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

Abstract

The present disclosure provides compounds of formula (I) that are useful in the treatment and inhibition of cancer, for example, in the treatment or inhibition of cancer characterized by KRAS G12C. Pharmaceutical formulations containing such compounds and processes for preparing such compounds are also provided. Formula (I).

Description

Cross Reference to Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 464,191, filed May 4, 2023, and U.S. Provisional Patent Application No. 63 / 615,742, filed December 28, 2023, the disclosures of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD

[0002] The present disclosure provides compounds useful for treating or inhibiting cancer, and in particular, for treating or inhibiting cancer characterized by KRAS G12C mutants. Also provided are pharmaceutical formulations containing such compounds, methods for making such compounds, and methods of using such compounds to treat or inhibit cancer. 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, GDP is exchanged for guanosine triphosphate (GTP) in a process facilitated by guanine nucleotide exchange factors (GEFs) such as SOS. The GTP-bound form of KRAS is in the “on state” and interacts with proteins such as RAF and PI3K to facilitate downstream signaling that leads to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP in a process facilitated by GAP (GTPase-activating protein), thereby returning to the off state.

[0004] KRAS mutations are found in approximately 30% of all human cancers and are extremely prevalent in three of the most deadly forms of cancer: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%). Overall, in the United States alone, more than 200,000 patients develop these cancers each year. One particular mutation, a glycine-to-cysteine substitution at position 12 (G12C), occurs in more than 40,000 patients each year. The KRAS G12C mutation disrupts the hydrolysis of GTP to GDP, thereby trapping KRAS in the on state and facilitating cancer cell proliferation.

[0005] The cysteine residue of G12C offers 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 data for colorectal cancer (CRC) are less compelling. Moreover, even in cases where patients respond to initial therapy, there are indications that the duration of response can be limited and that resistance can emerge rapidly.

[0006] Most inhibitors of KRAS mutants preferentially bind to the GDP-bound form of the protein. For example, the Amgen KRAS inhibitor AMG 510 and the Mirati KRAS inhibitor MRTX849 react at least 1000-fold faster with the GDP-bound form of KRAS G12C than with the GTP-bound form of the protein. One form of resistance that has been observed is that cancer cells increase signaling via RTKs, thereby increasing the amount of GTP-bound KRAS, which is less affected by current inhibitors. Thus, molecules that can bind and inhibit both the GDP-bound and GTP-bound forms of KRAS can have substantial utility.

[0007] What is needed are compounds that can be used to treat cancer, e.g., cancer characterized by KRAS G12C. Further needed are compounds that can be used to treat cancer characterized by KRAS G12C, wherein the compounds bind and inhibit both the inactive GDP-bound form and the active GTP-bound form of KRAS. Further needed are compounds that can be used to treat cancer characterized by KRAS G12C, wherein the compounds have improved inhibition of the GTP-bound form of KRAS G12C. SUMMARY

[0008] In one aspect, the present application provides a compound of Formula (I):

[0009] Formula (I),

[0010] or salts and / or isotopologues thereof; wherein:

[0011] X is -N(CH3)- or -0-;

[0012] X 1 -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;

[0013] q is 0 or 1;

[0014] R 1 is a 4-8 membered saturated heterocyclyl comprising one nitrogen as the sole heteroatom within the ring; wherein the heterocyclyl is substituted with 0, 1, 2, or 3 R 1A substituents;

[0015] R 1A is independently selected at each occurrence from the group consisting of halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl); or two geminal R1A Together with the carbon atom to which it is attached, it forms a C3-C4 cycloalkyl group substituted with 0, 1, or 2 halogen groups; or two twin R groups. 1A Together they form =CH2, =CHF, or =CF2;

[0016] R a It is H or CH3;

[0017] R 2 for or ;

[0018] R 3 It is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl;

[0019] R 4 It is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl;

[0020] R 5 It is H or -OH;

[0021] Y is either CH or N;

[0022] R 6 In each case, the group consisting of free halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, and -NH2 is selected independently; and

[0023] r can be 0, 1, 2, or 3;

[0024] The condition is that when q is 0, then R 1 Not for , , , , , or any of its enantiomers; when for or When R is any of its enantiomers, then 2 Not for ; and when for When R is any of its enantiomers, then 2 Not for or .

[0025] In some embodiments, including any of the embodiments in the preceding paragraph, the compound is selected from the group consisting of the compounds of Table 1, and all salts and isotopologues thereof.

[0026] In another aspect, a pharmaceutical formulation comprising a compound as described herein, including but not limited to a compound described in the preceding paragraph, and a pharmaceutically acceptable carrier, is provided, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0027] In another aspect, a method of treating or inhibiting cancer is provided, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including but not limited to a compound described in the preceding paragraph, or a pharmaceutical formulation, including but not limited to a pharmaceutical formulation described in the preceding paragraph, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In some embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In some embodiments, the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In some embodiments, including any of the preceding embodiments, the method is for treating cancer. In some embodiments, including any of the preceding embodiments, the method is for inhibiting cancer. In some embodiments, including any of the preceding embodiments, the cancer is a KRAS G12C-mediated cancer. In some embodiments, including any of the preceding embodiments, the subject has been diagnosed with 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.

[0028] In another aspect, uses of compounds as described herein, including but not limited to any of the foregoing embodiments, as a medicament are provided. In another aspect are uses of compounds as described herein, including but not limited to any of the foregoing embodiments, for treating or inhibiting cancer. In another aspect are uses of compounds as described herein, including but not limited to any of the foregoing embodiments, for the manufacture of a medicament for treating or inhibiting cancer. In some embodiments, including any of the foregoing embodiments, the use is for treating cancer. In some embodiments, including any of the foregoing embodiments, the use is for inhibiting cancer.

[0029] In another aspect, uses of compounds as described herein, including but not limited to any of the foregoing embodiments, as a medicament are provided. In another aspect are uses of compounds as described herein, including but not limited to any of the foregoing embodiments, for treating or inhibiting cancer. In another aspect are uses of compounds as described herein, including but not limited to any of the foregoing embodiments, for the manufacture of a medicament for treating or inhibiting cancer. In some embodiments, including any of the foregoing embodiments, the use is for treating cancer. In some embodiments, including any of the foregoing embodiments, the use is for inhibiting cancer.

[0030] It is understood that the descriptions 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 for all methods using compositions described herein, the compositions can comprise the recited components or steps, or can “consist essentially of the recited components or steps. When a composition is described as “consisting essentially of the recited components, the composition contains the recited components and can contain additional components that do not substantially affect the treated condition, but is free of any additional components that materially affect the treated condition; or, if the composition does contain additional components other than those recited that do materially affect the treated condition, the composition is free of additional components in a sufficient amount or quantity to materially affect the treated condition. When a method is described as “consisting essentially of the recited steps, the method contains the recited steps and can contain additional steps that do not substantially affect the treated condition, but the method is free of any additional steps that materially affect the treated condition. As a non-limiting specific example, when a composition is described as “consisting essentially of components, the composition can additionally contain any amount of a pharmaceutically acceptable carrier, vehicle, or diluent and other such components that do not substantially affect the treated condition.

[0031] Additional embodiments, features and advantages of the present disclosure will be apparent from the following detailed description and will be readily apparent to those skilled in the art by practice of the present disclosure. DETAILED DESCRIPTION

[0032] Provided herein are compounds useful for treating cancer, and methods of using such compounds to treat cancer. In some embodiments, the compounds are useful for treating cancers characterized by KRAS G12C. In some embodiments, the compounds advantageously inhibit both the inactive GDP-bound form and the activated GTP-bound form of KRAS G12C. In some embodiments, the compounds advantageously have improved inhibition of the GTP-bound form of KRAS G12C.

[0033] Definitions

[0034] As used herein, the abbreviations used are those conventional in the chemical and biological arts.

[0035] It is understood that the description of the structure of the compounds, including possible substitutions, is limited to those that are chemically possible.

[0036] Unless otherwise indicated, the absolute stereochemistry is as depicted. The “Example” column of Table 1 indicates the number of the synthesis example that corresponds to the structure provided in the same row of Table 1. A set of compounds each having the absolute stereochemistry in Table 1 can have multiple example numbers designated in the “Example” column. In such cases, each of the designated examples produces only one of those compounds. However, the absolute stereochemistry of the compounds has not been determined. For example, compounds 7-2 and 7-3 in Table 1 have “22 or 23” indicated in the “Example” column, meaning that only one of compounds 7-2 and 7-3 was obtained from Example 22 and only the other compound was obtained from Example 23. As another example, compounds 15-3, 15-4, 15-5, and 15-6 in Table 1 have “36 or 37” indicated in the “Example” column, meaning that only one of the four compounds was obtained from Example 36 and only one of the other three compounds was obtained from Example 37.

[0037] Compounds having (and) indicated in the stereochemistry column of Table 1 are mixtures of enantiomers, with the relative stereochemistry as shown. Compounds having a stereogenic center (where the configuration is not indicated in the depicted structure) and no indication in the stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds having a stereogenic center (where the configuration is indicated by a bold wedge or a hashed wedge in the structure) and no indication or labeled (abs) in the stereochemistry column of Table 1 are single enantiomers, with the absolute stereochemistry as indicated.

[0038] For example, compound 7-2 It is a single enantiomer having the stereochemistry indicated.

[0039] Bold or scattered non-wedge (i.e., rectangular) bonds in a compound indicate that the compound is a mixture of different diastereomers having a fixed cis or trans configuration.

[0040] For example, compound 7-1 Compound 7-2 and A mixture of 7-3.

[0041] In some cases, the stereochemistry column in Table 1 contains selections from ( abs )and( and Different indicators are used to refer to different stereocenters or stereocenter pairs of molecules.

[0042] For example, compound 27-1 "Amino-pyrrolidine- ( abs ")" indicates that the amino-pyrrolyl head group of the compound has the depicted (R,R) configuration; and "R" indicates that the compound has an amino-pyrrolyl head group with ... 1 - ( and ")" indicates the R of the compound 1 The group has (R) or (S) stereochemistry, such that the compound obtained from Example 55 is compound 27-2. With 27-3 A mixture.

[0043] Those skilled in the art will be able to separate racemic compounds into their respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization, etc. The reference to compounds as racemic mixtures is intended to also include individual enantiomers contained within the mixture.

[0044] In this document, reference to “about” includes (and describes) variations with respect to said value or parameter itself. For example, a reference to “about X” includes a description of “X”. As used herein, and unless otherwise stated, the terms “about” and “approximately” when used in conjunction with temperature, dosage, amount, or weight percentage of an ingredient in a composition or dosage form mean a dosage, amount, or weight percentage that a person skilled in the art would consider to provide a pharmacological effect equivalent to that obtained from a specified dosage, amount, or weight percentage. Specifically, the terms “about” and “approximately”, when used in this context, are contemplated to be within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dosage, amount, or weight percentage.

[0045] The terms "a" and "an," as used herein, mean one or more, unless otherwise indicated.

[0046] 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 as having a cancer or tumor with a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).

[0047] "Treatment" of a disorder with the compounds and methods discussed herein is defined as administering one or more compounds discussed herein, with or without additional therapeutic agents, to reduce or eliminate the disorder or one or more symptoms of the disorder, or to delay progression of the disorder or one or more symptoms of the disorder, or to reduce the severity of the disorder or one or more symptoms of the disorder.

[0048] "Inhibition" of a disorder with the compounds and methods discussed herein is defined as administering one or more compounds discussed herein, with or without additional therapeutic agents, to inhibit the clinical manifestations of the disorder, or to inhibit the manifestations of adverse symptoms of the disorder. The distinction between treatment and inhibition is that treatment occurs after the adverse symptoms of the disorder are manifested in a subject, while inhibition occurs before the adverse symptoms of the disorder are manifested in a subject. Inhibition can be partial, substantially complete, or complete. In some embodiments, genetic screening can be used to identify patients at risk for a disorder. Asymptomatic patients at risk of developing clinical symptoms of a disorder can then be administered the compounds and methods disclosed herein to inhibit the appearance of any adverse symptoms.

[0049] A "therapeutic use" of a compound discussed herein is defined as using one or more compounds discussed herein to treat or inhibit a disorder as defined herein. A "therapeutically effective amount" of a compound is an amount of a compound that, when administered to a subject, is sufficient to reduce or eliminate a disorder or one or more symptoms of a disorder, or to delay progression of a disorder or one or more symptoms of a disorder, or to reduce the severity of a disorder or one or more symptoms of a disorder, or to inhibit the clinical manifestations of a disorder, or to inhibit the manifestations of adverse symptoms of a disorder. A therapeutically effective amount can be given in one or more administrations.

[0050] "KRAS G12C-mediated cancer" is used interchangeably herein with "cancer characterized by KRAS G12C" and indicates that the cancer comprises cells containing a KRAS G12C mutant.

[0051] While the compounds described herein can exist and be used in neutral (non- salt) form, the description is intended to cover all salts of compounds described herein and methods of using such salts of compounds. In some embodiments, salts of compounds include pharmaceutically acceptable salts.

[0052] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that retains at least some of the desired pharmacological activities of the parent compound. Such salts include: (a) acid addition salts, formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids, e.g., 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-ethane- disulfonic 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-l-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 is found in S. M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference in its entirety. Remington's Pharmaceutical Sciences , 17th Ed., Mack Publishing Company, Easton, PA, 1985, incorporated herein by reference in its entirety.

[0053] When chemically relevant, all stereoisomers, including diastereomers and enantiomers, of the compounds are included herein. Also included are mixtures of the possible stereoisomers in any ratio, including but not limited to racemic mixtures. Unless otherwise specifically indicated, structures are intended to encompass all possible stereoisomers of the depicted compounds. If the stereochemistry of one or more portions of the molecule is explicitly indicated, the structure is intended to encompass all possible stereoisomers of the portions for which stereochemistry is not explicitly indicated.

[0054] An "isotopologue" herein refers to a compound having an isotopic composition that is different from its "natural" isotopic composition. "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. An atom containing its natural isotopic composition can also be referred to herein as a "non-enriched" atom. Unless otherwise specified, atoms of a compound recited herein are intended to represent any stable isotope of that atom. For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural isotopic composition. Descriptions herein of compounds also include all isotopologues of all compounds herein, in some embodiments partially deuterated or perdeuterated analogs. "Isotopically enriched" can also refer to a compound in which the isotopic composition of at least one atom contained therein is different from the natural isotopic composition of that atom. "Isotopically enriched" refers to the percentage of the natural isotopic abundance of a given atom that is replaced by incorporation of a certain isotope at that atom in a molecule. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the indicated position. Since the naturally occurring distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. Isotopic enrichment of compounds provided herein can be determined using routine analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0055] "Alkyl" means a straight chain, branched or a combination thereof, saturated monovalent hydrocarbon group having the specified number of carbons. For example, C1-C4 alkyl includes, for example, methyl, ethyl, propyl, 2-propyl, butyl, and the like.

[0056] "Alkylene" means a straight chain, branched or a combination thereof, saturated divalent hydrocarbon group having the specified number of carbons. For example, C1-C4 alkylene includes, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and the like.

[0057] "Alkenyl" means a straight chain or branched monovalent hydrocarbon group containing one or more double bonds and having the specified number of carbons. For example, C2-C4 alkenyl includes, for example, ethenyl, prop-1-en-2-yl, prop-1-en-1-yl, allyl, and the like.

[0058] "Alkynyl" means a straight chain or branched monovalent hydrocarbon group containing one or more triple bonds and having the specified number of carbons. For example, C2-C4 alkynyl includes, for example, ethynyl, propynyl, 2-propynyl, butynyl, and the like.

[0059] "Alkoxy" means the group -OR x where R x is an alkyl group as defined above, or -R x 'ORx "Group, wherein R x ' is alkylene and R x " is alkyl as defined above, wherein the fixed number of alkyl carbons in the alkoxy group equals the total number of carbons in R x ' and R x ". For example, C1-C4 alkoxy indicates, for example, methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, isobutoxy, t-butoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, the alkoxy group is -OR x group. In some embodiments, the alkoxy group is -R x OR x group. In some embodiments, when the nitrogen is substituted with an alkoxy group, the alkoxy group is not attached to the nitrogen via an oxygen or a carbon immediately adjacent to the oxygen in the alkoxy group. For example, a nitrogen substituted with an alkoxy group is not N-OR x or N-CH2-O-R x ".

[0060] "Alkoxyalkoxy" means -OR y group, wherein R y is an alkoxy group as defined above, provided that the point of attachment of R y is not an oxygen atom, or -R y OR y group, wherein R y ' is alkylene and R y " is an alkoxy group as defined above, provided that the point of attachment of R y " is not an oxygen atom, wherein the fixed number of alkyl carbons in the alkoxyalkoxy group equals the total number of carbons in R y ' and R y ". For example, C1-C6 alkoxyalkoxy indicates, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, and the like. In some embodiments, the alkoxyalkoxy group is -OR y group. In some embodiments, the alkoxyalkoxy group is -R y OR y group. In some embodiments, when the nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not attached to the nitrogen via an oxygen or a carbon immediately adjacent to the oxygen in the alkoxyalkoxy group. For example, a nitrogen substituted with an alkoxyalkoxy group is not N-OR y or N-CH2-O-R y ".

[0061] "Aminoalkyl" means an -NHR z group, wherein R z is alkyl as defined above, or -NR z R z is alkyl as defined above, or -NR z R z is alkyl as defined above, or -NR z "NH2group, wherein R z is alkyl as defined above, or -NR z "NHR z group, wherein R z is alkyl as defined above, and R z is alkyl as defined above, or -NR z "NR z R z is alkyl as defined above, and R z and R z are alkyl as defined above, wherein the specified number of alkyl carbons in the aminoalkyl group equals the total number of carbons in R z , R z , and R z , as applicable. For example, C1-C6 aminoalkyl indicates, for example, -NHCH3, -NHCH2CH3, -NHCH2(CH3)2, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -CH2NH2, -CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and the like. In some embodiments, the aminoalkyl group is -NHR z group. In some embodiments, the aminoalkyl group is -NR z R z group. In some embodiments, the aminoalkyl group is -NR z group. In some embodiments, the aminoalkyl group is -NR z NH2group. In some embodiments, the aminoalkyl group is -NR z "NHR z group. In some embodiments, the aminoalkyl group is -NR z "NR z R z group. In some embodiments, when an oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not attached to the oxygen via the nitrogen or the carbon immediately adjacent to the nitrogen in the aminoalkyl group. For example, an oxygen substituted with an aminoalkyl group is not O-NR z or O-CH2-NHR z .

[0062] "Aryl" refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system that provides 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracene). In some embodiments, "aryl" also includes cyclic systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or connection point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl cyclic system. Exemplary aryl groups include phenyl and naphthyl, wherein the connection point can be on any carbon atom. Exemplary aryl groups also include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc., wherein the connection point is on the phenyl group. In some embodiments, "aryl" does not include cyclic systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups.

[0063] "Cycloalkyl" refers to a monocyclic saturated monovalent hydrocarbon group with a specified number of carbon atoms. For example, C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] "Cycloalkylene" refers to a monocyclic saturated divalent hydrocarbon group with a specified number of carbon atoms. For example, C3-C6 cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0065] "Cyanoalkyl" refers to an alkyl group as defined above, which is replaced by a cyano group (-CN). Cyanoalkyl can also be called alkyl nitrile.

[0066] "Halogen" refers to fluorine, chlorine, bromine, or iodine. In some implementations, the halogen is fluorine or chlorine.

[0067] "Haloalkyl" means an alkyl group as defined above, which is substituted with one or more halogen atoms, such as one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.

[0068] "Haloalkoxy" refers to -OR a' Group, wherein R a' It is a haloalkyl group as defined above, or -R b' OR c' Group, wherein Rb' and R c' is alkyl or haloalkyl as defined above, wherein the specified number of carbon atoms of the alkyl group in haloalkoxy is equal to the total number of carbon atoms in R b' and R c' . Halogen atoms can be present in R b' or R c' or both, provided that at least one of R b' and R c' contains a halogen atom. For example, C1-C4 haloalkoxy indicates, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2, and the like. In some embodiments, the haloalkoxy is -OR a' group. In some embodiments, the haloalkoxy is -R b' OR c' group. When all of the halogen atoms in the haloalkoxy group are fluorine, it can be referred to herein as a fluoroalkoxy group. In some embodiments, when a nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not attached to the nitrogen via oxygen or a carbon immediately adjacent to the oxygen in the haloalkoxy group. For example, a nitrogen substituted with a haloalkoxy group is not N-OR a' or N-C(H) n (X) m -O-R" (wherein X is halogen and n and m are integers, provided that n+m = 2).

[0069] "Heteroalkyl" means an alkyl group as defined above in which one or more carbon atoms in the chain are replaced by a heteroatom, e.g., one to three heteroatoms, such as -CH2-O-CH2-, -CH2- NH-CH2-, -O-, -NH-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-NH-CH2-CH2-, and the like.

[0070] "Heterocyclyl" or "heterocycle" means, unless otherwise specified, a saturated or partially unsaturated ring-like group containing 3-12 ring atoms, of which 1-4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, with the remainder of the ring being C. Sulfur groups can be present as -S- or as -S(O)2-. Unless otherwise specified, heterocyclyl includes monocyclic rings as well as polycyclic rings, including fused, bridged, and spiro rings. "Heterocyclyl" or "heterocycle" also includes ring systems in which a heterocyclyl group as defined above is fused to one or more carbocyclyl groups, in which the point of attachment is on the carbocyclic or heterocyclic ring. In some embodiments, "heterocyclyl" or "heterocycle" also includes ring systems in which a heterocyclyl group as defined above is fused to one or more aryl or heteroaryl groups, in which the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members is continuous through the heterocyclyl ring system. In some embodiments, the heterocyclyl is monocyclic. In some embodiments, the heterocyclyl comprises two fused rings. In some embodiments, the heterocyclyl comprises two spiro rings. In some embodiments, the heterocyclyl comprises a bridged ring system.

[0071] "Carbocyclyl" or "carbocycle" means, unless otherwise specified, a saturated or partially unsaturated ring-like group containing 3-12 ring atoms, of which the ring atoms are C. Unless otherwise specified, carbocyclyl includes monocyclic rings as well as polycyclic rings, including fused, bridged, and spiro rings. In some embodiments, the carbocyclyl is monocyclic. In some embodiments, the carbocyclyl comprises two fused rings. In some embodiments, the carbocyclyl comprises two spiro rings. In some embodiments, the carbocyclyl comprises a bridged ring system.

[0072] Unless otherwise indicated, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms wherein one or more (in some embodiments, one, two, or three) ring atoms are heteroatoms independently selected from N, O, or S, the remaining ring atoms being carbon. In some embodiments, "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclyl rings, wherein the point of attachment is on the heteroaryl ring. In such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system, unless otherwise indicated. In some embodiments, "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not bearing a heteroatom (e.g., 5-indolyl). In some embodiments, "heteroaryl" does not include ring systems in which a heteroaryl ring is fused to a carbocyclic or heterocyclyl ring. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0073] "Spiro" cycloalkyl indicates that the cycloalkyl group is attached to the remainder of the compound via a spiro linkage. A "spiro" cycloalkyl substituent has two points of attachment to the same carbon of the moiety being substituted, thereby forming a spiro connection. For example, a cyclohexyl group substituted with "spiro C3-C4 cycloalkyl" indicates: or .

[0074] As used herein, "in need of treatment" means that a patient is treated by a physician or other caregiver after a disease has been diagnosed or the patient has been determined to be at risk of developing a disease. In some embodiments, the patient has been diagnosed with a KRAS G12C-mediated cancer. In some embodiments, the patient has been determined to be at risk of developing a KRAS G12C-mediated cancer.

[0075] “Administration,” “administer,” and the like, when applied to, for example, a patient, a cell, a tissue, an organ, or a biological fluid, means contacting the subject, cell, tissue, organ, or biological fluid with, for example, a compound of Formula (I), Formula (I’), or Formula (II), or a pharmaceutically acceptable salt and / or isotopologue thereof, a pharmaceutical composition comprising the same, or a diagnostic agent. In the case of a cell, administration includes contacting the agent with the cell (e.g., in vitro or ex vivo), as well as contacting the agent with a fluid, where the fluid is in contact with the cell.

[0076] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes situations where the event or circumstance occurs and situations where it does not.

[0077] “Pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise

[0078] As used herein, the term “disease” is intended to be generally synonymous with, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), as it all reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by distinctive signs and symptoms, and causes a decrease in the quality of life of a human or animal.

[0079] 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 coadministration of these therapeutic agents, in a substantially simultaneous manner, such as in a single capsule or tablet having a fixed ratio of active ingredients or in multiple, separate capsules or tablets for each active ingredient. 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 from the drug combination in treating the condition or disorder described herein.

[0080] Compounds

[0081] Provided herein are compounds of Formula (I). Unless the context requires otherwise, reference herein to “a compound of Formula (I)” or “Formula (I) compound” 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), and the compounds of Table 1. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided. In some embodiments, a compound of Formula (I) is provided as a pharmaceutically acceptable salt form. In some embodiments, a compound of Formula (I) is provided as the corresponding free base (i.e., not as a salt).

[0082] In one aspect, a compound of Formula (I) is provided:

[0083] Formula (I),

[0084] or a salt thereof and / or an isotopolog thereof; wherein:

[0085] X is -N(CH3)- or -O-;

[0086] X 1 -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;

[0087] q is 0 or 1;

[0088] R 1 is a 4-8 membered saturated heterocyclyl ring comprising one nitrogen as the only heteroatom within the ring; wherein the heterocyclyl ring is substituted with 0, 1, 2, or 3 R 1A substituents;

[0089] R 1A is independently selected at each occurrence from the group consisting of halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl); or two geminal R 1Atogether with the carbon atom to which they are attached form C3-C4cycloalkyl substituted with 0, 1, or 2 halo; or two geminal R 1A together form =CH2, =CHF, or =CF2;

[0090] R a is H or CH3;

[0091] R 2 is or ;

[0092] R 3 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl;

[0093] R 4 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl;

[0094] R 5 is H or -OH;

[0095] Y is CH or N;

[0096] R 6 is independently at each occurrence selected from the group consisting of halo, -OH, C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and

[0097] r is 0, 1, 2, or 3.

[0098] In some embodiments, when q is 0, then R 1 is not , , , , , or any enantiomer thereof. In some embodiments, when is or any enantiomer thereof, then R 2 is not . In some embodiments, when is or any enantiomer thereof, then R 2 is not . In some embodiments, when is or any enantiomer thereof, then R 2 is not In some embodiments, when R 1 is or any enantiomer thereof, then R 2 is not or In some embodiments, when is or any enantiomer thereof, then R 2 is not or .

[0099] In some embodiments, R 2 is In some embodiments, R 3 is selected from the group consisting of halo, C1-C4 alkyl, and C2-C3 alkynyl. In some embodiments, R 3 is selected from the group consisting of -F, -Cl, -Et, -CºCH, and -CºC-CH3. In some embodiments, R 4 is hydrogen or halo. In some embodiments, R 4 is hydrogen or -F. In some embodiments, R 5 is -OH. In some embodiments, R 5 is H.

[0100] In some embodiments, R 2 is , , , , , or In some embodiments, R 2 is .

[0101] In some embodiments, R 2 is In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R 6 is independently selected from the group consisting of -Cl, -OH, -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.

[0102] In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 6Ais -Cl or -CH3. In some embodiments, R 6B is -Cl or -CH3. In some embodiments, R 6C is -OH or -NH2.

[0103] In some embodiments, R 2 is , or .

[0104] In some embodiments, X is -N(CH3)-. In some embodiments, X is -O-.

[0105] In some embodiments, X 1 is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl. In some embodiments, X 1 is -CH3.

[0106] In some embodiments, the portion of the compound is , , , , , , , , , or . In some embodiments, the portion of the compound is , , , , , , , , , , , , , , , , , , , , or . In some embodiments, the portion of the compound is or . In some embodiments, the portion of the compound is .

[0107] In some embodiments, R 1 is substituted with 0, 1, 2, or 3 R 1A groups. or In some embodiments, R 1A is, independently at each occurrence, -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3. In some embodiments, two geminal R 1A groups together with the carbon atom to which they are attached form a cyclopropyl group substituted with 0, 1, or 2 fluorines. In some embodiments, two geminal R 1A groups together form =CH2, =CHF, or =CF2.

[0108] In some embodiments, R 1 is , , , , , , , , , , , , , , , , , , , , or In some embodiments, R 1 is , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or . In some embodiments, R 1 is . In some embodiments, R 1 is .

[0109] In some embodiments, R 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or . In some embodiments, R 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0110] In some embodiments, R a is H. In some embodiments, R a is CH3.

[0111] In one embodiment, a compound of Formula (I’)

[0112] Formula (I’)

[0113] or a salt thereof; and / or an isotopologue thereof; wherein:

[0114] R 1 is a 4-8 membered saturated carbocyclyl or heterocyclyl comprising one nitrogen as the sole heteroatom within the ring; wherein the carbocyclyl or the heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl;

[0115] R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; and

[0116] q is 0 or 1 ;

[0117] provided that when q is 0, R 1 is not , , , , , or any enantiomer thereof.

[0118] In one embodiment, the compound is of Formula (IA) or Formula (IB)

[0119] Formula (IA)

[0120] Formula (IB);

[0121] or a salt thereof; and / or an isotopologue thereof, wherein R 1 , R 3 and R 4 are as defined in any of the embodiments described herein.

[0122] In one embodiment, the compound is of Formula (IA).

[0123] In one embodiment, the compound is of Formula (IB).

[0124] In one embodiment, the compound is of Formula (I-a), Formula (I-b), or Formula (I-c):

[0125] Formula (I-a)

[0126] Formula (I-b)

[0127] Formula (I-c)

[0128] or a salt thereof; and / or an isotopologue thereof, wherein R 1 , R 3 and R 4 are as defined in any of the embodiments described herein.

[0129] In one embodiment, the compound is of Formula (I-a).

[0130] In one embodiment, the compound is of Formula (I-b).

[0131] In one embodiment, the compound is of Formula (I-c).

[0132] In an embodiment, the compound is of Formula (I-a-1) or Formula (I-a-2):

[0133] Formula (I-a-1)

[0134] Formula (I-a-2)

[0135] or a salt thereof; and / or an isotopolog thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0136] In an embodiment, the compound is of Formula (I-a-1).

[0137] In an embodiment, the compound is of Formula (I-a-2).

[0138] In an embodiment, the compound is of Formula (IA-a) or Formula (IB-a):

[0139] Formula (IA-a)

[0140] Formula (IB-a)

[0141] or a salt thereof; and / or an isotopolog thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0142] In an embodiment, the compound is of Formula (IA-a).

[0143] In an embodiment, the compound is of Formula (IB-a).

[0144] In an embodiment, the compound is of Formula (IA-a-1), Formula (IA-a-2), Formula (IB-a-1), or Formula (IB-a-2):

[0145] Formula (IA-a-1)

[0146] Formula (IA-a-2)

[0147] Formula (IB-a-1)

[0148] Formula (IB-a-2)

[0149] or its salts; and / or its isotopes, wherein R 1 R 3 and R 4 As defined in any of the embodiments described herein.

[0150] In one embodiment, the compound has the formula (IA-a-1).

[0151] In one embodiment, the compound has the formula (IA-a-2).

[0152] In one embodiment, the compound has the formula (IB-a-1).

[0153] In one embodiment, the compound has the formula (IB-a-2).

[0154] In one embodiment, the compound has formula (Ib-1) or formula (Ib-2):

[0155] Equation (Ib-1)

[0156] Equation (Ib-2)

[0157] or its salts; and / or its isotopes, wherein R 1 R 3 and R 4 As defined in any of the embodiments described herein.

[0158] In one embodiment, the compound has the formula (Ib-1).

[0159] In one embodiment, the compound has the formula (Ib-2).

[0160] In one embodiment, the compound has formula (IA-b) or formula (IB-b):

[0161] Formula (IA-b)

[0162] Formula (IB-b)

[0163] or its salts; and / or its isotopes, wherein R 1 R 3 and R 4 As defined in any of the embodiments described herein.

[0164] In one embodiment, the compound has the formula (IA-b).

[0165] In an embodiment, the compound is of Formula (IB-b).

[0166] In an embodiment, the compound is of Formula (IA-b-1), Formula (IA-b-2), Formula (IB-b-1), or Formula (IB-b-2):

[0167] Formula (IA-b-1)

[0168] Formula (IA-b-2)

[0169] Formula (IB-b-1)

[0170] Formula (IB-b-2)

[0171] or a salt thereof; and / or an isotopolog thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0172] In an embodiment, the compound is of Formula (IA-b-1).

[0173] In an embodiment, the compound is of Formula (IA-b-2).

[0174] In an embodiment, the compound is of Formula (IB-b-1).

[0175] In an embodiment, the compound is of Formula (IB-b-2).

[0176] In an embodiment, the compound is of Formula (I-c-1) or Formula (I-c-2):

[0177] Formula (I-c-1)

[0178] Formula (I-c-2)

[0179] or a salt thereof; and / or an isotopolog thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0180] In an embodiment, the compound is of Formula (I-c-1).

[0181] In an embodiment, the compound is of Formula (I-c-2).

[0182] In an embodiment, the compound is of Formula (IA-c) or Formula (IB-c):

[0183] Formula (IA-c)

[0184] Formula (IB-c)

[0185] or a salt thereof; and / or an isotopologues thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0186] In an embodiment, the compound is of Formula (IA-c).

[0187] In an embodiment, the compound is of Formula (IB-c).

[0188] In an embodiment, the compound is of Formula (IA-c-1), Formula (IA-c-2), Formula (IB-c-1), or Formula (IB-c-2):

[0189] Formula (IA-c-1)

[0190] Formula (IA-c-2)

[0191] Formula (IB-c-1)

[0192] Formula (IB-c-2)

[0193] or a salt thereof; and / or an isotopologues thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0194] In an embodiment, the compound is of Formula (IA-c-1).

[0195] In an embodiment, the compound is of Formula (IA-c-2).

[0196] In an embodiment, the compound is of Formula (IB-c-1).

[0197] In an embodiment, the compound is of Formula (IB-c-2).

[0198] In an embodiment, the compound is of Formula (I-d):

[0199] Formula (I-d)

[0200] or salts thereof; and / or isotopologues thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein. 1 3 4 are as defined in any of the embodiments described herein.

[0201] In one embodiment, the compound is of Formula (IA-d) or Formula (IB-d):

[0202] Formula (IA-d)

[0203] Formula (IB-d)

[0204] or salts thereof; and / or isotopologues thereof, wherein R 1 , R 3 , and R 4 are as defined in any of the embodiments described herein.

[0205] In one embodiment, the compound is of Formula (IA-d).

[0206] In one embodiment, the compound is of Formula (IA-d).

[0207] each R 3 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen, halo, and C3-C4 cycloalkyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen, halo, and C1-C4 haloalkyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, R 3 is selected from halo and C1-C4 alkyl. In one embodiment, R 3 is selected from halo and C2-C3 alkynyl. In one embodiment, each R 3 is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R3 Independently a halogen group. In one implementation, each R 3 Independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -C≡CH. In one embodiment, each R 3 Independently select from the groups consisting of -H, -F, -Cl, -Me, and -Et. In one implementation, each R 3 Independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 3 Each R is independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one implementation, each R 3 Independently selected from the groups consisting of -H, -F, -Cl, and -C≡CH. In one implementation, each R 3 The group consisting of -H, -F, and -Cl is selected independently. In one implementation, R 3 Selected from -F, -Cl, -Et, and -C≡CH. In one implementation, R 3 Selected from -F, -Cl, and -Et. In one implementation, R 3 Selected from -F, -Cl, and -C≡CH. In one implementation, each R 3 The group consisting of -F and -Cl is selected independently. In one implementation, R 3 For -F. In one implementation, R 3 For -Cl. In one implementation, R 3 For -Et. In one implementation, R 3 It is -C≡CH.

[0208] As typically defined in this article, each R 4 Independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl. In one embodiment, each R 4 Independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, and C2-C3 alkynyl. In one embodiment, each R 4 The group is independently selected from the group consisting of hydrogen, halogen groups, and C1-C4 alkyl groups. In one embodiment, each R 4 The group is independently selected from the group consisting of hydrogen, halogen groups, and C3-C4 cycloalkyl groups. In one embodiment, each R 4 Independently selected from the group consisting of hydrogen, halogen groups, and C1-C4 haloalkyl groups. In one embodiment, each R 4is independently selected from the group consisting of hydrogen, halo, and C2-C3 alkynyl. In one embodiment, each R 4 is independently selected from the group consisting of hydrogen and halo. In one embodiment, each R 4 is independently halo. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, -Me, -Et, -cyclopropyl, -CF3, and -CºCH. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, -Me, and -Et. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -cyclopropyl. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -CF3. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, -Cl, and -CºCH. In one embodiment, each R 4 is independently selected from the group consisting of -H, -F, and -Cl. In one embodiment, each R 4 is independently selected from the group consisting of -F and -Cl. In one embodiment, R 4 is selected from -H and -F. In one embodiment, R 4 is -H. In one embodiment, R 4 is -F.

[0209] R 1 is a 4-8 membered saturated carbocyclyl or heterocyclyl ring containing one nitrogen as the sole heteroatom within the ring, wherein the carbocyclyl or the heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, provided that in formula (I), when q is 0, R 1 is not , , , , , or any enantiomer thereof.

[0210] In one embodiment, R 1a 4-8 membered saturated bicyclic carbon ring group or bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring, wherein the carbon ring group or the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In one embodiment, R 1 a 4-8 membered saturated heterocyclic group comprising one nitrogen as the sole heteroatom within the ring, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In one embodiment, R 1 a 4-8 membered saturated monocyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy. In one embodiment, R 1 a 4-8 membered saturated bicyclic heterocyclic group comprising one nitrogen as the sole heteroatom within the ring, wherein the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy.

[0211] In one embodiment, the carbon ring group or the heterocyclic group of R 1 is unsubstituted or substituted with one substituent selected from halo, hydroxyl, or spiro C3-C4cycloalkyl. In one embodiment, the carbon ring group or the heterocyclic group of R 1 is unsubstituted or substituted with one fluoro or spiro C3-C4cycloalkyl. In one embodiment, the carbon ring group or the heterocyclic group of R 1 is selected from the group consisting of: , and wherein R d is as defined in any one of the embodiments described herein. In one embodiment, the carbon ring group or the heterocyclic group of R 1 is or wherein R d is as defined herein. In one embodiment, the carbon ring group or the heterocyclic group of R 1 is selected from , and . In one embodiment, the carbon ring group or the heterocyclic group of R 1 is selected from the group consisting of , and .

[0212] In one embodiment, R 1 is wherein R d is as defined in any of the embodiments described herein. In one embodiment, R 1 is In one embodiment, R 1 is selected from and In one embodiment, R 1 is .

[0213] In one embodiment, R 1 is In one embodiment, R 1 is .

[0214] As generally defined herein, q is 0 or 1. In one embodiment, q is 0, provided that in formula (I), when q is 0, R 1 is not , , , , , or any enantiomer thereof. In one embodiment, q is 1.

[0215] As generally defined herein, R d is H or F. In one embodiment, R d is H. In one embodiment, R d is F.

[0216] In one embodiment, the compound is selected from the compounds of Table 1, or a salt thereof; and / or an isotopologue thereof. In one embodiment, the compound is not a salt.

[0217] In one embodiment, the compound is a salt. In one embodiment, the salt is a formate salt. In one embodiment, the salt is a trifluoroacetate salt. In one embodiment, the salt is a pharmaceutically acceptable salt.

[0218] In one embodiment, provided herein are the compounds of Table 1, or a salt thereof and / or an isotopologue thereof. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0219] Table 1.

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] In some variations, any of the compounds described herein, e.g., a compound of Formula (I) or a compound of Table 1, can be deuterated (e.g., a hydrogen atom is replaced with a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner analogous to the preparation of the corresponding non-deuterated compound. Hydrogen atoms can also be replaced with deuterium atoms using other methods known in the art.

[0237] Any formula given herein is intended to represent compounds having the structure depicted by the formula, as well as certain variations or forms. In particular, any compound given by any formula herein can have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the formula, and mixtures thereof in all proportions, are intended to be included within the scope of the formula. Thus, any formula given herein is intended to represent both the racemate and the individual enantiomers and diastereomers, as well as mixtures thereof in all proportions. In addition, certain structures can exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any formula given herein is intended to represent any one of the hydrates, solvates, and amorphous forms, and mixtures thereof, of such compounds, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0238] Representative examples of the compounds detailed herein, including intermediates and final compounds, are depicted in the tables herein and elsewhere. It is understood that in one aspect, any of the compounds can be used in the methods detailed herein, including (where applicable) intermediate compounds that can be isolated and administered to a subject.

[0239] The compounds depicted herein can exist in salt form, even if a salt is not depicted, and it is understood that the compositions and methods provided herein encompass all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms of the compounds, as would be fully appreciated by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0240] In one variation, the compounds herein are synthetic compounds prepared for administration to a subject. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier are provided. In another variation, methods of administering the compounds are provided. The purified forms of the compounds, the pharmaceutical compositions, and the methods of administration are suitable for any of the compounds detailed herein or forms thereof.

[0241] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , X, X 1 , q, r, R 1A , R 6A , R6B , R 6C , R x , R x , R x , R y , R y , R y , R z , R z , R z , R a' , R b' , R c' , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , X, X 1 , q, r, R 1A , R 6A , R 6B , R 6C , R x , R x , R x , R y , R y , R y , R z , R z , R z , R a' , R b' , R c' , R

[0242] As used herein, when any variable occurs more than one time in a chemical formula, its definition in each occurrence is independent of its definition at every other occurrence.

[0243] Methods for treating cancer

[0244] The compounds of Formula (I) and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, can be used to treat cancer, including but not limited to various types of cancer, including, for example, lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. More particularly, cancers that can 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, for example, glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In some embodiments, 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 with 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.

[0245] In one aspect, there is provided 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.

[0246] In one aspect, there is provided 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 inhibiting a cancer. In one embodiment, when the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In one embodiment, the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the compound or pharmaceutical formulation is configured for administration in a therapeutically effective amount.

[0247] In one aspect, there is provided a compound of Formula (I) as described in any of the embodiments herein or a pharmaceutical formulation as described in any of the embodiments herein for use in the manufacture of a medicament to treat or inhibit a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In one embodiment, the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical formulation.

[0248] In one aspect, there is provided use of a compound of Formula (I) as described in any of the embodiments described herein, or a pharmaceutical preparation as described in any of the embodiments described herein, for the manufacture of a medicament for treating or inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In one embodiment, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In one embodiment, the cancer is selected from the group consisting of glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is a KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with a KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical preparation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent. In one embodiment, the medicament comprises a therapeutically effective amount of the compound or pharmaceutical preparation.

[0249] In one aspect, there is provided use of a compound of Formula (I) as described in any of the embodiments described herein, or a pharmaceutical preparation as described in any of the embodiments described herein, for the manufacture of a medicament for treating or inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0250] In one embodiment, the cancer is selected from the group consisting of: lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In another embodiment, the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, melanoma of the skin, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia. Leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, non-small cell lung cancer (NSCLC), and melanoma. In one embodiment, the cancer is KRAS G12C-mediated cancer. In one embodiment, the subject has been diagnosed with KRAS G12C-mediated cancer. In one embodiment, the compound or pharmaceutical preparation is configured for administration together with a therapeutically effective amount of additional chemotherapeutic agent. In one embodiment, the use relates to a therapeutically effective amount of the compound or composition.

[0251] In some implementation schemes (including any of the foregoing implementation schemes), the subject and / or the cancer is resistant or refractory to treatment with certain KRAS inhibitors (e.g., G12C KRAS inhibitors).

[0252] The compound of formula (I) and its pharmaceutically acceptable salts and / or isotopes (including embodiments disclosed herein) can be used in a method of inhibiting KRAS G12C in cells by contacting cells for which KRAS G12C activity needs to be inhibited with an amount of the compound that effectively inhibits KRAS G12C activity. Inhibition may be partial or complete. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo.

[0253] test

[0254] The compounds of Formula (I) and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, can be tested by, for example, the methods described in the Examples below, or by known and generally accepted cellular and / or animal models.

[0255] The ability of compounds of Formula (I) and pharmaceutically acceptable salts and / or isotopologues thereof to inhibit the activity of the GTP-bound form of KRAS G12C can be tested using, for example, the in vitro assay described in Examples 69 and 70 below. Example 69 describes determining the half maximal inhibition (IC50) of KRAS G12C loaded with the GTP analog GMPPNP binding to cRaf as a Ras Binding Domain (RBD) for various compounds. 50 Example 70 describes determining the half maximal inhibition (IC50) of KRAS G12C loaded with the GTP analog GMPPNP binding to PI3K a as a Ras Binding Domain (RBD) for various compounds. 50 Example 71 describes testing the ability of compounds to inhibit cell viability in MCF10A G12C / A59G mutants, which abrogate GTPase activity, thereby preventing GTP hydrolysis to GDP.

[0256] Pharmaceutical compositions

[0257] The terms pharmaceutical composition and pharmaceutical preparation are used interchangeably throughout.

[0258] In general, the compounds of Formula (I) of the present disclosure and pharmaceutically acceptable salts and / or isotopologues thereof (which can also be referred to herein as “compounds” or “compounds of the present disclosure”) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities, in similar dosages and according to dosage regimes that result in similar utility. Therapeutically effective amounts of the compounds of the present disclosure can range from about 0.01 to about 500 mg per kilogram body weight of a patient per day, which can be administered in single or multiple doses. In some embodiments, suitable dosage levels can be from about 0.1 to about 250 mg / kg per day; or from about 0.5 to about 100 mg / kg per day. Suitable dosage levels can be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range the dosage can be from about 0.05 to about 0.5, from about 0.5 to about 5 or from 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, 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 for the symptomatic adjustment of the dosage to the patient to be treated. The actual amount of a compound of the present disclosure (i.e., active ingredient) will depend on 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 utilized, the route and form of administration, and other factors.

[0259] In general, the compounds of the present disclosure will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal or via a patch), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The most preferred route of administration is oral, using a convenient daily dosage regimen that 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.

[0260] The choice of formulation depends on various factors such as the drug administration mode (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.

[0261] Compositions typically comprise a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, aid administration, and do not adversely affect the therapeutic benefit of a compound of the present disclosure. Such excipient can be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is nontoxic and essentially physiologically compatible.

[0262] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, especially for injectable solutions, include water, saline, dextran aqueous solution, and glycols.

[0263] The compound can be formulated for parenteral administration by injection (e.g., via bolus injection or continuous infusion). Formulations for injection may be in unit dosage forms, such as in ampoules or multi-dose containers, with added preservatives. The composition may be in the form of suspensions, solutions, or emulsions, for example, in oily or aqueous media, and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The formulation may be present in unit or multi-dose containers (e.g., sealed ampoules and vials) and may be in powder form or stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the previously described types.

[0264] Formulations intended for parenteral administration include aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that promote isotonicity between the formulation and the intended recipient's blood; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or polydextrose. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of high-concentration solutions.

[0265] In addition to the formulations previously described, the compounds can also be formulated as reservoir formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0266] For buccal or sublingual administration, the composition may be in the form of tablets, lozenges, tablets, or gels formulated in a conventional manner. Such compositions may contain the active ingredient in a flavoring base (e.g., sucrose and gum arabic or tragacanth gum).

[0267] The compounds can 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.

[0268] Certain compounds of the present disclosure can be administered topically, i.e., applied externally to the epidermis or buccal cavity and instilled into the ear, eye, and nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0269] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the inflammation site via the skin, e.g., gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration can constitute, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can constitute up to 10% w / w. In other embodiments, it can constitute less than 5% w / w. In certain embodiments, the active ingredient can constitute 2% w / w to 5% w / w. In other embodiments, it can constitute 0.1% to 1% w / w of the formulation.

[0270] For administration by inhalation, the compounds can be conveniently delivered from an insufflator, a nebulizer, pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs can 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 can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the present disclosure can take the form of a dry powder composition, e.g., a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder can be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulation are described in Remington's Pharmaceutical Sciences, E. W. Martin, ed. (Mack Publishing Company, 20th edition, 2000).

[0271] The level of compound in the formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain from about 0.01-99.99% by weight (wt%) of the compound of the present disclosure based on the total formulation, the remainder being one or more suitable pharmaceutical excipients. For example, the compound can be present at a level of about 1-80% by weight.

[0272] Combinations and Combination Therapy

[0273] The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or the other drugs can have utility. Such other drugs can be administered, by a route and in an amount commonly used therewith, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs and the compound of the present disclosure is envisioned. However, combination therapy also envisions that a compound of the present disclosure and one or more other drugs can be administered on different overlapping

[0274] Accordingly, pharmaceutical compositions of the present disclosure also include those that contain one or more other drug substances in addition to a compound of the present disclosure.

[0275] The combinations referred to above can include a compound of the present disclosure and one other pharmaceutical agent, but also include combinations with two or more other active pharmaceutical agents. Likewise, a compound of the present disclosure can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which a compound of the present disclosure is useful. Such other drugs can be administered, by a route and in an amount commonly used therewith, contemporaneously or sequentially with a compound of the present disclosure. Where a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs and the compound of the present disclosure is envisioned. Accordingly, pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients in addition to a compound of the present disclosure. The proportion of compound of the present disclosure and other active ingredient(s) in such compositions will vary depending on the particular compound and active ingredient(s) included in the composition. Generally, the dose of each active ingredient will be that which is effective in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which the active ingredient(s) is / are useful.

[0276] In the case where a subject has or is at risk of having cancer, the subject can be treated with a compound of the present disclosure in any combination with one or more other anti-cancer agents.

[0277] In some embodiments, the compounds of the present disclosure are used in combination with a CDK 4 / 6 inhibitor. Examples of CDK 4 / 6 inhibitors suitable for use in the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4- ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5- (piperazin-1-yl)pyridin-2-yl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one) and ribociclib (7- cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 6-carboxamide), while the CDK 4 / 6 inhibitor trilaciclib (2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)- 7',8'-dihydro-6'H-spiro-[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]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 (6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1- (methylsulfonyl)-4-piperidyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one).

[0278] In another embodiment, the compounds of the present disclosure are used in combination with a Raf family kinase inhibitor. Examples of Raf family kinase inhibitors suitable for use in the provided compositions and methods include, but are not limited to, encorafenib (LGX818): (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1- isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamic acid methyl ester; 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'- morpholinyl-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridinyl]-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-methylpyridinecarboxamide; LY 3009120: 1-(3,3- dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrano[2,3-d]pyrimidin-6-yl)phenyl)urea; Lifirafenib (BGB-283); 5-(((1R,1aS,6bS)-1-(6-(trifluoro-methyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-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-oxopyrimidin-yloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridyl]-N'-methylsulfamide.

[0279] In another embodiment, the compounds of this 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-1-yl)-2-methylpyrimidin-4-yl)amino)thiazolyl-5-carboxamide); ponatinib (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide); and vandetanib. (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine); Bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carboxynitrile); Saracatinib (N-(5-chlorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine); KX2-391 (N-benzyl-2-(5-(4-(2-morpholinylethoxy)phenyl)pyridin-2-yl)acetamide); SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indololin-5-sulfonamide); PP1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); WH-4-023 ((2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate 2,6-dimethylphenyl ester); and KX-01 (N-benzyl-2-(5-(4-(2-morpholinylethoxy)phenyl)pyridin-2-yl)acetamide). In one embodiment, the Src inhibitor is dasatinib. In one embodiment, the Src inhibitor is zicatinib. In one embodiment, the Src inhibitor is ponatinib. In one embodiment, the Src inhibitor is vandetanib. In another embodiment, the Src inhibitor is KX-01.

[0280] In another embodiment, the compounds of the present disclosure are used in combination with SHP-2 inhibitors including, but not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 (3(3S,4S)-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(2,3-dichlorophenyl)pyrazin-2-yl)methanol), RMC-4360 (Revolution Medicines), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

[0281] In another embodiment, the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for use in the provided compositions and methods include, but are not limited to, Everolimus, Rapamycin, Zotarolimus (ABT-578), ridaforolimus (Deforolimus; MK-8669), Sapanisertib (INK128; 5-(4-amino-l- isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine), Torin-1; 1-(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-dimorpholinopyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-amine); GDC-0941 (pictilisib); 4-[2-(lH-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-methylmorpholinyl)-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-methylmorpholinyl)pyrido[2,3-d]pyrimidin-7-yl)-N- methylbenzamide).

[0282] 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 inhibitor is the only active agent in the provided compositions and methods. In one embodiment, the pan ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan ErbB family inhibitors suitable for use in the provided compositions and methods include, but are not limited to, Afatinib; Dacomitinib; Canertinib; Poziotinib, AV 412 (N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1- piperazin-1-ylbutyn-1-yl]-6-quinazolinyl]-2-propenamide); 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 use in the provided compositions and methods include, but are not limited to, erlotinib, gefitinib, sapitinib; varlitinib; TAK-285 (N-[2-[4-[3-chloro-4-[3- (trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3- methylbutanamide); AEE788 (S)-(6-(4-((4-ethylpiperazin-1-ylmethyl)phenyl]-N-(1- phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); tarloxotinib 3-[N-[4-(3-bromo-4-chlorophenylamino)- pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5- ylmethyl)-2(E)-propen-1-aminium bromide); BMS 599626 (3S)-3-morpholinomethyl-([4-[[1- [(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6- yl]carbamate dihydrochloride); and GW 583340 (N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[2- [2-(methylsulfonyl)ethylaminomethyl]thiazol-4-yl]quinazolin-4-amine dihydrochloride).

[0283] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of the following two: AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4- amine hydrochloride); AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3- phenylpropyl)-2-propenamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4- phenylbutyl)-2-propenamide; AG 825 (E-3-[3-benzothiazol-2-ylsulfanylmethyl)-4- hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714 (2-methoxy-N-[(2E)-3- [4-[3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino]quinazolin-6-yl]-2-propen-1- yl]acetamide; BIBU 1361 (N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)- piperidin-1-yl]pyrimido[5,4-d]pyrimidine-4-amine dihydrochloride); BIBU 1382; (N 8 -(3-chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidine-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 (N 4 -(3-bromophenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine).

[0284] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody. Antibodies targeting EGFR and / or HER2, including monoclonal antibodies, antibody conjugates, and bispecific antibodies, are well known, and several are commercially available for research and human clinical use. Examples of anti-EGFR antibodies suitable for use in the provided compositions and methods include necitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for use in the provided compositions and methods include pertuzumab, trastuzumab, and trastuzumab emtansine.

[0285] 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 use in the provided compositions and methods include, but are not limited to, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors, such as Pembrolizumab (Keytruda®), Nivolumab (Opdivo®), Cemiplimab (Libtayo®), Atezolizumab (Tecentriq®), Avelumab (Bavencio®), Durvalumab (Imfinzi™), Ipilimumab (Yervoy®), Relatlimab, Opdualag, and Dostarlimab (Jemperli).

[0286] The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other anti-neoplastic compounds (e.g., chemotherapeutics), or used in combination with other therapies (e.g., radiation or surgical intervention), as pre- or post-operative adjuncts.

[0287] Enumerated Embodiments

[0288] The following enumerated embodiments represent some aspects of the present invention.

[0289] Group A.

[0290] Embodiment 1. A compound of formula (I’):

[0291] Formula (I')

[0292] or salts thereof; and / or isotopologues thereof; wherein:

[0293] R 1 is a 4-8 membered saturated carbocyclyl or heterocyclyl ring comprising one nitrogen as the sole heteroatom within the ring; wherein said carbocyclyl or said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4alkyl, spiro C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, and C1-C4haloalkoxy; R 3 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl;

[0294] R 4 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl; and

[0295] q is 0 or 1;

[0296] provided that when q is 0, R 1 is not , , , , , or any enantiomer thereof.

[0297] Embodiment 2. The compound of Embodiment 1, wherein the compound is of Formula (IA) or Formula (IB)

[0298] Formula (IA)

[0299] Formula (IB);

[0300] or salts thereof; and / or isotopologues thereof.

[0301] Embodiment 3. The compound of Embodiment 2, wherein the compound is of Formula (IA).

[0302] Embodiment 4. The compound of Embodiment 2, wherein the compound is of Formula (1B).

[0303] Embodiment 5. The compound of Embodiment 1, wherein the compound is of Formula (I-a), Formula (I-b), or Formula (I-c):

[0304] Embodiment 5. The compound of Embodiment 1, wherein the compound is of Formula (I-a), Formula (I-b), or Formula (I-c): Formula (I-a)

[0305] Formula (I-b)

[0306] Formula (I-c)

[0307] or a salt thereof; and / or an isotopologue thereof.

[0308] Embodiment 6. The compound of Embodiment 5, wherein the compound is of Formula (I-a).

[0309] Embodiment 7. The compound of Embodiment 5, wherein the compound is of Formula (I-b).

[0310] Embodiment 8. The compound of Embodiment 5, wherein the compound is of Formula (I-c).

[0311] Embodiment 9. The compound of Embodiment 1, wherein the compound is of Formula (I-a-1) or Formula (I-a-2):

[0312] Formula (I-a-1)

[0313] Formula (I-a-2)

[0314] or a salt thereof; and / or an isotopologue thereof.

[0315] Embodiment 10. The compound of Embodiment 9, wherein the compound is of Formula (I-a-1).

[0316] Embodiment 11. The compound of Embodiment 9, wherein the compound is of Formula (I-a-2).

[0317] Embodiment 12. The compound of Embodiment 1, wherein the compound is of Formula (IA-a) or Formula (IB-a):

[0318] Formula (IA-a)

[0319] Formula (IB-a)

[0320] or a salt thereof; and / or an isotopologue thereof.

[0321] Embodiment 13. The compound of Embodiment 12, wherein the compound is of Formula (IA-a).

[0322] Embodiment 14. The compound of Embodiment 12, wherein the compound is of Formula (IB-a).

[0323] 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):

[0324] Formula (IA-a-1)

[0325] Formula (IA-a-2)

[0326] Formula (IB-a-1)

[0327] Formula (IB-a-2)

[0328] or a salt thereof; and / or an isotopologue thereof.

[0329] Embodiment 16. The compound of Embodiment 15, wherein the compound is of Formula (IA-a-1).

[0330] Embodiment 17. The compound of Embodiment 15, wherein the compound is of Formula (IA-a-2).

[0331] Embodiment 18. The compound of Embodiment 15, wherein the compound is of Formula (IB-a-1).

[0332] Embodiment 19. The compound of Embodiment 15, wherein the compound is of Formula (IB-a-2).

[0333] Embodiment 20. The compound of Embodiment 1, wherein the compound is of Formula (I-b-1) or Formula (I-b-2):

[0334] Formula (I-b-1)

[0335] Formula (I-b-2)

[0336] or a salt thereof; and / or an isotopologue thereof.

[0337] Embodiment 21. The compound of Embodiment 20, wherein the compound is of Formula (I-b-1).

[0338] Embodiment 22. The compound of Embodiment 20, wherein the compound is of Formula (I-b-2).

[0339] Embodiment 23. The compound of Embodiment 1, wherein the compound is of Formula (IA-b) or Formula (IB-b):

[0340] Formula (IA-b)

[0341] Formula (IB-b)

[0342] or a salt thereof; and / or an isotopologue thereof.

[0343] Embodiment 24. The compound of Embodiment 23, wherein the compound is of Formula (IA-b).

[0344] Embodiment 25. The compound of Embodiment 23, wherein the compound is of Formula (IB-b).

[0345] 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):

[0346] Formula (IA-b-1)

[0347] Formula (IA-b-2)

[0348] Formula (IB-b-1)

[0349] Formula (IB-b-2)

[0350] or a salt thereof; and / or an isotopologue thereof.

[0351] Embodiment 27. The compound of Embodiment 26, wherein the compound is of Formula (IA-b-1).

[0352] Embodiment 28. The compound of Embodiment 26, wherein the compound is of Formula (IA-b-2).

[0353] Embodiment 29. The compound of Embodiment 26, wherein the compound is of Formula (IB-b-1).

[0354] Embodiment 30. The compound of Embodiment 26, wherein the compound is of Formula (IB-b-2).

[0355] Embodiment 31. The compound of Embodiment 1, wherein the compound is of Formula (I-c-1) or Formula (I-c-2):

[0356] Formula (I-c-1)

[0357] Formula (I-c-2)

[0358] or salts thereof; and / or isotopologues thereof.

[0359] Embodiment 32. The compound of Embodiment 31, wherein the compound is of Formula (I-c-1).

[0360] Embodiment 33. The compound of Embodiment 31, wherein the compound is of Formula (I-c-2).

[0361] Embodiment 34. The compound of Embodiment 1, wherein the compound is of Formula (IA-c) or Formula (IB-c):

[0362] Formula (IA-c)

[0363] Formula (IB-c)

[0364] or salts thereof; and / or isotopologues thereof.

[0365] Embodiment 35. The compound of Embodiment 34, wherein the compound is of Formula (IA-c).

[0366] Embodiment 36. The compound of Embodiment 34, wherein the compound is of Formula (IB-c).

[0367] 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):

[0368] Formula (IA-c-1)

[0369] Formula (IA-c-2)

[0370] Formula (IB-c-1)

[0371] Formula (IB-c-2)

[0372] or salts thereof; and / or isotopologues thereof.

[0373] Embodiment 38. The compound of Embodiment 37, wherein the compound is of Formula (IA-c-1).

[0374] Embodiment 39. The compound of Embodiment 37, wherein the compound is of Formula (IA-c-2).

[0375] Embodiment 40. The compound of Embodiment 37, wherein the compound is of Formula (IB-c-1).

[0376] Embodiment 41. The compound of Embodiment 37, wherein the compound is of Formula (IB-c-2).

[0377] Embodiment 42. The compound of Embodiment 1, wherein the compound is of Formula (I-d).

[0378] Formula (I-d)

[0379] or a salt thereof; and / or an isotopologues thereof.

[0380] Embodiment 43. The compound of Embodiment 1, wherein the compound is of Formula (IA-d) or Formula (IB-d):

[0381] Formula (IA-d)

[0382] Formula (IB-d)

[0383] or a salt thereof; and / or an isotopologues thereof.

[0384] Embodiment 44. The compound of Embodiment 43, wherein the compound is of Formula (IA-d).

[0385] Embodiment 45. The compound of Embodiment 43, wherein the compound is of Formula (IA-d).

[0386] Embodiment 46. The compound of any one of Embodiments 1-45, wherein R 3 is selected from halo, C1-C4alkyl, and C2-C3alkynyl.

[0387] Embodiment 47. The compound of any one of Embodiments 1-45, wherein R 3 is selected from halo and C1-C4alkyl.

[0388] Embodiment 48. The compound of any one of Embodiments 1-45, wherein R 3 is selected from halo and C2-C3alkynyl.

[0389] Embodiment 49. The compound of any one of Embodiments 1-45, wherein R 3 is halo.

[0390] Embodiment 50. The compound of any one of embodiments 1-45, wherein R 3 is selected from -F, -Cl, -Et, and -CºCH.

[0391] Embodiment 51. The compound of any one of embodiments 1-45, wherein R 3 is selected from -F, -Cl, and -Et.

[0392] Embodiment 52. The compound of any one of embodiments 1-45, wherein R 3 is selected from -F, -Cl, and -CºCH.

[0393] Embodiment 53. The compound of any one of embodiments 1-45, wherein R 3 is selected from -F and -Cl.

[0394] Embodiment 54. The compound of any one of embodiments 1-45, wherein R 3 is -F.

[0395] Embodiment 55. The compound of any one of embodiments 1-45, wherein R 3 is -Cl.

[0396] Embodiment 56. The compound of any one of embodiments 1-45, wherein R 3 is -Et.

[0397] Embodiment 57. The compound of any one of embodiments 1-45, wherein R 3 is -CºCH.

[0398] Embodiment 58. The compound of any one of embodiments 1-57, wherein R 4 is selected from hydrogen and halo.

[0399] Embodiment 59. The compound of any one of embodiments 1-57, wherein R 4 is selected from -H and -F.

[0400] Embodiment 60. The compound of any one of embodiments 1-57, wherein R 4 is -H.

[0401] Embodiment 61. The compound of any one of embodiments 1-57, wherein R 4 is -F.

[0402] Embodiment 62. The compound of any one of embodiments 1-41 and 46-61, wherein R 1is a 4-8 membered saturated heterocyclyl comprising one nitrogen as the sole heteroatom within the ring atoms, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0403] Embodiment 63. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is a 4-8 membered saturated heterocyclyl comprising one nitrogen as the sole heteroatom within the ring atoms, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0404] Embodiment 64. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is a 4-8 membered saturated heterocyclyl comprising one nitrogen as the sole heteroatom within the ring atoms, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0405] Embodiment 65. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is a 4-8 membered saturated heterocyclyl comprising one nitrogen as the sole heteroatom within the ring atoms, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0406] Embodiment 66. The compound of any one of embodiments 62-65, wherein R 1 said carbocyclyl or said heterocyclyl of R is unsubstituted or substituted with one substituent selected from halo, hydroxyl, or spiro C3-C4 cycloalkyl.

[0407] Embodiment 67. The compound of any one of embodiments 62-65, wherein R 1 said carbocyclyl or said heterocyclyl of R is unsubstituted or substituted with one substituent selected from fluoro or spiro C3-C4 cycloalkyl.

[0408] Embodiment 68A. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is selected from the group consisting of: , or wherein R d is H or F.

[0409] Embodiment 68B. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is , , , , , , , , , , , , , , , , , , or .

[0410] Embodiment 68C. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 or .

[0411] Embodiment 69. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is or , wherein R d is H or F.

[0412] Embodiment 70. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is , wherein R d is H or F.

[0413] Embodiment 71. The compound of any one of embodiments 68-70, wherein R d is H.

[0414] Embodiment 72. The compound of any one of embodiments 68-70, wherein R d is F.

[0415] Embodiment 73. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is selected from and .

[0416] Embodiment 74. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is .

[0417] Embodiment 75. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is .

[0418] Embodiment 76. The compound of any one of embodiments 1-61, wherein R 1 is .

[0419] Embodiment 77. The compound of any one of embodiments 1-41 and 46-61, wherein R 1 is selected from , and the group consisting of

[0420] Embodiment 78. The compound of any one of embodiments 1-61, wherein R 1 is .

[0421] Embodiment 79. The compound of any one of embodiments 1-78, wherein the compound is selected from the group consisting of:

[0422] , , , , , , , , , , , , , , and

[0423] or a salt thereof; and / or an isotopolog of the same.

[0424] Embodiment 80. The compound of any one of embodiments 1-79, wherein the compound is not a salt.

[0425] Embodiment 81. The compound of any one of embodiments 1-79, wherein the compound is a salt.

[0426] Embodiment 82. The compound of embodiment 81, wherein the salt is a formate salt.

[0427] Embodiment 83. The compound of embodiment 81, wherein the salt is a trifluoroacetate salt.

[0428] Embodiment 84. The compound of embodiment 81, wherein the salt is a pharmaceutically acceptable salt.

[0429] Embodiment 85. A pharmaceutical preparation comprising the compound of any one of embodiments 1-84 and a pharmaceutically acceptable carrier, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0430] Embodiment 86. A method of treating or inhibiting cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 85, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0431] Embodiment 87. The method of embodiment 86, wherein the cancer is selected from the group consisting of: lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0432] Embodiment 88. The method of embodiment 86, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0433] Embodiment 89. The method of any one of embodiments 86-88, wherein the cancer is a KRAS G12C-mediated cancer.

[0434] Embodiment 90. The method of any one of embodiments 86-88, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0435] Embodiment 91. The method of any one of embodiments 86-88, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0436] Embodiment 92. A compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 for use as a medicament.

[0437] Embodiment 93. The compound of any one of embodiments 1-84 or the pharmaceutical preparation of embodiment 77 for use in treating or inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0438] Embodiment 94. The compound or pharmaceutical preparation for use of embodiment 93, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0439] Embodiment 95. The compound or pharmaceutical preparation for use of embodiment 93, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0440] Embodiment 96. The compound or pharmaceutical preparation for use of any one of embodiments 93-95, wherein the cancer is a KRAS G12C-mediated cancer.

[0441] Embodiment 97. The compound or pharmaceutical preparation for use of any one of embodiments 93-95, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0442] Embodiment 98. The compound or pharmaceutical preparation for use of any one of embodiments 93-97, wherein the compound or the pharmaceutical preparation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0443] Embodiment 99. The compound or pharmaceutical formulation for use of any one of embodiments 93-98, wherein the compound or the pharmaceutical formulation is configured for administration in a therapeutically effective amount.

[0444] Embodiment 100. The compound of any one of embodiments 1-84 or the pharmaceutical formulation according to embodiment 77, for use in the manufacture of a medicament to treat or inhibit a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0445] Embodiment 101. The compound or pharmaceutical formulation for use of embodiment 100, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0446] Embodiment 102. The compound or pharmaceutical formulation for use of embodiment 100, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0447] 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.

[0448] Embodiment 104. The compound or pharmaceutical formulation for use of any one of embodiments 100-102, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0449] Embodiment 105. The compound or pharmaceutical formulation for use of any one of embodiments 100-104, wherein the compound or the pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0450] 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 the composition.

[0451] Embodiment 107. Use of a compound of any one of embodiments 1-84 or a pharmaceutical formulation according to embodiment 77 for the manufacture of a medicament to treat or inhibit a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0452] Embodiment 108. The use of embodiment 107, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0453] Embodiment 109. The use of embodiment 107, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0454] Embodiment 110. The use of any one of embodiments 107-109, wherein the cancer is a KRAS G12C-mediated cancer.

[0455] Embodiment 111. The use of any one of embodiments 107-109, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0456] Embodiment 112. The use of any one of embodiments 107-111, wherein the compound or the pharmaceutical preparation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0457] Embodiment 113. The use of any one of embodiments 107-112, wherein the medicament comprises a therapeutically effective amount of the compound or the pharmaceutical preparation.

[0458] Embodiment 114. Use of a compound of any one of embodiments 1-84 or a pharmaceutical preparation according to embodiment 77 for treating or inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0459] Embodiment 115. The use of embodiment 114, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0460] Embodiment 116. The use of embodiment 114, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0461] Embodiment 117. The use of any one of embodiments 114-116, wherein the cancer is a KRAS G12C-mediated cancer.

[0462] Implementation Scheme 118. The use as described in any one of Implementation Schemes 114-116, wherein the subject has been diagnosed with KRAS G12C-mediated cancer.

[0463] Implementation Scheme 119. The use as described in any one of Implementation Schemes 114-118, wherein the compound or the pharmaceutical preparation is configured for administration together with a therapeutically effective amount of an additional chemotherapeutic agent.

[0464] Implementation Scheme 120. Use as described in any one of Implementation Schemes 114-119, wherein the use relates to a therapeutically effective amount of the compound or the composition.

[0465] Group B.

[0466] 1. A compound of formula (I''):

[0467] Formula (I''),

[0468] or its salts and / or its isotopes; wherein:

[0469] X is -N(CH3)- or -O-;

[0470] X 1 It is -CH3, -CH2CH3, -CH=CH2 or cyclopropyl, each of which is substituted by 0, 1 or 2 independent substituents selected from the group consisting of halogen, -OH and -OCH3;

[0471] q is 0 or 1;

[0472] R 1 A 4-8 member saturated heterocyclic group containing a nitrogen atom as the only heteroatom within the ring atom, wherein the heterocyclic group is surrounded by 0, 1, 2 or 3 R atoms. 1A replace;

[0473] R 1A In each case, the group consisting independently of halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl) is selected; or two twin R groups are selected. 1A Together with the carbon atom to which it is attached, it forms a C3-C4 cycloalkyl group substituted with 0, 1, or 2 halogen groups; or two twin R groups. 1A Together they form =CH2, =CHF, or =CF2;

[0474] R a It is H or CH3;

[0475] R 2 for or ;

[0476] R 3 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl;

[0477] R 4 is selected from the group consisting of hydrogen, halo, C1-C4alkyl, C3-C4cycloalkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, and C2-C3alkynyl;

[0478] R 5 is H or -OH;

[0479] Y is CH or N;

[0480] R 6 is independently at each occurrence selected from the group consisting of halo, -OH, C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, and -NH2; and

[0481] r is 0, 1, 2, or 3;

[0482] provided that when q is 0, then R 1 is not , , , , , or any enantiomer thereof; when is or any enantiomer thereof, then R 2 is not ; and when is or any enantiomer thereof, then R 2 is not or .

[0483] 2. The compound of Embodiment 1, or a salt and / or isotopologue thereof, wherein R 2 is .

[0484] 3. The compound of Embodiment 2, or a salt and / or isotopologue thereof, wherein R 3 is selected from the group consisting of halo, C1-C4alkyl, and C2-C3alkynyl.

[0485] 4. The compound of Embodiment 2, or a salt and / or isotopologue thereof, wherein R 3is selected from the group consisting of -F, -CI, -Et, -CºCH, and -CºC-CH3.

[0486] 5. The compound of any one of embodiments 2-4, or salts and / or isotopologues thereof, wherein R 4 is hydrogen or halo.

[0487] 6. The compound of any one of embodiments 2-4, or salts and / or isotopologues thereof, wherein R 4 is hydrogen or -F.

[0488] 7. The compound of any one of embodiments 2-6, or salts and / or isotopologues thereof, wherein R 5 is -OH.

[0489] 8. The compound of any one of embodiments 2-6, or salts and / or isotopologues thereof, wherein R 5 is H.

[0490] 9. The compound of embodiment 2, or salts and / or isotopologues thereof, wherein R 2 is , , , , , or .

[0491] 10. The compound of embodiment 1, or salts and / or isotopologues thereof, wherein R 2 is .

[0492] 11. The compound of embodiment 10, or salts and / or isotopologues thereof, wherein Y is CH.

[0493] 12. The compound of embodiment 10, or salts and / or isotopologues thereof, wherein Y is N.

[0494] 13. The compound of any one of embodiments 10-12, or salts and / or isotopologues thereof, wherein R 6 is independently at each occurrence selected from the group consisting of -CI, -OH, -CH3, -CF3, cyclopropyl, and -NH2.

[0495] 14. The compound of any one of embodiments 10-13, or salts and / or isotopologues thereof, wherein r is 3.

[0496] 15. The compound of any one of embodiments 10-13, or salts and / or isotopologues thereof, wherein R 2 is .

[0497] 16. The compound of any one of embodiments 10-13, or a salt and / or isotopologue thereof, wherein R 2 is , wherein R 6A is cyclopropyl or -CF3; R 6B is -Cl or -CH3; and R 6C is -OH or -NH2.

[0498] 17. The compound of embodiment 10, or a salt and / or isotopologue thereof, wherein R 2 is , , .

[0499] 18. The compound of any one of embodiments 1-17, or a salt and / or isotopologue thereof, wherein X is -N(CH3)-.

[0500] 19. The compound of any one of embodiments 1-17, or a salt and / or isotopologue thereof, wherein X is -O-.

[0501] 21. The compound of any one of embodiments 1-19, or a salt and / or isotopologue thereof, wherein X 1 is -CH3.

[0502] 20. The compound of any one of embodiments 1-19, or a salt and / or isotopologue thereof, wherein X 1 is -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2, or cyclopropyl.

[0503] 22. The compound of any one of embodiments 1-17, or a salt and / or isotopologue thereof, wherein the portion of the compound is , , , , , , , , , , or .

[0504] 23. The compound of any one of embodiments 1-17, or a salt and / or isotopologue thereof, wherein the portion of the compound is , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0505] 24. The compound of any one of Embodiments 1-23, or a salt and / or isotopologue thereof, wherein R 1 is or substituted with 0, 1, 2, or 3 R 1A .

[0506] 25. The compound of any one of Embodiments 1-24, or a salt and / or isotopologue thereof, wherein R 1A is, at each occurrence, independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3; or two geminal R 1A together with the carbon atom to which they are attached form a cyclopropyl substituted with 0, 1, or 2 fluorines; or two geminal R 1A together form =CH2, =CHF, or =CF2.

[0507] 26. The compound of any one of Embodiments 1-25, or a salt and / or isotopologue thereof, wherein R 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0508] 27. The compound of any one of embodiments 1-25, or salts and / or isotopologues thereof, wherein R 1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0509] 28. The compound of any one of embodiments 1-27, wherein R a is H.

[0510] 29. The compound of any one of embodiments 1-27, wherein R a is CH3.

[0511] 30. The compound of embodiment 1, or salts and / or isotopologues thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

[0512] 31. The compound of any one of embodiments 1-30, or a salt and / or isotopologue thereof, wherein the salt is a pharmaceutically acceptable salt.

[0513] 32. A pharmaceutical preparation comprising the compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt and / or isotopologue thereof, and a pharmaceutically acceptable carrier.

[0514] 33. A method of treating or inhibiting cancer, comprising: administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt and / or isotopologue thereof, or the pharmaceutical preparation of embodiment 32.

[0515] 34. The method of embodiment 33, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0516] 35. The method of embodiment 33, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0517] 36. The method of any one of embodiments 33-35, wherein the cancer is a KRAS G12C-mediated cancer.

[0518] 37. The method of any one of embodiments 33-35, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0519] 38. The method of any one of embodiments 33-35, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0520] 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.

[0521] 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 inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0522] 41. The compound or a pharmaceutically acceptable salt thereof and / or an isotopologue thereof or a pharmaceutical formulation for use according to embodiment 40, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0523] 42. The compound or a pharmaceutically acceptable salt thereof and / or an isotopologue thereof or a pharmaceutical formulation for use according to embodiment 40, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0524] 43. The compound or a pharmaceutically acceptable salt thereof and / or an isotopologue thereof or a pharmaceutical formulation for use according to any one of embodiments 38-40, wherein the cancer is a KRAS G12C-mediated cancer.

[0525] 44. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 40-42, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0526] 45. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 40-44, wherein the compound or the pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0527] 46. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 40-45, wherein the compound or the pharmaceutical formulation is configured for administration in a therapeutically effective amount.

[0528] 47. A compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof of any one of embodiments 1-31 or a pharmaceutical formulation according to embodiment 30, for use in the manufacture of a medicament to treat or inhibit a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0529] 48. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of embodiment 47, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0530] 49. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of embodiment 47, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0531] 50. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 47-49, wherein the cancer is a KRAS G12C-mediated cancer.

[0532] 51. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 47-49, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0533] 52. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 47-51, wherein the compound or the pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0534] 53. The compound or pharmaceutically acceptable salt thereof and / or isotopologue thereof or pharmaceutical formulation for use of any one of embodiments 47-52, wherein the agent comprises a therapeutically effective amount of the compound or the composition.

[0535] 54. Use of a compound or a pharmaceutically acceptable salt thereof and / or an isotopologue thereof of any one of embodiments 1-31 or a pharmaceutical formulation according to embodiment 32 for the manufacture of a medicament to treat or inhibit a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0536] 55. The use of embodiment 54, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0537] 56. The use of embodiment 54, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0538] 57. The use of any one of embodiments 54-56, wherein the cancer is a KRAS G12C-mediated cancer.

[0539] 58. The use of any one of embodiments 54-56, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0540] 59. The use of any one of embodiments 54-58, wherein the compound or the pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0541] 60. The use of any one of embodiments 54-59, wherein the medicament comprises a therapeutically effective amount of the compound or the pharmaceutical formulation.

[0542] 61. The compound of any one of embodiments 1-31 or a pharmaceutically acceptable salt thereof and / or an isotopologue thereof or the pharmaceutical formulation of embodiment 30 for use in treating or inhibiting a cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0543] 62. The use of embodiment 61, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0544] 63. The use of embodiment 61, wherein the cancer is selected from the group consisting of glioblastoma multiforme, low grade glioma, head and neck squamous cell carcinoma, papillary thyroid cancer, anaplastic thyroid cancer, follicular thyroid cancer, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0545] 64. The use of any one of embodiments 61-63, wherein the cancer is a KRAS G12C-mediated cancer.

[0546] 65. The use of any one of embodiments 61-63, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0547] 66. The use of any one of embodiments 61-65, wherein the compound or the pharmaceutical formulation is configured for administration with a therapeutically effective amount of an additional chemotherapeutic agent.

[0548] 67. The use of any one of embodiments 61-66, wherein use involves a therapeutically effective amount of the compound or the composition.

[0549] General synthetic methods

[0550] The compounds in Table 1 of the disclosure are prepared according to or can be prepared according to the methods described in the Methods section or variations thereof that will be within the knowledge of persons of skill in the art.

[0551] The starting materials and reagents used in preparing these compounds are available from commercial suppliers (e.g., MilliporeSigma., Bachem., etc.) or are prepared by methods known to those of skill in the art following procedures set out in, for example, the references that follow: 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 Supplemental (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 merely illustrate some methods by which the compounds of the disclosure can be synthesized and various modifications to these schemes can be made and will be suggested to one of ordinary skill in the art upon a review of this disclosure. Isolation and purification of starting materials and intermediates and final products of the reactions can be effected by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0552] Unless otherwise indicated, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, for example, from about 0 °C to about 125 °C and further for example, at about room temperature (or ambient temperature), e.g., about 20 °C.

[0553] In some embodiments, the compounds provided herein can be synthesized according to Method 1.

[0554] Method 1.

[0555] wherein X', q, R 1 and R 3 are as defined for formula (I) or any variation thereof as detailed herein.

[0556] An exemplary embodiment of Method 1 is shown in Method la.

[0557] Method la.

[0558] wherein X', q, R 1 and R 3 as defined for formula (I) or any variation thereof as detailed herein.

[0559] An exemplary embodiment of Method 1 is further shown in the following steps.

[0560]

[0561] Step 1: 3-(benzyl(methyl)amino)-(X') q tert-butyl pyrrolidine-1-carboxylate

[0562] To a solution of 3-amino-(X') q tert-butyl pyrrolidine-1-carboxylate (1.0 equiv) in methanol [0.5 M] at 0 °C was added sodium cyanoborohydride (2.0 equiv), acetic acid (1.0 equiv) and benzaldehyde (1.1 equiv) 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 to dryness in vacuo and purified by column chromatography to give 3-[benzyl(methyl)amino]-(X') q tert-butyl pyrrolidine-1-carboxylate.

[0563]

[0564] Step 2: (X') q tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate

[0565] To a solution of carbon supported palladium in methanol [0.16 M] was added cis-3- [benzyl(methyl)amino]-(X') q tert-butyl pyrrolidine-1-carboxylate (1.0 equiv) and the mixture was stirred under a hydrogen atmosphere at 40 °C for 2 h. The reaction mixture was then filtered and the filtrate was concentrated to dryness in vacuo to give (X') q tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate.

[0566]

[0567] Step 3: 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') qtert-butyl pyrrolidine-1-carboxylate

[0568] To a solution of (X') q - tert-butyl 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - tert-butyl pyrrolidine-1-carboxylate.

[0569]

[0570] Step 4: 3-((7-chloro-8-fluoro-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - tert-butyl pyrrolidine-1-carboxylate.

[0571] To a solution of R 1 - methanol (1.5 equiv) and 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - pyrrolidine-1-carboxylic acid (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 sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 3-((7-chloro-8-fluoro-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - tert-butyl pyrrolidine-1-carboxylate.

[0572]

[0573] Step 5: 3-((8-fluoro-7-(7-R 3 - 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') qtert-butyl pyrrolidine-1-carboxylate

[0574] to ((7-R 3 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R 1 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R q -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R 3 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R 1 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R q -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R

[0575]

[0576] Step 6: 3-((7-(8-ethynyl-7-R 3 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R 1 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R q -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R

[0577] to 3-((8-fluoro-7-(7-R 3 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R 1 -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R q -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.5 equiv) and 3-((7-chloro-8-fluoro-2-((R N , N- To a solution of 7-(8-ethynyl-7-R 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)-N-methyl-N-(X') q - pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0578]

[0579] Step 7: 7-(8-ethynyl-7-R 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)-N-methyl-N-(X') q - pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0580] To a solution of 7-(8-ethynyl-7-R 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)-N-methyl-N-(X') q - pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (as trifluoroacetate salt)

[0581]

[0582] Step 8: ((7-(8-ethynyl-7-R 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - pyrrolidin-1-yl)prop-2-en-1-one

[0583] To a solution of 7-(8-ethynyl-7-R 3 - naphthalen-1-yl)-8-fluoro-2-((R1 - methoxy)-N-methyl-N-(X') q To a solution of (7-(8-ethynyl-7- R 3 - naphthalen-1-yl)-8-fluoro-2-((R 1 - methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-(X') q - pyrrolidin-1-yl)prop-2-en-1-one.

[0584] Examples

[0585] 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 practice the present disclosure. The preparations should not be construed as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0586] The following abbreviations are used in this section:

[0587]

[0588]

[0589] Unless otherwise indicated, all reagents were obtained from commercial suppliers and used without further purification.

[0590] Synthetic Examples

[0591]

[0592] Example 1-1: Synthesis of compound 1-1; cis-1-((-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-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) Example 1-2 and 1-3: Isolation of compounds 1-2 and 1-3; 1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-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-((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 (from Example 1-1) SFC separation

[0593]

[0594] Step 1: cis-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0595] To a solution of cis-3-amino-2-methyl-pyrrolidine-l-carboxylic acid tert-butyl ester (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 vacuum and purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate / pet. ether) to afford cis-3-(benzyl(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester (1 g, crude) as colorless oil which was used in the next step without any further purification: 1 H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.28 (m, 1H), 7.27 - 7.24 (m, 3H), 7.20 - 7.16 (m, 1H), 4.08 (s, 1H), 3.99 (br s, 1H), 3.63 - 3.50 (m, 1H), 3.47 - 3.31 (m, 1H), 3.29 - 3.16 (m, 1H), 2.77 - 2.59 (m, 1H), 2.03 - 1.99 (m, 3H), 1.97 (s, 1H), 1.88 - 1.74 (m, 1H), 1.40 (d, J = 2.0 Hz, 9H), 1.14 - 1.06 (m, 3H). LCMS Rt = 0.338 min, m / z = 304.2 [M + H] + .

[0596]

[0597] Step 2: cis-2-Methyl-3-(methylamino)pyrrolidine-l-carboxylic acid tert-butyl ester

[0598] To a solution of palladium on carbon (200 mg, 10% purity) in methanol (10 mL) was added cis-3-[benzyl(methyl)amino]-2-methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester (500 mg, 1.6 mmol), the mixture was stirred at 40 °C under hydrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuum to get cis-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester (300 mg, crude) as colorless oil which was used in the next step without any further purification: 1 H NMR (400 MHz, chloroform-d) δ 4.02 - 3.76 (m, 1H), 3.25 - 2.98 (m, 2H), 2.90 - 2.72 (m, 1H), 2.34 (s, 3H), 1.79 (br s, 2H), 1.36 (s, 9H), 1.02 - 0.88 (m, 3H). LCMS Rt = 0.295 min, m / z = 214.2 [M + H] + .

[0599]

[0600] Step 3: cis-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0601] To a solution of cis-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester (252.54 mg, 1.18 mmol) and 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (350 mg, 1.39 mmol) in dioxane (5 mL) was added N,N-diisopropylethylamine (537.53 mg, 4.16 mmol), 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 sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 65-70% ethyl acetate / pet. ether) to get cis-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester (350 mg, 58.67%) as yellow solid. LCMS Rt = 0.651 min, m / z = 429.1 [M + H] + .

[0602]

[0603] Step 4: cis-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester

[0604] To a solution of ((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methanol (66.60 mg, 418.31 pmol) and cis-3-[(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-methyl- amino]-2-methyl-pyrrolidine-l-carboxylic acid tert-butyl ester (120 mg, 278.87 pmol) in dioxane (2 mL) was added N,N-diisopropylethylamine (108.13 mg, 836.62 pmol) and 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 80-100% ethyl acetate in petroleum ether) to give cis-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester (150 mg, 97.26%) as a yellow solid. LCMS Rt = 1.491 min, m / z = 552.2 [M + H] + .

[0605]

[0606] Step 5: cis-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0607] To a solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (306.81 mg, 678.07 μmol) and cis-3-((7-chloro-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester (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-l,l'- biphenyl)[2-(2'-amino-l,l'-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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 85-100% ethyl acetate / pet. ether) to give cis-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-l-carboxylic acid tert-butyl ester (180 mg, crude), which was used in the next step without any further purification. LCMS Rt = 0.624 min, m / z = 842.5 [M + H] + .

[0608]

[0609] Step 6: cis-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0610] To a solution of cis-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 213.50 μmol) in N,N-dimethylformamide (3 mL) was added cesium fluoride (324.31 mg, 2.13 mmol) and the mixture was stirred at 20 °C for 1 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-25% methanol / dichloromethane) to give cis-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.478 min, m / z = 686.3 [M+ H] + .

[0611]

[0612] Step 7: cis-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine

[0613] To a solution of cis-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 94.65 pmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (32.38 mg, 283.94 pmol) and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to dryness in vacuum to give 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) which was used in the next step without any further purification. LCMS Rt = 0.365 min, m / z = 586.3 [M + H] + .

[0614]

[0615] 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

[0616] 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 vacuum and purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 40%-70% B over 8.0 min) to give cis-1-((2RS,3RS)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-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 (5-95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.226 min, ESI+ found [M+H] + = 641.3.

[0617]

[0618] 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 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 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) 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) ​ ​

[0619] Purification 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) by SFC (Column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); Mobile phase: [CO2-EtOH (0.1% NH4OH)]; B%: 50%, Isocratic elution mode) afforded the following as arbitrarily assigned:

[0620] ​ ​ ​ (peak 1, retention time = 1.467 min) (33.02 mg) as a white solid: 1 HNMR (400 MHz, chloroform-d) δ = 9.21 - 9.16 (m, 1H), 8.02 - 7.93 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.31 (m, 1H), 6.57 - 6.36 (m, 2H), 5.77 - 5.68 (m, 1H), 5.45 - 5.20 (m, 1H), 5.10 - 4.89 (m, 2H), 4.45 - 4.15 (m, 2H), 3.94 - 3.81 (m, 1H), 3.68 (s, 1H), 3.63 (s, 3H), 3.48 - 3.14 (m, 3H), 3.01 (s, 1H), 2.86 (s, 1H), 2.59 - 2.28 (m, 3H), 2.27 - 2.09 (m, 2H), 2.04 - 1.86 (m, 3H), 1.13 (d, J= 4.9 Hz, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.226 min, ESI+ found [M+H] + = 641.3; and

[0621] ​ ​ ​ (peak 2, retention time = 1.617 min) (30.58 mg) as a white solid: 1 HNMR (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 / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.226 min, ESI+ found [M+H] + = 641.3.

[0622]

[0623] ​ ​ ​

[0624]

[0625] Step 1: tert-Butyl (3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1- carboxylate

[0626] The reductive amination reaction was carried out in a similar manner as Method #1, Step 1. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford (3R,4R)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a white solid (5.25 g, 70.49%): 1 H NMR (400 MHz, chloroform-d) δ 7.30 - 7.20 (m, 5H), 3.60 - 3.50 (m, 2H), 3.38 - 3.31 (m, 1H), 3.29 - 3.05 (m, 3H), 2.79 - 2.66 (m, 1H), 2.38 - 2.24 (m, 1H), 1.97 (s, 3H), 1.39 (s, 9H), 0.99-0.97 (dd, J LCMS Rt = 0.323 min, m / z = 304.2 [M + H] + .

[0627]

[0628] Step 2: (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester

[0629] The deprotection of Bn group was carried out in a similar manner as Method #1, Step 2. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuum to afford (3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester as a white solid (3.54 g, crude), which was used in the next step without any further purification. LCMS Rt = 0.282 min, m / z = 214.2 [M + H] + .

[0630]

[0631] Step 3: (3R,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4- methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0632] The substitution reaction was carried out in a manner similar to step 3 of method #1. The crude residue was diluted with a 10:1 mixture of petroleum ether and ethyl acetate (10:1) (10 mL) and the resulting precipitate was filtered to give (3R,4R)-3-((2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (9.25 g, crude product) as a yellow solid, which was used in the next step without any further purification. LCMS Rt = 0.578 min, m / z = 429.1 [M+ H]+.

[0633]

[0634] Step 4: (3R,4R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0635] The substitution reaction was carried out in a manner similar to step 4 of method #1. The mixture was concentrated to dryness under vacuum and then passed through reversed-phase HPLC (column: Phenomenex luna C18 250*150mm*15um; mobile phase:

[0636] [H2O (0.1% TFA) - ACN]; gradient: purification was performed over 20.0 min at 30%-60% B) to obtain a yellow solid (3R,4R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (7.77 g, 54.24%, trifluoroacetate). LCMS Rt = 2.194 min, m / z = 552.2 [M + H] + .

[0637]

[0638] Step 5: (3R,4R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0639] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by reverse phase HPLC (Column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile Phase: [H2O (10mM NH4HCO3) - ACN]; Gradient: 85%-95% B over 8.0 min) to give (3R,4R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (285 mg, 75.16%) as a white solid. LCMS Rt = 0.639 min, m / z = 842.5 [M + H] + .

[0640]

[0641] Step 6: (3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4- methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0642] A deprotection reaction of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give (3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, crude), which was used in the next step without any further purification. LCMS Rt = 0.454 min, m / z = 686.3 [M + H] + .

[0643]

[0644] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4R)-4-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4- amine

[0645] Deprotection of the Boc group was carried out in a similar manner as in Method #1 Step 7. The mixture was concentrated to dryness in vacuo to give 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 which was used in the next step without any further purification. LCMS Rt = 0.335 min, m / z = 586.3 [M + H] + .

[0646]

[0647] 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

[0648] The acylation reaction was carried out in a similar manner as in 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 in 8.0 min) to give 1-((3R,4R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-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: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.30 - 9.17 (m, 1H), 8.21 - 8.07 (m, 2H), 7.74 - 7.64 (m, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.27 (dd, J = 2.1, 16.7Hz, 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 = 4.6Hz, 2H), 3.08 (s, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.86 (m, 1H), 2.24 - 2.14 (m, 3H), 2.12 (br d, J = 2.6 Hz, 1H), 2.10 - 2.02 (m, 1H), 1.90 - 1.81 (m, 2H), 1.21 - 1.07 (m, 3H). LCMS Rt = 2.997 min, m / z = 640.3 [M + H] + . LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.997 min, ESI+ found [M+H] = 640.3.

[0649]

[0650] ​ ​ (amino)-4-methylpyrrolidone-1-yl)prop-2-en-1-one (Method 1)

[0651]

[0652] Step 1: tert-Butyl (3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1- carboxylate

[0653] The reductive amination reaction was carried out in a similar manner as Method #1, Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) to afford tert-butyl (3R,4S)-3-(benzyl(methyl)amino)-4-methylpyrrolidine-1-carboxylate as a yellow oil (5 g, 67.13%). LCMS Rt = 0.298 min, m / z = 304.2 [M + H]+.

[0654]

[0655] Step 2: (3S,4R)-3-methyl-4-(methylamino)pyrrolidine-1 -carboxylate

[0656] Deprotection of the Bn group was carried out in a similar manner as in Method #1 Step 2. The reaction mixture was concentrated in vacuo to give (3S,4R)-3-methyl-4- (methylamino)pyrrolidine-1 -carboxylate as a white oil (3.2 g, crude) which was used in the next step without any further purification. LCMS Rt = 0.508 min, m / z = 214.2 [M + H]+.

[0657]

[0658] Step 3: (3R,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidine-1 -carboxylate

[0659] The substitution reaction was carried out in a similar manner as in Method #1 Step 3. The mixture was filtered and concentrated in vacuo to give (3R,4S)-3-((2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1 -carboxylate as a yellow solid (5.7 g, 66.88%) and used in the next step without further purification. LCMS Rt = 0.572 min, m / z = 429.1 [M + H] + .

[0660]

[0661] Step 4: (3R,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1- carboxylate

[0662] The substitution reaction was carried out in a similar manner as Method #1 Step 4. The mixture was concentrated to dryness in vacuo and purified by reverse phase HPLC (Column: Welch Xtimate C18 250*100mm#10um; Mobile Phase: [Water (10mM NH4HCO3) - ACN]; Gradient: 15%-45% B in 20.0 min) to give (3R,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-l- carboxylic acid tert-butyl ester (2.5 g, 34.74%) as a yellow solid. LCMS Rt = 0.406 min, m / z = 552.2 [M + H] + .

[0663]

[0664] Step 5: (3R,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0665] The Suzuki reaction was carried out in a similar manner as Method #1 Step 5. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 30-100% ethyl acetate / pet. ether) to give (3R,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-l-carboxylic acid tert-butyl ester (400 mg, 52.48%) as a yellow solid and used in the next step without further purification. LCMS Rt = 0.616 min, m / z = 842.5 [M + H] + .

[0666]

[0667] Step 6: (3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-4-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0668] Deprotection of the TIPS group was carried out in a similar manner as in Method #1 Step 6. The mixture was filtered and concentrated to dryness in vacuum to give (3R,4S)-3-((7-(8- ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine- 1-carboxylic acid tert-butyl ester (400 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.451 min, m / z = 686.3 [M + H] + .

[0669]

[0670] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,4S)-4- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0671] Deprotection of the Boc group was carried out in a similar manner as in Method #1 Step 7. The mixture was concentrated in vacuum and purified by reverse phase HPLC (column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [water (0.1% TFA) - ACN]; gradient: 10%-40% B in 8.0 min) to give 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-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%, trifluoroacetic acid salt) as a yellow oil. LCMS Rt = 0.358 min, m / z = 586.3 [M + H] + .

[0672]

[0673] Step 8: 1-((3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0674] The acylation reaction was performed in a similar manner as Step 8 of Method #1. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (10 mM NH4HC03)-ACN]; gradient: 45%-75% B over 8.0 min) to give 1-((3R,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow solid (56.50 mg, 29.62%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.31 - 9.17 (m, 1H), 8.23 - 8.09 (m, 2H), 7.76 - 7.64 (m, 2H),7.48 (t, J = 9.0 Hz, 1H), 6.61 (ddd, J = 10.5, 13.1, 16.8 Hz, 1H), 6.33 -6.21 (m, 1H), 5.77 - 5.66 (m, 1H), 5.41 - 5.17 (m, 1H), 5.12 - 4.89 (m, 1H),4.27 - 4.20 (m, 1H), 4.19 - 4.14 (m, 1H), 4.13 (br d, J = 3.3 Hz, 2H), 3.73 -3.51 (m, 1H), 3.46 (s, 3H), 3.34 - 3.27 (m, 1H), 3.16 (br d, J = 6.2 Hz, 2H),3.10 - 3.05 (m, 1H), 2.96 - 2.86 (m, 1H), 2.84 - 2.62 (m, 1H), 2.22 - 2.17(m, 3H), 2.13 (br d, J= 2.4 Hz, 1H), 2.08 (br s, 1H), 1.89 (br dd, J = 7.0, 11.0 Hz, 2H), 1.17 (d, J = 6.5 Hz, 3H). LCMS Rt = 2.993 min, m / z = 640.3 [M + H] + . LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.993 min, ESI+ found [M+H] = 640.3.

[0675]

[0676] Example 4: Synthesis of compound 3-1; 1-((2S,4R)-4-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) (amino)-2-methylpyrrolidone-1-yl)prop-2-en-1-one (Method 1)

[0677]

[0678] Step 1: (2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0679] The substitution reaction was carried out in a similar manner as Method #1 Step 3. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to get (2S,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester as yellow oil (800 mg, 93.87%): 1 H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 5.21 - 5.11 (m, 1H), 3.96 - 3.84 (m, 2H), 3.36 (s, 3H), 3.30 (t, J = 10.3 Hz, 1H), 2.53 - 2.45 (m, 1H), 1.78 - 1.69 (m, 1H), 1.42 (s, 9H), 1.33 (d, J = 6.0 Hz, 3H). LCMS Rt = 0.568 min, m / z = 429.1 [M + H] + .

[0680]

[0681] Step 2: (2S,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester

[0682] The substitution reaction was carried out in a similar manner as 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 / pet. ether) to afford (2S,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester as a yellow solid (300 mg, 31.12%): 1 H NMR 1HNMR (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] + .

[0683]

[0684] Step 3: (2S,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0685] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2S,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (300 mg, 65.60%) as a yellow solid. LCMS Rt = 0.639 min, m / z = 842.5 [M + H] + .

[0686]

[0687] Step 4: (2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0688] Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The mixture was filtered and purified by reverse phase HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.1% TFA) - ACN]; gradient: 30%-60% B over 8.0 min) to give (2S,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 84.23%, trifluoroacetate salt) as a yellow solid. LCMS Rt = 1.839 min, m / z = 686.3 [M + H] + .

[0689]

[0690] Step 5: 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrazin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5S)-5-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin- 4-amine

[0691] Deprotection of the Boc group was carried out in a similar manner as for Method #1 Step 7. The mixture was concentrated in vacuo to give 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) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.341 min, m / z = 586.3 [M + H] + .

[0692]

[0693] 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

[0694] The acylation reaction was carried out in a similar manner as for Method #1 Step 8. The residue was purified by reverse phase HPLC (Column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile Phase: [water (10 mM NH4HCO3) - ACN]; Gradient: 30%-60% B in 8.0 min) to give 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 light yellow amorphous solid: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.18 (d, J = 2.3 Hz, 1H), 8.17 - 8.11 (m, 2H), 7.72 - 7.66 (m, 2H), 7.47 (t, J= 9.0 Hz, 1H), 6.68 - 6.51 (m, 1H), 6.31 - 6.19 (m, 1H), 5.74 - 5.64 (m, 1H), 5.36 - 5.10 (m, 2H), 4.38 - 4.24 (m, 1H), 4.19 (brs, 2H), 4.14 - 4.10 (m, 1H), 3.75 - 3.54 (m, 1H), 3.47 (s, 3H), 3.30 - 3.24 (m, 1H), 3.20 - 3.11 (m, 2H), 3.07 (s, 1H), 2.95 - 2.87 (m, 1H), 2.76 - 2.53 (m, 1H), 2.25 - 2.18 (m, 1H), 2.13 - 2.00 (m, 3H), 1.94 - 1.90 (m, 1H), 1.89 - 1.82 (m, 2H), 1.44 (d, J = 6.1 Hz, 3H) LCMS Rt = 2.976 min, m / z = 640.3 [M+ H] + . LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.976 min, ESI+ found [M+H] = 640.3.

[0695]

[0696] Example 5: Synthesis of compound 3-3; 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) (amino)-2-methylpyrrolidone-1-yl)prop-2-en-1-one (Method 1)

[0697]

[0698] Step 1: (2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0699] The reductive amination reaction was performed in a similar manner as Method #1 Step 1. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to afford (2R,4R)-4-(benzyl(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a colorless oil (720 mg, 47.37%): 1 HNMR (400 MHz, Methanol-d4) δ 7.35 - 7.23 (m, 5H), 4.00 (quintet, J = 6.1 Hz, 3H) LCMS Rt = 2.976 min, m / z = 640.3 [M+ H] 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).

[0700]

[0701] Step 2: (2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester

[0702] Deprotection of the Bn group was performed in a similar manner as Method #1 Step 2. The reaction mixture was concentrated in vacuo to give (2R,4R)-2-methyl-4-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester (510 mg, crude) as a yellow oil and used as is in the next step: 1 H NMR (400 MHz, Methanol-d4) δ 3.95 (br s, 1H), 3.55 (br s, 1H), 3.31 - 3.09 (m, 2H), 2.35 (s, 3H), 1.94 - 1.80 (m, 2H), 1.46 (s, 9H), 1.20 (br d, J = 6.3 Hz, 3H).

[0703]

[0704] Step 3: (2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0705] The substitution reaction was performed in a similar manner as Method #1 Step 3. The mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2R,4R)-4-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester (700 mg, 85.03%) as a yellow solid. LCMS Rt = 0.572 min, m / z = 429.1 [M + H] + .

[0706]

[0707] Step 4: (2R,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester

[0708] The substitution reaction was carried out in a similar manner as 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) to afford (2R,4R)-4-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (580 mg, 70.51%). LCMS Rt = 0.657 min, m / z = 552.2 [M + H] + .

[0709]

[0710] Step 5: (2R,4R)-4-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0711] The Suzuki reaction was carried out in a similar manner as Method #1 Step 5. The mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford (2R,4R)-4-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester as a brown solid (790 mg, 95.96%). LCMS Rt = 1.041 m / z = 842.5 [M + H] + .

[0712]

[0713] Step 6: (2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0714] The deprotection of the TIPS group was performed in a similar manner as Step 6 of Method #1. The mixture was concentrated to dryness in vacuo to give (2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester (590 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS Rt = 1.838 min, m / z = 686.3 [M + H] + .

[0715]

[0716] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((3R,5R)-5- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0717] The deprotection of the Boc group was performed in a similar manner as Step 7 of Method #1. The mixture was concentrated in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-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 which was used in the next step without further purification. LCMS Rt = 0.347 min, m / z = 586.3 [M + H] + .

[0718]

[0719] Step 8: 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0720] The acylation reaction was performed in a similar manner as Step 8 of Method #1. The residue was concentrated in vacuo and 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) to give 1-((2R,4R)-4-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one as a light yellow solid (75.66 mg, 39.76%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.17 - 9.11 (m, 1H), 8.16 - 8.07 (m, 2H), 7.71 - 7.61 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.25 (dt, J = 1.8, 16.9 Hz, 1H), 5.67 (ddd, J = 2.3, 10.4, 12.7 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.36 - 5.17 (m, 1H), 4.42 (br d, J= 3.3 Hz, 1H), 4.22 - 4.11 (m,2H), 4.11 - 3.83 (m, 1H), 3.79 - 3.61 (m, 1H), 3.39 (s, 3H), 3.28 - 3.22 (m,1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.04 (m, 1H), 2.93 - 2.85 (m, 1H), 2.63 -2.36 (m, 1H), 2.23 - 2.12 (m, 3H), 2.09 - 1.98 (m, 2H), 1.89 - 1.83 (m, 2H),1.34 - 1.24 (m, 3H). LCMS Rt = 2.976 min, m / z = 640.3 [M + H] + LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.976 min, ESI+ found [M+H] = 640.3.

[0721]

[0722] Example 6: Synthesis of compound 2-2; 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) (amino)-4-methylpyrrolidone-1-yl)prop-2-en-1-one (Method 1)

[0723]

[0724] Step 1: (3S,4S)-3-[benzyl(methyl)amino]-4-methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester

[0725] The reductive amination reaction was performed in a similar manner as Method #1 Step 1. The reaction mixture was purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate / pet. ether) to afford (3S,4S)-3-[benzyl(methyl)amino]-4-methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester as a colorless oil (850 mg, 55.92%): 1 H NMR (400 MHz, Chloroform-d) δ 7.36 - 7.24 (m, 5H), 3.75 (br t, J = 6.2 Hz, 1H), 3.66 - 3.60 (m,1H), 3.55 (dd, J = 7.6, 9.8 Hz, 1H), 3.44 (br dd, J= 5.3, 9.7 Hz, 1H), 3.36- 3.30 (m, 1H), 3.29 - 3.17 (m, 1H), 2.84 - 2.75 (m, 1H), 2.44 - 2.37 (m,1H), 2.05 (s, 3H), 1.48 (s, 9H), 1.07 (br d, J = 6.5 Hz, 3H).

[0726]

[0727] Step 2: tert-Butyl (3S,4S)-3-methyl-4-(methylamino)pyrrolidine-1-carboxylate

[0728] Deprotection of the Bn group was performed in a similar manner as Method #1, Step 2. The reaction mixture was concentrated in vacuo to give tert-butyl (3S,4S)-3-methyl-4- (methylamino)pyrrolidine-1-carboxylate (580 mg, crude) as a colorless oil, which was used in the next step without further purification: 1 H NMR (400 MHz, Chloroform-d) δ 3.50 - 3.38 (m, 2H), 3.28 - 3.03 (m, 3H), 2.42 (s, 3H), 2.37 - 2.28 (m, 1H), 1.45 (s, 9H), 1.00 - 0.95 (m, 3H).

[0729]

[0730] Step 3: tert-Butyl (3S,4S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidine-1-carboxylate

[0731] The substitution reaction was performed in a similar manner as Method #1, Step 3. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 0-100% ethyl acetate / petroleum ether) to give 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] + .

[0732]

[0733] Step 4: (3S,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4- methylpyrrolidine-1 -carboxylate

[0734] The substitution reaction was carried out in a similar manner as Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100-200 mesh, 50-100% ethyl acetate / pet. ether) to afford (3S,4S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4- methylpyrrolidine-1 -carboxylate as a yellow solid (1.02 g, 95.62%). LCMS Rt = 0.427 min, m / z = 552.2 [M + H] + .

[0735]

[0736] Step 5: (3S,4S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-1 -carboxylate

[0737] The Suzuki reaction was carried out in a similar manner as Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to afford (3S,4S)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4- methylpyrrolidine-1 -carboxylate as a brown solid (490 mg, 80.36%). LCMS Rt = 1.122 min, m / z = 842.5 [M + H] + .

[0738]

[0739] Step 6: (3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0740] Deprotection of the TIPS group was performed in a similar manner as Step 6 of Method #1. The filtrate was concentrated to dryness in vacuo to give (3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-4-methylpyrrolidine-l-carboxylic acid tert-butyl ester (450 mg, crude) as a brown solid which was used in the next step without further purification. LCMS Rt = 0.451 min, m / z = 686.3 [M + H] + .

[0741]

[0742] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrozin-7a(5H)-yl)methoxy)-N-methyl-N-((3S,4S)-4-methylpyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine

[0743] Deprotection of the Boc group was performed in a similar manner as Step 7 of Method #1. The reaction mixture was concentrated to dryness in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrozin-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 which was used in the next step without further purification. LCMS Rt = 0.358 min, m / z = 586.3 [M + H] + .

[0744]

[0745] Step 8: 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidin-1-yl)prop-2-en-1-one

[0746] The acylation reaction was performed in a similar manner as Method #1 Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 30%-65% B over 8.0 min) to give 1-((3S,4S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 4-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow amorphous solid (24.23 mg, 21.42%): 1H NMR (400 MHz, Acetoni trile-d3) δ 9.23 - 9.18 (m, 1H), 8.15 - 8.08 (m, 2H), 7.70 - 7.63 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.25 (dd, J = 2.0, 16.8 Hz, 1H), 5.69 (br d, J = 10.4 Hz, 1H), 5.63 - 5.43 (m, 1H), 5.36 - 5.15 (m, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 3.97 (m, 2H), 3.96 - 3.82 (m, 2H), 3.51 - 3.46 (m, 1H), 3.44 (t, J = 4.4 Hz, 3H), 3.36 - 3.28 (m, 1H), 3.27 - 3.22 (m, 1H), 3.19 - 3.10 (m, 2H), 3.09 - 3.03 (m, 1H), 3.01 - 2.86 (m, 2H), 2.19 - 2.16 (m, 1H), 2.10 (br d, J = 2.6 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.92 - 1.81 (m, 2H), 1.11 (t, J = 7.7 Hz, 3H). LCMS Rt = 2.992 min, m / z = 640.3 [M + H] + LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.992 min, ESI+ found [M+H] = 640.3.

[0747]

[0748] Example 7: Synthesis of compound 5; 1-((R)-3-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2-(((S)- 5-Methyl-5-azaspiro[2,4]hept-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine- 1-yl)prop-2-en-1-one (Method 1)

[0749]

[0750] Step 1: (S)-(5-methyl-5-azaspiro[2.4]heptan-6-yl)methanol

[0751] 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) 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 and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give (S)-(5-methyl-5-azaspiro[2.4]heptan-6-yl)methanol (260 mg, crude) as a white solid and used in the next step without further purification: 1 H NMR (400 MHz, Chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 - 2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4, 12.5 Hz, 1H), 0.54 - 0.40 (m, 4H). J H NMR (400 MHz, Chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 - 2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4, 12.5 Hz, 1H), 0.54 - 0.40 (m, 4H). J H NMR (400 MHz, Chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 - 2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4, 12.5 Hz, 1H), 0.54 - 0.40 (m, 4H). J H NMR (400 MHz, Chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 - 2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4, 12.5 Hz, 1H), 0.54 - 0.40 (m, 4H). J H NMR (400 MHz, Chloroform-d) δ 3.63 (dd, J = 3.6, 10.8 Hz, 1H), 3.38 (dd, J = 2.1, 10.8 Hz, 1H), 2.63 - 2.60 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.51 (m, 1H), 2.28 (s, 3H), 1.89 (dd, J = 8.6, 12.6 Hz, 1H), 1.68 (dd, J = 7.4, 12.5 Hz, 1H), 0.54 - 0.40 (m, 4H).

[0752]

[0753] Step 2: (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 -carboxylic acid tert-butyl ester

[0754] The substitution reaction was performed in a similar manner as Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane / methanol) to give (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 -carboxylic acid tert-butyl ester (300 mg, 31.96%) as a white solid. LCMS Rt = 0.633 min, m / z = 520.24 [M + H] + .

[0755]

[0756] Step 3: (R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1 -carboxylic acid tert-butyl ester

[0757] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% dichloromethane / methanol) to give (R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((S)-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1 -carboxylic acid tert-butyl ester as a brown solid (300 mg, 64.24%): 1 HNMR (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 = 8.8 Hz, 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] + .

[0758]

[0759] Step 4: (R)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-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 -carboxylic acid tert-butyl ester

[0760] Deprotection of the TIPS group was carried out in a similar manner as in Method #1 Step 6. The mixture was concentrated to dryness in vacuo to give (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- carboxylic acid tert-butyl ester (100 mg, crude) as a brown oil which was used in the next step without any further purification. LCMS Rt = 0.468 min, m / z = 654.3 [M + H] + .

[0761]

[0762] 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

[0763] Deprotection of the Boc group was carried out in a similar manner as in Method #1 Step 7. The mixture was concentrated to dryness in vacuo to give 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 which was used in the next step without further purification. LCMS Rt = 0.353 min, m / z = 554.3 [M + H] + .

[0764]

[0765] 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

[0766] The acylation reaction was performed in a similar manner as 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 in 8.0 min) to give 1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-5-methyl-5- azaspiro[2.4]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: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.17 (br s, 1H), 8.16 - 8.08 (m, 2H), 7.71 - 7.65 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H), 6.66 - 6.52 (m, 1H), 6.25 (br d, J = 16.8 Hz, 1H), 5.73 - 5.64 (m, 1H), 5.45 - 5.29 (m, 1H), 4.57 - 4.51 (m, 1H), 4.40 - 4.34 (m, 1H), 4.14 - 3.93 (m, 1H), 3.92 - 3.79 (m, 1H), 3.74 - 3.62 (m, 1H), 3.61 - 3.45 (m, 1H), 3.43 (s, 3H), 3.32 - 3.25 (m, 1H), 2.93 - 2.85 (m, 1H), 2.66 (br d, J = 8.9 Hz, 1H), 2.52 (br d, J = 8.8 Hz, 1H), 2.41 (d, J = 1.9 Hz, 3H), 2.33 - 2.24 (m, 2H), 2.05 (br dd, J = 8.0, 12.4 Hz, 1H), 1.69 (br dd, J = 7.5, 12.5 Hz, 1H), 0.62 - 0.48 (m, 4H). LCMS Rt = 2.928 min, m / z = 608.3 [M + H] +LCMS (5-95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.928 min, ESI+ found [M+H]=608.3.

[0767]

[0768] Example 8: Synthesis of compound 2-4; 1-((3S,4R)-3-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) (amino)-4-methylpyrrolidone-1-yl)prop-2-en-1-one

[0769] 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.22 - 9.15 (m, 1H), 8.15 - 8.09 (m, 2H), 7.70 - 7.62 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 6.57 (ddd, J = 10.4, 13.3, 16.8 Hz, 1H), 6.27 - 6.20 (m, 1H), 5.67 (ddd, J = 2.2, 4.2, 10.4 Hz, 1H), 5.37 - 5.16 (m, 1H), 5.08 - 4.86 (m, 1H), 4.21 - 4.16 (m, 1H), 4.15 - 4.01 (m, 2H), 4.01 - 3.93 (m, 1H), 3.70 - 3.46 (m, 1H), 3.45 - 3.42 (m, 3H), 3.30 - 3.23 (m, 1H), 3.20 - 3.11 (m, 2H), 3.05 (s, 1H), 2.93 - 2.84 (m, 1H), 2.81 - 2.61 (m, 1H), 2.23 - 2.15 (m, 2H), 2.11 - 2.03 (m, 2H), 1.91 - 1.81 (m, 3H), 1.17 - 1.11 (m, 3H). LCMS (5-95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.998 min, ESI+ found [M+H] + = 641.3.

[0770]

[0771] Example 9: Synthesis of compound 3-4; 1-((2S,4S)-4-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) (amino)-2-methylpyrrolidone-1-yl)prop-2-en-1-one

[0772] 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 / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 2.985 min, ESI+ found [M+H] + = 641.3.

[0773]

[0774] Example 10: Synthesis of compound 3-2; 1-((2R,4S)-4-((7-(8-ethynyl-7-fluoronaphth-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl (yl)amino)-2-methylpyrrolidone-1-yl)prop-2-en-1-one

[0775] 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 / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 3.003 min, ESI+ Found [M+H] + = 641.3.

[0776]

[0777] 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- 2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0778] 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 / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.982 min, ESI+ found [M+H] + = 623.3.

[0779]

[0780] 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)

[0781]

[0782] Step 1: (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H- pyr azin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0783] To a solution of (2R,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (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 4A molecular 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 under a nitrogen atmosphere for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD CI 8 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3) - ACN]; gradient: 60%-90% B over 8.0 min) to give (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-carboxylic acid tert-butyl ester (600 mg, 32.70%) as a white solid: 1 H NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 7.58 - 7.50 (m, 4H), 7.41 - 7.25 (m, 6H), 4.95 - 4.78 (m, 1H), 4.51- 4.32 (m, 2H), 4.13 - 3.93 (m, 1H), 3.70 - 3.46 (m, 2H), 3.45 - 3.25 (m, 5H), 3.06 - 2.93 (m, 1H), 2.85 - 2.57 (m, 1H), 2.54 - 2.33 (m, 1H), 2.31 - 2.20 (m, 2H), 2.17 - 2.07 (m, 2H), 2.06 - 1.95 (m, 2H), 1.94 - 1.73 (m, 2H), 1.40 (s, 9H), 1.03 - 0.95 (m, 12H). LCMS Rt = 2.396 min, m / z = 789.2 / 790.2 [M+ H] + .

[0784]

[0785] Step 2: (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0786] A mixture of (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 633.35 pmol), ((2-fluoro-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (429.87 mg, 950.03 pmol), 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 pmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 60%-90% B over 8.0 min) to give (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyrazin-7a(5H)- yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (420 mg, 55.56%, trifluoroacetic acid 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 = 10.1 Hz, 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] + .

[0787]

[0788] Step 3: (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- hydroxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0789] To a solution of (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyr azin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)py rido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 185.27 pmol, trifluoroacetate salt) in dichloromethane (2 mL) was added triethylsilane (0.1 mL, 0.74 mmol) and trifluoroacetic acid (0.1 mL, 1.29 mmol). The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were washed with saturated lithium chloride (3 x 5 mL) and dried over sodium sulfate and concentrated in vacuo to give (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyr azin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)py rido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 185.27 pmol, trifluoroacetate salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.432 min, m / z = 685.2 [M + H] N,N To a solution of (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyr azin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)py rido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 185.27 pmol, trifluoroacetate salt) in dichloromethane (2 mL) was added triethylsilane (0.1 mL, 0.74 mmol) and trifluoroacetic acid (0.1 mL, 1.29 mmol). The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were washed with saturated lithium chloride (3 x 5 mL) and dried over sodium sulfate and concentrated in vacuo to give (2R,3R)-3-((2-(((2R,7aS)-2-((tert-butyldiphenylsilyl)oxy)tetrahydro-1H-pyr azin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)py rido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 185.27 pmol, trifluoroacetate salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.432 min, m / z = 685.2 [M + H] + .

[0790]

[0791] 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-pyr azin-2-ol

[0792] 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 pmol) in HCl / ethyl acetate (2M, 2 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to dryness in vacuo to give (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8- fluoro-4-(methyl((2R,3R)-2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (106 mg, crude, hydrochloride salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.339 min, m / z = 585.2 [M + H] + .

[0793]

[0794] 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

[0795] 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 pmol, hydrochloride) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (43.01 mg, 511.98 pmol) and prop-2-enoyl chloride (10.81 mg, 119.46 pmol) and the mixture was stirred at 0 °C under nitrogen atmosphere for 10 min. The reaction mixture was concentrated to dryness in vacuum and purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 30%-65% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- hydroxytetrahydro-1H-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: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.24 (d, J = 4.8 Hz, 1H), 8.18 - 8.11 (m, 2H), 7.69 (d, J = 4.8 Hz, 2H), 7.47 (t, J = 9.1 Hz, 1H), 6.61 (dd, J = 10.3, 16.7 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.74 - 5.66 (m, 1H), 5.04 - 4.79 (m, 2H), 4.55 - 4.38 (m, 1H), 4.31 - 4.06 (m, 2H), 3.94 - 3.72 (m, 1H), 3.72 - 3.65 (m, 1H), 3.62 (d, J = 4.9 Hz, 3H), 3.61 - 3.50 (m, 1H), 3.29 (s, 1H), 3.19 - 3.08 (m, 1H), 2.95 (td, J= 5.2, 16.5 Hz, 1H), 2.89 - 2.77 (m, 1H), 2.61 - 2.48 (m, 2H), 2.47 - 2.32 (m, 2H), 1.88 - 1.78 (m, 3H), 1.71 - 1.63 (m, 1H), 1.17 - 1.05 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 2.705 min, ESI+ found [M+H] + = 639.3.

[0796]

[0797] 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)

[0798]

[0799] Step 1: (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester

[0800] To a solution of (2S,4S)-O1-tert-butyl O2-methyl 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (25 g, 85.27%) as a white solid: 1H 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] + .

[0801]

[0802] Step 2: (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine- 1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester

[0803] To a solution of (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (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-l-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 sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to afford (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (15 g, 60.18%) as a white solid. LCMS Rt = 0.716 min, m / z = 448.2 / 450.1 [M + H] + .

[0804]

[0805] Step 3: (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester

[0806] To a solution of (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2- (chloromethyl)allyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (11 g, 24.55 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (29.46 mL, 29.46 mmol, 1 M 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (6 g, 73.22%) as a white solid. LCMS Rt = 0.458 min, m / z = 334.0 / 336.0 [M + H] + .

[0807]

[0808] Step 4: (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester

[0809] To a solution of (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (7 g, 20.97 mmol) in dichloromethane (100 mL) was added bis(2-methoxyethyl)amino)sulfur trifluoride (9.28 g, 41.94 mmol) at -78 °C. The mixture was stirred at 20 °C 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (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] + .

[0810]

[0811] Step 5: (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylic acid methyl ester

[0812] Deprotection of the Boc group was carried out in a similar manner as method #1 step 7. The mixture was concentrated to dryness in vacuum to give (2S,4R)-2-(2- (chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylic acid methyl ester (2.6 g, crude, trifluoroacetate salt) as a white solid which was used in the next step without any further purification. LCMS Rt = 0.174 min, m / z = 236.0 / 238.0 [M + H] + .

[0813]

[0814] Step 6: (2R,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)-carboxylic acid methyl ester

[0815] To a solution of (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylic acid methyl ester (2.6 g, 11.03 mmol, trifluoroacetate 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 vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2R,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)-carboxylic acid methyl ester (1.7 g, 77.35%) as a white solid. LCMS Rt = 0.146 min, m / z = 200.1 [M + H] + .

[0816]

[0817] Step 7: (6'R,7a'S)-6'-fluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)- carboxylic acid methyl ester

[0818] To a solution of (2R,7aS)-2-fluoro-6-methylene-tetrahydro-lH-pyrrolizine-7a(5H)- carboxylic acid methyl ester (1.6 g, 8.03 mmol) in dichloromethane (50 mL) was added diethylzinc (40.16 mL, 40.16 mmol, 1M in toluene) and iodomethane (21.51 g, 80.31 mmol) at 0 °C under nitrogen. The mixture was stirred at 20 °C under nitrogen atmosphere for 12 h. The reaction mixture was quenched with saturated ammonium chloride (300 mL) at 0 °C and extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford (6'R,7a'S)-6'-fluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)- carboxylic acid methyl ester (300 mg, 30%) as a white solid: 1 H NMR (400 MHz, Chloroform-d) δ 5.29 - 5.12 (m, 1H), 3.67 (s, 3H), 3.25 - 3.21 (m, 1H), 3.17 - 3.09 (m, 2H), 2.84 (dd, J = 1.2, 8.8 Hz, 1H), 2.35 - 2.23 (m, 2H), 2.23 - 2.17 (m, 1H), 2.14 - 2.08 (m, 1H), 0.55 - 0.42 (m, 4H). LCMS Rt = 0.520 min, m / z = 214.1 [M + H] + .

[0819]

[0820] Step 8: ((6'R,7a'S)-6'-fluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)- yl)methanol

[0821] To a solution of (6'R,7a'S)-6'-fluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'- pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (250 mg, 1.17 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum hydride (1.41 mL, 3.52 mmol, 2.5 M 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 sulfate and concentrated in vacuo to give ((6'R,7a'S)-6'-fluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-yl)methanol (200 mg, crude) which was used in the next step without any further purification: 1 H NMR (400 MHz, Chloroform-d) δ 5.35 - 5.14 (m, 1H), 3.51 (d, J = 10.3 Hz, 1H), 3.29 (d, J = 10.5 Hz, 1H), 3.20 - 3.15 (m, 2H), 3.14 - 3.02 (m, 1H), 2.79 (dd, J = 1.1, 9.3 Hz, 1H), 2.28 - 2.21 (m, 1H), 2.21 - 2.13 (m, 1H), 2.11 - 2.06 (m, 1H), 1.45 - 1.41 (m, 1H), 0.59 - 0.47 (m, 4H).

[0822]

[0823] Step 9: (2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-l -carboxylic acid tert-butyl ester

[0824] A substitution reaction was performed in a similar manner as Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give (2R,3R)-3-((7-chloro-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrozine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow solid (120 mg, 47.98%). LCMS R, = 0.422 min, m / z = 579.2 / 581.2 [M + H] + .

[0825]

[0826] Step 10: (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrozine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0827] A Suzuki reaction was performed in a similar manner as Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H20 (10mM NH4HC03)-ACN]; gradient: 65%-95% B in 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrozine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester as a brown solid (20 mg, 13.33%): 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] + .

[0828]

[0829] Step 11: (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)- 6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0830] The deprotection of the TIPS group was carried out in a similar manner as Step 6 of Method #1. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)- 6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (8 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.494 min, m / z = 713.4 [M + H] + .

[0831]

[0832] Step 12: 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'- fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-N- methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0833] The deprotection of the Boc group was carried out in a similar manner as Step 7 of Method #1. The mixture was concentrated to dryness in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (7.3 mg, crude, hydrochloride salt) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.376 min, m / z = 613.4 [M + H] + .

[0834]

[0835] Step 13: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)- 6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0836] The acylation reaction was performed in a similar manner as Method #1 Step 8. The crude product was purified by reverse phase HPLC (Column: Waters Xbridge BEH C18 100*30mm*10um; Mobile Phase: [H20 (10mM NH4HCO3) - ACN]; Gradient: 45%-80% B over 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one as a light yellow solid (1.11 mg, 13.77%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.09 (m, 2H), 7.70 -7.64 (m, 2H), 7.45 (t, J = 9.1 Hz, 1H), 6.64 - 6.53 (m, 1H), 6.32 - 6.19 (m, 1H), 5.68 (dd, J = 2.3, 10.3 Hz, 1H), 5.41 - 5.22 (m, 1H), 4.97 - 4.81 (m, 2H), 4.46 - 4.24 (m, 2H), 3.90 - 3.66 (m, 1H), 3.61 (d, J = 5.4 Hz, 3H), 3.59- 3.45 (m, 1H), 3.26 (d, J = 8.5 Hz, 1H), 3.16 (d, J = 8.8 Hz, 2H), 3.13 -3.08 (m, 1H), 2.75 (d, J = 8.0 Hz, 1H), 2.65 - 2.47 (m, 1H), 2.44 - 2.27 (m, 2H), 2.24 (s, 3H), 1.15 - 1.05 (m, 3H), 0.53 (s, 4H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 4.113 min, ESI+ found [M+H] + = 667.3.

[0837]

[0838] 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) Example 20: Synthesis of compound 12; 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-

[0839]

[0840] Step 1: (2R, 3R)-3-((7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester

[0841] A substitution reaction was performed in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give (2R, 3R)-3-((7-chloro-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (340 mg, 57.48%). LCMS Rt = 0.391 min, m / z = 509.2 / 510.2 [M + H] + .

[0842]

[0843] Step 2: (2R, 3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0844] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 40%-70% B in 8.0 min) to give (2R, 3R)-3-((8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester as a yellow solid (260 mg, 55.21%, trifluoroacetate salt). LCMS Rt = 0.602 min, m / z = 799.5 [M + H] +.

[0845]

[0846] Step 3: 8-Fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-N- methyl-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine

[0847] Deprotection of the Boc group was carried out in a similar manner as in Method #1 Step 7. The mixture was concentrated to dryness in vacuo to give 8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-N-methyl-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, crude, hydrochloride salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.507 min, m / z = 699.5 [M + H] + .

[0848]

[0849] Step 4: 7-(8-Ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-N-methyl-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine

[0850] Deprotection of the TIPS group was carried out in a similar manner as in Method #1 Step 6. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-N-methyl-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine (81 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.315 min, m / z = 543.2 [M + H] + .

[0851]

[0852] 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

[0853] The acylation reaction was performed in a similar manner as Method #1 Step 8. The residue was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 30%-60% B in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow solid (28.48 mg, 31.90%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.23 (s, 1H), 8.15 - 8.07 (m, 2H), 7.69 - 7.63 (m, 2H), 7.44 (t, J = 9.0 Hz, 1H), 6.58 (dd, J = 10.3, 16.8 Hz, 1H), 6.32 - 6.20 (m, 1H), 5.68 (dd, J = 2.2, 10.3 Hz, 1H), 4.99 - 4.79 (m, 2H), 4.53 - 4.41 (m, 1H), 4.37 - 4.25 (m, 1H), 3.88 - 3.65 (m, 1H), 3.62 - 3.46 (m, 4H), 3.28 (s, 1H), 3.07 - 2.97 (m, 1H), 2.68 (d, J = 4.8 Hz, 1H), 2.60 - 2.46 (m, 1H), 2.41 (s, 3H), 2.37 (d, J= 6.3 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.07 - 1.97 (m, 1H), 1.83 - 1.66 (m, 3H),1.15 - 1.03 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.814 min, ESI+ found [M+H] + = 597.3.

[0854]

[0855] (((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) Example 21: Synthesis of compound 7-1; 1-(cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,

[0856]

[0857] Step 1: (2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0858] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give (2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow solid (220 mg, 88.06%). LCMS Rt = 0.471 min, m / z = 691.4 [M + H] + .

[0859]

[0860] Step 2: 7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0861] Deprotection of the Boc group was performed in a similar manner as for Method #1 Step 7. The mixture was concentrated to dryness in vacuo to give 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) which was used in the next step without any further purification. LCMS Rt = 0.566 min, m / z = 591.3 [M + H] + .

[0862]

[0863] 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

[0864] The acylation reaction was performed in a similar manner as for 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 in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-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: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.30 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.96 (dd, J = 6.1, 8.9 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.41 (t, J = 9.4 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.29 (dd,J = 10.3, 15.9 Hz, 1H), 5.70 (d, J = 10.0 Hz,1H), 5.38 - 5.17 (m, 1H), 5.01 - 4.86 (m, 2H), 4.29 - 4.11 (m, 2H), 3.91 -3.67 (m, 1H), 3.63 (d, J = 6.1 Hz, 3H), 3.60 - 3.48 (m, 1H), 3.20 - 3.05 (m,3H), 2.96 - 2.85 (m, 1H), 2.68 - 2.46 (m, 2H), 2.43 - 2.20 (m, 3H), 2.12 (s,1H), 2.07 - 2.00 (m, 1H), 1.93 - 1.80 (m, 3H), 1.17 - 1.06 (m, 3H), 0.88 -0.79 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 3.261 min, ESI+ found [M+H] + = 645.3.

[0865]

[0866] 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) Example 22 and 23: Synthesis of compounds 7-2 and 7-3; 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-

[0867]

[0868] Step 1: cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0869] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (Column: Phenomenex Luna C18 75*30mm*3um; Mobile Phase: [H20 (0.1% TFA) - ACN]; Gradient: 25%-55% B over 8.0 min) to give (2R,3R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (25 mg, 33.05%, trifluoroacetic acid salt) as a yellow solid. LCMS Rt = 1.615 min, m / z = 697.3 / 698.3 [M + H] + .

[0870]

[0871] 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

[0872] Deprotection of the Boc group was performed in a similar manner to Method #1 Step 7. The mixture was concentrated to dryness in vacuo to give 7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (25 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.352 min, m / z = 597.3 / 598.4 [M + H] + .

[0873]

[0874] 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

[0875] The acylation reaction was performed in a similar manner as 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) to give 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 as a yellow solid (10.75 mg, 46.88%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.28 (d, J = 4.2 Hz, 1H), 8.19 - 8.14 (m, 1H), 8.13 - 8.07 (m, 1H), 7.72 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.34 - 6.21 (m, 1H), 5.70 (d, J = 10.4 Hz, 1H), 5.39 - 5.17 (m, 1H), 5.00 - 4.83 (m, 2H), 4.31 - 3.79 (m, 3H), 3.77 - 3.50 (m, 5H), 3.21 - 3.05 (m, 3H), 2.97 - 2.85 (m, 1H), 2.68 - 2.33 (m, 2H), 2.14 - 2.11 (m, 1H), 2.10 - 2.03 (m, 1H), 1.92 - 1.80 (m, 3H), 1.16 - 1.08 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 3.007 min, ESI+ found [M+H] + = 651.0 / 652.0.

[0876]

[0877] ​ ​ (7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-l-yl)prop-2-en-l-one 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl) (7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-l-yl)prop-2-en-l-one (Method 1)

[0878]

[0879] Step 1: cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozalin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0880] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 25%-55% B over 8.0 min) to give cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozalin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (110 mg, 39.66%, trifluoroacetate salt). LCMS Rt = 1.624 min, m / z = 697.3 / 698.3 [M + H] + .

[0881]

[0882] Step 2: 7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozalin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0883] A Boc deprotection reaction was performed in a similar manner to Method #1 Step 7. The reaction mixture was concentrated in vacuo to give 7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozalin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine as a yellow solid (80 mg, crude, trifluoroacetate salt), which was used in the next step without any further purification. LCMS Rt = 0.350 min, m / z = 597.3 / 598.3 [M + H] + .

[0884]

[0885] Step 3: 1-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-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-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0886] The acylation reaction was performed in a similar manner as 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) to give 1-(cis-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-1-yl)prop-2-en-1-one as a white solid (40 mg, 45.81%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 - 3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d,J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.957 min, ESI+ found [M+H] + = 651.4 / 652.4.

[0887] 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 the following as arbitrarily assigned:

[0888] Example 22: l-((2R,3R)-3-((7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-l-yl)prop-2-en-l-one Example 23: l-((2S,3S)-3-((7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (peak 1, retention time = 1.508 min) (10.22 mg, 11.69%) as a white solid: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.36 - 9.21 (m, 1H), 8.20 - 8.14 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.55 (t, J = 8.9 Hz, 1H), 6.62 (dd, J = 10.2, 16.8 Hz, 1H), 6.34 - 6.24 (m, 1H), 5.70 (d, J= 10.3 Hz,1H), 5.44 - 5.18 (m, 1H), 5.05 - 4.82 (m, 2H), 4.33 - 4.17 (m, 2H), 3.96 -3.52 (m, 5H), 3.31 - 3.11 (m, 3H), 3.01 - 2.88 (m, 1H), 2.73 - 2.53 (m, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 7.6 Hz, 2H), 2.08 (d, J = 7.1 Hz, 1H), 1.95- 1.82 (m, 3H), 1.13 (dd, J = 6.3, 14.4 Hz, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate over 6 min) retention time 2.957 min, ESI+ experimental value [M+H] + = 651.4 / 652.4; and

[0889] (7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-l-yl)prop-2-en-l-one Example 24: Synthesis of compound 8-1; l-(cis-3-((7-(7,8-difluoronaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (Method 1) Example 25 and 26: Synthesis of compounds 8-2 and 8-3; l-((2R,3R)-3-((7-(7,8- difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyr azin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-l-yl)prop- 2-en-l-one and l-((2S,3S)-3-((7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (Method 1) (Peak 2, retention time = 1.787 min) (10.22 mg, 11.69%), white solid: 1 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 / water + 0.03% ammonium bicarbonate over 6 min) retention time 2.956 min, ESI+ experimental value [M+H] + = 651.4 / 652.4.

[0890]

[0891] Example 25: l-((2R,3R)-3-((7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (7-(8-chloro-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidin-l-yl)prop-2-en-l-one Example 26: l-((2S,3S)-3-((7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyr azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one

[0892]

[0893] Step 1: cis-3-((7-(7,8-difluoronaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0894] The Suzuki reaction was carried out in a manner similar to step 5 of Method #1. The crude product was purified by reversed-phase HPLC (column: Phenomenexluna C18 100*40mm*3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain a yellow solid cis-3-((7-(7,8-difluoronaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 97.42%, trifluoroacetate). LCMS Rt = 0.461 min, m / z = 681.6 [M + H] + .

[0895]

[0896] Step 2: 7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(cis-2-methylpyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine

[0897] The deprotection of Boc was carried out in a similar manner as in Method #1 Step 7. The reaction mixture was concentrated in vacuo to give 7-(7,8-difluoronaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N- (cis-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (120 mg, crude, trifluoroacetate salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.332 min, m / z = 581.3 [M + H] + .

[0898]

[0899] Step 3: l-(cis-3-((7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-l-yl)prop-2-en-l-one

[0900] The acylation reaction was carried out in a similar manner as in Method #1 Step 8. The resulting residue was purified by reverse phase HPLC (Column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile Phase: [H20 (10mM NH4HC03)-ACN]; Gradient: 35%-65% B in 8.0 min) to give l-(cis-3-((7-(7,8-difluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-l-yl)prop-2-en-l-one (54.77 mg, 49.95%) as a light yellow amorphous solid: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 3.8 Hz, 1H), 8.18 - 8.09 (m, 1H), 7.92 (ddd, J= 1.7, 5.0, 9.2 Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.60 - 7.52 (m, 1H), 6.61 (dd, J = 10.2, 16.7 Hz, 1H), 6.28 (dd, J = 9.3, 16.5 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.37 - 5.19 (m, 1H), 4.93 (d, J = 9.0 Hz, 2H), 4.29 - 4.06(m, 2H), 3.92 - 3.67 (m, 1H), 3.63 (d, J = 6.8 Hz, 3H), 3.59 - 3.42 (m, 1H), 3.20 - 3.11 (m, 2H), 3.08 (s, 1H), 2.95 - 2.87 (m, 1H), 2.64 - 2.35 (m, 2H), 2.14 - 2.03 (m, 3H), 1.94 - 1.88 (m, 2H), 1.87 - 1.79 (m, 1H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate over 6 min) retention time 2.981 min, ESI+ experimental value [M+H] + = 635.1.

[0901]

[0902] ​ ​ ​ ​ ​

[0903] Further purification of a mixture (100 mg) of cis-3-((7-(7,8-difluoronaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)prop-2-en-1-one diastereomers yielded the following substances as specified:

[0904] ​ ​ ​ (peak 2, retention time = 1.639 min) (31.69 mg, 14.63%) as a white solid: 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (d, J = 3.3 Hz, 1H), 8.22 - 8.04 (m, 1H), 7.91 (ddd, J = 1.5, 5.1, 9.1 Hz, 1H), 7.71 (d, J = 5.5 Hz, 2H), 7.56 (dt, J = 7.7, 9.6 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.28 (dd, J = 8.5, 16.3 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.39 - 5.15 (m, 1H), 4.92 (d, J = 7.3 Hz, 2H), 4.30 - 4.06 (m, 2H), 3.95 - 3.47 (m, 5H), 3.22 - 3.04 (m, 3H), 2.99 - 2.83 (m, 1H), 2.70 - 2.46 (m, 1H), 2.43 - 2.21 (m, 2H), 2.12 (d, J = 3.5 Hz, 2H), 1.94 - 1.82 (m, 3H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 2.910 min, ESI+ found [M+H] + = 635.3; and

[0905] ​ Hydrogen-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) Alkan-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 = 10.1 Hz, 1H), 5.41 - 5.16 (m, 1H), 4.92 (s, 2H), 4.32 - 4.03 (m, 2H), 3.94 - 3.50 (m, 5H), 3.21 - 3.04 (m, 3H), 2.99 - 2.86 (m, 1H), 2.72- 2.47 (m, 1H), 2.46 - 2.20 (m, 2H), 2.14 - 2.05 (m, 2H), 1.94 - 1.79 (m, 3H), 1.12 (s, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) Ret Time 2.908 min, ESI+ found [M+H] + = 635.4.

[0906]

[0907] 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) N,N

[0908]

[0909] Step 1: tert-Butyl (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1- carboxylate

[0910] 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 and 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 and 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 sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give tert-butyl (2R,3S)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1 -carboxylate (600 mg, 74.01%) as a colourless oil. LCMS Rt = 0.344 min, m / z = 305.2 [M + H] + .

[0911]

[0912] Step 2: tert-Butyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylate

[0913] 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 under hydrogen (50 Psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give tert-butyl (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylate (470 mg, crude) as a yellow oil which was used in the next step without further purification: 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] + .

[0914]

[0915] Step 3: (2R, 3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0916] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (550 mg, 2.18 mmol) in 1,4-dioxane (8 mL) was added Example 28: Synthesis of Compound 1-5; 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro- diisopropylethylamine (844.69 mg, 6.54 mmol) and (2R,3S)-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester (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 sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to afford (2R,3S)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester (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] + .

[0917]

[0918] Step 4: (2R, 3S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester

[0919] The substitution reaction was performed in a similar manner as Method # 1, Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give (2R, 3S)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester as a white solid (794 mg, 79.11%): 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] + .

[0920]

[0921] Step 5: tert-Butyl (2R,3S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0922] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give tert-butyl (2R,3S)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-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] + .

[0923]

[0924] Step 6: (2R, 3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0925] Deprotection of the TIPS group was performed in a similar manner as Method #1 Step 6. The reaction mixture was concentrated in vacuo to give (2R, 3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester (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] + .

[0926]

[0927] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2R,3S)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0928] Deprotection of Boc was carried out in a similar manner as in Method #1, Step 7. The reaction mixture was concentrated in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-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 salt) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.356 min, m / z = 587.3 [M + H] + .

[0929]

[0930] Step 8: 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0931] The acylation reaction was performed in a similar manner as Step 8 of Method #1. 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) to give 1-((2R,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow amorphous solid (34.94 mg, 34.26%): 1 HNMR (400 MHz, chloroform-d) δ 9.14 - 9.09 (m, 1H), 8.03 - 7.90 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.30 (m, 1H), 6.55 - 6.39 (m, 2H), 5.81 - 5.72 (m, 1H), 5.44- 5.20 (m, 1H), 5.18 - 5.08 (m, 1H), 4.51 - 4.27 (m, 3H), 4.15 - 3.80 (m, 2H), 3.79 - 3.58 (m, 1H), 3.42 (s, 3H), 3.34 - 3.16 (m, 2H), 3.09 - 2.80 (m, 2H), 2.67 - 2.51 (m, 1H), 2.36 - 2.11 (m, 4H), 2.06 - 2.88 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 3.055 min, ESI+ found [M+H] + = 641.3.

[0932]

[0933] 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)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-(fluoromethylidene)-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) N,N

[0934]

[0935] Step 1: (2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0936] The reductive amination was performed in a similar manner as Method #2 Step 1. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (2S,3R)-3-(benzyl(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow oil (400 mg, crude) which was used in the next step without any further purification. LCMS Rt = 0.339 min, m / z = 305.3 [M + H] + .

[0937]

[0938] Step 2: (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0939] The debenzylation reaction was performed in a similar manner as Method #2 Step 2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (2S,3R)-2-methyl-3-(methylamino)pyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow oil (250 mg, crude) which was used in the next step without any further purification.

[0940]

[0941] Step 3: (2S,3R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0942] The substitution reaction was performed in a similar manner as Method #2 Step 3. The reaction mixture was concentrated in vacuo to dryness to give (2S,3R)-3-((2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow solid (200 mg, crude) which was used in the next step without any further purification. LCMS Rt = 0.583 min, m / z = 430.1 / 432.0 [M + H] + .

[0943]

[0944] Step 4: (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester

[0945] The substitution reaction was performed in a similar manner as Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford (2S,3R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylic acid tert-butyl ester as a yellow solid (200 mg, 62.25%). LCMS Rt = 0.421 min, m / z = 553.3 / 555.2 [M + H] + .

[0946]

[0947] Step 5: (2S,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0948] The Suzuki reaction was performed in a similar manner as Method #1 Step 5. The reaction mixture was concentrated to dryness in vacuo to afford (2S,3R)-3-((8-fluoro-7-(7- fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine- 1-carboxylic acid tert-butyl ester as a brown oil (280 mg, crude), which was used in the next step without any further purification. LCMS Rt = 0.646 min, m / z = 843.5 [M + H] + .

[0949]

[0950] Step 6: (2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0951] Deprotection of the TIPS group was carried out in a similar manner as in Method #2, Step 6. The reaction mixture was concentrated in vacuo to give (2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-l-carboxylic acid tert-butyl ester (230 mg, crude) as a brown solid which was used in the next step without any further purification. LCMS Rt = 0.649 min, m / z = 687.3 [M + H] + .

[0952]

[0953] Step 7: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((2S,3R)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0954] Boc deprotection was carried out in a similar manner as in Method #1, Step 7. The reaction mixture was concentrated in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-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 salt) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.342 min, m / z = 587.2 [M + H] + .

[0955]

[0956] Step 8: 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0957] The acylation reaction was performed in a similar manner as Step 8 of Method #1. 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) to give 1-((2S,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one as a yellow amorphous solid (12.41 mg, 97.15%): 1 HNMR (400 MHz, chloroform-d) δ 9.15 (s, 1H), 8.01 - 7.93 (m, 2H), 7.67 - 7.56 (m,2H), 7.35 (t, J = 8.8 Hz, 1H), 6.55 - 6.38 (m, 2H), 5.80 - 5.72 (m, 1H), 5.45- 5.23 (m, 1H), 5.19 - 5.09 (m, 1H), 4.55 - 4.21 (m, 3H), 4.20 - 3.88 (m,2H), 3.82 - 3.65 (m, 1H), 3.47 - 3.41 (m, 3H), 3.38 - 3.14 (m, 2H), 3.11 -2.96 (m, 1H), 2.95 - 2.82 (m, 1H), 2.58 (d, J = 9.8 Hz, 1H), 2.44 - 2.17 (m,4H), 2.11 - 1.89 (m, 3H), 1.49 - 1.42 (m, 3H). LCMS (5% to 95% acetonitrile / water + 0.03% ammonium bicarbonate in 6 min) retention time 3.056 min, ESI+ found [M+H] + = 641.3.

[0958]

[0959] 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-(fluoromethylidene)-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) Example 31: Synthesis of Compound 14-1; 1-((2R,3R)-3-((2-((2-(difluoromethyl)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) N,N

[0960]

[0961] Step 1: (R)-4-(fluoromethylene)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester

[0962] Potassium tert-butoxide (22.14 g, 197.32 mmol) was subjected to treatment at -78°C. Example 32 and 33: Synthesis of Compound 14-2 and 14-3; 1-((2R,3R)-3-((2-(((S)-2-(difluoromethyl)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-(difluoromethyl)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) 2-((fluoromethyl)sulfonyl)pyridine (20.74 g, 118.39 mmol) and 1-(tert-butyl)-2-methyl 4-oxopyrrolidine-1,2-dicarboxylic acid (24 g, 98.66 mmol) were added to a solution of dimethylformamide (210 mL). 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 sulfate and concentrated under vacuum. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 (250*70mm, 15 μm); mobile phase: [H2O (0.1% TFA); gradient: 30%-65% B over 20.0 min) to obtain a yellow oily 1-(tert-butyl)-2-methyl 4-(fluoromethylene)pyrrolidine-1,2-dicarboxylic acid. LCMS Rt = 1.694 min, m / z = 260.1 [M + H] + .

[0963]

[0964] Step 2: (R)-(4-(fluoromethylene)-1-methylpyrrolidone-2-yl)methanol

[0965] To a solution of (R)-4-(fluoromethylidene)pyrrolidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (3.4 g, 13.11 mmol) in tetrahydrofuran (80 mL) was added lithium aluminum 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 sulfate and concentrated in vacuo to afford (R)-(4-(fluoromethyl)-l-methylpyrrolidin-2-yl)methanol (1.3 g, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.137 min, m / z = 146.2 [M + H] + .

[0966]

[0967] Step 3: (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethyl)-l- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester and (2R,3R)-3-((7-chloro-8- fluoro-2-(((R,E)-4-(fluoromethyl)-l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester

[0968] The substitution reaction was carried out in a similar manner as Method #1 Step 4. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H20 (0.1% TFA) - ACN]; gradient: 15%-45% B over 8.0 min) to afford (2R,3R)-3-((7-chloro-8-fluoro-2-(((R)-4-(fluoromethyl)-l- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1 -carboxylic acid tert-butyl ester as a yellow solid (550 mg, 35.25%). LCMS Rt = 1.397 min, m / z = 539.2 / 541.2 [M + H] + .

[0969] The diastereomeric mixture of Z-alkene and E-alkene was separated by SFC (550 mg) to afford the following as arbitrarily assigned:

[0970] (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethyl)-l-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester (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

[0971] (2R,3R)-3-((7-chloro-8-fluoro-2-(((R,Z)-4-(fluoromethyl)-l-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l- carboxylic acid tert-butyl ester (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] + .

[0972] SFC (Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile Phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, Isocratic elution mode).

[0973]

[0974] Step 4: (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((R,E)-4-(fluoromethyl)-l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[0975] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,E)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylate as a yellow solid (380 mg, 79.69%). LCMS Rt = 0.594 min, m / z = 829.4 [M + H] + .

[0976]

[0977] Step 5: (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4- (fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0978] Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to give (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (120 mg, crude), which was used in the next step without any further purification. LCMS Rt = 0.439 min, m / z = 673.3 [M + H] + .

[0979]

[0980] Step 6: 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0981] The deprotection reaction of Boc was carried out in a similar manner as Method #1 Step 7. The reaction mixture was concentrated in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylidene)-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 salt) as a white solid which was used in the next step without any further purification. LCMS Rt = 0.339 min, m / z = 573.3 [M + H] + .

[0982]

[0983] Step 7: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0984] The acylation reaction was carried out in a similar manner as 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 in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,E)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (19.05 mg, 16.83%) as a white solid: 1 H NMR (400MHz, Acetonitrile-d3) d 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 / water + 0.03% ammonium bicarbonate in 6 min) Retention time 2.986 min, ESI+ found [M+H] + = 627.3.

[0985]

[0986] ​ ​ ​

[0987]

[0988] Step 1: (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-(((R,Z)-4-(fluoromethyl)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0989] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The crude product was purified by reverse phase HPLC (Column: Phenomenex Luna C18 75*30mm*3um; Mobile Phase: [H20 (0.1% TFA) - ACN]; Gradient: 45%-85% B over 8.0 min) to give (2R,3R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R,Z)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (200 mg, 72.24%, trifluoroacetic acid salt) as a yellow solid. LCMS Rt = 2.324 min, m / z = 829.4 [M + H] + .

[0990]

[0991] Step 2: (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0992] Deprotection of the TIPS group was performed in a similar manner to Method #1 Step 6. The reaction mixture was concentrated in vacuo to give (2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, crude) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.461 min, m / z = 673.2 [M + H] + .

[0993]

[0994] Step 3: 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0995] The deprotection reaction of Boc was carried out in a similar manner as Method #1 Step 7. The reaction mixture was concentrated in vacuo to give 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4-(fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (180 mg, crude, trifluoroacetate salt) as a yellow oil which was used in the next step without any further purification. LCMS Rt = 0.355 min, m / z = 573.2 [M + H] + .

[0996]

[0997] Step 4: 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4- (fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one

[0998] The acylation reaction was carried out in a similar manner as 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 in 8.0 min) to give 1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((R,Z)-4- (fluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)prop-2-en-1-one (15.70 mg, 8.94%) as a yellow solid: 1 H NMR (400MHz, Acetonitrile-d3) d 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 / water + 0.03% ammonium bicarbonate over 6 min) retention time 2.997 min, ESI+ experimental value [M+H] + = 627.3.

[0999]

[1000] ​ ​ ​

[1001]

[1002] Step 1: Ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-formate

[1003] Potassium tert-butoxide (10.63 g, 94.69 mmol) was added at -78°C under a nitrogen atmosphere. ​ Ethyl 2,5-dioxotetrahydro-1H-pyrrolazin-7a(5H)-carboxylate (10 g, 47.35 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (10.97 g, 56.81 mmol) were added to a solution of dimethylformamide (400 mL). The mixture was stirred at 30 °C under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL), diluted with hydrochloric acid (10 mL, 12 M, in water), and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / petroleum ether) to give ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazin-7a(5H)-carboxylate (5.45 g, 46.94%) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ 4.29 (d, J = 14.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 14.1 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.73 (td, J = 9.7, 16.9 Hz, 1H), 2.55 (ddd, J = 1.8, 9.3, 13.1 Hz, 1H), 2.48 - 2.27 (m, 2H), 2.07 (td, J = 10.1, 13.2 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). LCMS Rt = 0.394 min, m / z = 246.4 [M + H] + .

[1004]

[1005] Step 2: (2-(difluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

[1006] To a solution of ethyl 2-(difluoromethyl)-5-oxotetrahydro-lH-pyrrolizin-7a(5H)- carboxylate (5 g, 20.39 mmol) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (203.90 mL, 20.39 mmol, 1 M in toluene) at 0 °C, the reaction solution was stirred at 25 °C under nitrogen atmosphere for 1 h. 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 vacuum to afford (2-(difluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (3.3 g, crude) as yellow oil. LCMS Rt = 0.091 min, m / z = 190.3 [M + H] + .

[1007]

[1008] Step 3: (2R,3R)-3-((7-chloro-2-((2-(difluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine- 1-carboxylic acid tert-butyl ester

[1009] A substitution reaction was performed in a similar manner to Method #1 Step 4. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2R,3R)-3-((7-chloro-2-((2- (difluoromethyl)tetrahydro-lH-pyrrazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l -carboxylate as a yellow oil (310 mg, 45.76%). LCMS Rt = 0.419 min, m / z = 583.2 / 585.1 [M + H] + .

[1010]

[1011] Step 4: (2R,3R)-3-((2-((2-(Difluoromethyl)tetrahydro-lH-pyrrazin-7a(5H)- yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester

[1012] A Suzuki reaction was performed in a similar manner to Method #1 Step 5. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate / pet. ether) to give (2R,3R)-3-((2-((2-(difluoromethyl)tetrahydro-lH-pyrrazin-7a(5H)- yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-l-carboxylic acid tert-butyl ester as a yellow solid (310 mg, 69.00%). LCMS Rt = 1.890 min, m / z = 873.6 [M + H] + .

[1013]

[1014] Step 5: 2-((2-(Difluoromethyl)tetrahydro-lH-pyrrazin-7a(5H)-yl)methoxy)-8-fluoro-7- (7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-N-methyl-N-((2R,3R)-2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[1015] The deprotection of the Boc was carried out in a similar manner as in Method #1 Step 7. The reaction mixture was concentrated in vacuo to give 2-((2-(difluoromethyl)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 which was used in the next step without any further purification. LCMS Rt = 0.495 min, m / z = 773.4 [M + H] + .

[1016]

[1017] Step 6: 2-((2-(difluoromethyl)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

[1018] The deprotection of the TIPS group was carried out in a similar manner as in Method #1 Step 6. The reaction mixture was concentrated in vacuo to give 2-((2-(difluoromethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methyl-N-((2R,3R)-2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS Rt = 0.360 min, m / z = 617.3 [M + H] + .

[1019]

[1020] Step 7: 1-((2R,3R)-3-((2-((2-(difluoromethyl)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

[1021] The acylation reaction was performed in a similar manner as 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) to give 1-((2R,3R)-3-((2-((2-(difluoromethyl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-7-(8- ethynyl-7-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)prop-2- en-1-one as a yellow solid (10.57 mg, 23.91%): 1 H NMR (400 MHz, Acetonitrile-d3) δ 9.25 (s, 1H), 8.24 - 8.08 (m, 2H), 7.77 - 7.58 (m, 2H), 7.48 (t, J = 9.1 Hz, 1H), 6.66 - 6.55 (m, 1H), 6.42 - 6.17 (m, 1H), 5.83 - 5.62 (m, 1H),5.03 - 4.80 (m, 2H), 4.33 - 4.10 (m, 2H), 3.70 (d, J = 14.1 Hz, 2H), 3.63 (d, J = 7.1 Hz, 3H), 3.41 - 3.26 (m, 2H), 3.10 - 3.03 (m, 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 / water + 0.1% trifluoroacetic acid in 6 min) Ret Time 2.494 min, ESI+ found [M+H] + = 671.2.

[1022]

[1023] ​ ​ ​ ((2R,3R)-3-((2-(((S)-2-(difluoromethyl)tetrahydro-1H-pyrrazin-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) ((2R,3R)-3-((2-(((S)-2-(difluoromethyl)tetrahydro-1H-pyrrazin-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) Example 32: 1-((2R,3R)-3-((2-(((S)-2-(difluoromethyl)tetrahydro-1H-pyrrazin-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

[1024] A mixture of diastereomers of l-((2R,3R)-3-((2-((2-(difluoromethyl)tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-l-yl)prop-2-en-l-one (50 mg) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to give the following as any of the designated:

[1025] Example 33: 1-((2R,3R)-3-((2-(((R)-2-(difluoromethyl)tetrahydro-1H-pyrrazin-7a(5H)- yl)methoxy)-7-(8-ethynyl-7-fluo...

Claims

1. A compound of formula (I): Formula (I), or its salts and / or its isotopes; wherein: X is -N(CH3)- or -O-; X 1 It is -CH3, -CH2CH3, -CH=CH2 or cyclopropyl, each of which is substituted by 0, 1 or 2 independent substituents selected from the group consisting of halogen, -OH and -OCH3; q is 0 or 1; R 1 A 4-8 member saturated heterocyclic group containing a nitrogen atom as the only heteroatom within the ring atom, wherein the heterocyclic group is surrounded by 0, 1, 2 or 3 R atoms. 1A replace; R 1A In each case, the group consisting independently of halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -C(O)(C1-C4 alkyl) is selected; or two twin R groups are selected. 1A Together with the carbon atom to which it is attached, it forms a C3-C4 cycloalkyl group substituted with 0, 1, or 2 halogen groups; or two twin R groups. 1A Together they form =CH2, =CHF, or =CF2; R a It is H or CH3; R 2 for or ; R 3 It is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl; R 4 It is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl; R 5 It is H or -OH; Y is either CH or N; R 6 In each case, the group consisting of free halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, and -NH2 is selected independently; and r can be 0, 1, 2, or 3; The condition is that when q is 0, then R 1 Not for , , , , , or any of its enantiomers; when for or When R is any of its enantiomers, then 2 Not for ; and when for When R is any of its enantiomers, then 2 Not for or .

2. The compound of claim 1 or its salt and / or its isotopes, wherein R 2 for .

3. The compound of claim 2 or its salt and / or its isotope, wherein R 3 Choose from the group consisting of free halogen groups, C1-C4 alkyl groups, and C2-C3 alkynyl groups.

4. The compound of claim 2 or its salt and / or its isotope, wherein R 3 Choose the group consisting of -F, -Cl, -Et, -C≡CH, and -C≡C-CH3.

5. The compound or its salt and / or isotope as described in any one of claims 2-4, wherein R 4 It can be hydrogen or a halogen group.

6. The compound or its salt and / or isotope as described in any one of claims 2-4, wherein R 4 It can be hydrogen or -F.

7. The compound or its salt and / or isotope as described in any one of claims 2-6, wherein R 5 It is -OH.

8. The compound or its salt and / or isotope as described in any one of claims 2-6, wherein R 5 For H.

9. The compound of claim 2 or its salt and / or its isotope, wherein R 2 for , , , , , or .

10. The compound of claim 1 or its salt and / or its isotope, wherein R 2 for .

11. The compound of claim 10 or its salt and / or its isotope, wherein Y is CH.

12. The compound of claim 10 or its salt and / or its isotope, wherein Y is N.

13. The compound or its salt and / or isotope as described in any one of claims 10-12, wherein R 6 In each case, the group consisting of -Cl, -OH, -CH3, -CF3, cyclopropyl, and -NH2 is chosen independently.

14. The compound or its salt and / or its isotope as claimed in any one of claims 10-13, wherein r is 3.

15. The compound or its salt and / or isotope as described in any one of claims 10-13, wherein R 2 for .

16. The compound or its salt and / or isotope as described in any one of claims 10-13, wherein R 2 for , where R 6A Cyclopropyl or -CF3; R 6B It is -Cl or -CH3; and R 6C It can be -OH or -NH2.

17. The compound of claim 10 or its salt and / or isotope, wherein R 2 for , or .

18. The compound or its salt and / or its isotope as claimed in any one of claims 1-17, wherein X is -N(CH3)-.

19. The compound or its salt and / or its isotope as claimed in any one of claims 1-17, wherein X is -O-.

20. The compound or its salt and / or isotope as claimed in any one of claims 1-19, wherein X 1 It can be -CH3, -CH2F, -CH2OCH3, -CH2CH3, -CH(OH)CH3, -CH=CH2 or cyclopropyl.

21. The compound or its salt and / or isotope as described in any one of claims 1-19, wherein X 1 It is -CH3.

22. The compound or its salt and / or isotope as claimed in any one of claims 1-17, wherein the compound... Part of , , , , , , , , , or .

23. The compound or its salt and / or isotope as claimed in any one of claims 1-17, wherein the compound... Part of , , , , , , , , , , , , , , , , , , , , or .

24. The compound or its salt and / or isotope as described in any one of claims 1-23, wherein R 1 For 0, 1, 2 or 3 R 1A Replacement or .

25. The compound or its salt and / or isotope as described in any one of claims 1-24, wherein R 1A In each case, it is independently -F, -OH, -CH3, -OCH3, -OCF3, -OCHF2, or -C(O)CH3; or two twin Rs. 1A Together with the carbon atom it is attached to, it forms a cyclopropyl group substituted with 0, 1, or 2 fluorine atoms; or two twin R groups. 1A Together they form =CH2, =CHF, or =CF2.

26. The compound or its salt and / or isotope as claimed in any one of claims 1-25, wherein R 1 for , , , , , , , , , , , , , , , , , , , or .

27. The compound or its salt and / or isotope as claimed in any one of claims 1-25, wherein R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

28. The compound according to any one of claims 1-27, wherein R a For H.

29. The compound according to any one of claims 1-27, wherein R a It is CH3.

30. The compound of claim 1 or its salt and / or its isotope, wherein the compound is selected from the group consisting of the compounds in Table 1.

31. The compound or its salt and / or isotope as claimed in any one of claims 1-30, wherein the salt is a formate.

32. The compound or its salt and / or its isotope as claimed in any one of claims 1-31, wherein the salt is a pharmaceutically acceptable salt.

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

34. A method for treating or inhibiting cancer, the method comprising: Administer to a subject in need a therapeutically effective amount of any one of claims 1-32, or a pharmaceutically acceptable salt thereof and / or an isotope thereof, or a pharmaceutical preparation according to claim 33.

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

36. The method of claim 34, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal carcinoma, urothelial carcinoma of the bladder, prostate adenocarcinoma, serous cystadenocarcinoma of the ovary, endometrial cancer of the uterine body, squamous cell carcinoma and endocervical adenocarcinoma of the cervix, melanoma of the skin, acute lymphoblastic leukemia, and acute myeloid leukemia. Chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, 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 with KRASG12C-mediated cancer.

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

40. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof and / or an isotope thereof, or a pharmaceutical preparation according to claim 33, used as a pharmaceutical preparation.

41. The compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof and / or an isotope thereof, or a pharmaceutical preparation of claim 33, for treating or inhibiting cancer in a subject of need, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

42. The compound for use as claimed in claim 41, or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation thereof, wherein the cancer is selected from the group consisting of: lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

43. The compound for use as claimed in claim 41, or a pharmaceutically acceptable salt thereof and / or its isotope or pharmaceutical preparation, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal carcinoma, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine body, cervical squamous carcinoma and cervical adenocarcinoma, melanoma of the skin, acute lymphoblastic leukemia. Cellular leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, non-small cell lung cancer (NSCLC) and melanoma.

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

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

46. ​​The compound for use as claimed in any one of claims 40-45, or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation thereof, wherein said compound or said pharmaceutical preparation is configured for administration together with a therapeutically effective amount of an additional chemotherapeutic agent.

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

48. The compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof and / or an isotope thereof, or a pharmaceutical preparation of claim 33, for use in the manufacture of a pharmaceutical agent for treating or inhibiting cancer in a subject of need.

49. The compound for use as claimed in claim 48, or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation thereof, wherein the cancer is selected from the group consisting of: lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer and bladder cancer.

50. The compound for use as claimed in claim 48, or a pharmaceutically acceptable salt thereof and / or its isotope or pharmaceutical preparation, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal cell carcinoma, urothelial carcinoma of the bladder, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine body, cervical squamous carcinoma and cervical adenocarcinoma, melanoma of the skin, acute lymphoblastic leukemia. Cellular leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, non-small cell lung cancer (NSCLC) and melanoma.

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

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

53. The compound for use as claimed in any one of claims 48-52, or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation thereof, wherein said compound or said pharmaceutical preparation is configured for administration together with a therapeutically effective amount of an additional chemotherapeutic agent.

54. The compound for use as claimed in any one of claims 48-53, or a pharmaceutically acceptable salt thereof and / or an isotope thereof, or a pharmaceutical preparation thereof, wherein the pharmaceutical preparation comprises a therapeutically effective amount of the compound or the composition.

55. Use of the compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation of claim 33 for the manufacture of an agent for the treatment or inhibition of cancer in a subject of need.

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

57. The use as claimed in claim 55, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal carcinoma, urothelial carcinoma of the bladder, prostate adenocarcinoma, serous cystadenocarcinoma of the ovary, endometrial cancer of the uterine body, squamous cell carcinoma and endocervical adenocarcinoma of the cervix, melanoma of the skin, acute lymphoblastic leukemia, and acute myeloid leukemia. Chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, non-small cell lung cancer (NSCLC) and melanoma.

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

59. The use as claimed in any one of claims 55-57, wherein the subject has been diagnosed with KRASG12C-mediated cancer.

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

61. The use according to any one of claims 55-60, wherein the pharmaceutical agent comprises a therapeutically effective amount of the compound or the pharmaceutical preparation.

62. The use of the compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof and / or an isotope thereof or a pharmaceutical preparation of claim 33 for the treatment or inhibition of cancer in a subject of need.

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

64. The use as described in claim 62, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder cancer, pancreatic adenocarcinoma, clear cell renal carcinoma, urothelial carcinoma of the bladder, prostate adenocarcinoma, serous cystadenocarcinoma of the ovary, endometrial cancer of the uterine body, squamous cell carcinoma and endocervical adenocarcinoma of the cervix, melanoma of the skin, acute lymphoblastic leukemia, and acute myeloid leukemia. Chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, low-grade glioma of the brain, diffuse large B-cell lymphoma, esophageal adenocarcinoma, renal chromophobe carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic syndrome, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, Wilms' tumor in children, acute lymphoblastic leukemia in children, chronic lymphocytic leukemia, mature B-cell malignancies, neuroblastoma in children, non-small cell lung cancer (NSCLC) and melanoma.

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

66. The use as claimed in any one of claims 62-64, wherein the subject has been diagnosed with KRASG12C-mediated cancer.

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

68. The use as claimed in any one of claims 62-67, wherein the use relates to a therapeutically effective amount of the compound or the composition.

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