated for 60-90 minutes, followed by excitation of the donor beads at 680 nm and reading the sample at 570 Emission at nm. All incubations were performed at room temperature. For the 10-point dose response curve, the final highest compound concentration was 50 µM at a 1:3 titration. Final assay conditions were 1.5 nM KRAS G12C, 100 nM RBD, 1.25 ug/ml AlphaScreen donor beads, and 10 ug/ml AlphaLISA acceptor beads. _IC50s were determined using nonlinear regression fit of the [inhibitor] versus response (4 parameters). Compounds tested exhibited _IC50s less than 20 nM.

A counter-assay was also set up to exclude inhibitors of the AlphaScreen technology itself. The compound plate was incubated with buffer alone for approximately 2 hours as above. AlphaScreen beads were added as above, except that an irrelevant biotinylated His-tagged peptide was used instead of RBD. Samples were read and analyzed as above. Example 71: MCF10A (G12C or G12C-A59G)-KRAS cell viability assay

MCF10A (ATCC, catalog number CRL-10317) cells were maintained in MEBM (Lonza, catalog number CC-3151) containing 1% horse serum (Sigma, catalog number H1270), MEGM Mammary Epithelial Cell Growth Medium SingleQuotsKit (Lonza, catalog number CC-4146) and 25ng/ml cholera toxin (Sigma, catalog number C8052). These cells were transduced with KRAS G12C or G12C/A59G, followed by puromycin selection to generate stable expressing cells. For cell viability assay, 1000 MCF10A KRAS G12C or MCF10A G12C/A59G cells were plated in 384-well spheroid microplates (Corning, catalog #3830). The next day, cells were treated with compounds (10uM top concentration, 3-fold dilutions, and 11 doses). 10uM Tremetinib (MCE, catalog #HY-10999/CS-0060) was used as a control. Tecan: HP D300E was used to dispense compounds. After five days of incubation, cell viability was measured using a BioTek plate reader using the celltiter-glo luminescence assay kit (Promega, catalog #G7573) according to the manufacturer's protocol. The data were then imported and processed in Dotmatics, where the EC50 was calculated using a Lavenberg-Marquardt 4-parameter fitting procedure with differential gradients. Example 72: Treatment of human patients

A therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1) can be administered to a human patient suffering from cancer (e.g., a KRAS-mediated cancer as disclosed herein). Treatment can slow or stop tumor growth, reduce tumor size or mass, or eradicate the tumor in the patient.

The disclosures of all publications, patents, patent applications, and published patent applications cited herein are hereby incorporated by reference in their entirety.

Although the above invention has been described in considerable detail by way of illustration and examples for the purpose of clear understanding, it is obvious to those skilled in the art that some minor changes and modifications will be practiced. Therefore, the description and examples should not be interpreted as limiting the scope of the invention.

Claims (67)

A compound of formula (I), Formula (I), or a salt thereof and/or an isotopologue thereof; wherein: X is -N(CH ₃ )- or -O-; X ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ or cyclopropyl, each of which is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, -OH and -OCH ₃ ; q is 0 or 1; R ¹ is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring atom, wherein the heterocyclic group is substituted by 0, 1, 2 or 3 R ^1A ; R ^1A is independently selected from halogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C _4- halogen alkoxy and -C(O)(C ₁ -C ₄ alkyl); or two zygote R ^1A together with the carbon atom to which they are attached form a C ₃ -C ₄ cycloalkyl substituted with 0, 1 or 2 halogen groups; or two zygote R ^1A together form =CH ₂ , =CHF or =CF ₂ ; ^Ra is H or CH ₃ ; R ² is or ; R ³ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁴ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen, C ₁ -C ₄ halogenoxy and C ₂ -C ₃ alkynyl; R ⁵ is H or -OH; Y is CH or N; R ⁶ is independently selected from the group consisting of halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogen, C ₃ -C ₄ cycloalkyl and -NH ₂ ; and r is 0, 1, 2 or 3; provided that when q is 0, then R ¹ is not , , , , , or any mirror image thereof; when for or or any mirror image isomer thereof, then R ² is not ; and when for or any mirror image isomer thereof, then R ² is not or . The compound or salt thereof and/or isotopologue of claim 1, wherein R ² is . The compound or salt thereof and/or isotopologue of claim 2, wherein R ³ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₂ -C ₃ alkynyl. The compound or salt thereof and/or isotopologue of claim 2, wherein R ³ is selected from the group consisting of -F, -Cl, -Et, -C≡CH and -C≡C-CH ₃ . The compound or salt thereof and/or isotopologue according to any one of claims 2 to 4, wherein R ⁴ is hydrogen or halogen. The compound or salt thereof and/or isotopologue according to any one of claims 2 to 4, wherein R ⁴ is hydrogen or -F. The compound or salt thereof and/or isotopologue according to any one of claims 2 to 6, wherein R ⁵ is -OH. The compound or salt thereof and/or isotopologue according to any one of claims 2 to 6, wherein R ⁵ is H. The compound or its salt and/or its isotope according to claim 2, wherein R ² is , , , , , or . The compound or salt thereof and/or isotopologue of claim 1, wherein R ² is . The compound or its salt and/or its isotopologue according to claim 10, wherein Y is CH. The compound or its salt and/or its isotopologue according to claim 10, wherein Y is N. The compound or salt thereof and/or isotopologue as claimed in any one of claims 10 to 12, wherein R ⁶ in each case is independently selected from the group consisting of -Cl, -OH, -CH ₃ , -CF ₃ , cyclopropyl and -NH ₂ . The compound or salt thereof and/or isotopologue according to any one of claims 10 to 13, wherein r is 3. The compound or salt thereof and/or isotopologue of any one of claims 10 to 13, wherein R ² is . The compound or salt thereof and/or isotopologue of any one of claims 10 to 13, wherein R ² is , wherein R ^6A is cyclopropyl or -CF ₃ ; R ^6B is -Cl or -CH ₃ ; and R ^6C is -OH or -NH ₂ . The compound or its salt and/or its isotope according to claim 10, wherein R ² is , or . The compound or salt thereof and/or isotopologue according to any one of claims 1 to 17, wherein X is -N(CH ₃ )-. The compound or salt thereof and/or isotopologue according to any one of claims 1 to 17, wherein X is -O-. The compound or salt thereof and/or isotopologue according to any one of claims 1 to 19, wherein X ¹ is -CH ₃ , -CH ₂ F, -CH ₂ OCH ₃ , -CH ₂ CH ₃ , -CH(OH)CH ₃ , -CH=CH ₂ or cyclopropyl. The compound or salt thereof and/or isotopologue according to any one of claims 1 to 19, wherein X ¹ is -CH ₃ . The compound or salt thereof and/or isotopologue of any one of claims 1 to 17, wherein the Part of , , , , , , , , , or . The compound or salt thereof and/or isotopologue according to any one of Examples 1 to 17, wherein Part of , , , , , , , , , , , , , , , , , , , , or . The compound or salt thereof and/or isotopologue of any one of claims 1 to 23, wherein R ¹ is substituted with 0, 1, 2 or 3 R ^1A or . The compound or salt thereof and/or isotopologue of any one of claims 1 to 24, wherein R ^1A is independently -F, -OH, -CH ₃ , -OCH ₃ , -OCF ₃ , -OCHF ₂ or -C(O)CH ₃ in each case; or two bis-position R ^1A together with the carbon atom to which they are attached form a cyclopropyl substituted with 0, 1 or 2 fluorine atoms; or two bis-position R ^1A together form =CH ₂ , =CHF or =CF ₂ . The compound or salt thereof and/or isotopologue of any one of claims 1 to 25, wherein R ¹ is , , , , , , , , , , , , , , , , , , , or . The compound or salt thereof and/or isotopologue of any one of claims 1 to 25, wherein R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound of any one of claims 1 to 27, wherein ^Ra is H. The compound of any one of claims 1 to 27, wherein ^Ra is _CH3 . The compound or salt thereof and/or isotopologue of claim 1, wherein the compound is selected from the group consisting of compounds in Table 1. The compound or salt and/or isotopologue thereof according to any one of claims 1 to 30, wherein the salt is a pharmaceutically acceptable salt. A pharmaceutical formulation comprising the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof and a pharmaceutically acceptable carrier. A method for treating or inhibiting cancer, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation of claim 32. The method of claim 33, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. The method of claim 33, wherein the cancer is selected from the group consisting of: polymorphic neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium carcinoma, cervical squamous carcinoma and cervical endometrial carcinoma, skin melanoma tumor, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms tumor (pediatric Wilms' tumor), pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. The method of any one of claims 33 to 35, wherein the cancer is a KRAS G12C-mediated cancer. The method of any one of claims 33 to 35, wherein the individual is diagnosed with KRAS G12C-mediated cancer. The method of any one of claims 33 to 35, further comprising administering to the individual a therapeutically effective amount of an additional chemotherapeutic agent. The compound of any one of claims 1 to 31 or its pharmaceutically acceptable salt and/or its isotope or the pharmaceutical formulation of claim 32, for use as a medicament. The compound of any one of claims 1 to 31 or its pharmaceutically acceptable salt and/or its isotope or the pharmaceutical formulation of claim 32 is used for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. The compound for use according to claim 40 or its pharmaceutically acceptable salt and/or its isotope or pharmaceutical formulation, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. The compound for use according to claim 40 or its pharmaceutically acceptable salt and/or its isotope or pharmaceutical formulation, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, pulmonary squamous cell carcinoma, cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic Leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal Melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. The compound for use according to any one of claims 38 to 40, or a pharmaceutically acceptable salt thereof and/or an isotopologue or a pharmaceutical formulation thereof, wherein the cancer is a KRAS G12C-mediated cancer. The compound for use according to any one of claims 40 to 42, or a pharmaceutically acceptable salt thereof and/or an isotopologue or a pharmaceutical formulation thereof, wherein the individual is diagnosed with KRAS G12C-mediated cancer. A compound for use according to any one of claims 40 to 44, or a pharmaceutically acceptable salt thereof and/or an isotopologue thereof, or a pharmaceutical formulation thereof, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent. A compound for use according to any one of claims 40 to 45, or a pharmaceutically acceptable salt thereof and/or an isotopologue thereof, or a pharmaceutical formulation thereof, wherein the compound or the pharmaceutical formulation is configured for administration in a therapeutically effective amount. The compound of any one of claims 1 to 31 or its pharmaceutically acceptable salt and/or its isotope or the pharmaceutical formulation of claim 30 is used for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. The compound for use according to claim 47 or its pharmaceutically acceptable salt and/or its isotope or pharmaceutical formulation, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. The compound for use according to claim 47 or its pharmaceutically acceptable salt and/or its isotope or pharmaceutical formulation, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, pulmonary squamous cell carcinoma, cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic Leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma myeloma, uterine carcinoma sarcoma, mesothelioma, adrenocortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, renal papillary carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal Melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. The compound for use according to any one of claims 47 to 49, or a pharmaceutically acceptable salt thereof and/or an isotopologue or a pharmaceutical formulation thereof, wherein the cancer is a KRAS G12C-mediated cancer. The compound for use according to any one of claims 47 to 49, or a pharmaceutically acceptable salt thereof and/or an isotopologue or a pharmaceutical formulation thereof, wherein the individual is diagnosed with KRAS G12C-mediated cancer. A compound for use according to any one of claims 47 to 51, or a pharmaceutically acceptable salt thereof and/or an isotopologue thereof, or a pharmaceutical formulation thereof, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent. A compound for use according to any one of claims 47 to 52, or a pharmaceutically acceptable salt thereof and/or an isotopologue thereof, or a pharmaceutical formulation thereof, wherein the medicament comprises a therapeutically effective amount of the compound or the composition. A use of a compound as claimed in any one of claims 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation as claimed in claim 32 for the manufacture of a medicament for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. The use of claim 54, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. The use of claim 54, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, 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, Colon cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic Myeloid leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastasis Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. The use of any one of claims 54 to 56, wherein the cancer is a KRAS G12C-mediated cancer. The use of any one of claims 54 to 56, wherein the individual is diagnosed with KRAS G12C-mediated cancer. The use of any one of claims 54 to 58, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent. The use of any one of claims 54 to 59, wherein the medicament comprises a therapeutically effective amount of the compound or the pharmaceutical formulation. A use of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt and/or an isotopologue thereof or a pharmaceutical formulation according to claim 30 for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. The use of claim 61, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer. The use of claim 61, wherein the cancer is selected from the group consisting of: multiform neuroblastoma, low-grade neuroglioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, degenerative thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, Colon cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, corpus endometrium cancer, cervical squamous carcinoma and cervical gland cancer, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic Myeloid leukemia, plasma cell myeloma, uterine carcinoma, mesothelioma, adrenal cortical carcinoma, low-grade neuroglioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal carcinoma, papillary renal carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastasis Colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, neuroglioma, esophageal/gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancy, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. The use of any one of claims 61 to 63, wherein the cancer is a KRAS G12C-mediated cancer. The use of any one of claims 61 to 63, wherein the individual is diagnosed with KRAS G12C-mediated cancer. The use of any one of claims 61 to 65, wherein the compound or the pharmaceutical formulation is configured for administration together with a therapeutically effective amount of an additional chemical therapeutic agent. The use of any one of claims 61 to 66, wherein the use involves a therapeutically effective amount of the compound or the composition.