Pyrido[4,3-d]pyrimidine derivatives as mutant kras g12c inhibitors for the treatment of cancer

Abstract

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

Description

PYRIDO[4,3-D]PYRIMIDINE DERIVATIVES AS MUTANT KRAS G12C INHIBITORS FOR THE TREATMENT OF CANCERCross-reference to related applications

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 464,191, filed on May 4, 2023, and U.S. Provisional Patent Application No. 63 / 615,742, filed on December 28, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety.Field of the Disclosure

[0002] The present disclosure provides compounds useful in treating or suppressing cancer, and in particular, useful in treating or suppressing cancers characterized by the KRAS G12C mutant. Also provided are pharmaceutical formulations containing such compounds, processes for preparing such compounds, and methods of using such compounds in the treatment or suppression of cancers.Background

[0003] 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, the GDP is exchanged to 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 that leads to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP, thus returning to the off-state, in a process facilitated by GAPs (GTPase- activating Proteins).

[0004] KRAS mutations are found in approximately 30% of all human cancers, and are highly prevalent among three of the deadliest forms of cancer: pancreatic (95%), colorectal (45%), and lung (35%). Together, these cancers occur in more than 200,000 patients annually in the US alone. One particular mutation, a glycine to cysteine substitution at position 12 (G12C), occurs in more than 40,000 patients per year. The KRAS G12C mutation impairs hydrolysis of GTP to GDP, thus trapping KRAS in the on-state and promoting cancer cell proliferation.

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

[0006] 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 with the GDP-bound form of KRAS G12C at least 1000-fold more rapidly than with the GTP-bound form of the protein. One form of resistance that has been observed is for cancer cells to increase signaling through RTKs, thus increasing the amount of GTP-bound KRAS, which is less affected by current inhibitors. Thus, creating a molecule that could bind to and inhibit both the GDP- and GTP-bound forms of KRAS could have substantial utility.

[0007] What is needed are compounds useful in the treatment of cancer, such as cancers characterized by KRAS G12C. What is further needed are compounds useful in the treatment of cancers characterized by KRAS G12C, wherein the compounds bind to and inhibit both the inactive GDP- and activated GTP-bound forms of KRAS. What is further needed are compounds useful in the treatment of cancers characterized by KRAS G12C, wherein the compound has improved inhibition of the GTP-bound form of KRAS G12C. Summary

[0008] In one aspect, the invention provides a compound of Formula (I):Formula (I), or a salt thereof, and / or an isotopologue thereof; wherein: X is -N(CH3)- or -O-; X1is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is 0 or 1; R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 R1A; R1Ain each instance is independently selected from the group consisting of halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and -C(O)(C1-C4alkyl); or twogeminal R1A, together with the carbon atom to which they are attached, form C3-C4cycloalkyl substituted with 0, 1, or 2 halo; or two geminal R1Atogether form =CH2, =CHF, or =CF2; Rais H or CH3;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R5is H or -OH; Y is CH or N; R6in each instance is independently selected from the group consisting of halo, -OH, C1- C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and r is 0, 1, 2, or 3;.

[0009] 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.

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

[0011] In another aspect provided is a method of treating or suppressing cancer comprising: administering a therapeutically effective amount of a compound as described herein, including but not limited to a compound described in the preceding paragraphs, or a pharmaceutical formulation, including but not limited to the pharmaceutical formulation described in the preceding paragraphs, to a subject in need thereof, 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, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. In some embodiments, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma,kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC) and melanoma. In some embodiments, including any of the foregoing embodiments, the method is for treating the cancer. In some embodiments, including any of the foregoing embodiments, the method is for suppressing the 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 subject has been diagnosed as having a KRAS G12C mediated cancer. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

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

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

[0014] It is to be understood that the description of compounds, compositions, formulations, and methods of treatment described herein include “comprising”, “consisting of”, and “consisting essentially of”embodiments. In some embodiments, for all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listedcomponents or steps, or can “consist essentially of”the listed components or steps. When a composition is described as “consisting essentially of”the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of”the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. 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 pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0015] Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and through practice of the present disclosure. Detailed Description

[0016] Provided herein are compounds useful in treating cancer, and methods of using such compounds for treating cancer. In some embodiments, the compounds are useful in treating cancers characterized by KRAS G12C. In some embodiments, the compounds advantageously inhibit both the inactive GDP- and activated GTP-bound forms of KRAS G12C. In some embodiments, the compounds advantageously have improved inhibition of the GTP-bound form of KRAS G12C. Definitions

[0017] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.

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

[0019] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. The “Ex.”column of Table 1 indicates the synthetic example number corresponding to the structure provided in the same row of Table 1. A set of compounds, each with absolute stereochemistry in Table 1, may have multiple example numbers assigned in the “Ex.”column. Insuch case, each of the assigned examples produced just one of those compounds. However, the absolute stereochemistry of that compound has not been determined. For example, compounds 7-2 and 7-3 in Table 1 have “22 or 23”indicated in the “Ex.”column, meaning that just one of compounds 7-2 and 7-3 was obtained from Example 22 and just 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 “Ex.”column, meaning that just one of the four compounds was obtained from Example 36, and just one of the other three compounds was obtained from Example 37.

[0020] Compounds with an (and) designation in the stereochemistry column of Table 1 are mixtures of enantiomers wherein the relative stereochemistry is as shown. Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted and that have no designation in the Stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds that have a stereogenic center where the configuration is indicated by bold wedges or hashed wedges in the structure, and that have no designation in the Stereochemistry column of Table 1 or that are marked with (abs) are single enantiomers wherein the absolute stereochemistry is as indicated.

[0021] For example, compoundsingle enantiomer with the stereochemistry as indicated.

[0022] A bold or hashed non-wedged (i.e., rectangular) bond in a compound indicates that the compound is a mixture of different diastereomers with fixed cis- or trans-configuration.

[0024] In some instances, the Stereochemistry column of Table 1 contains different indicators selected from (abs) and (and) to refer to different stereocenters or pairs of stereocenters of the molecule.

[0025] For example, “Amino-pyrrolidine – (abs)”for compound 27-1indicates that the amino-pyrrolidinyl headgroup of the compound has (R,R) configuration as drawn; and “R1– (and)”indicates that the R1group of the compound has either (R) or (S) stereochemistry such that the compound obtained from Example.

[0026] A person of skill in the art would be able to separate racemic compounds into the respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization and the like. References to compounds that are racemic mixtures are meant to also include the individual enantiomers contained in the mixture.

[0027] Reference to “about”a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X”includes description of “X”. As used herein, and unless otherwise specified, the terms “about”and “approximately,”when used in connection with temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms “about”and “approximately,”when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent.

[0028] The terms “a”and “an,”as used in herein mean one or more, unless context clearly dictates otherwise.

[0029] The terms “subject,”“individual,”and “patient”mean an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses. In some embodiments, the subject has been identified or diagnosed ashaving a cancer or tumor having a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).

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

[0031] “Suppression”of a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disorder, or to suppress the manifestation of adverse symptoms of the disorder. The distinction between treatment and suppression is that treatment occurs after adverse symptoms of the disorder are manifest in a subject, while suppression occurs before adverse symptoms of the disorder are manifest in a subject. Suppression may be partial, substantially total, or total. In some embodiments, genetic screening can be used to identify patients at risk of the disorder. The compounds and methods disclosed herein can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disorder, in order to suppress the appearance of any adverse symptoms.

[0032] “Therapeutic use”of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disorder, as defined herein. A “therapeutically effective amount”of a compound is an amount of the compound, which, when administered to a subject, is sufficient to reduce or eliminate either the disorder or one or more symptoms of the disorder, or to retard the progression of the disorder or of one or more symptoms of the disorder, or to reduce the severity of the disorder or of one or more symptoms of the disorder, or to suppress the clinical manifestation of a disorder, or to suppress the manifestation of adverse symptoms of a disorder. A therapeutically effective amount can be given in one or more administrations.

[0033] A “KRAS G12C mediated cancer”is used interchangeably herein with a “cancer characterized by KRAS G12C”, and indicates that the cancer comprises cells which contain the KRAS G12C mutant.

[0034] While the compounds described herein can occur and can be used as the neutral (non-salt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In some embodiments, the salts of the compounds comprise pharmaceutically acceptable salts.

[0035] A “pharmaceutically acceptable salt”of a compound means a salt that is pharmaceutically acceptable to humans and / or animals, and which, upon administration, retains at least some of the desired pharmacological activity of the parent compound. 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 formed 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, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (b) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0036] Included herein, when chemically relevant, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.

[0037] “Isotopologue”refers herein to a compound which differs in its isotopic composition from its “natural”isotopic composition. “Isotopic composition”refers to the amount of each isotope present for a given atom, and “natural isotopic composition”refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched”atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom.For example, unless otherwise stated, when a position is designated specifically as “H”or “hydrogen,”the position is understood to have hydrogen at its natural isotopic composition. The description of compounds herein also includes all isotopologues, in some embodiments, partially deuterated or perdeuterated analogs, of all compounds herein. “Isotopically enriched”may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopic enrichment”refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, 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 one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0038] “Alkyl”means a linear, branched, or a combination thereof, saturated monovalent hydrocarbon radical having the defined number of carbons. For example, C1-C4alkyl includes e.g., methyl, ethyl, propyl, 2-propyl, butyl, and the like.

[0039] “Alkylene”means a linear, branched, or a combination thereof, saturated divalent hydrocarbon radical having the defined number of carbons. For example, C1-C4alkylene includes e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and the like.

[0040] “Alkenyl”means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having the defined number of carbons. For example, C2-C4alkenyl includes e.g., vinyl, prop-1-en-2-yl, prop-1-en-1-yl, allyl and the like.

[0041] “Alkynyl”means a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having the defined number of carbons. For example, C2-C4alkyne includes e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.

[0042] “Alkoxy”means an -ORxradical where Rxis alkyl as defined above, or a -Rx’ORx”radical where Rx’ is an alkylene and Rx”is an alkyl group as defined above where the defined number of alkyl carbons in the alkoxy group are equal to the total number of carbons in Rx’ and Rx”. For example, C1-C4alkoxy indicates e.g., methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, tert-butoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, alkoxy is a -ORxradical. In some embodiments, alkoxy is a -Rx’ORx”radical. In some embodiments, when a nitrogen is substituted with an alkoxy group, the alkoxy group is notlinked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the alkoxy group. For example, the alkoxy-substituted nitrogen is not N-ORxor N-CH2-O-Rx”.

[0043] “Alkoxyalkoxy”means an -ORyradical where Ryis alkoxy as defined above, provided that the attachment point of Ryis not an oxygen atom, or a -Ry’ORy”radical where Ry’ is an alkylene and Ry”is an alkoxy group as defined above, provided that the attachment point of Ry”is not an oxygen atom, where the defined number of alkyl carbons in the alkoxyalkoxy group are equal to the total number of carbons in Ry’and Ry”. For example, C1-C6alkoxyalkoxy indicates e.g., - OCH2OCH3, - OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2OCH3, -CH2OCH2CH2OCH3, - CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3and the like. In some embodiments, alkoxyalkoxy is a -ORyradical. In some embodiments, alkoxyalkoxy is a -Ry’ORy”radical. In some embodiments, when a nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not linked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the alkoxyalkoxy group. For example, the alkoxyalkoxy-substituted nitrogen is not N- ORyor N-CH2-O-Ry”.

[0044] “Aminoalkyl”means an -NHRzradical where Rzis alkyl as defined above, or a -NRzRz’radical where Rzand Rz’are alkyl groups as defined above, or an -Rz”NH2radical where Rz”is an alkylene group as defined above, or an -Rz”NHRzradical where Rz”is an alkylene group as defined above and Rz’is an alkyl group as defined above, or a -Rz”NRzRz’radical where Rz”is an alkylene group as defined above and Rzand Rz’are alkyl groups as defined above, where the defined number of alkyl carbons in the aminoalkyl group is equal to the total number of carbons in Rz, Rz’and Rz”as applicable. For example, C1-C6aminoalkyl indicates e.g., -NHCH3, - NHCH2CH3, -NHCH2(CH3)2, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -CH2NH2, - CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2and the like. In some embodiments, aminoalkyl is an -NHRzradical. In some embodiments, aminoalkyl is an - NRzRz’radical. In some embodiments, an aminoalkyl is an -Rz”NH2radical. In some embodiments, aminoalkyl is a -Rz”NHRzradical. In some embodiments, aminoalkyl is a - Rz”NRzRz’radical. In some embodiments, when an oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not linked to the oxygen via the nitrogen or a carbon that is immediately adjacent to the nitrogen in the aminoalkyl group. For example, the aminoalkyl- substituted oxygen is not O-NRzor O-CH2-NHRz.

[0045] “Aryl”refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g.,naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). In some embodiments, “aryl”also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl and naphthyl, wherein the attachment point can be on any carbon atom. Exemplary aryl groups also include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, wherein the attachment point is on the phenyl group. In some embodiments, “aryl”excludes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups.

[0046] “Cycloalkyl”means a monocyclic saturated monovalent hydrocarbon radical having the defined number of carbon atoms. For example, C3-C6cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] “Cycloalkylene”means a monocyclic saturated divalent hydrocarbon radical having the defined number of carbon atoms. For example, C3-C6cycloalkylene includes cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0048] “Cyanoalkyl”means an alkyl radical as defined above, which is substituted with a cyano group (–CN). A cyanoalkyl can also be referred to as an alkylnitrile.

[0049] “Halo”means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro or chloro.

[0050] “Haloalkyl”means an alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

[0051] “Haloalkoxy”means an -ORa’radical where Ra’is haloalkyl as defined above, or a - Rb’ORc’radical where Rb’and Rc’are alkyl or haloalkyl groups as defined above where the defined number of alkyl carbons in the haloalkoxy group are equal to the total number of carbons in Rb’and Rc’. Halo atom(s) may be present in Rb’, or Rc’, or both, provided that at least one of Rb’and Rc’comprises a halo atom. For example, C1-C4haloalkoxy indicates e.g., -OCF3, -OCHF2, - CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2, and the like. In some embodiments, haloalkoxy is a -ORa’radical. In some embodiments, haloalkoxy is a -Rb’ORc’radical. When all of the halo atom(s) in the haloalkoxy group are fluoro, it can be referred to in this Application asfluoroalkoxy. In some embodiments, when a nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not linked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the haloalkoxy group. For example, the haloalkoxy-substituted nitrogen is not N-ORa’or N-C(H)n(X)m-O-R”(wherein X is a halogen and n and m are integers, provided that n+m=2).

[0052] “Hydroxyalkyl”means an alkyl radical as defined above, which is substituted with one or more hydroxyl (-OH) groups, e.g., one to three hydroxyl groups, e.g., -CH2OH, -CH2CH2OH, - C(OH)(CH3)2, -CH(OH)CH3and the like.

[0053] A “heterocyclic group”or “heterocycle”, unless otherwise specified, means a saturated or partially unsaturated cyclic group comprising 3-12 ring atoms, in which 1-4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, the remaining rings being C. The sulfur group may be present either as -S- or as -S(O)2-. Unless otherwise specified, the heterocyclic group includes single as well as multiple ring systems including fused, bridged, and spiro ring systems. “Heterocyclic group”or “heterocycle”also includes ring systems wherein the heterocyclic group, as defined above, is fused with one or more carbocyclic groups wherein the point of attachment is either on the carbocycle or heterocycle ring In some embodiments, “heterocyclic group”or “heterocycle”also includes ring systems wherein the heterocyclic group, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. In some embodiments, the heterocyclic group is a single ring. In some embodiments, the heterocyclic group comprises two fused rings. In some embodiments, the heterocyclic group comprises two spiro rings. In some embodiments, the heterocyclic group comprises a bridged ring system.

[0054] A “carbocyclic group”or “carbocycle”, unless otherwise specified, means a saturated or partially unsaturated cyclic group comprising 3-12 ring atoms, in which the ring atoms are C. Unless otherwise specified, the carbocyclic group includes single as well as multiple ring systems including fused, bridged, and spiro ring systems. In some embodiments, the carbocyclic group is a single ring. In some embodiments, the carbocyclic group comprises two fused rings. In some embodiments, the carbocyclic group comprises two spiro rings. In some embodiments, the carbocyclic group comprises a bridged ring system.

[0055] “Heteroaryl”means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more (in some embodiments, one, two, or three) ring atoms are heteroatom(s) independently selected from N, O, or S, the remaining ring atoms beingcarbon. In some embodiments, “heteroaryl”includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, In such instances, unless otherwise specified, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. In some embodiments, “heteroaryl”also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2– indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). In some embodiments, “heteroaryl”excludes ring systems wherein the heteroaryl ring is fused with a carbocyclyl or heterocyclyl group. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0056] A “spiro”cycloalkyl group indicates that the cycloalkyl group is linked to the remaining portion of the compound through a spiro linkage. A “spiro”cycloalkyl substituent has two attachments that connect to the same carbon of the moiety that is substituted, forming a spiro connection. For example, a cyclohexyl group that is substituted with a “spiro C3-C4cycloalkyl”group indicates:.

[0057] “In need of treatment”as used herein means the patient is being treated by a physician or other caregiver after diagnoses of the disease, or a determination that the patient is at risk for developing the disease. In some embodiments, the patient has been diagnosed as having a KRAS G12C mediated cancer. In some embodiments, the patient has been determined to be at risk of developing a KRAS G12C mediated cancer.

[0058] “Administration”, “administer”and the like, as they apply to, for example, a patient, cell, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I), (I’), or (I’’), or a pharmaceutically acceptable salt and / or isotopologue thereof, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[0059] “Optional”or “optionally”means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0060] A “pharmaceutically acceptable carrier or excipient”means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier / excipient”as used in the specification and claims includes both one and more than one such excipient.

[0061] The term “disease”as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,”“syndrome,”and “condition”(as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0062] The term “combination therapy”means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule or a 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 use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. Compounds

[0063] Provided herein are compounds of Formula (I). Unless the context requires otherwise, reference throughout this specification to “a compound of Formula (I)”or “compounds of Formula (I)”refers to all embodiments of Formula (I) including, for example, compounds of Formulas (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-b), (IA-c), (IA-d), (IA-a-1), (IA-a-2), (IA-b-1), (IA-b-2), (IA-c-1), (IA-c-2), (IB-a), (IB-b), (IB-c), (IB-d), (IB-a-1), (IB-a-2), (IB-b-1), (IB-b-2), (IB-c-1), (IB-c-2), as well as the compounds of Table 1. In some embodiments, provided are compounds of Formula (I) or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (I) are provided as pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (I) are provided as the corresponding free base (i.e., are not salts).

[0064] In one aspect, provided is a compound of Formula (I):Formula (I), or a salt thereof, and / or an isotopologue thereof; wherein: X is -N(CH3)- or -O-; X1is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is 0 or 1; R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 R1A; R1Ain each instance is independently selected from the group consisting of halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and -C(O)(C1-C4alkyl); or two geminal R1A, together with the carbon atom to which they are attached, form C3-C4cycloalkyl substituted with 0, 1, or 2 halo; or two geminal R1Atogether form =CH2, =CHF, or =CF2; Rais H or CH3;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R5is H or -OH; Y is CH or N;R6in each instance is independently selected from the group consisting of halo, -OH, C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and r is 0, 1, 2, or 3.

[0065] In some embodiments, when q is 0, then R1is not, , , any enantiomers thereof. In some embodiments, wheny enantiomer thereof, then R2is not. In some embodiments,any enantiomer thereof, then R2is not.

[0066] In some embodiments,. some embodiments, R3is selected from the group consisting of halo, C1-C4alkyl, and C2-C3alkynyl. In some embodiments, R3is selected from the group consisting of –F, –Cl, –Et, –C≡CH, and –C≡C-CH3. In some embodiments, R4is hydrogen or halo. In some embodiments, R4is hydrogen or –F. In some embodiments, R5is -OH. In some embodiments, R5is H.

[0067] In some embodiments,,

[0068] In some embodiments,. some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R6in each instance is independently selected from the group consisting of -Cl, -OH, -CH3, -CF3, cyclopropyl, and -NH2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0069] In some embodiments,. some embodiments,. In some embodiments, R6Ais cyclopropyl or -CF3. In some embodiments, R6Bis -Cl or -CH3. In some embodiments, R6Cis -OH or -NH2.

[0070] In some embodiments,

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

[0072] In some embodiments, X1is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, - CH=CH2, or cyclopropyl. In some embodiments, X1is -CH3.

[0074] In some embodiments,HN substituted with 0, 1, 2, or 3 R1A. In some embodiments, R1Ain each instance is independently -F, -OH, -CH3, -OCH3, -OCF3, - OCHF2, or -C(O)CH3. In some embodiments, two geminial R1A, together with the carbon atom to which they are attached, form cyclopropyl substituted with 0, 1, or 2 fluoro. In some embodiments, two geminal R1Atogether form =CH2, =CHF, or =CF2.some embodiments, R1is. In some embodiments, R1is..

[0077] In some embodiments, Rais H. In some embodiments, Rais CH3.

[0078] In an embodiment, provided is a compound of Formula (I’)Formula (I’) or a salt thereof; and / or an isotopologue thereof; wherein: R1is a 4-8 membered saturated carbocyclic or heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl; and q is 0 or 1;provided that when q is 0, R1is not,any enantiomers thereof.

[0079] In an embodiment the compound is of Formula (IA) or Formula (IB)o u a ; or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0080] In an embodiment the compound is of formula (IA).

[0081] In an embodiment the compound is of Formula (1B).

[0082] In an embodiment, the compound is of Formula (I-a), Formula (I-b) or Formula (I-c):Formula (I-a)or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0083] In an embodiment, the compound is of Formula (I-a).

[0084] In an embodiment, the compound is of Formula (I-b).

[0085] In an embodiment, the compound is of Formula (I-c).

[0086] In an embodiment, the compound is of Formula (I-a-1) or Formula (I-a-2):o u a -a- ) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0087] In an embodiment, the compound is of Formula (I-a-1).

[0088] In an embodiment, the compound is of Formula (I-a-2).

[0089] In an embodiment the compound is of Formula (IA-a) or Formula (IB-a):or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0090] In an embodiment the compound is of Formula (IA-a).

[0091] In an embodiment the compound is of Formula (IB-a).

[0092] In an embodiment the compound is of Formula (IA-a-1), Formula (IA-a-2), Formula (IB-a- 1) or Formula (IB-a-2):o u a -a- ) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0093] In an embodiment the compound is of Formula (IA-a-1).

[0094] In an embodiment the compound is of Formula (IA-a-2).

[0095] In an embodiment the compound is of Formula (IB-a-1).

[0096] In an embodiment the compound is of Formula (IB-a-2).

[0097] In an embodiment, the compound is of Formula (I-b-1) or Formula (I-b-2):o u a - - or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0098] In an embodiment, the compound is of Formula (I-b-1).

[0099] In an embodiment, the compound is of Formula (I-b-2).

[0100] In an embodiment the compound is of Formula (IA-b) or Formula (IB-b):o u a - or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0101] In an embodiment the compound is of Formula (IA-b).

[0102] In an embodiment the compound is of Formula (IB-b).

[0103] In an embodiment the compound is of Formula (IA-b-1), Formula (IA-b-2), Formula (IB- b-1) or Formula (IB-b-2):o u a - - ) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein

[0104] In an embodiment the compound is of Formula (IA-b-1).

[0105] In an embodiment the compound is of Formula (IA-b-2).

[0106] In an embodiment the compound is of Formula (IB-b-1).

[0107] In an embodiment the compound is of Formula (IB-b-2).

[0108] In an embodiment, the compound is of Formula (I-c-1) or Formula (I-c-2):o u a -c- ) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0109] In an embodiment, the compound is of Formula (I-c-1).

[0110] In an embodiment, the compound is of Formula (I-c-2).

[0111] In an embodiment the compound is of Formula (IA-c) or Formula (IB-c):or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0112] In an embodiment the compound is of Formula (IA-c).

[0113] In an embodiment the compound is of Formula (IB-c).

[0114] In an embodiment the compound is of Formula (IA-c-1), Formula (IA-c-2), Formula (IB-c- 1) or Formula (IB-c-2):o u a -c- ) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0115] In an embodiment the compound is of Formula (IA-c-1).

[0116] In an embodiment the compound is of Formula (IA-c-2).

[0117] In an embodiment the compound is of Formula (IB-c-1).

[0118] In an embodiment the compound is of Formula (IB-c-2).

[0119] In an embodiment the compound is of Formula (I-d):Formula (I-d) or a salt thereof; and / or an isotopologue thereof, wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0120] In an embodiment the compound is of Formula (IA-d) or Formula (IB-d):o u a -d) or a salt thereof; and / or an isotopologue thereof wherein R1, R3and R4are as defined in any of the embodiments described herein.

[0121] In an embodiment the compound is of Formula (IA-d).

[0122] In an embodiment the compound is of Formula (IA-d).

[0123] As generally defined herein, each R3is independently selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4haloalkyl and C2-C3alkynyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen, halo and C1-C4alkyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen, halo and C3-C4cycloalkyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen, halo and C1-C4haloalkyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen, halo and C2-C3alkynyl. In an embodiment, R3is selected from halo and C1-C4alkyl. In an embodiment, R3is selected from halo and C2-C3alkynyl. In an embodiment, each R3is independently selected from the group consisting of hydrogen and halo. In an embodiment, each R3is independently halo. In an embodiment, each R3is independently selected from the group consisting of –H, –F, –Cl, – Me, –Et, –cyclopropyl, –CF3and –C≡CH. In an embodiment, each R3is independently selected from the group consisting of –H, –F, –Cl, –Me and –Et. In an embodiment, each R3is independently selected from the group consisting of –H, –F, –Cl and –cyclopropyl. In an embodiment, each R3is independently selected from the group consisting of –H, –F, –Cl and –CF3. In an embodiment, each R3is independently selected from the group consisting of –H, –F, – Cl and –C≡CH. In an embodiment, each R3is independently selected from the group consisting of –H, –F and –Cl. In an embodiment, R3is selected from –F, –Cl, –Et, and –C≡CH. In an embodiment, R3is selected from –F, –Cl, and –Et. In an embodiment, R3is selected from –F, –Cl and –C≡CH. In an embodiment, each R3is independently selected from the group consisting of –F and –Cl. In an embodiment, R3is –F. In an embodiment, R3is –Cl. In an embodiment, R3is –Et. In an embodiment, R3is –C≡CH.

[0124] As generally defined herein, each R4is independently selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4haloalkyl and C2-C3alkynyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen, halo and C1-C4alkyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen, halo and C3-C4cycloalkyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen, halo and C1-C4haloalkyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen, halo and C2-C3alkynyl. In an embodiment, each R4is independently selected from the group consisting of hydrogen and halo. In an embodiment, each R4is independently halo. In an embodiment, each R4is independently selected from the group consisting of –H, –F, –Cl, –Me, –Et, –cyclopropyl, –CF3and –C≡CH. In an embodiment, each R4is independently selected from the group consisting of – H, –F, –Cl, –Me and –Et. In an embodiment, each R4is independently selected from the group consisting of –H, –F, –Cl and –cyclopropyl. In an embodiment, each R4is independently selected from the group consisting of –H, –F, –Cl and –CF3. In an embodiment, each R4is independently selected from the group consisting of –H, –F, –Cl and –C≡CH. In an embodiment, each R4is independently selected from the group consisting of –H, –F and –Cl. In an embodiment, each R4is independently selected from the group consisting of –F and –Cl. In an embodiment, R4is selected from –H and –F. In an embodiment, R4is –H. In an embodiment, R4is –F.

[0125] As generally defined herein, R1is a 4-8 membered saturated carbocyclic or heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl,and C1-C4haloalkoxy, provided that in Formula (I), when q is 0, R1is not, ,any enantiomers thereof.

[0126] In an embodiment, R1is a 4-8 membered saturated bicyclic carbocyclic or bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In an embodiment, R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1- C4 alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In an embodiment, R1is a 4-8 membered saturated monocyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In an embodiment, R1is a 4-8 membered saturated bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy.

[0127] In an embodiment, the carbocyclic or heterocyclic group of R1is unsubstituted, or substituted with one substituent selected from halo, hydroxy or spiro C3-C4cycloalkyl. In an embodiment, the carbocyclic or heterocyclic group of R1is unsubstituted, or substituted with one fluoro or spiro C3-C4cycloalkyl. In an embodiment, R1is selected from the group consisting of:wherein Rdis as defined in any of the embodiments described herein. In an embodiment,wherein Rdis as defined

[0128] In an embodiment,wherein Rdis as defined in any of the embodiments described herein. In an embodiment, R1is. In an embodiment, R1is selected from. .

[0129] In an embodiment, R1is. In an embodiment, R1is.

[0130] As generally defined herein, q is 0 or 1. In an embodiment, q is 0, provided that in Formula (I), when q is 0, R1is notany enantiomers thereof. In an embodiment, q is 1.

[0131] As generally defined herein, Rdis H or F. In an embodiment, Rdis H. In an embodiment, Rdis F.

[0132] In an embodiment, the compound is selected from the compounds of Table 1 or a salt thereof; and / or an isotopologue thereof. In an embodiment, the compound is not a salt.

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

[0134] In an embodiment, provided herein are compounds of Table 1, or a salt thereof, and / or an isotopologue thereof. In some embodiments, salt is a pharmaceutically acceptable salt. Table 1.

[0135] In some variations, any of the compounds described herein, such as a compound of Formula (I), or a compound of Table 1 may 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 the corresponding non- deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.

[0136] Any formula given herein, such as Formula (I), is intended to represent compounds having structures 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 enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.

[0137] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

[0138] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, asis well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0139] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0140] Any 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’, 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’, as if each combination had been individually and specifically described.

[0141] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. Methods For Treatment of Cancer

[0142] The compounds of Formula (I) and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, are useful for the treatment of cancer, which include but are not limited to, various types of cancer including e.g. lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. More particularly, cancers that may be treated by the compounds of Formula (I) and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, include, but are not limited to cancers such as glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma,mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, 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 subject has been diagnosed as having a KRAS G12C mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject has been determined to be at risk of developing a KRAS G12C mediated cancer.

[0143] In an aspect, provided is a compound of Formula (I) as described in any of the embodiments described herein or a pharmaceutical formulation as described in any of the embodiments described herein for use as a medicament.

[0144] In an aspect, provided is a compound of Formula (I) as described in any of the embodiments described herein or a pharmaceutical formulation as described in any of the embodiments described herein for use in treating or suppressing cancer. In an embodiment, when the compound is a salt, the salt is a pharmaceutically acceptable salt. In an embodiment, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. In an embodiment, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors,thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In an embodiment, the cancer is a KRAS G12C mediated cancer. In an embodiment, the subject has been diagnosed as having a KRAS G12C mediated cancer. In an embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In an embodiment, the compound or pharmaceutical formulation is configured for administration in a therapeutically effective amount.

[0145] In an aspect, provided is a compound of Formula (I) as described in any of the embodiments described herein or a pharmaceutical formulation as described in any of the embodiments described herein for use in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In an embodiment, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. In an embodiment, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In an embodiment, the cancer is a KRAS G12C mediated cancer. In anembodiment, the subject has been diagnosed as having a KRAS G12C mediated cancer. In an embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In an embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

[0146] In an aspect, provided is a use of a compound of Formula (I) as described in any of the embodiments described herein or a pharmaceutical formulation as described in any of the embodiments described herein in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In an embodiment, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. In an embodiment, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In an embodiment, the cancer is a KRAS G12C mediated cancer. In an embodiment, the subject has been diagnosed as having a KRAS G12C mediated cancer. In an embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In an embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

[0147] In an aspect, provided is a use of a compound of Formula (I) as described in any of the embodiments described herein or a pharmaceutical formulation as described in any of the embodiments described herein for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0148] In an embodiment, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. In an embodiment, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In an embodiment, the cancer is a KRAS G12C mediated cancer. In an embodiment, the subject has been diagnosed as having a KRAS G12C mediated cancer. In an embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In an embodiment, use involves a therapeutically effective amount of the compound or composition.

[0149] In some embodiments, including any of the foregoing embodiments, the subject and / or the cancer is resistant or refractory to treatment with certain KRAS inhibitors (e.g., G12C KRAS inhibitors).

[0150] The compounds of Formula (I), and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, may be used for methods for inhibiting KRAS G12C in a cell, by contacting the cell in which inhibition of KRAS G12Cactivity is desired with an amount of the compound effective to inhibit KRAS G12C activity. Inhibition may be partial or total. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. Testing

[0151] The compounds of Formula (I), and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, may be tested by, for example, methods described in the Examples below, or by known and generally accepted cell and / or animal models.

[0152] The ability of compounds of Formula (I), and pharmaceutically acceptable salts and / or isotopologues thereof, to inhibit activity of the GTP-bound form of KRAS G12C can be tested using methods such as the in vitro assay described in Examples 69 and 70 below. Example 69 describes determining, for various compounds, the half-maximal inhibition (IC50) of KRAS G12C loaded with GTP analogue GMPPNP from binding to cRaf, as the Ras-binding domain (RBD). Example 70 describes determining, for various compounds, the half-maximal inhibition (IC50) of KRAS G12C loaded with GTP analogue GMPPNP from binding to PI3Kα, as the Ras-binding domain (RBD). Example 71 describes testing compounds for the ability to inhibit cell viability in MCF10A G12C / A59G mutant, which abrogates GTPase activity, thus preventing hydrolysis of GTP to GDP. Pharmaceutical Compositions

[0153] The terms pharmaceutical composition and pharmaceutical formulation are used interchangeably throughout.

[0154] In general, the compounds of Formula (I), and pharmaceutically acceptable salts and / or isotopologues thereof, of this disclosure (also may be referred to herein as “compounds”or “compounds of this disclosure”) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In some embodiments, a suitable dosage level may be from 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 can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of a compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0155] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0156] 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.

[0157] The compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0158] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0159] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoulesand vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0160] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which 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 which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0161] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0162] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0163] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0164] Certain compounds of the disclosure may be administered topically, that is by non- systemic administration. This includes the application of the compounds externally to the epidermis or the buccal cavity and the instillation of such compounds into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0165] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation 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, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation.

[0166] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise 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 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 dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

[0167] The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %. Combinations and Combination Therapies

[0168] The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is contemplated. However, the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.

[0169] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of the present disclosure.

[0170] The above combinations include combinations of a compound of this disclosure not only with one other drug, but also with two or more other active drugs. Likewise, a compound of this disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of this disclosure is useful. Such other drugs may be administered contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, a therapeutically effective dose of each will be used.

[0171] Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of this disclosure in any combination with one or more other anti- cancer agents.

[0172] In some embodiments, the compounds of the present disclosure are used in combination with a CDK 4 / 6 inhibitor. Examples of CDK 4 / 6 inhibitors suitable for the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4-ethylpiperazin-l - yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-l-isopropyl-2-methyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-amine); palbociclib (6-acetyl-8- cyclopentyl-5-methyl-2-((5-(piperazin-l - yl)pyridin-2-yl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one) and ribociclib (7-cyclopentyl-N,N- dimethyl-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide) whereas the CDK 4 / 6 inhibitor trilaciclib (2'-((5-(piperazin-l -yl)pyridin-2-yl)amino)-7’,8'- dihydro-6’H-spiro-[cyclohexane-l,9’- pyrazino[l’,2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one) is in late stage clinical trials. Another CDK 4 / 6 inhibitor useful in the methods herein is the CDK 2 / 4 / 6 inhibitor PF-06873600 (pyrido[2,3- d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(lR,2R)-2- hydroxy-2-methylcyclopentyl]-2-[[l- (methylsulfonyl)-4-piperidinyl]amino]).

[0173] In another embodiment the compounds of the present disclosure are used in combination with Raf family kinase inhibitors. Examples of Raf family kinase inhibitors suitable for theprovided compositions and methods include, but are not limited to, encorafenib (LGX818): methyl (S)-(1-((4-(3-(5-chloro- 2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol- 4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin- 5-yl)-3a,7a- dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3- fluoropyrrolidine-1-sulfonamide; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran- 4-yl)oxy)-[3,3'- bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2- hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)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-(((lR,laS,6bS)-1-(6-(trifhioro-methyl)- 1H-benzo[d]imidazol-2-yl)-la,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)methyl)-3,4- dihydro-1,8-naphthyridin-2(1H)-one; Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)- phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; CEP-32496: 1-(3- ((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2- methylpropan-2-yl)isoxazol- 3-yl)urea; CCT196969: 1-(3-(tert-butyl)-1-phenyl- 1H-pyrazol-5- yl)-3-(2-fluoro-4-((3-oxo-3,4- dihydropyrido [2,3 -b]pyrazin-8-yl)oxy)phenyl)urea; and R05126766: N-[3-fluoro-4-[[4-methyl- 2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl] methyl]-2-pyridinyl]-N' -methylsulfamide.

[0174] In another embodiment the compounds of the present disclosure are used in combination with Src family kinases. Examples of Src family kinase inhibitors suitable for the provided compositions and methods include, but are not limited to, Dasatinib (N-(2-chloro-6- methylphenyl)-2-((6-(4-(2- hydroxyethyl)piperazin-l-yl)-2-methylpyrimidin-4-yl)amino)thiazole- 5-carboxamide); Ponatinib (3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4- methylpiperazin-l-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-l -yl)- propoxy)quinoline-3- carbonitrile); Saracatinib (N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-(2-(4- methylpiperazin-l- yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine); KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide); SU6656 ((Z)-N,N- dimethyl-2-oxo-3- ((4,5,6,7-tetrahydro-lH-indol-2-yl)methylene)indoline-5-sulfonamide); PP1 (l- (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-l-yl)phenyl)amino)pyrimidin-4-yl)carbamate) and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide). In one embodiment, the Src inhibitor is Dasatinib. In one embodiment, the Src inhibitor is Saracatinib. Inone embodiment, the Src inhibitor is Ponatinib. In one embodiment, the Src inhibitor is Vandetanib. In one embodiment, the Src inhibitor is KX-01.

[0175] In another embodiment the compounds of the present disclosure are used in combination with a SHP-2 inhibitor which include, but are not limited to SHP-099 (6-(4-amino-4- methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride), RMC-4550 (3(3S,4S)-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)pyrazin-2- yl)methanol), RMC-4360 (Revolution Medicines), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

[0176] In another embodiment the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for the provided compositions and methods include, but are not limited to, Everolimus, Rapamycin, Zotarolimus (ABT-578), ridaforolimus (Deforolimus; MK-8669), Sapanisertib (INK128; 5-(4-amino-l-isopropyl-lH- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine), Torin-1; l-(4-(4-propionylpiperazin-l- yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][l,6]naphthyridin-2(lH)-one, dactolisib (BEZ235); 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH- imidazo[4,5-c]quinolin-l -yl)phenyl)propanenitrile, buparlisib (5-(2,6-dimorpholin-4-ylpyrimidin- 4-yl)-4- (trifluoromethyl)pyridin-2-amine); GDC-0941 (pictilisib); 4-[2-(1H-indazol-4-yl)-6-[(4- methylsulfonylpiperazin-l -yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine); GDC-0349 ((S)- l-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin- 2-yl)phenyl)urea), VS-5584 (SB2343) (5-(8-methyl-2-morpholin-4-yl-9-propan-2-yl-purin-6- yl)pyrimidin-2-amine) and vistusertib (AZD-2014; 3-(2,4-bis((S)-3-methylmorpholino)pyrido- [2,3-d]pyrimidin-7-yl)-N-methylbenzamide).

[0177] In another embodiment the compounds of the present disclosure are used in combination with a pan ErbB family inhibitor. In one embodiment the KRAS and pan ErbB family inhibitors are the only active agents in the provided compositions and methods. In one embodiment, the pan ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan ErbB family inhibitors suitable for the provided compositions and methods include, 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-piperazin-1-butyn-1-yl]-6-quinazolinyl]-2-prepenamide); PF 6274484 N- 4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide) and HKI 357 N- (2(E)-N-[[4-[[3-chloro-4-[(fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]- 4-(dimethylamino)-2-butenamide). In another embodiment, the pan ErbB family inhibitor is a reversible inhibitor. Examples of reversible pan ErbB family inhibitors suitable for the provided compositions and methods include, 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-methylbutanamide); AEE788 (S)-(6-(4-((4-ethylpiperazin- 1 -ylmethyl)phenyl]-N-(l -phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); tarloxotinib 3-[N-[4- (3-bromo-4-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(l- methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propen-l-aminium bromide); BMS 599626 ((3S)- 3- morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5- methylpurrolo[2,1-f][1,2,4]triazine-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).

[0178] 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 two of: AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride); AG 555 ((E)-2-cyano-3-(3,4-dihydoxyphenyl)-N-(3-phenylpropyl)-2-propenamide); AG 556 ((E)-2- cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-propenamide; AG 825 (E-3-[3-benzothiazol- 2- ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714 (2- methoxy-N-[(2E)-3-[4-[3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino]quinazolin-6-yl]-2- propen-1-yl]acetamide; BIBU 1361 (N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)- piperidin-l-yl]pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride); BIBU 1382; (N8-(3-chloro-4- fluorophenyl)-N2-(1-methyl-4-piperidinyl)pyrimidino[5,4-d]pyrimidin-4-amine dihydrochloride), JNJ 28871063 (5E-4-amino-6-[4-(benzyloxy)-3-chlorophenylamino]-pyrimidine-5-carbaldehyde N-[2-(4-morpholinyl)ethyl]oxime hydrochloride); PD 153035 (4-(3-bromophenylamino)-6,7- dimethoxyquinazoline hydrochloride); and PD 158780 (N4-(3-bromophenyl)-N6-methyl- pyrido[3,4-d]pyrimidine-4,6-diamine).

[0179] In one embodiment, the pan ErbB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or combination of an anti-EGFR antibody and anti-HER2 antibody. Antibodies, including monoclonal antibodies, antibody conjugates and bispecific antibodies, targeting EGFR and / or HER2 are well known and several antibodies are commercially available for research and human clinical use. Examples of anti-EGFR antibodies suitable for the provided compositions and methods include necitumumab, panitumumab and cetuximab. Examples of anti-HER2 antibodies suitable for the provided compositions and methods include, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0180] In some embodiments, the compounds of the present disclosure are used in combination with an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors suitable for the provided compositions and methods include, but are not limited to, PD-1, PD-L1, CTLA-4, andLAG-3 inhibitors, such as Pembrolizumab (Keytruda®), Nivolumab (Opdivo®), Cemiplimab (Libtayo®), Atezolizumab (Tecentriq®), Avelumab (Bavencio®), Durvalumab (ImfinziTM), Ipilimumab (Yervoy®), Relatlimab, Opdualag, and Dostarlimab (Jemperli).

[0181] The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. Enumerated Embodiments

[0182] The following enumerated embodiments are representative of some aspects of the invention. Set A. Embodiment 1. A compound of Formula (I’):or a salt thereof; and / or an isotopologue thereof; wherein: R1is a 4-8 membered saturated carbocyclic or heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy and C2-C3alkynyl; and q is 0 or 1;provided that when q is 0, R1is not,any enantiomers thereof. Embodiment 2. The compound of embodiment 1, wherein the compound is of Formula (IA) or Formula (IB)o u a ; or a salt thereof; and / or an isotopologue thereof. Embodiment 3. The compound of embodiment 2, wherein the compound is of formula (IA). Embodiment 4. The compound of embodiment 2, wherein the compound is of Formula (1B). Embodiment 5. The compound of embodiment 1, wherein the compound is of Formula (I- a), Formula (I-b) or Formula (I-c):Embodiment 6. The compound of embodiment 5, wherein the compound is of Formula (I- a). Embodiment 7. The compound of embodiment 5, wherein the compound is of Formula (I- b). Embodiment 8. The compound of embodiment 5, wherein the compound is of Formula (I- c). Embodiment 9. The compound of embodiment 1, wherein the compound is of Formula (I-a- 1) or Formula (I-a-2):Formula (I-a-1)Formula (I-a-2) or a salt thereof; and / or an isotopologue thereof. Embodiment 10. The compound of embodiment 9, wherein the compound is of Formula (I-a- 1). Embodiment 11. The compound of embodiment 9, wherein the compound is of Formula (I-a- 2). Embodiment 12. The compound of embodiment 1, wherein the compound is of Formula (IA- a) or Formula (IB-a):or a salt thereof; and / or an isotopologue thereof. Embodiment 13. The compound of embodiment 12, wherein the compound is of Formula (IA-a). Embodiment 14. The compound of embodiment 12, wherein the compound is of Formula (IB-a). Embodiment 15. The compound of embodiment 1, wherein the compound is of Formula (IA- a-1), Formula (IA-a-2), Formula (IB-a-1) or Formula (IB-a-2):o u a -a- or a salt thereof; and / or an isotopologue thereof. Embodiment 16. The compound of embodiment 15, wherein the compound is of Formula (IA-a-1). Embodiment 17. The compound of embodiment 15, wherein the compound is of Formula (IA-a-2). Embodiment 18. The compound of embodiment 15, wherein the compound is of Formula (IB-a-1). Embodiment 19. The compound of embodiment 15, wherein the compound is of Formula (IB-a-2).Embodiment 20. The compound of embodiment 1, wherein the compound is of Formula (I-b- 1) or Formula (I-b-2):o ua - -) or a salt thereof; and / or an isotopologue thereof. Embodiment 21. The compound of embodiment 20, wherein the compound is of Formula (I- b-1). Embodiment 22. The compound of embodiment 20, wherein the compound is of Formula (I- b-2). Embodiment 23. The compound of embodiment 1, wherein the compound is of Formula (IA- b) or Formula (IB-b):o ua -or a salt thereof; and / or an isotopologue thereof. Embodiment 24. The compound of embodiment 23, wherein the compound is of Formula (IA-b). Embodiment 25. The compound of embodiment 23, wherein the compound is of Formula (IB-b). Embodiment 26. The compound of embodiment 1, wherein the compound is of Formula (IA- b-1), Formula (IA-b-2), Formula (IB-b-1) or Formula (IB-b-2):or a salt thereof; and / or an isotopologue thereof.Embodiment 27. The compound of embodiment 26, wherein the compound is of Formula (IA-b-1). Embodiment 28. The compound of embodiment 26, wherein the compound is of Formula (IA-b-2). Embodiment 29. The compound of embodiment 26, wherein the compound is of Formula (IB-b-1). Embodiment 30. The compound of embodiment 26, wherein the compound is of Formula (IB-b-2). Embodiment 31. The compound of embodiment 1, wherein the compound is of Formula (I-c- 1) or Formula (I-c-2):Embodiment 32. The compound of embodiment 31, wherein the compound is of Formula (I- c-1). Embodiment 33. The compound of embodiment 31, wherein the compound is of Formula (I- c-2). Embodiment 34. The compound of embodiment 1, wherein the compound is of Formula (IA- c) or Formula (IB-c):Embodiment 35. The compound of embodiment 34, wherein the compound is of Formula (IA-c). Embodiment 36. The compound of embodiment 34, wherein the compound is of Formula (IB-c). Embodiment 37. The compound of embodiment 1, wherein the compound is of Formula (IA- c-1), Formula (IA-c-2), Formula (IB-c-1) or Formula (IB-c-2):o u a -c- ) or a salt thereof; and / or an isotopologue thereof. Embodiment 38. The compound of embodiment 37, wherein the compound is of Formula (IA-c-1). Embodiment 39. The compound of embodiment 37, wherein the compound is of Formula (IA-c-2). Embodiment 40. The compound of embodiment 37, wherein the compound is of Formula (IB-c-1). Embodiment 41. The compound of embodiment 37, wherein the compound is of Formula (IB-c-2). Embodiment 42. The compound of embodiment 1, wherein the compound is of Formula (I- d):or a salt thereof; and / or an isotopologue thereof. Embodiment 43. The compound of embodiment 1, wherein the compound is of Formula (IA- d) or Formula (IB-d):o u a -d) or a salt thereof; and / or an isotopologue thereof. Embodiment 44. The compound of embodiment 43, wherein the compound is of Formula (IA-d). Embodiment 45. The compound of embodiment 43, wherein the compound is of Formula (IA-d). Embodiment 46. The compound of any one of embodiments 1-45, wherein R3is selected from halo, C1-C4alkyl, and C2-C3alkynyl. Embodiment 47. The compound of any one of embodiments 1-45, wherein R3is selected from halo and C1-C4alkyl. Embodiment 48. The compound of any one of embodiments 1-45, wherein R3is selected from halo and C2-C3alkynyl. Embodiment 49. The compound of any one of embodiments 1-45, wherein R3is halo. Embodiment 50. The compound of any one of embodiments 1-45, wherein R3is selected from –F, –Cl, –Et, and –C≡CH. Embodiment 51. The compound of any one of embodiments 1-45, wherein R3is selected from –F, –Cl, and –Et. Embodiment 52. The compound of any one of embodiments 1-45, wherein R3is selected from –F, –Cl and –C≡CH. Embodiment 53. The compound of any one of embodiments 1-45, wherein R3is selected from –F and –Cl. Embodiment 54. The compound of any one of embodiments 1-45, wherein R3is –F.Embodiment 55. The compound of any one of embodiments 1-45, wherein R3is –Cl. Embodiment 56. The compound of any one of embodiments 1-45, wherein R3is –Et. Embodiment 57. The compound of any one of embodiments 1-45, wherein R3is –C≡CH. Embodiment 58. The compound of any one of embodiments 1-57, wherein R4is selected from hydrogen and halo. Embodiment 59. The compound of any one of embodiments 1-57, wherein R4is selected from –H and –F. Embodiment 60. The compound of any one of embodiments 1-57, wherein R4is –H. Embodiment 61. The compound of any one of embodiments 1-57, wherein R4is –F. Embodiment 62. The compound of any one of embodiments 1-41 and 46-61, wherein R1is a 4-8 membered saturated bicyclic carbocyclic or bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1- C4 alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. Embodiment 63. The compound of any one of embodiments 1-41 and 46-61, wherein R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1- C4haloalkyl, and C1-C4haloalkoxy. Embodiment 64. The compound of any one of embodiments 1-41 and 46-61, wherein R1is a 4-8 membered saturated monocyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. Embodiment 65. The compound of any one of embodiments 1-41 and 46-61, wherein R1is a 4-8 membered saturated bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. Embodiment 66. The compound of any one of embodiments 62-65, wherein the carbocyclic or heterocyclic group of R1is unsubstituted, or substituted with one substituent selected from halo, hydroxy or spiro C3-C4cycloalkyl.Embodiment 67. The compound of any one of embodiments 62-65, wherein the carbocyclic or heterocyclic group of R1is unsubstituted, or substituted with one fluoro or spiro C3-C4cycloalkyl. Embodiment 68A. The compound of any one of embodiments 1-41 and 46-61, wherein R1is selected from the group consisting of:Embodiment 68B. The compound of any one of embodiments 1-41 and 46-61, wherein R1isEmbodiment 68C. The compound of any one of embodiments 1-41 and 46-61, wherein R1is. Embodiment 69. The compound of any one of embodiments 1-41 and 46-61, wherein R1is. Embodiment 70. The compound of any one of embodiments 1-41 and 46-61, wherein R1iswherein Rdis H or F. Embodiment 71. The compound of any one of embodiments 68-70, wherein Rdis H. Embodiment 72. The compound of any one of embodiments 68-70, wherein Rdis F. Embodiment 73. The compound of any one of embodiments 1-41 and 46-61, wherein R1is selected from. Embodiment 74. The compound of any one of embodiments 1-41 and 46-61, wherein R1is.Embodiment 75. The compound of any one of embodiments 1-41 and 46-61, wherein R1is. Embodiment 76. The compound of any one of embodiments 1-61, wherein R1is. Embodiment 77. The compound of any one of embodiments 1-41 and 46-61, wherein R1is selected from the group consistingEmbodiment 78. The compound of any one of embodiments 1-61, wherein. Embodiment 79. The compound of any one of embodiments 1-78, wherein the compound isEmbodiment 80. The compound of any one of embodiments 1-79, wherein the compound is not a salt. Embodiment 81. The compound of any one of embodiments 1-79, wherein the compound is a salt. Embodiment 82. The compound of embodiment 81, wherein the salt is a formate salt. Embodiment 83. The compound of embodiment 81, wherein the salt is a trifluoroacetate salt. Embodiment 84. The compound of embodiment 81, wherein the salt is a pharmaceutically acceptable salt. Embodiment 85. A pharmaceutical formulation comprising the compound of any one of embodiments 1-84, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. Embodiment 86. A method of treating or suppressing cancer comprising: administering a therapeutically effective amount of a compound of any one of embodiments 1-84, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt, or a pharmaceutical formulation according to embodiment 85, to a subject in need thereof. Embodiment 87. The method of embodiment 86, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.Embodiment 88. The method of embodiment 86, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, 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 subject has been diagnosed as having a KRAS G12C mediated cancer. Embodiment 91. The method of any one of embodiments 86 to 88, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent. Embodiment 92. A compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 for use as a medicament. Embodiment 93. A compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77, for use in treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. Embodiment 94. The compound or pharmaceutical formulation for use of embodiment 93, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.Embodiment 95. The compound or pharmaceutical formulation for use of embodiment 93, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. Embodiment 96. The compound or pharmaceutical formulation for use of any one of embodiments 93-95, wherein the cancer is a KRAS G12C mediated cancer. Embodiment 97. The compound or pharmaceutical formulation for use of any one of embodiments 93-95, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. Embodiment 98. The compound or pharmaceutical formulation for use of any one of embodiments 93-97, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. Embodiment 99. The compound or pharmaceutical formulation for use of any one of embodiments 93-98, wherein the compound or pharmaceutical formulation is configured for administration in a therapeutically effective amount. Embodiment 100. A compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 for use in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.Embodiment 101. The compound or pharmaceutical formulation for use of embodiment 100, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. Embodiment 102. The compound or pharmaceutical formulation for use of embodiment 100, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. Embodiment 103. The compound or pharmaceutical formulation for use of any one of embodiments 100-102, wherein the cancer is a KRAS G12C mediated cancer. Embodiment 104. The compound or pharmaceutical formulation for use of any one of embodiments 100-102, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. Embodiment 105. The compound or pharmaceutical formulation for use of any one of embodiments 100-104, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. Embodiment 106. The compound or pharmaceutical formulation for use of any one of embodiments 100-105, wherein the medicament comprises a therapeutically effective amount of the compound or composition. Embodiment 107. Use of a compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 in the manufacturing of a medicament for treating orsuppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. Embodiment 108. The use of embodiment 107, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. Embodiment 109. The use of embodiment 107, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. Embodiment 110. The use of any one of embodiments 107-109, wherein the cancer is a KRAS G12C mediated cancer. Embodiment 111. The use of any one of embodiments 107-109, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. Embodiment 112. The use of any one of embodiments 107-111, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. Embodiment 113. The use of any one of embodiments 107-112, wherein the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.Embodiment 114. Use of a compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. Embodiment 115. The use of embodiment 114, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. Embodiment 116. The use of embodiment 114, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. Embodiment 117. The use of any one of embodiments 114-116, wherein the cancer is a KRAS G12C mediated cancer. Embodiment 118. The use of any one of embodiments 114-116, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. Embodiment 119. The use of any one of embodiments 114-118, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. Embodiment 120. The use of any one of embodiments 114-119, wherein use involves a therapeutically effective amount of the compound or composition.Set B. 1. A compound of Formula (I’’):Formula (I’’), or a salt thereof, and / or an isotopologue thereof; wherein: X is -N(CH3)- or -O-; X1is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is 0 or 1; R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 R1A; R1Ain each instance is independently selected from the group consisting of halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and -C(O)(C1-C4alkyl); or two geminal R1A, together with the carbon atom to which they are attached, form C3-C4cycloalkyl substituted with 0, 1, or 2 halo; or two geminal R1Atogether form =CH2, =CHF, or =CF2; Rais H or CH3;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R5is H or -OH; Y is CH or N;R6in each instance is independently selected from the group consisting of halo, -OH, C1- C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and r is 0, 1, 2, or 3;2. The compound of embodiment 1, or a salt thereof, and / or an isotopologue thereof, wherein. 3. The compound of embodiment 2, or a salt thereof, and / or an isotopologue thereof, wherein R3is selected from the group consisting of halo, C1-C4alkyl, and C2-C3alkynyl. 4. The compound of embodiment 2, or a salt thereof, and / or an isotopologue thereof, wherein R3is selected from the group consisting of –F, –Cl, –Et, –C≡CH, and –C≡C-CH3.5. The compound of any one of embodiments 2-4, or a salt thereof, and / or an isotopologue thereof, wherein R4is hydrogen or halo. 6. The compound of any one of embodiments 2-4, or a salt thereof, and / or an isotopologue thereof, wherein R4is hydrogen or –F. 7. The compound of any one of embodiments 2-6, or a salt thereof, and / or an isotopologue thereof, wherein R5is -OH. 8. The compound of any one of embodiments 2-6, or a salt thereof, and / or an isotopologue thereof, wherein R5is H. 9. The compound of embodiment 2, or a salt thereof, and / or an isotopologue thereof, whereinnd of embodiment 1, or a salt thereof, and / or an isotopologue thereof, wherein. 11. The compound of embodiment 10, or a salt thereof, and / or an isotopologue thereof, wherein Y is CH. 12. The compound of embodiment 10, or a salt thereof, and / or an isotopologue thereof, wherein Y is N. 13. The compound of any one of embodiments 10-12, or a salt thereof, and / or an isotopologue thereof, wherein R6in each instance is independently selected from the group consisting of -Cl, - OH, -CH3, -CF3, cyclopropyl, and -NH2.14. The compound of any one of embodiments 10-13, or a salt thereof, and / or an isotopologue thereof, wherein r is 3. 15. The compound of any one of embodiments 10-13, or a salt thereof, and / or an isotopologue thereof, wherein. 16. The compound of any one of embodiments 10-13, or a salt thereof, and / or an isotopologue thereof, whereinwherein R6Ais cyclopropyl or -CF3; R6Bis -Cl or -CH3; and R6Cis -OH or -NH2. 17. The compound of embodiment 10, or a salt thereof, and / or an isotopologue thereof, wherein18. The compound of any one of embodiments 1-17, or a salt thereof, and / or an isotopologue thereof, wherein X is -N(CH3)-. 19. The compound of any one of embodiments 1-17, or a salt thereof, and / or an isotopologue thereof, wherein X is -O-. 21. The compound of any one of embodiments 1-19, or a salt thereof, and / or an isotopologue thereof, wherein X1is -CH3. 20. The compound of any one of embodiments 1-19, or a salt thereof, and / or an isotopologue thereof, wherein X1is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl.22. The compound of any one of embodiments 1-17, or a salt thereof, and / or an isotopologue, , , or . 23. The compound of any one of embodiments 1-17, or a salt thereof, and / or an isotopologue24. The compound of any one of embodiments 1-23, or a salt thereof, and / or an isotopologuethereof, whereinsubstituted with 0, 1, 2, or 3 R1A.25. The compound of any one of embodiments 1-24, or a salt thereof, and / or an isotopologue thereof, wherein R1Ain each instance is independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3; or two geminial R1A, together with the carbon atom to which they are attached, form cyclopropyl substituted with 0, 1, or 2 fluoro; or two geminal R1Atogether form =CH2, =CHF, or =CF2. 26. The compound of any one of embodiments 1-25, or a salt thereof, and / or an isotopologue27. The compound of any one of embodiments 1-25, or a salt thereof, and / or an isotopologue. 28. The compound of any one of embodiments 1-27, wherein Rais H. 29. The compound of any one of embodiments 1-27, wherein Rais CH3. 30. The compound of embodiment 1, or a salt thereof, and / or an isotopologue thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.31. The compound of any one of embodiments 1-30, or a salt thereof, and / or an isotopologue thereof, wherein the salt is a pharmaceutically acceptable salt. 32. A pharmaceutical formulation comprising the compound of any one of embodiments 1- 31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, and a pharmaceutically acceptable carrier. 33. A method of treating or suppressing cancer comprising: administering a therapeutically effective amount of a compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 32, to a subject in need thereof. 34. The method of embodiment 33, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. 35. The method of embodiment 33, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.36. The method of any one of embodiments 33 to 35, wherein the cancer is a KRAS G12C mediated cancer. 37. The method of any one of embodiments 33 to 35, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. 38. The method of any one of embodiments 33 to 35, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent. 39. A compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 32, for use as a medicament. 40. A compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 32, for use in treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. 41. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of embodiment 40, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. 42. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of embodiment 40, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma,mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. 43. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 38-40, wherein the cancer is a KRAS G12C mediated cancer. 44. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 40-42, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. 45. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 40-44, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. 46. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 40-45, wherein the compound or pharmaceutical formulation is configured for administration in a therapeutically effective amount. 47. A compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 30 for use in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. 48. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of embodiment 47, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.49. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of embodiment 47, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. 50. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 47-49, wherein the cancer is a KRAS G12C mediated cancer. 51. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 47-49, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. 52. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 47-51, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. 53. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of embodiments 47-52, wherein the medicament comprises a therapeutically effective amount of the compound or composition.54. Use of a compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 32 in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. 55. The use of embodiment 54, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. 56. The use of embodiment 54, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. 57. The use of any one of embodiments 54-56, wherein the cancer is a KRAS G12C mediated cancer. 58. The use of any one of embodiments 54-56, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.59. The use of any one of embodiments 54-58, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. 60. The use of any one of embodiments 54-59, wherein the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation. 61. Use of a compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to embodiment 30, for treating or suppressing 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, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers. 63. The use of embodiment 61, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.64. The use of any one of embodiments 61-63, wherein the cancer is a KRAS G12C mediated cancer. 65. The use of any one of embodiments 61-63, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer. 66. The use of any one of embodiments 61-65, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. 67. The use of any one of embodiments 61-66, wherein use involves a therapeutically effective amount of the compound or composition. General Synthetic Methods

[0183] Compounds in Table 1 of the instant disclosure were prepared or can be prepared according to methods described in the Examples section or variations thereof that would be within the knowledge of one of skill in the art.

[0184] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as MilliporeSigma., Bachem., etc. or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0185] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.

[0186] In some embodiments, compounds provided herein may be synthesized according to Method 1.Method 1., wherein X’, q, R1, and R3are as defined for Formula (I), or any variation thereof detailed herein.

[0187] An exemplary embodiment of Method 1 is shown in Method 1a. Method 1a.Boc Boc Boc, wherein X’, q, R1, and R3are as defined for Formula (I), or any variation thereof detailed herein.

[0188] An exemplary embodiment of Method 1 is further shown in the following steps.Step 1: tert-butyl-3-(benzyl(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate

[0189] To a solution of tert-butyl-3-amino-(X’)q-pyrrolidine-1-carboxylate (1.0 equiv.) in methanol [0.5 M] was added sodium cyanoborohydride (2.0 equiv.), acetic acid (1.0 equiv.) and benzaldehyde (1.1 equiv) at 0 °C for 1 h. Then, formaldehyde (3.0 equiv.) was added to the mixture and the reaction was stirred at 0 °C for 2 h. The reaction mixture was concentrated todryness in vacuo and purified by column chromatography affording tert-butyl-3- [benzyl(methyl)amino]-(X’)q-pyrrolidine-1-carboxylate. BocStep 2: tert-butyl-(X’)q-3-(methylamino)pyrrolidine-1-carboxylate

[0190] To a solution of palladium on carbon in methanol [0.16 M] was added cis-tert-butyl-3- [benzyl(methyl)amino]-(X’)q-pyrrolidine-1-carboxylate (1.0 equiv.) and the mixture was stirred at 40 °C for 2 h under hydrogen atmosphere. The reaction mixture was then filtered and the filtrate was concentrated to dryness in vacuo affording tert-butyl-(X’)q-3-(methylamino)pyrrolidine-1- carboxylate.Step 3: tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate

[0191] To a solution of tert-butyl-(X’)q-3-(methylamino)pyrrolidine-1-carboxylate (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 h. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography affording tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate.Step 4: tert-butyl-3-((7-chloro-8-fluoro-2-((R1-methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate

[0192] To a solution of R1-methanol (1.5 equiv.) and tert-butyl-3-((2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate (1.0 equiv.) in dioxane [0.14 M] was added N,N-diisopropylethylamine (3.1 equiv.), and the mixture was stirred at 80 °C for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography affording tert-butyl-3-((7-chloro-8-fluoro-2-((R1- methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate.Step 5: tert-butyl-3-((8-fluoro-7-(7-R3-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-((R1-methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate

[0193] To a solution of ((7-R3-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (2.5 equiv.) and tert-butyl-3-((7-chloro-8-fluoro-2-((R1- methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate (1.0 equiv.) in a mixture of 1,4-dioxane / water [2:1 v / v, 0.1 M] was added potassium phosphate (3.0 equiv.) and Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino- 1,1′-biphenyl)]palladium(II) (0.2 equiv.) and the mixture was stirred at 80 °C for 2 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography affording tert-butyl-3-((8-fluoro-7-(7-R3-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R1-methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate.Step 6: tert-butyl-3-((7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1- methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate

[0194] To a solution of tert-butyl-3-((8-fluoro-7-(7-R3-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((R1-methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidine-1-carboxylate (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 h. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography affording tert-butyl-3-((7-(8-ethynyl- 7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- (X’)q-pyrrolidine-1-carboxylate.Step 7: 7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)-N-methyl-N- (X’)q-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0195] To a solution of tert-butyl-3-((7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1- 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.), the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to dryness in vacuo affording 7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)-N-methyl-N-(X’)q-pyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine (as trifluoroacetate salt).Step 8: ((7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-(X’)q-pyrrolidin-1-yl)prop-2-en-1-one

[0196] To a solution of 7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)-N-methyl- N-(X’)q-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (trifluoroacetate salt) (1.0 equiv.) in a mixture of tetrahydrofuran and water [3:1 v / v, 0.07 M] was added sodium bicarbonate (3.0 equiv.), prop-2-enoyl chloride (0.9 equiv.) and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then concentrated to dryness in vacuo and purified by reverse phase HPLC to afford ((7-(8-ethynyl-7-R3-naphthalen-1-yl)-8-fluoro-2-((R1-methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-(X’)q-pyrrolidin-1-yl)prop-2-en-1-one. Examples

[0197] The following preparations of compounds of Formula (I) and pharmaceutically acceptable salts thereof are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0198] The following abbreviations are used in this section:

[0199] All reagents were obtained from commercial suppliers and used without further purification unless otherwise stated.Synthetic ExamplesExample 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-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-tert-butyl-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0200] To a solution of cis-tert-butyl-3-amino-2-methyl-pyrrolidine-1-carboxylate (1 g, 4.99 mmol) in methanol (10 mL) was 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 h, then formaldehyde (1.22 g, 14.98 mmol) was added to the mixture, the mixture was stirred at 0°C for 2 h. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) affording cis- tert-butyl-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (1 g, crude) as a colorless oil, used in next step without any further purification:1H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.28 (m, 1H), 7.27 - 7.24 (m, 3H), 7.20 - 7.16 (m, 1H), 4.08(s, 1H), 3.99 (br s, 1H), 3.63 - 3.50 (m, 1H), 3.47 - 3.31 (m, 1H), 3.29 - 3.16 (m, 1H), 2.77 - 2.59 (m, 1H), 2.03 -1.99 (m, 3H), 1.97 (s, 1H), 1.88 - 1.74 (m, 1H), 1.40 (d, J = 2.0 Hz, 9H), 1.14 - 1.06 (m, 3H). LCMS Rt = 0.338 min, m / z = 304.2 [M + H]+.Step 2: cis-tert-butyl-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate

[0201] To a solution of palladium on carbon (200 mg, 10% purity) in methanol (10 mL) was added cis-tert-butyl-3-[benzyl(methyl)amino]-2-methyl-pyrrolidine-1-carboxylate (500 mg, 1.6mmol), the mixture was stirred at 40°C for 2 h under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording cis-tert-butyl-2- methyl-3-(methylamino)pyrrolidine-1-carboxylate (300 mg, crude) as a colorless oil used in the next step without any further purification:1H 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-tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0202] To a solution of cis-tert-butyl-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (252.54 mg, 1.18 mmol) and 2,4,7-trichloro-8-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), the mixture was stirred at 0°C for 1 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 65-70% ethyl acetate in petroleum ether) affording cis-tert-butyl-3-((2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (350 mg, 58.67%) as a yellow solid. LCMS Rt = 0.651 min, m / z = 429.1 [M + H]+.Step 4: cis-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

[0203] To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (66.60 mg, 418.31 μmol) and cis-tert-butyl-3-[(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-methyl- amino]-2-methyl-pyrrolidine-1-carboxylate (120 mg, 278.87 μmol) in dioxane (2 mL) was addedN,N-diisopropylethylamine (108.13 mg, 836.62 μmol), the mixture was stirred at 80°C for 1 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 80-100% ethyl acetate in petroleum ether) affording cis-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 (150 mg, 97.26%) as a yellow solid. LCMS Rt = 1.491 min, m / z = 552.2 [M + H]+.Step 5: cis-tert-butyl-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-methylpyrrolidine-1- carboxylate

[0204] To a solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (306.81 mg, 678.07 μmol) and cis-tert-butyl-3-((7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (150 mg, 271.23 μmol) in dioxane (2 mL) and water (1 mL) was added potassium phosphate (172.72 mg, 813.68 μmol) and Chloro(2- dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) (42.68 mg, 54.25 μmol), the mixture was stirred at 80°C for 2 h. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 85-100% ethyl acetate in petroleum ether) affording cis-tert-butyl-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-methylpyrrolidine-1- carboxylate (180 mg, crude) as a yellow solid, used in next step without any further purification. LCMS Rt = 0.624 min, m / z = 842.5 [M + H]+.Step 6: cis-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-methylpyrrolidine-1-carboxylate

[0205] To a solution of cis-tert-butyl-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 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), the mixture was stirred at 20°C for 1 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-25% methanol in dichloromethane) affording cis- 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-methylpyrrolidine- 1-carboxylate (130 mg, crude) as a brown solid, used in 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

[0206] To a solution of cis-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-methylpyrrolidine-1-carboxylate (65 mg, 94.65 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (32.38 mg, 283.94 μmol), the mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated to dryness in vacuo affording 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 (65 mg, crude, trifluoroacetate salt) as a brown oil 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0207] To a solution of cis-7-(8-ethynyl-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 (65 mg, 92.77 μmol, trifluoroacetate salt) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (23.38 mg, 278.30 μmol), prop-2-enoyl chloride (7.56 mg, 83.49 μmol), the mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:40%-70% B over 8.0 min) affording cis-1-((2RS,3RS)-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-methylpyrrolidin-1-yl)prop-2-en-1-one (10.11 mg, 15.63%) as a yellow solid: 1H NMR (400 MHz, Chloroform-d) δ 9.18 (br s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 2.97 (m, 1H), 2.91 - 2.81 (m, 1H), 2.48 - 2.34 (m, 2H), 2.28 - 2.14 (m, 2H), 2.04 - 1.89 (m, 3H), 1.74 - 1.59 (m, 3H), 1.20 - 1.07 (m, 3H). LCMS Rt = 2.226 min, m / z = 641.3 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.226 min, ESI+ found [M+H]+= 641.3.Examples 1-2 & 1-3: Separation 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-pyrrolizin-7a -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-(((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 (SFC separation from Example 1-1)

[0208] The mixture of cis-diastereomers of 1-(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-methylpyrrolidin-1-yl)prop-2-en-1-one (100 mg) was purified by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um); mobile phase: [CO2-EtOH(0.1% NH4OH)]; B%: 50%, isocratic elution mode) to give arbitrarily assigned: Example 1-2: 1-((2S,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-methylpyrrolidin-1-yl)prop-2-en-1-one (Peak 1, retention time = 1.467 min) (33.02 mg) as a white solid:1H NMR (400 MHz, Chloroform-d) δ = 9.21 - 9.16 (m, 1H), 8.02 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.31 (m, 1H), 6.57 - 6.36 (m, 2H), 5.77 - 5.68 (m, 1H), 5.45 - 5.20 (m, 1H), 5.10 - 4.89 (m, 2H), 4.45 - 4.15 (m, 2H), 3.94 - 3.81 (m, 1H), 3.68 (s, 1H), 3.63 (s, 3H), 3.48 - 3.14 (m, 3H), 3.01 (s, 1H), 2.86 (s, 1H), 2.59 - 2.28 (m, 3H), 2.27 - 2.09 (m, 2H), 2.04 - 1.86 (m, 3H), 1.13 (d,^J^= 4.9 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.226 min, ESI+ found [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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one (Peak 2, retention time = 1.617 min) (30.58 mg) as a white solid:1H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.04 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.38 - 7.33 (m, 1H), 6.53 - 6.39 (m, 2H), 5.76 - 5.70 (m, 1H), 5.41 - 5.21 (m, 1H), 5.06 - 4.88 (m, 2H), 4.32 - 4.25 (m, 1H), 3.92 - 3.84 (m, 1H), 3.65 - 3.60 (m, 3H), 3.34 - 3.11 (m, 3H), 3.05 - 2.97 (m, 1H), 2.91 - 2.81 (m, 1H), 2.48 - 2.34 (m, 2H), 2.28 - 2.14 (m, 2H), 2.04 - 1.89 (m,3H), 1.74 - 1.59 (m, 3H), 1.20 - 1.07 (m, 3H).^ LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) 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-pyrrolizin-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: tert-butyl (3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1- carboxylate

[0209] The reductive amination reaction was prepared in a similar fashion to Method #1, Step 1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (3R,4R)-3-(benzyl(methyl)amino)-4- methylpyrrolidine-1-carboxylate (5.25 g, 70.49%) as a white solid:1H 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: tert-butyl (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate

[0210] The deprotection of Bn group was prepared in a similar fashion to Method #1, Step 2. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording tert- butyl (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate (3.54 g, crude) as a white solidused in the next step without any further purification. LCMS Rt = 0.282 min, m / z = 214.2 [M + H]+.Step 3: tert-butyl (3R,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate

[0211] The substitution reaction was prepared in a similar fashion 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 affording tert-butyl (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, used in next step without any further purification. LCMS Rt = 0.578 min, m / z = 429.1 [M + H]+.Step 4: tert-butyl (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-carboxylate

[0212] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Phenomenex luna C18250*150mm*15um; mobile phase: [H2O (0.1%TFA) - ACN]; gradient: 30%-60% B over 20.0 min) affording tert-butyl (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-carboxylate (7.77 g, 54.24%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 2.194 min, m / z = 552.2 [M + H]+.Step 5: tert-butyl (3R,4R)-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)-4-methylpyrrolidine-1- carboxylate

[0213] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 85%-95% B over 8.0 min) affording tert- butyl (3R,4R)-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)-4-methylpyrrolidine-1-carboxylate (285 mg, 75.16%) as a white solid. LCMS Rt = 0.639 min, m / z = 842.5 [M + H]+.Step 6: tert-butyl (3R,4R)-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-carboxylate

[0214] The deprotection of TIPS group reaction was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording tert-butyl (3R,4R)-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-carboxylate (110 mg, crude) as a yellow oil used in 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

[0215] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 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 (110 mg, crude, trifluoroacetate salt) as a yellow oil used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0216] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O (10mM NH4HCO3) -ACN]; gradient: 45%-75% B over 8.0 min) affording 1-((3R,4R)-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-methylpyrrolidin-1-yl)prop-2-en-1-one (43.90 mg, 39.87%) as a white solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one (Method 1) BocStep 1: tert-butyl (3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1- carboxylate

[0217] The reductive amination reaction was prepared in a similar fashion to Method #1, Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 10%- 20% ethyl acetate in petroleum ether) affording tert-butyl (3R,4S)-3-(benzyl(methyl)amino)-4- methylpyrrolidine-1-carboxylate (5 g, 67.13%) as a yellow oil. LCMS Rt = 0.298 min, m / z = 304.2 [M + H]+.Step 2: tert-butyl (3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate

[0218] The deprotection of Bn group was prepared in a similar fashion to Method #1, Step 2. The reaction mixture was concentrated in vacuo affording tert-butyl (3S,4R)-3-methyl-4- (methylamino)pyrrolidine-1-carboxylate (3.2 g, crude) as a white oil used in next step without any further purification. LCMS Rt = 0. 508 min, m / z = 214.2 [M + H]+.Step 3: tert-butyl (3R,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate

[0219] The substitution reaction was prepared in a similar fashion to Method #1, Step 3. The mixture was filtered and concentrated in vacuo affording tert-butyl (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: tert-butyl (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-carboxylate

[0220] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Welch Xtimate C18250*100mm#10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 15%-45% B over 20.0 min) affording tert-butyl (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-carboxylate (2.5 g, 34.74%) as a yellow solid. LCMS Rt = 0.406 min, m / z = 552.2 [M + H]+.Step 5: tert-butyl (3R,4S)-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)-4-methylpyrrolidine-1- carboxylate

[0221] The Suzuki reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (3R,4S)-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)-4-methylpyrrolidine- 1-carboxylate (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: tert-butyl (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-carboxylate

[0222] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The mixture was filtered and concentrated to dryness in vacuo affording tert-butyl (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- carboxylate (400 mg, crude) as a yellow solid used in 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

[0223] The deprotection of Boc group reaction was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated in vacuo and purified by reverse phase HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [water (0.1%TFA)-ACN]; gradient:10%- 40% B over 8.0 min) affording 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 (300 mg, 73.51%, trifluoroacetate salt) 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0224] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (56.50 mg, 29.62%) as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.993 min, ESI+ found [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-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: tert-butyl (2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0225] The substitution reaction was prepared in a similar fashion to Method #1, Step 3. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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:1H 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: tert-butyl (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-carboxylate

[0226] The substitution reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (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-carboxylate (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: tert-butyl (2S,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

[0227] The Suzuki reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (2S,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 (300 mg, 65.60%) as a yellow solid. LCMS Rt = 0.639 min, m / z = 842.5 [M + H]+.Step 4: tert-butyl (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-carboxylate

[0228] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The mixture was filtered and purified by reverse phase HPLC (column: 3 Phenomenex Luna C1875*30mm*3um; mobile phase: [water (0.1%TFA)-ACN]; gradient: 30%-60% B over 8.0 min) affording tert-butyl (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-carboxylate (120 mg, 84.23%, trifluoroacetate salt) 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-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0229] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (80 mg, crude, hydrochloride salt) as a yellow solid used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0230] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (29.99 mg, 36.19%) as a pale yellow amorphous solid:1H NMR (400 MHz, Acetonitrile-d3) δ 9.18 (d, J = 2.3 Hz, 1H), 8.17 - 8.11 (m, 2H), 7.72 - 7.66 (m, 2H), 7.47 (t, J = 9.0 Hz, 1H), 6.68 - 6.51 (m, 1H), 6.31 - 6.19 (m, 1H), 5.74 - 5.64 (m, 1H), 5.36 - 5.10 (m, 2H), 4.38 - 4.24 (m, 1H), 4.19 (br s, 2H), 4.14 - 4.10 (m, 1H), 3.75 - 3.54 (m, 1H), 3.47 (s, 3H), 3.30 - 3.24 (m, 1H), 3.20 - 3.11 (m, 2H), 3.07 (s, 1H), 2.95 - 2.87 (m, 1H), 2.76 - 2.53 (m, 1H), 2.25 - 2.18 (m, 1H), 2.13 - 2.00 (m, 3H), 1.94 - 1.90 (m, 1H), 1.89 - 1.82 (m, 2H), 1.44 (d, J = 6.1 Hz, 3H) LCMS Rt = 2.976 min, m / z = 640.3 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.976 min, ESI+ found [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-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: tert-butyl (2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1- carboxylate

[0231] The reductive amination reaction was prepared in a similar fashion to Method #1, Step 1. The reaction mixture was concentrated to dyness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (720 mg, 47.37%) as a colorless oil:1H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.23 (m, 5H), 4.00 (quin, J = 6.6 Hz, 1H), 3.65 - 3.60 (m, 1H), 3.58- 3.47 (m, 2H), 3.29 - 3.15 (m, 2H), 2.12 (s, 3H), 2.08 - 1.86 (m, 2H), 1.47 (s, 9H), 1.19 (br d, J = 6.4 Hz, 3H).Step 2: tert-butyl (2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1-carboxylate

[0232] The deprotection of Bn group was prepared in a similar fashion to Method #1, Step 2. The reaction mixture was concentrated in vacuo affording tert-butyl (2R,4R)-2-methyl-4- (methylamino)pyrrolidine-1-carboxylate (510 mg, crude) as a yellow oil and used as is in the next step:1H 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: tert-butyl (2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0233] The substitution reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (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: tert-butyl (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-carboxylate

[0234] The substitution reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (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-carboxylate (580 mg, 70.51%) as a yellow solid. LCMS Rt = 0.657 min, m / z = 552.2 [M + H]+.Step 5: tert-butyl (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

[0235] The Suzuki reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (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 (790 mg, 95.96%) as a brown solid. LCMS Rt = 1.041 m / z = 842.5 [M + H]+.Step 6: tert-butyl (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-carboxylate

[0236] The deprotection of TIPS group reaction was prepared in a similar fashion to Method #1, Step 6. The mixture was concentrated to dryness in vacuo affording tert-butyl (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-carboxylate (590 mg, crude) as a yellow solid used into the next step without further purification. LCMS Rt = 1.838min, 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,5R)-5- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0237] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5R)-5- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, crude, hydrochloride salt) as a yellow solid used into the next step without further purification. LCMS Rt = 0.347min, 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0238] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was concentrated in vacuo and purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (75.66 mg 39.76%) as a pale yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.976 min, ESI+ found [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-pyrrolizin-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: tert-butyl (3S,4S)-3-[benzyl(methyl)amino]-4-methyl-pyrrolidine-1- carboxylate

[0239] The reductive amination reaction was prepared in a similar fashion 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 in petroleum ether) affording tert-butyl (3S,4S)-3- [benzyl(methyl)amino]-4-methyl-pyrrolidine-1-carboxylate (850 mg, 55.92%) as a colorless oil:1H 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: tert-butyl (3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate

[0240] The deprotection of Bn group was prepared in a similar fashion to Method #1, Step 2. The reaction mixture was concentrated in vacuo affording tert-butyl (3S,4S)-3-methyl-4- (methylamino)pyrrolidine-1-carboxylate (580 mg, crude) as a colorless oil used into the next stepwithout further purification:1H NMR (400 MHz, Chloroform-d) δ 3.50 - 3.38 (m, 2H), 3.28 - 3.03 (m, 3H), 2.42 (s, 3H), 2.37 - 2.28 (m,1H), 1.45 (s, 9H), 1.00 - 0.95 (m, 3H).Step 3: tert-butyl (3S,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylate

[0241] The substitution reaction was prepared in a similar fashion to Method #1, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 0- 100% ethyl acetate in petroleum ether) affording tert-butyl (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: tert-butyl (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-carboxylate

[0242] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 50- 100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (1.02 g, 95.62%) as a yellow solid. LCMS Rt = 0.427 min, m / z = 552.2 [M + H]+.Step 5: tert-butyl (3S,4S)-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)-4-methylpyrrolidine-1- carboxylate

[0243] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (3S,4S)-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)-4-methylpyrrolidine-1- carboxylate (490 mg,80.36%) as a brown solid. LCMS Rt = 1.122 min, m / z = 842.5 [M + H]+.Step 6: tert-butyl (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-carboxylate

[0244] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The filtered was concentrated to dryness in vacuo affording tert-butyl (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-carboxylate (450 mg, crude) as a brown solid used into 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

[0245] The deprotection of Boc group reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated to dryness in vacuo affording 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 (220 mg, crude, trifluoroacetate salt) as a yellow solid used into 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0246] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 30%-65% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (24.23 mg, 21.42%) as a yellow amorphous solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.992 min, ESI+ found [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]heptan-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]heptan-6-yl)methanol

[0247] 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 Hydride (2.5 M, 1.16 mL) (in tetrahydrofuran) at 0°C. The mixture was stirred at 70°C for 2 h. The reaction mixture was quenched with sodium sulfate decahydrate (100 mg) at 0°C, dried over sodium sulphate. The mixture was filtered and filtrate was concentrated in vacuo affording (S)-(5-methyl-5- azaspiro[2.4]heptan-6-yl)methanol (260 mg, crude) as a white solid and used in the next step without further purification:1H 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: tert-butyl (R)-3-((7-chloro-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0248] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane in methanol) affording tert-butyl (R)-3-((7-chloro-8-fluoro-2-(((S)-5-methyl-5- azaspiro[2.4]heptan-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: tert-butyl (R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0249] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane in ethyl acetate) affording tert-butyl (R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 64.24%) as a brown solid:1H NMR (400 MHz, Chloroform-d) δ 9.13 (br s, 1H), 7.90 - 7.80 (m, 2H), 7.54 - 7.45 (m, 2H), 7.27 (t, J = 8.8Hz, 1H), 5.34 (br d, J = 6.3 Hz, 1H), 4.69 - 4.25 (m, 2H), 3.92 - 3.45 (m, 3H), 3.34 (br d, J = 4.0 Hz, 3H), 2.66 - 2.43(m, 3H), 2.32 (br d, J = 3.3 Hz, 1H), 2.18 - 2.06 (m, 2H), 1.80 - 1.49 (m, 3H), 1.42 (s, 9H), 1.20 - 1.16 (m, 3H), 1.03 -0.86 (m, 2H), 0.83 - 0.78 (m, 18H), 0.53 - 0.46 (m, 4H). LCMS Rt = 0.628 min, m / z = 810.5 [M + H]+.Step 4: tert-butyl (R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5- methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate

[0250] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The mixture was concentrated to dryness in vacuo affording tert-butyl (R)-3-((7-(8-ethynyl-7- fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (100 mg, crude) as a brown oil, used in 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]heptan-6-yl)methoxy)-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0251] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1- yl)-8-fluoro-N-methyl-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)-N-((R)-pyrrolidin- 3-yl)pyrido[4,3-d]pyrimidin-4-amine (90 mg, crude) as a yellow solid used into 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]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1- yl)prop-2-en-1-one

[0252] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 25%-75% B over 8.0min) affording 1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5-methyl-5- azaspiro[2.4]heptan-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:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0253] 1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0254] 1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0255] 1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0256] 1H NMR (400 MHz, Chloroform-d) δ 9.30 - 9.10 (m, 1H), 8.01 - 7.93 (m, 2H), 7.66 - 7.58 (m, 2H), 7.35 (t, J = 8.8 Hz, 1H), 6.52 - 6.39 (m, 2H), 5.77 - 5.68 (m, 1H), 5.11 - 4.91 (m, 2H), 4.75 - 4.58 (m, 1H), 4.50 - 4.36 (m, 1H), 3.92 - 3.83 (m, 1H), 3.64 - 3.60 (m, 3H), 3.10 - 2.97 (m, 1H), 2.90 - 2.82 (m, 1H), 2.79 - 2.69 (m, 1H), 2.65 - 2.59 (m, 1H), 2.56 - 2.50 (m, 3H), 2.43 - 2.34 (m, 1H), 2.20 - 2.11 (m, 1H), 1.86 - 1.56 (m, 3H), 1.20 - 1.10 (m, 3H), 0.69 - 0.63 (m, 1H), 0.59 - 0.48 (m, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.982 min, 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-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: tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert- butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0257] To a solution of tert-butyl (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-((tert- butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.839 g, 4.64 mmol) and 4Å molecule sieves (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 for 12 h under nitrogen atmosphere. 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 sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:60%-90% B over 8.0 min) affording tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylate (600 mg, 32.70%) as a white solid: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: tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert- butyldiphenylsilyl)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-carboxylate

[0258] A mixture of tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert- butyldiphenylsilyl)oxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 633.35 μmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (429.87 mg, 950.03 μmol), potassium phosphate (403.32 mg, 1.90 mmol) and [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 for 3 times, and then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. 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 sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:60%- 90% B over 8.0 min) affording tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert- butyldiphenylsilyl)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-carboxylate (420 mg, 55.56%, trifluoroacetic salt) as a yellow solid:1H NMR (400 MHz, Dimethyl sulfoxide-d6) δ 9.39 (d, J = 11.2 Hz, 1H), 8.26 - 8.16 (m, 2H), 7.73 - 7.67 (m, 1H), 7.66 - 7.58 (m, 6H), 7.53 - 7.46 (m, 3H), 7.45 - 7.40 (m, 3H), 4.88 (d, J = 5.5 Hz, 1H), 4.74 (d, J = 10.1Hz, 1H), 4.63 - 4.52 (m, 1H), 4.45 (d, J = 8.9 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.54 (s, 1H), 3.38 - 3.33 (m, 1H), 2.52 - 2.50 (m, 3H), 2.36 (dd, J = 5.6, 13.7 Hz, 3H), 2.21 (s, 2H), 2.15 (d, J = 11.8 Hz, 2H), 1.79 (s, 4H), 1.46 (s, 9H), 1.39 (d, J = 3.9 Hz, 1H), 1.20 - 1.16 (m, 2H), 1.08 (s, 9H), 1.02 - 1.00 (m, 1H), 0.85 (d, J = 6.4 Hz, 18H), 0.61 (dt, J = 7.0, 14.2 Hz, 3H). LCMS Rt = 2.706 min, m / z = 1079.5 [M + H]+.Step 3: tert-butyl (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-carboxylate

[0259] To a solution of tert-butyl (2R,3R)-3-((2-(((2R,7aS)-2-((tert- butyldiphenylsilyl)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-carboxylate (200 mg, 185.27 μmol, trifluoroacetic salt) in N,N- dimethylformaldehyde (1 mL) was added cesium fluoride (562.86 mg, 3.71 mmol). The mixturewas stirred at 50 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were was washed with saturated lithium chloride (3 x 5 mL), and dried over sodium sulphate and concentrated in vacuo affording tert-butyl (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-carboxylate (126 mg, crude) as a yellow oil 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

[0260] To a solution of tert-butyl (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-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 affording (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 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0261] 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) was added sodium bicarbonate (43.01 mg, 511.98 μmol) and prop-2-enoyl chloride (10.81 mg, 119.46 μmol), and then the mixture was stirred at 0 °C for 10 min under nitrogen atmosphere. The reaction mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-65% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (8.48 mg, 7.08%) as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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’-pyrrolizin]- 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

[0262] To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (20 g, 81.54 mmol) in dichloromethane (100 mL) 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 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (25 g, 85.27%) as a white solid: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: 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2- (chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate

[0263] To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (20 g, 55.63 mmol) in tetrahydrofuran (300 mL) was added lithium hexamethyldisilazane (83.44 mL, 83.44 mmol, 1 M in tetrahydrofuran). The mixture was stirred at -78 °C for 2 h under nitrogen atmosphere. 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 for 10 h under nitrogen atmosphere. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording 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: 1-(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4- hydroxypyrrolidine-1,2-dicarboxylate

[0264] 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 tetrabutyl ammonium fluoride (29.46 mL, 29.46 mmol, 1M in tetrahydrofuran). The mixture was stirred at 20 °C for 1 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording 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: 1-(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine- 1,2-dicarboxylate

[0265] To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4- hydroxypyrrolidine-1,2-dicarboxylate (7 g, 20.97 mmol) in dichloromethane (100 mL) was added (bis-(2-methoxyethyl)amino)sulfur trufluoride (9.28 g, 41.94 mmol) at -78 °C. The mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording 1-(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4- fluoropyrrolidine-1,2-dicarboxylate (3.7 g, 52.54%) as a white solid:1H 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

[0266] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording methyl (2S,4R)-2-(2- (chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate (2.6 g, crude, trifluoroacetic salt) as a white solid used in next step without any further purification. LCMS Rt = 0.174 min, m / z = 236.0 / 238.0 [M + H]+.Step 6: methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)- carboxylate

[0267] To a solution of methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2- carboxylate (2.6 g, 11.03 mmol, trifluoroacetic salt) in methanol (5 mL) was added ammonia (20 mL, 140.00 mmol, 7M in methanol). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording methyl (2R,7aS)-2-fluoro-6- methylenetetrahydro-1H-pyrrolizine-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: methyl (6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'- pyrrolizine]-7a'(5'H)-carboxylate

[0268] To a solution of methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (1.6 g, 8.03 mmol) in dichloromethane (50 mL) was added diethylzinc (40.16 mL, 40.16 mmol, 1M in toluene) and diiodomethane (21.51 g, 80.31 mmol) at 0 °C under nitrogen. The mixture was stirred at 20°C for 12 h under nitrogen atmosphere. The reaction mixture wasquenched 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording methyl (6'R,7a'S)-6'-fluorodihydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (300 mg, 30%) as a white solid:1H 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'-pyrrolizin]- 7a'(5'H)-yl)methanol

[0269] To a solution of methyl (6’R,7a’S)-6’-fluorodihydro-1’H,3’H-spiro[cyclopropane-1,2’- pyrrolizine]-7a’(5’H)-carboxylate (250 mg, 1.17 mmol) in tetrahydrofuran (4 mL) was added lithium aluminium tetrahydride (1.41 mL, 3.52 mmol, 2.5M in tetrahydrofuran). The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with sodium sulfate decahydrate (200 mg) at 0 °C. The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording ((6’R,7a’S)-6’-fluorodihydro-1’H,3’H-spiro[cyclopropane-1,2’-pyrrolizin]- 7a’(5’H)-yl)methanol (200 mg, crude) as a colourless oil used in next step without any further purification:1H 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: tert-butyl (2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro- 1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0270] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'- fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (120 mg, 47.98%) as a yellow solid. LCMS Rt = 0.422 min, m / z = 579.2 / 581.2 [M + H]+.Step 10: tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0271] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:65%-95% B over 8.0 min) affording tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizin]-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:1H 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: tert-butyl (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'-pyrrolizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0272] The deprotection of TIPS group reaction was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording tert-butyl (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'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (8 mg, crude) as a brown solid used in 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'-pyrrolizin]-7a'(5'H)-yl)methoxy)-N-methyl- N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0273] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1- yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-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 used in 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'-pyrrolizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en- 1-one

[0274] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-80% B over 8.0 min) affording 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'-pyrrolizin]-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%) as a pale yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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: tert-butyl (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-carboxylate

[0275] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (340 mg, 57.48%) as a yellow solid. LCMS Rt = 0.391 min, m / z = 509.2 / 510.2 [M + H]+.Step 2: tert-butyl (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-carboxylate

[0276] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:40%-70% B over 8.0 min) affording tert-butyl (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-carboxylate (260 mg, 55.21%, trifluoroacetic 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

[0277] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 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 used in 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

[0278] The deprotection of TIPS group reaction was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording 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 used in 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

[0279] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) affording 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:1H NMR (400 MHz, Acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.07 (m, 2H), 7.69 - 7.63 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.58 (dd, J = 10.3, 16.8 Hz, 1H), 6.32 - 6.20 (m, 1H), 5.68 (dd, J = 2.2, 10.3 Hz, 1H), 4.99 - 4.79 (m, 2H), 4.53 - 4.41 (m, 1H), 4.37 - 4.25 (m, 1H), 3.88 - 3.65 (m, 1H), 3.62 - 3.46 (m, 4H), 3.28 (s, 1H), 3.07 - 2.97 (m, 1H), 2.68 (d, J = 4.8 Hz, 1H), 2.60 - 2.46 (m, 1H), 2.41 (s, 3H), 2.37 (d, J = 6.3 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.07 - 1.97 (m, 1H), 1.83 - 1.66 (m, 3H), 1.15 - 1.03 (m, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) 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-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: tert-butyl (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-carboxylate

[0280] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate inpetroleum ether) affording tert-butyl (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-carboxylate (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

[0281] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 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 used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0282] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min) affording 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-methylpyrrolidin-1-yl)prop-2-en-1-one (27.03 mg, 14.28%) as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-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: tert-butyl 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-carboxylate

[0283] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:25%-55% B over 8.0 min) affording tert-butyl (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-carboxylate (25 mg, 33.05%, trifluoroacetic 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

[0284] The deprotection of Boc group was prepared in a similar fashion to Method #1, Step 7. The mixture was concentrated to dryness in vacuo affording 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 salt) as a yellow oil used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0285] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (10.75 mg, 46.88%) as a yellow solid:1H 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 = 10.4Hz, 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.007 min, ESI+ found [M+H]+= 651.0 / 652.0.Examples 22 & 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-tert-butyl-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-carboxylate

[0286] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:25%-55% B over 8.0 min) affording cis-tert-butyl-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-carboxylate (110 mg, 39.66%, trifluoroacetic salt) 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

[0287] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 (80 mg, crude, trifluoroacetic salt) as a yellow solid, used in 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

[0288] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-75% B over 8.0 min) affording 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 (40 mg, 45.81%) as a white solid: 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.957min, ESI+ found [M+H]+=651.4 / 652.4.

[0289] The mixture of cis-diastereomers of 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 (30 mg) was further purified by SFC [SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2- EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode)] to give arbitrarily assigned: Example 22: 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (Peak 1, retention time = 1.508 min) (10.22 mg, 11.69%) as a white solid:1H NMR (400 MHz, Acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 - 3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.957 min, ESI+ found [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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one (Peak 2, retention time = 1.787 min) (10.22 mg, 11.69%) as a white solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-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-tert-butyl-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-carboxylate

[0290] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:30%-60% B over 8.0 min) affording cis-tert- butyl-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- carboxylate (280 mg, 97.42%, trifluoroacetic salt) 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

[0291] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 (120 mg, crude, trifluoroacetic salt) as a yellow oil, used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0292] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min) affording 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-methylpyrrolidin-1-yl)prop-2-en-1-one (54.77 mg, 49.95%) as a pale yellow amorphous solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.981 min, ESI+ found [M+H]+= 635.1.Examples 25 & 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 -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)

[0293] The mixture of cis-diastereomers of 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-methylpyrrolidin-1-yl)prop-2-en-1-one (100 mg) was further purified by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2- EtOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to give arbitrarily assigned: Example 25: 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 (Peak 2, retention time = 1.639 min) (31.69 mg, 14.63%) as a white solid:1H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.22 - 8.04 (m, 1H), 7.91 (ddd, J = 1.5, 5.1, 9.1Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.56 (dt, J = 7.7, 9.6 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.28 (dd, J = 8.5, 16.3 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.39 - 5.15 (m, 1H), 4.92 (d, J = 7.3 Hz, 2H), 4.30 - 4.06 (m, 2H), 3.95 - 3.47 (m, 5H), 3.22 - 3.04 (m, 3H), 2.99 - 2.83 (m, 1H), 2.70 - 2.46 (m, 1H), 2.43 - 2.21 (m, 2H), 2.12 (d, J = 3.5 Hz, 2H), 1.94 - 1.82 (m, 3H), 1.12 (s, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.910min, ESI+ found [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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one (Peak 1, retention time = 1.446 min) (29.88 mg, 13.93%) as a white solid:1H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.13 (dt, J = 2.2, 4.7 Hz, 1H), 7.92 (ddd, J = 1.5, 5.1, 9.2 Hz, 1H), 7.71 (d, J = 5.4 Hz, 2H), 7.56 (dt, J = 7.6, 9.6 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.28 (dd, J = 9.8, 16.4 Hz, 1H), 5.70 (d, J = 10.1Hz, 1H), 5.41 - 5.16 (m, 1H), 4.92 (s, 2H), 4.32 - 4.03 (m, 2H), 3.94 - 3.50 (m, 5H), 3.21 - 3.04 (m, 3H), 2.99 - 2.86 (m,1H), 2.72 - 2.47 (m, 1H), 2.46 - 2.20 (m, 2H), 2.14 - 2.05 (m, 2H), 1.94 - 1.79 (m, 3H), 1.12 (s, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.908min, 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-pyrrolizin-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: tert-butyl (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1- carboxylate

[0294] To a solution of tert-butyl (2R,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (400 mg, 2.00 mmol), benzaldehyde (233.14 mg, 2.20 mmol) and acetic acid (119.94 mg, 2.00 mmol) in methanol (5 mL) was added sodium cyanoborohydride (251.02 mg, 3.99 mmol) at 0 °C, the mixture was stirred at 0 °C for 1 h. Then formaldehyde (486.23 mg, 5.99 mmol, 37% purity in water) was added to the above solution at 0°C, the mixture was stirred at 0 °C for 2 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (2R,3S)-3- (benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 74.01%) as a colorless oil. LCMS Rt = 0.344 min, m / z = 305.2 [M + H]+.Step 2: tert-butyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate

[0295] To a solution of tert-butyl (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1- carboxylate (600 mg, 1.97 mmol) in methanol (6 mL) was added Pd / C (300 mg, 281.9 μmol, 10% purity). The mixture was stirred at 45°C for 12 h under hydrogen (50 Psi). The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo affording tert-butyl (2R,3S)-2- methyl-3-(methylamino)pyrrolidine-1-carboxylate (470 mg, crude) as a yellow oil, used in next step without further purification:1H NMR (400 MHz, Chloroform-d) δ 3.77 - 3.61 (m, 1H), 3.44 - 3.34 (m, 1H), 2.86 - 2.79 (m, 1H), 2.45 - 2.41 (m, 3H), 2.13 - 1.96 (m, 1H), 1.76 - 1.65 (m, 2H), 1.47 - 1.44 (m, 9H), 1.22 (s, 3H). LCMS Rt = 0.280 min, m / z = 215.3 [M + H]+.Step 3: tert-butyl (2R,3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0296] 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) were added N,N-diisopropylethylamine (844.69 mg, 6.54 mmol) and tert-butyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (443.53 mg, 2.07 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (2R,3S)-3-((2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (780 mg, 82.37%) as a yellow solid:1H NMR (400 MHz, Chloroform-d) δ 9.09 - 8.91 (m, 1H), 5.21 - 5.05 (m, 1H), 4.08 - 3.89 (m, 1H), 3.88 - 3.70 (m, 1H), 3.54 - 3.47 (m, 1H), 3.47 - 3.44 (m, 3H), 2.52 - 2.38 (m, 1H), 2.17 - 2.07 (m, 1H), 1.52 - 1.47 (m, 9H), 1.43 - 1.35 (m, 3H). LCMS Rt = 0.585 min, m / z = 430.1 / 431.0 [M + H]+.Step 4: tert-butyl (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-carboxylate

[0297] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (794 mg, 79.11%) as a white solid:1H 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: tert-butyl (2R,3S)-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-methylpyrrolidine-1- carboxylate

[0298] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (2R,3S)-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-methylpyrrolidine-1- carboxylate (500 mg, 65.60%) as an orange solid:1H NMR (400 MHz, Chloroform-d) δ 9.30 - 9.11 (m, 1H), 7.97 - 7.89 (m, 2H), 7.62 - 7.52 (m, 2H), 7.34 (t, J = 8.8 Hz, 1H), 5.27 - 5.04 (m, 1H), 4.10 - 3.71 (m, 4H), 3.58 - 3.43 (m, 3H), 3.43 - 3.38 (m, 2H), 3.31 - 3.22 (m, 2H), 3.18 - 2.87 (m, 2H), 2.55 - 2.34 (m, 3H), 2.11 (s, 4H), 2.02 - 1.96 (m, 1H), 1.54 - 1.52 (m, 3H), 1.51 - 1.50 (m,9H), 1.20 (s, 3H), 0.92 - 0.84 (m, 18H). LCMS Rt = 0.628 min, m / z = 843.4 [M + H]+.Step 6: tert-butyl (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-carboxylate

[0299] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was concentrated in vacuo affording tert-butyl (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-carboxylate (366 mg, crude) as a yellow solid:1H NMR (400 MHz, Chloroform-d) δ 9.14 - 9.09 (m, 1H), 8.00 - 7.92 (m, 2H), 7.65 - 7.56 (m, 2H), 7.37 - 7.32 (m, 1H), 5.40 - 5.21 (m, 1H), 5.11 - 5.00 (m, 1H), 4.29 - 4.18 (m, 1H), 4.07 - 3.71 (m, 3H), 3.44 - 3.40 (m, 3H), 3.25 (s, 3H), 3.19 (s, 2H), 3.00 (d, J = 5.4 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.32 - 2.26 (m, 1H), 2.23 - 2.13 (m, 3H), 1.99 - 1.90 (m, 3H), 1.50 (s, 9H), 1.21 (d, J = 6.8 Hz, 3H). LCMS 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

[0300] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 (90 mg, crude, hydrochloride) as a yellow solid, used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0301] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (34.94 mg, 34.26%) as a yellow amorphous solid: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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.055 min, 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-pyrrolizin-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: tert-butyl (2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1- carboxylate

[0302] The reductive amination was prepared in a similar fashion 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 sulphate and concentrated in vacuo affording tert-butyl (2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate (400 mg, crude) as a yellow oil, used in next step without any further purification. LCMS Rt = 0.339 min, m / z = 305.3 [M + H]+.Step 2: tert-butyl (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate

[0303] The debenzylation reaction was prepared in a similar fashion to Method #2, Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo affording tert-butyl (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (250 mg, crude) as a yellow oil, used in next step without any further purification.Step 3: tert-butyl (2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0304] The substitution reaction was prepared in a similar fashion to Method #2, Step 3. The reaction mixture was concentrated to dryness in vacuo affording tert-butyl (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, used in next step without any further purification. LCMS Rt = 0.583 min, m / z = 430.1 / 432.0 [M + H]+.Step 4: tert-butyl (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-carboxylate

[0305] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (200 mg, 62.25%) as a yellow solid. LCMS Rt = 0.421 min, m / z = 553.3 / 555.2 [M + H]+.Step 5: tert-butyl (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-methylpyrrolidine-1- carboxylate

[0306] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The reaction mixture was concentrated to dryness in vacuo affording tert-butyl (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-methylpyrrolidine- 1-carboxylate (280 mg, crude) as a brown oil, used in next step without any further purification. LCMS Rt = 0.646 min, m / z = 843.5 [M + H]+.Step 6: tert-butyl (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-carboxylate

[0307] The deprotection of TIPS group was prepared in a similar fashion to Method #2, Step 6. The reaction mixture was concentrated in vacuo affording tert-butyl (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-carboxylate (230 mg, crude) as a brown solid, used in 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

[0308] The Boc deprotection reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 (90 mg, crude, hydrochloride) as a yellow solid, used in 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0309] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-65% B over 8.0 min) affording 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-methylpyrrolidin-1-yl)prop-2-en-1-one (12.41 mg, 97.15%) as a yellow amorphous solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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: 1-(tert-butyl) 2-methyl (R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate

[0310] 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 (R)-4-oxopyrrolidine-1,2-dicarboxylate (24 g, 98.66 mmol) at - 78 °C. The mixture was stirred at 30 °C for 1 h. 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 sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 (250*70mm,15 um);mobile phase: [H2O(0.1%TFA);gradient:30%-65% B over 20.0 min) affording 1-(tert-butyl) 2-methyl (R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylate (3.4g, 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

[0311] To a solution of 1-(tert-butyl) 2-methyl (R)-4-(fluoromethylene)pyrrolidine-1,2- dicarboxylate (3.4 g, 13.11 mmol) in tetrahydrofuran (80 mL) was added lithium aluminium hydride (20.98 mL, 2.5 M in tetrahydrofuran, 52.45 mmol) at 0 °C. The mixture was stirred at 70 °C for 1 h. 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 sulphate and concentrated in vacuo affording (R)-(4-(fluoromethylene)-1- methylpyrrolidin-2-yl)methanol (1.3g, crude) as yellow oil, used in next step without any further purification. LCMS Rt = 0.137 min, m / z = 146.2 [M + H]+.Step 3: tert-butyl (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-carboxylate and tert-butyl (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-carboxylate

[0312] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min) affording tert-butyl (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-carboxylate (550 mg, 35.25%) as a yellow solid. LCMS Rt = 1.397 min, m / z = 539.2 / 541.2 [M + H]+.

[0313] The diastereomeric mixture of Z- and E- alkenes (550 mg) were separated by SFC to give arbitrarily assigned: tert-butyl (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-carboxylate (Peak 2, retention time = 1.618 min) (200 mg, 11.83%) as a yellow solid. LCMS Rt = 1.397 min, m / z = 539.2 / 541.2 [M + H]+; and tert-butyl (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,E)-4-(fluoromethylene)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (Peak 1, retention time = 1.411 min) (360 mg, 21.29%) as a yellow solid. LCMS Rt = 1.397 min, m / z = 539.2 / 541.2 [M + H]+. SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [CO2- EtOH(0.1%NH3H2O)]; B%:50%, isocratic elution mode).Step 4: tert-butyl (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-carboxylate

[0314] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate inpetroleum ether) affording tert-butyl (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-carboxylate (380 mg, 79.69%) as a yellow solid. LCMS Rt = 0.594 min, m / z = 829.4 [M + H]+.Step 5: tert-butyl (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-carboxylate

[0315] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was concentrated in vacuo affording tert-butyl (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-carboxylate (120 mg, crude) as a yellow solid, used in next step without any further purification. LCMS Rt = 0.439Step 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

[0316] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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, used in 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

[0317] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%-65% B over 8.0 min) affording 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:1H NMR (400 MHz, Acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.09 (m, 2H), 7.69 (d, J = 4.5 Hz, 2H), 7.48 (t, J = 9.0 Hz, 1H), 6.83 - 6.53 (m, 2H), 6.36 - 6.21 (m, 1H), 5.77 - 5.63 (m, 1H), 5.08 - 4.82 (m, 2H), 4.62 - 4.33 (m, 2H), 3.94 - 3.67 (m, 1H), 3.63 (d, J = 4.3 Hz, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.28 (s, 1H), 2.90 (dd, J = 2.5, 10.0 Hz, 1H), 2.83 - 2.71 (m, 2H), 2.69 - 2.44 (m, 2H), 2.41 (s, 3H), 2.40 - 2.20 (m, 2H), 1.21 - 1.02 (m, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) retention time 2.986 min, ESI+ found [M+H]+= 627.3.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: tert-butyl (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-carboxylate

[0318] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:45%-85% B over 8.0 min) affording tert-butyl (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-carboxylate (200 mg, 72.24%, trifluoroacetic salt) as a yellow solid. LCMS Rt = 2.324 min, m / z = 829.4 [M + H]+.Step 2: tert-butyl (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

[0319] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was concentrated in vacuo affording tert-butyl (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, used in 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

[0320] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 salt) as a yellow oil, used in 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

[0321] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) affording 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:1H NMR (400 MHz, Acetonitrile-d3) δ 9.26 (s, 1H), 8.25 - 8.06 (m, 2H), 7.70 (d, J = 4.8 Hz, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.73 - 6.42 (m, 2H), 6.34 - 6.22 (m, 1H), 5.77 - 5.61 (m, 1H), 5.01 - 4.81 (m, 2H), 4.65 - 4.36 (m, 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 - 2.75 (m, 1H), 2.70 - 2.49 (m, 2H), 2.43 (s, 3H), 2.41 - 2.32 (m, 2H), 1.21 - 1.04 (m, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 mins) 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: ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate

[0322] 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 for 1 h under nitrogen atmosphere. 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 sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (5.45 g, 46.94%) as a yellow oil:1H NMR (400 MHz, Chloroform-d) δ 4.29 (d, J = 14.5 Hz, 1H), 4.16 (q, J = 7.1Hz, 2H), 3.67 (d, J = 14.1Hz, 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, 13.1Hz, 1H), 2.48 - 2.27 (m, 2H), 2.07 (td, J = 10.1, 13.2 Hz, 1H), 1.22 (t, J = 7.1Hz, 3H). LCMS Rt = 0.394 min, m / z = 246.4 [M + H]+.Step 2: (2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0323] The solution of ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (5 g, 20.39 mmol) in tetrahydrofuran (50 mL) was added diisobutylaluminium hydride (203.90 mL, 20.39 mmol, 1 M in toluene) at 0 °C, the reaction solution stirred at 25 °C for 1 h under nitrogen atmosphere. 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 affording (2-(difluoromethylene)tetrahydro-1H-pyrrolizin-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: tert-butyl (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-carboxylate

[0324] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (310 mg, 45.76%) as a yellow oil. LCMS Rt = 0.419 min, m / z = 583.2 / 585.1 [M + H]+.Step 4: tert-butyl (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-carboxylate

[0325] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (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-carboxylate (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

[0326] The deprotection of Boc reaction was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 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 (50 mg, crude, hydrochloride) as a yellow oil, used in 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

[0327] The deprotection of TIPS group was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was concentrated in vacuo affording 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, used in 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

[0328] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The resulting residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-75% B over 8.0 min) affording 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 (10.57 mg, 23.91%) as a yellow solid:1H 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, 1H), 2.73 - 2.60 (m, 2H), 2.48 - 2.34 (m, 2H), 2.11 (s, 1H), 2.09 - 2.01 (m, 1H), 1.94 - 1.77 (m, 4H), 1.19 - 1.03 (m, 3H). LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 mins) retention time 2.494 min, ESI+ found [M+H]+= 671.2.Examples 32 & 33: Synthesis of Compounds 14-2 and 14-3; 1-((2R,3R)-3-((2-(((S)-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 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)

[0329] The mixture of diastereomers (50 mg) of 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 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1% NH3H2O)];B%:40%, isocratic elution mode) to give arbitrarily assigned: Example 32: 1-((2R,3R)-3-((2-(((S)-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 (Peak 1, retention time = 0.626 min) (20.16 mg, 48.89%) as a white solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.111 min, ESI+ found [M+H]+= 671.3; and Example 33: 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 (Peak 2, retention time = 0.733 min) (19.62 mg, 47.44%) as a white solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-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: ethyl (E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate and ethyl (Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate

[0330] 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 h. Then ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (23 g, 108.89 mmol) was added to the above solution at -78 °C. The mixture was stirred at -78°C for 1.5 h under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride (100 mL) at 0°C and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*150mm*15um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:20%-50% B over 20.0 min) affording ethyl (E)-2-(fluoromethylene)-5- oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (700 mg, 2.83%) as a yellow oil:1H NMR (400 MHz, Chloroform-d) δ 6.70 - 6.45 (m, 1H), 4.40 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 7.1Hz, 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]+.ethyl (Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (700 mg, 2.83%) as a yellow oil:1H 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, 7.1Hz, 3H). LCMS Rt = 1.436 min, m / z = 228.2 [M + H]+.Step 2: (E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0331] 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 hydride (1.72 mL, 4.29 mmol, 2.5 M in tetrahydrofuran) at 0 °C under nitrogen atmosphere. The mixture was stirred at 70 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with sodium sulfate decahydrate (14.20 g) at 0 °C and dried over sodium sulphate. The resulting precipitate was filtered and the filtrate was concentrated in vacuo affording (E)-(2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (550 mg, crude) as a yellow oil, used into the next step without further purification. LCMS Rt = 0.284 min, m / z = 172.3 [M + H]+.Step 3: tert-butyl (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-carboxylate

[0332] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min) affording tert-butyl (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-carboxylate (250 mg, 18.91%, trifluoroacetic salt) as a yellow solid. LCMS Rt = 0.409 min, m / z = 565.3 / 567.3 [M + H]+.Step 4: tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((E)-2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylate

[0333] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:65%-95% B over 8.0 min) affording tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylate (100 mg, 33.04%) as a yellow solid. LCMS Rt = 0.620 min, m / z = 855.4 [M + H]+.Step 5: tert-butyl (2R,3R)-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

[0334] The deprotection of TIPS was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was filtered and the filtrate was concentrated in vacuo affording tert-butyl (2R,3R)-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 used into 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-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0335] The deprotection of Boc was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8- fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-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, used into 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0336] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-70% B over 8.0 min) affording 1-((2R,3R)-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-methylpyrrolidin-1-yl)prop-2-en-1-one (3.31 mg, 9.34%) was obtained as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) 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-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: (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0337] To a solution of ethyl (Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (740 mg, 3.26 mmol) in tetrahydrofuran (6 mL) was added lithium aluminum hydride (1.95 mL, 4.88 mmol, 2.5 M in tetrahydrofuran) at 0°C under nitrogen atmosphere. The mixture was stirred at 70°C for 2 h under nitrogen atmosphere. The reaction mixture was quenched with sodium sulfate decahydrate (1 g) at 0°C and dried over sodium sulphate. The resulting precipitate was filtered and concentrated in vacuo affording (Z)-(2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol (600 mg, crude) as a yellow oil, used into the next step without further purification:1H 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: tert-butyl (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-carboxylate

[0338] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 250*50mm*15um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 10.0 min) affording tert-butyl (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-carboxylate (350 mg, 36.96%, trifluoroacetic salt) as a yellow solid. LCMS Rt = 0.401 min, m / z = 565.3 / 567.3 [M + H]+.Step 3: tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((Z)-2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylate

[0339] The Suzuki reaction was prepared in a similar fashion to Method #1, Step 5. The residue was purified by reverse phase HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:45%-75% B over 8.0 min) affording tert-butyl (2R,3R)- 3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((Z)-2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (110 mg, 18.32%, trifluoroacetic salt) as a yellow solid:1H 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 - 1.86 (m, 7H), 1.79 - 1.64 (m, 1H), 1.48 - 1.38 (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: tert-butyl (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-carboxylate

[0340] The deprotection of TIPS was prepared in a similar fashion to Method #1, Step 6. The reaction mixture was filtered and concentrated in vacuo affording tert-butyl (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- carboxylate (16 mg, crude) as a white solid, used into 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-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0341] The deprotection of Boc was prepared in a similar fashion to Method #1, Step 7. The reaction mixture was concentrated in vacuo affording 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8- fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-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, used into 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0342] The acylation reaction was prepared in a similar fashion to Method #1, Step 8. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-65% B over 8.0 min) affording 1-((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-methylpyrrolidin-1-yl)prop-2-en-1-one (2.87 mg, 18.62%) as a white solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.036 min, ESI+ found [M+H]+= 653.3.Examples 36 & 37: Synthesis of two of Compounds 15-3 to 15-6 (Method 1)

[0343] The mixture of diastereomers (30 mg) of 1-((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-methylpyrrolidin-1-yl)prop-2-en-1- one was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1% NH3H2O)]; B%:35%, isocratic elution mode) to give arbitrarily assigned: Example 36: (Peak 1, retention time = 1.244 min) (8.85 mg, 29.13%) as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.054 min, ESI+ found [M+H]+= 653.3; and Example 37: (Peak 2, retention time = 1.339 min) (8.85 mg, 29.13%) as a yellow solid:1H 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 in water + 0.03% ammonium bicarbonate over 6 mins) retention time 3.052 min, 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-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: tert-butyl (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-carboxylate

[0344] The substitution reaction was prepared in a similar fashion to Method #1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% tetrahydrofuran in ethyl acetate) affording tert-butyl (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-carboxylate (550 mg, 86.52%) as a yellow oil. LCMS Rt = 0.413 min, m / z = 547.3 / 549.3 [M + H]+.Step 2: tert-butyl (2R,3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin- 7a(5H)...

Claims

Claims What is claimed is:

1. A compound of Formula (I):Formula (I), or a salt thereof, and / or an isotopologue thereof; wherein: X is -N(CH3)- or -O-; X1is -CH3, -CH2CH3, -CH=CH2, or cyclopropyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, and -OCH3; q is 0 or 1; R1is a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring atoms, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 R1A; R1Ain each instance is independently selected from the group consisting of halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and -C(O)(C1-C4alkyl); or two geminal R1A, together with the carbon atom to which they are attached, form C3-C4cycloalkyl substituted with 0, 1, or 2 halo; or two geminal R1Atogether form =CH2, =CHF, or =CF2; Rais H or CH3;R3is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R4is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; R5is H or -OH;Y is CH or N; R6in each instance is independently selected from the group consisting of halo, -OH, C1- C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and r is 0, 1, 2, or 3;.

2. The compound of claim 1, or a salt thereof, and / or an isotopologue thereof, wherein R2is.

3. The compound of claim 2, or a salt thereof, and / or an isotopologue thereof, wherein R3is selected from the group consisting of halo, C1-C4alkyl, and C2-C3alkynyl.

4. The compound of claim 2, or a salt thereof, and / or an isotopologue thereof, wherein R3is selected from the group consisting of –F, –Cl, –Et, –C≡CH, and –C≡C-CH3.

5. The compound of any one of claims 2-4, or a salt thereof, and / or an isotopologue thereof, wherein R4is hydrogen or halo.

6. The compound of any one of claims 2-4, or a salt thereof, and / or an isotopologue thereof, wherein R4is hydrogen or –F.

7. The compound of any one of claims 2-6, or a salt thereof, and / or an isotopologue thereof, wherein R5is -OH.

8. The compound of any one of claims 2-6, or a salt thereof, and / or an isotopologue thereof, wherein R5is H.

9. The compound of claim 2, or a salt thereof, and / or an isotopologue thereof, wherein R2is10. The compound of claim 1, or a salt thereof, and / or an isotopologue thereof, wherein R2is.

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

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

13. The compound of any one of claims 10-12, or a salt thereof, and / or an isotopologue thereof, wherein R6in each instance is independently selected from the group consisting of -Cl, - OH, -CH3, -CF3, cyclopropyl, and -NH2.

14. The compound of any one of claims 10-13, or a salt thereof, and / or an isotopologue thereof, wherein r is 3.

15. The compound of any one of claims 10-13, or a salt thereof, and / or an isotopologue thereof, wherein.

16. The compound of any one of claims 10-13, or a salt thereof, and / or an isotopologue thereof, wherein, wherein R6Ais cyclopropyl or -CF3; R6Bis -Cl or -CH3; and R6Cis -OH or -NH2.

17. The compound of claim 10, or a salt thereof, and / or an isotopologue thereof, wherein R2is18. The compound of any one of claims 1-17, or a salt thereof, and / or an isotopologue thereof, wherein X is -N(CH3)-.

19. The compound of any one of claims 1-17, or a salt thereof, and / or an isotopologue thereof, wherein X is -O-.

20. The compound of any one of claims 1-19, or a salt thereof, and / or an isotopologue thereof, wherein X1is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl.

21. The compound of any one of claims 1-19, or a salt thereof, and / or an isotopologue thereof, wherein X1is -CH3.

22. The compound of any one of claims 1-17, or a salt thereof, and / or an isotopologue thereof,23. The compound of any one of claims 1-17, or a salt thereof, and / or an isotopologue thereof,24. The compound of any one of claims 1-23, or a salt thereof, and / or an isotopologue thereof,wherein25. The compound of any one of claims 1-24, or a salt thereof, and / or an isotopologue thereof, wherein R1Ain each instance is independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or - C(O)CH3; or two geminial R1A, together with the carbon atom to which they are attached, form cyclopropyl substituted with 0, 1, or 2 fluoro; or two geminal R1Atogether form =CH2, =CHF, or =CF2.

26. The compound of any one of claims 1-25, or a salt thereof, and / or an isotopologue thereof,27. The compound of any one of claims 1-25, or a salt thereof, and / or an isotopologue thereof,28. The compound of any one of claims 1-27, wherein Rais H.

29. The compound of any one of claims 1-27, wherein Rais CH3.

30. The compound of claim 1, or a salt thereof, and / or an isotopologue thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

31. The compound of any one of claims 1-30, or a salt thereof, and / or an isotopologue thereof, wherein the salt is a formate salt.

32. The compound of any one of claims 1-31, or a salt thereof, and / or an isotopologue thereof, wherein the salt is a pharmaceutically acceptable salt.

33. A pharmaceutical formulation comprising the compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, and a pharmaceutically acceptable carrier.

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

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

36. The method of claim 34, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uvealmelanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

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

38. The method of any one of claims 34 to 36, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.

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

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

41. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to claim 33, for use in treating or suppressing cancer in a subject in need thereof, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

43. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of claim 41, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladderurothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

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

45. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 41-43, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.

46. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 40-45, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

47. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 40-46, wherein the compound or pharmaceutical formulation is configured for administration in a therapeutically effective amount.

48. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to claim 33, for use in the manufacturing of a medicament for treating or suppressing cancer in a subject in need thereof.

49. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of claim 48, wherein the cancer is selected from thegroup consisting of: lung, colorectal, pancreatic, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.

50. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of claim 48, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

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

52. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 48-50, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.

53. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 48-52, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

54. The compound, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or pharmaceutical formulation for use of any one of claims 48-53, wherein the medicament comprises a therapeutically effective amount of the compound or composition.

55. Use of a compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof, or a pharmaceutical formulation according to claim 33 in the manufacturing of a medicament for treating or suppressing cancer in a subject in need thereof.

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

57. The use of claim 55, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

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

59. The use of any one of claims 55-57, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.

60. The use of any one of claims 55-59, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

61. The use of any one of claims 55-60, wherein the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

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

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

64. The use of claim 62, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

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

66. The use of any one of claims 62-64, wherein the subject has been diagnosed as having a KRAS G12C mediated cancer.

67. The use of any one of claims 62-66, wherein the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

68. The use of any one of claims 62-67, wherein the use involves a therapeutically effective amount of the compound or composition.

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