METHODS FOR TREATMENT OF CANCER

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

FIELD OF THE DISCLOSURE

The present disclosure provides compounds useful in treating or suppressing cancer, and in particular, useful in treating or suppressing cancers characterized by the KRAS G12C mutant.

Also provided are pharmaceutical formulations containing such compounds, processes for preparing such compounds, and methods of using such compounds in the treatment or suppression of cancers.

BACKGROUND

KRAS is a molecular switch. Under normal physiological conditions, the protein is bound to guanosine diphosphate (GDP) in the “off state.” In response to signaling through receptor tyrosine kinases (RTKs) such as EGFR, the GDP is exchanged to guanosine triphosphate (GTP) in a process facilitated by guanine nucleotide exchange factors (GEFs) such as SOS. The GTP-bound form of KRAS is in the “on state,” and interacts with proteins such as RAF and PI3K to promote downstream signaling that leads to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP, thus returning to the off-state, in a process facilitated by GAPs (GTPase-activating Proteins).

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

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

Most inhibitors of KRAS mutants bind preferentially to the GDP-bound form of the protein. For example, Amgen KRAS inhibitor AMG 510 and Mirati KRAS inhibitor MRTX849 react with the GDP-bound form of KRAS G12C at least 1000-fold more rapidly than with the GTP-bound form of the protein. One form of resistance that has been observed is for cancer cells to increase signaling through RTKs, thus increasing the amount of GTP-bound KRAS, which is less affected by current inhibitors. Thus, creating a molecule that could bind to and inhibit both the GDP- and GTP-bound forms of KRAS could have substantial utility.

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

SUMMARY

In one aspect, the invention provides a compound of Formula (A), Formula (B) or Formula (C):

In one embodiment, the compound is selected from the group consisting of:

or a salt thereof; and/or an isotopologue thereof.

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

In another aspect provided is a method of treating or suppressing cancer comprising: administering a therapeutically effective amount of a compound as described herein, including but not limited to a compound described in the preceding paragraphs, or a pharmaceutical formulation, including but not limited to the pharmaceutical formulation described in the preceding paragraphs, to a subject in need thereof, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

In another aspect is provided is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, as a medicament.

In another aspect provided is a compound as described herein, including but not limited to any of the foregoing embodiments or a pharmaceutical formulation as described herein for use as a medicament.

In an aspect, provided is a compound as described herein, including but not limited to any of the foregoing embodiments or a pharmaceutical formulation as described in any of the embodiments described herein for use in treating or suppressing cancer.

In an aspect, provided is a compound as described herein, including but not limited to any of the foregoing embodiments or a pharmaceutical formulation as described in any of the embodiments described herein for use in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

In an aspect, provided is a use of a compound as described herein, including but not limited to any of the foregoing embodiments or a pharmaceutical formulation as described in any of the embodiments described herein in the manufacturing of a medicament for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

In an aspect, provided is a use of a compound as described herein, including but not limited to any of the foregoing embodiments or a pharmaceutical formulation as described in any of the embodiments described herein for treating or suppressing cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

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

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

DETAILED DESCRIPTION

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

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

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

Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds with an (or) designation in the “Stereochemistry” column of Table 1 are single enantiomers wherein the absolute stereochemistry was arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section). Compounds with an (and) designation in the stereochemistry column of Table 1 are mixtures of enantiomers wherein the relative stereochemistry is as shown. Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted and that have no designation in the Stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds that have no designation in the Stereochemistry column of Table 1 or that are marked with (abs) are single enantiomers wherein the absolute stereochemistry is as indicated. For example, compound 2 is a single enantiomer with the stereochemistry as indicated.

Compound 51 is a mixture of stereoisomers wherein the stereochemistry at the methylenenitrile on the piperazine is absolute as shown, the stereochemistry at the fluoropyrolizine is absolute as shown and stereocenter on the the azetidine group is a mixture of R and S.

In some instances, the Stereochemistry column of Table 1 contains different indicators selected from (abs) (or) and (and) to refer to different stereocenters of the molecule. For example, Compound 15 includes a notation of “(abs) piperazine, (and) fluorocyclopropyl” in the stereochemistry column of Table 1.

The compound is a a mixture of two stereoisomers, wherein the stereochemistry at the methylenenitrile on the piperazine is absolute as shown, the stereochemistry at the fluoropyrolizine is absolute as shown and the fluorocyclopropy group is a mixture of trans (R,S) and trans (S,R) isomers (prepared from a racemic trans fluorocyclopropyl intermediate).

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

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

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

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 having a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).

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

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

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

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

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

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

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

“Alkyl” means a linear, branched, cyclic, or a combination thereof, saturated monovalent hydrocarbon radical having the defined number of carbons. For example, C1-C4 alkyl includes e.g., methyl, ethyl, propyl, 2-propyl, butyl, cyclopropyl, cyclobutyl, and the like. In one embodiment, alkyl is a linear or branched monovalent hydrocarbon radical having the defined number of carbons (“acyclic alkyl”). In one embodiment, alkyl is a cyclic monovalent hydrocarbon radical having the defined number of carbons (“cycloalkyl”).

“Alkylene” means a linear, branched, cyclic, or a combination thereof, saturated divalent hydrocarbon radical having the defined number of carbons. For example, C1-C4 alkylene includes e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and the like. In one embodiment, alkylene is a linear or branched divalent hydrocarbon radical having the defined number of carbons (“acyclic alkylene”). In one embodiment, alkylene is a cyclic divalent hydrocarbon radical having the defined number of carbons (“cycloalkylene”). “C0 alkylene” is means a bond. For example, C0-C2 alkylene includes a bond, methylene, ethylene, and the like.

“Alkenyl” means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having the defined number of carbons. For example, C2-C4 alkenyl includes e.g., vinyl, prop-1-en-2-yl, prop-1-en-1-yl, allyl and the like.

“Alkynyl” means a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having the defined number of carbons. For example, C2-C4 alkyne includes e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.

“Alkoxy” means an —ORx radical where RX is alkyl as defined above, or a —Rx′ORx″ radical where Rx′ is an alkylene and Rx″ is an alkyl group as defined above where the defined number of alkyl carbons in the alkoxy group are equal to the total number of carbons in Rx′ and Rx″. For example, C1-C4 alkoxy indicates e.g., methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, tert-butoxy, cyclopropoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, alkoxy is a —ORx radical. In some embodiments, alkoxy is a —Rx′ORx″ radical. In some embodiments, when a nitrogen is substituted with an alkoxy group, the alkoxy group is not linked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the alkoxy group. For example, the alkoxy-substituted nitrogen is not N—OR or N—CH2—O—Rx″.

“Alkoxyalkoxy” means an —ORy radical where Ry is alkoxy as defined above, provided that the attachment point of R is not an oxygen atom, or a —Ry′ORy″ radical where Ry′ is an alkylene and Ry″ is an alkoxy group as defined above, provided that the attachment point of Ry″ is not an oxygen atom, where the defined number of alkyl carbons in the alkoxyalkoxy group are equal to the total number of carbons in Ry′ and Ry″. For example, C1-C6 alkoxyalkoxy indicates e.g., —OCH2OCH3, —OCH2CH2OCH3, —OCH2CH2OCH3, —CH2OCH2OCH3, —CH2OCH2CH2OCH3, —CH2OCH2CH2OCH2CH3, —CH2CH2OCH2CH2OCH2CH3 and the like. In some embodiments, alkoxyalkoxy is a —ORy radical. In some embodiments, alkoxyalkoxy is a —Ry′ORy″ radical. In some embodiments, when a nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not linked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the alkoxyalkoxy group. For example, the alkoxyalkoxy-substituted nitrogen is not N—OyR or N—CH2—O—Ry″.

“Aminoalkyl” means an —NHRz radical where Rz is alkyl as defined above, or a —NRzRz′ radical where Rz and Rz′ are alkyl groups as defined above, or an —Rz″NH2 radical where Rz″ is an alkylene group as defined above, or an —Rz″NHRz radical where Rz″ is an alkylene group as defined above and Rz′ is an alkyl group as defined above, or a —Rz″NRzRz′ radical where Rz″ is an alkylene group as defined above and Rz and Rz′ are alkyl groups as defined above, where the defined number of alkyl carbons in the aminoalkyl group is equal to the total number of carbons in Rz, Rz′ and Rz″ as applicable. For example, C1-C6 aminoalkyl indicates e.g., —NHCH3, —NHCH2CH3, —NHCH2(CH3)2, —N(CH3)2, —N(CH3)CH2CH3, —N(CH2CH3)2, —CH2NH2, —CH2CH2NH2, —CH2NHCH3, —CH2N(CH3)2, —CH2CH2NHCH3, —CH2CH2N(CH3)2 and the like. In some embodiments, aminoalkyl is an —NHRz radical. In some embodiments, aminoalkyl is an —NRzRz′ radical. In some embodiments, an aminoalkyl is an —Rz″NH2 radical. In some embodiments, aminoalkyl is a —Rz″NHRz radical. In some embodiments, aminoalkyl is a —Rz″NRzRz′ radical. In some embodiments, when an oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not linked to the oxygen via the nitrogen or a carbon that is immediately adjacent to the nitrogen in the aminoalkyl group. For example, the aminoalkyl-substituted oxygen is not O—NHRz or O—CH2—NHRz.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). In some embodiments, “aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl and naphthyl, wherein the attachment point can be on any carbon atom. Exemplary aryl groups also include indenyl, tetrahydronaphthyl, indolinyl, benzodihydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, wherein the attachment point is on the phenyl group. In some embodiments, “aryl” excludes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups.

“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical having the defined number of carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

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

“Haloalkyl” means an alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., —CH2Cl, —CF3, —CHF2, —CH2CF3, —CF2CF3,

—CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

“Haloalkoxy” means an —ORa radical where Ra is haloalkyl as defined above, or a —RbORc radical where Rb and Rc are alkyl or haloalkyl groups as defined above where the defined number of alkyl carbons in the haloalkoxy group are equal to the total number of carbons in Rb and Rc. Halo atom(s) may be present in Rb, or Rc, or both, provided that at least one of Rb and Rc comprises a halo atom. For example, C1-C4 haloalkoxy indicates e.g., —OCF3, —OCHF2, —CH2OCF3, —CH2CH(F)CH2OCH3, —CH2CH(F)CH2OCHF2, and the like. In some embodiments, haloalkoxy is a —ORa radical. In some embodiments, haloalkoxy is a —RbORc radical. When all of the halo atom(s) in the haloalkoxy group are fluoro, it can be referred to in this Application as fluoroalkoxy. In some embodiments, when a nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not linked to the nitrogen via the oxygen or a carbon that is immediately adjacent to the oxygen in the haloalkoxy group. For example, the haloalkoxy-substituted nitrogen is not N—ORa or N—C(H)n(X)m—O—R″.

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

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

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

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more (in some embodiments, one, two, or three) ring atoms are heteroatom(s) independently selected from N, O, or S, the remaining ring atoms being carbon. In some embodiments, “heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, In such instances, unless otherwise specified, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. In some embodiments, “heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, “heteroaryl” excludes ring systems wherein the heteroaryl ring is fused with a carbocyclyl or heterocyclyl group.

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

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

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

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

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

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule or a tablet having a fixed ratio of active ingredients or in multiple, separate capsules or tablets for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

Compounds

In one aspect, the invention provides compound of Formula (A), Formula (B) or Formula (C)

Throughout the description, references to compounds of Formula (A), Formula (B) and Formula (C) are meant to encompass all subgenera and subcombinations of those formulae described herein, including compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula IXa as well as compounds of Table 1.

In an embodiment, the compound of Formula (A), Formula (B) or Formula (C) as described in any of the embodiments described herein is not a salt. In an embodiment, the compound of Formula (A), Formula (B) or Formula (C) as described in any of the embodiments described herein is a salt. In an embodiment, the salt is a formate salt. In an embodiment, the salt is a trifluoroacetate salt. In an embodiment, the salt is a pharmaceutically acceptable salt.

In an embodiment, provided is a compound of Formula (A), Formula (B) or Formula (C)

In an embodiment, the compound is of Formula (A) or Formula (B). In an embodiment, the compound is of Formula (A) or Formula (C). In an embodiment, the compound is of Formula (B) or Formula (C). In an embodiment, the compound is of Formula (A). In an embodiment, the compound is of Formula (B). In an embodiment, the compound is of Formula (C).

As generally defined herein, Ring A is a 6-10 membered aryl or a 5-10 membered heteroaryl, each substituted with 0, 1, 2 or 3 substituents independently selected from halo, —OH, —NH2, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, the 6-10 membered aryl or the 5-10 membered heteroaryl of Ring A is unsubstituted. In an embodiment, the 6-10 membered aryl or the 5-10 membered heteroaryl of Ring A is substituted with 1 substituent as described above. In an embodiment, the 6-10 membered aryl or the 5-10 membered heteroaryl of Ring A is substituted with 2 substituents as described above. In an embodiment, the 6-10 membered aryl or the 5-10 membered heteroaryl of Ring A is substituted with 3 substituents as described above.

In an embodiment, Ring A is selected from the group consisting of naphthalen-1-yl, phenyl, isoquinolin-1-yl, pyridin-2-yl, 1-H-indazol-3-yl and 1-H-indazol-4-yl, each substituted as described in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of naphthalenyl (e.g., naphthalen-1-yl), phenyl and pyridinyl (e.g., pyridin-2-yl), each substituted as described in any of the embodiments described herein.

In an embodiment of any of the above embodiments, the naphthalenyl is naphthalen-1-yl. In an embodiment any of the above embodiments, the pyridinyl is pyridin-2-yl. In an embodiment any of the above embodiments, the isoquinolinyl is isoquinolin-1-yl. In an embodiment of any of the above embodiments the 1-H-indazolyl is 1-H-indazol-3-yl or 1-H-indazol-4-yl. In an embodiment the 1-H-indazolyl is 1-H-indazol-3-yl. In an embodiment the 1-H-indazolyl is 1-H-indazol-4-yl.

In an embodiment, Ring A is selected from the group consisting of naphthalen-1-yl, phenyl, isoquinolin-1-yl and pyridin-2-yl, each substituted as described in any of the embodiments described herein. In an embodiment, Ring A is selected from the group consisting of naphthalen-1-yl and phenyl, each substituted as described in any of the embodiments described herein.

In an embodiment each of the naphthalenyl (e.g., naphthalen-1-yl), phenyl, isoquinolinyl (e.g., isoquinolin-1-yl), pyridinyl (e.g., pyridin-2-yl) and 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) groups of Ring A can be unsubstituted. In an embodiment, each of the naphthalenyl (e.g., naphthalen-1-yl), phenyl, isoquinolinyl (e.g., isoquinolin-1-yl), pyridinyl (e.g., pyridin-2-yl) and 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) of ring A is substituted with 1 substituent independently selected from the substituents described in any of the embodiments described above. In an embodiment, each of the naphthalenyl (e.g., naphthalen-1-yl), phenyl, isoquinolinyl (e.g., isoquinolin-1-yl), pyridinyl (e.g., pyridin-2-yl) and 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) of ring A is substituted with 2 substituents independently selected from the substituents described in any of the embodiments described above. In an embodiment, each of the naphthalenyl (e.g., naphthalen-1-yl), phenyl, isoquinolinyl (e.g., isoquinolin-1-yl), pyridinyl (e.g., pyridin-2-yl) and 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) of ring A is substituted with 3 substituents independently selected from the substituents described in any of the embodiments described above.

In an embodiment, Ring A is naphthalenyl (e.g., naphthalen-1-yl) substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 0, 1 or 2 substituents independently selected from halo, C1-C4 acyclic alkyl and C2-C3 alkynyl. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 0, 1 or 2 substituents independently selected from —F, —Cl, -Me, -Et and ethynyl. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is unsubstituted. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 1 or 2 substituents independently selected from —F, —Cl, -Et and ethynyl. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 1 or 2 substituents independently selected from —F and —Cl. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 1 or 2 instances of —F. In an embodiment, the naphthalenyl (e.g., naphthalen-1-yl) is substituted with 1 or 2 instances of —Cl. In an embodiment, the naphthalenyl is naphthalen-1-yl.

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment of the embodiments described above, the isoquinolinyl is isoquinolinyl-1-yl.

In an embodiment, Ring A is selected from the group consisting of

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is selected from the group consisting of

In an embodiment, Ring A is selected from the group consisting of

In an embodiment, Ring A is

In an embodiment Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is pyridinyl (e.g., pyridin-2-yl) substituted with 0, 1, 2 or 3 substituents independently selected from halo, —OH, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, the pyridinyl (e.g., pyridin-2-yl) is substituted with 1, 2 or 3 substituents independently selected from —NH2, C1-C4 acyclic alkyl and C1-C4 haloalkyl. In an embodiment, the pyridinyl (e.g., pyridin-2-yl) is substituted with 1, 2 or 3 substituents independently selected from —NH2, -Me and —CF3. In an embodiment of the embodiments described above, the pyridinyl is pyridin-2-yl. In an embodiment, Ring A is

In an embodiment, Ring A is 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) substituted with 0, 1, 2 or 3 substituents independently selected from halo, —OH, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, the 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) is substituted with 1 or 2 substituents independently selected from halo and acyclic C1-C4 alkyl. In an embodiment, the 1-H-indazolyl (e.g., 1-H-indazol-3-yl, 1-H-indazol-4-yl) is substituted with 1 or 2 substituents independently selected from —F, —Cl and -Me. In an embodiment, of any of the above embodiments, the 1-H-indazolyl is selected from the group consisting of 1-H-indazol-3-yl and 1-H-indazol-4-yl. In an embodiment, the 1-H-indazolyl is 1-H-indazol-3-yl. In an embodiment, the 1-H-indazolyl is 1-H-indazol-4-yl. In an embodiment, Ring A is selected from

In an embodiment, Ring A is

In an embodiment, Ring A is

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rg, Rh, Ri, Rj, Rk, Rm, Rn, Ro and Rp are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rg, Rh, Ri, Rj, Rk and Rm are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rj, Rk, Rm, Rn, Ro and Rp are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rg, Rh, Ri, Rn, Ro and Rp are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, R9, Rh and Ri are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rn, Ro and Rp are as defined in any of the embodiments described herein.

In an embodiment, Ring A is selected from the group consisting of

wherein each R3, R4, Rj, Rk and Rm are as defined in any of the embodiments described herein.

In an embodiment, Ring A is

wherein each R3 and R4 are as defined in any of the embodiments described herein. In an embodiment, Ring A is

wherein each Rg, Rh and Ri are as defined in any of the embodiments described herein.

In an embodiment, Ring A is

wherein each Rj, Rk and R are as defined in any of the embodiments described herein. In an embodiment, Ring A is

wherein each Rn, Ro and Rp are as defined in any of the embodiments described herein.

As generally defined herein, R1 is

wherein Rd is as defined in any of the embodiments described herein. In an embodiment, the Rd group and the attachment to the methylene linker are in a trans configuration. In one embodiment, when Rd is not H, the stereochemistry at the quaternary carbon of R1 is (S) and the stereochemistry at the carbon connected to Rd is (R). In an embodiment, R1 is

In an embodiment, R1 is

In an embodiment, R1 is

In an embodiment, R1 is

As generally defined herein, R2 is R2c, wherein

R2c is

wherein R is as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of and

wherein Re is as defined in any of the embodiments described herein.

In an embodiment, R2c is

wherein Re is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re is as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of:

wherein Re1, Re2 and Re3 are as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of:

wherein Re1, Re2 and Re3 are as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re2 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re3 is as defined in any of the embodiments described herein.

In an embodiment, the stereochemistry at the methylenenitrile group of R2c is (S). In an embodiment, R2c is

wherein Re is as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of

wherein Re is as defined in any of the embodiments described herein.

In an embodiment, R2c is

wherein R is as defined in any of the embodiments described herein. In an embodiment, R2c

is wherein Re is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re is as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of:

wherein Re1, Re2 and Re3 are as defined in any of the embodiments described herein.

In an embodiment, R2c is selected from the group consisting of:

wherein Re1, Re2 and Re3 are as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c

is wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, R2c is

wherein Re2 is as defined in any of the embodiments described herein. In an embodiment, R2c

is wherein Re3 is as defined in any of the embodiments described herein.

As generally defined herein, each R3 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each R3 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, R3 is selected from the group consisting of hydrogen, fluoro, and chloro. In an embodiment, R3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl and C2-C3 alkynyl. In an embodiment, R3 is selected from the group consisting of hydrogen, —F, —Cl, -Et and ethynyl. In an embodiment, R3 is selected from the group consisting of hydrogen and fluoro. In an embodiment, R3 is selected from the group consisting of hydrogen and —F. In an embodiment, R3 is —F. In an embodiment, R3 is hydrogen.

As generally defined herein, each R4 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each R4 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, R4 is selected from the group consisting of hydrogen, fluoro, and chloro. In an embodiment, R4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl and C2-C3 alkynyl. In an embodiment, R4 is selected from the group consisting of hydrogen, —F, —Cl, -Et and ethynyl. In an embodiment, R4 is selected from the group consisting of hydrogen, —F, —Cl, -Et and ethynyl. In an embodiment, R4 is selected from the group consisting of —F, —Cl, -Et and ethynyl. In an embodiment, R4 is selected from the group consisting of —F and —Cl. In an embodiment, R4 is —F. In an embodiment, R4 is -Et and ethynyl. In an embodiment, R4 is ethynyl. In an embodiment, R4 is chloro. In an embodiment, R4 is hydrogen.

As generally defined herein, each R is independently selected from C1-C4 alkyl, C1-C6 alkoxy and —CH2-(4-6 membered heterocycle). In an embodiment, R5 is C1-C4 alkyl. In an embodiment, R is selected from -Me, -Et and -iPr. In an embodiment, R5 is -Me.

As generally defined herein, each R6 is independently selected from C1-C4 alkyl, C1-C6 alkoxy and —CH2-(4-6 membered heterocycle). In an embodiment, R6 is independently selected from -Me, -Et, —Pr, —iPr, —CH2CH2OMe and

In an embodiment, R6 is independently selected from -Me, —CH2CH2OMe and

In an embodiment, R6 is -Me. In an embodiment, R6 is —CH2CH2OMe. In an embodiment, R6 is

As generally defined herein, Rd is H, —F or —OH. In an embodiment, R is selected from the group consisting of H and —F. In an embodiment, Rd is —OH. In an embodiment, Rd is H. In an embodiment, Rd is F.

As generally defined herein, Re is selected from the group consisting of R, Re2 or Re3, wherein Re1, Re2 and Re3 are as defined in any of the embodiments described herein. In an embodiment, Re is selected from Re1 and Re2 wherein Re1 and Re2 are as defined in any of the embodiments described herein. In an embodiment, Re is selected from Re1 and Re3 wherein Re1 and Re3 are as defined in any of the embodiments described herein. In an embodiment, Re is selected from Re2 and Re3 wherein Re2 and Re3 are as defined in any of the embodiments described herein.

In an embodiment, Re is Re1 wherein Re1 is as defined in any of the embodiments described herein. In an embodiment, Re is Re2 wherein Re2 is as defined in any of the embodiments described herein. In an embodiment, R is Re3 wherein Re3 is as defined in any of the embodiments described herein.

In an embodiment, the heterocycle of RW is unsubstituted. In an embodiment, the heterocycle of Re1 is substituted with 1 substituent as described above. In an embodiment, the heterocycle of Re1 is substituted with 2 substituents as described above. In an embodiment, the heterocycle of Re1 is substituted with 3 substituents as described above. In an embodiment, the heterocycle of Re1 is substituted with 4 substituents as described above.

In an embodiment, the monocyclic heterocycle of Re1 is substituted with 0 or 1 instances of C1-C4 alkyl. In an embodiment, the monocyclic heterocycle of Re1 is substituted with 0 or 1 instances of -Me, -iPr or cyclopropyl. In an embodiment, the monocyclic heterocycle of Re1 is substituted with 0 or 1 instances of —iPr. In an embodiment, the monocyclic heterocycle of Re1 is substituted with 0 or 1 instances of cyclopropyl. In an embodiment, the monocyclic heterocycle of Re1 is substituted with 0 or 1 instance of methyl. In an embodiment, Re1 is selected from the group consisting of azetidinyl and oxetanyl, each substituted with 0 or 1 instances of C1-C4 alkyl.

In an embodiment, Re1 is selected from the group consisting of azetidinyl and oxetanyl, each substituted with 0 or 1 substituents independently selected from -Me, -iPr or cyclopropyl. In an embodiment, Re1 is selected from the group consisting of azetidinyl and oxetanyl, each substituted with 0 or 1 instances of-Me. In an embodiment, Re1 is selected from the group consisting of azetidinyl and oxetanyl, each substituted with 1 instance of -Me. In an embodiment, Re1 is selected from azetidinyl, pyrrolidinyl and morpholinyl substituted with 0 or 1 instance of-Me.

In an embodiment, Re1 is azetidinyl substituted with 0 or 1 instances of C1-C4 alkyl.

In an embodiment, Re1 is azetidinyl substituted with 0 or 1 substituents independently selected from -Me, -iPr or cyclopropyl. In an embodiment, Re1 is azetidinyl substituted with 0 or 1 instance of-Me. In an embodiment, Re1 is azetidinyl substituted with 0 or 1 instance of cyclopropyl. In an embodiment, Re1 is azetidinyl substituted with 0 or 1 instance of —Pr. In an embodiment, Re1 is N-methyl azetidinyl.

In an embodiment, Re1 is oxetanyl substituted with 0 or 1 instances of C1-C4 alkyl. In an embodiment, Re1 is oxetanyl substituted with 0 or 1 instance of-Me.

In an embodiment, the attachment point for the monocyclic heterocycle is on a carbon atom.

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is a 4-10 membered heterocycle containing a nitrogen atom and one or two additional heteroatoms selected from oxygen and sulfur, including sulfur dioxide, selected from the group consisting of a 4-8 member monocyclic heterocycle, a 6-10 member fused bicyclic heterocycle, a 6-10 member bridged heterocycle and a 6-10 member spiro heterocycle, each substituted with 0, 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, 4-6 membered heterocycle, —C(O)C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl.

In an embodiment, Re1 is a 4-10 membered heterocycle containing a nitrogen atom and one or two additional heteroatoms selected from oxygen and sulfur, including sulfur dioxide, selected from the group consisting of a 4-8 member monocyclic heterocycle, a 6-10 member fused bicyclic heterocycle, a 6-10 member bridged heterocycle and a 6-10 member spiro heterocycle, each substituted with 0, 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl.

In an embodiment, the heterocycle of Re1 is unsubstituted. In an embodiment, the heterocycle of Re1 is substituted with 1 substituent as described above. In an embodiment, the heterocycle of Re1 is substituted with 2 substituents as described above. In an embodiment, the heterocycle of Re1 is substituted with 3 substituents as described above. In an embodiment, the heterocycle of Re1 is substituted with 4 substituents as described above. In an embodiment of any of the embodiments of Re1 described above, each of the substituents is independently selected from halo, C1-C4 alkyl, 4-6 membered heterocycle, —C(O)C1-C6 alkyl, C1-C6 alkoxy, and C1-C4 haloalkoxy. In an embodiment of any of the embodiments described above, each of the substituents is halo. In an embodiment of any of the embodiments described above, each of the substituents is C1-C4 alkyl. In an embodiment of any of the embodiments described above, each of the substituents is a 4-6 membered heterocycle. In an embodiment of any of the embodiments described above, each of the substituents is —C(O)C1-C6 alkyl. In an embodiment of any of the embodiments described above, each of the substituents is C1-C6 alkoxy. In an embodiment of any of the embodiments described above, each of the substituents is C1-C4 haloalkoxy.

In an embodiment of any of the embodiments described above, each of the substituents is independently selected from —F, -Me, —OMe, —OEt, —OCHF2, —C(═O)Me and oxetanyl. In an embodiment of any of the embodiments described above, each of the substituents is —F. In an embodiment of any of the embodiments described above, each of the substituents is -Me. In an embodiment of any of the embodiments described above, each of the substituents is —OMe. In an embodiment of any of the embodiments described above, each of the substituents is —OEt. In an embodiment of any of the embodiments described above, each of the substituents is —OCHF2. In an embodiment of any of the embodiments described above, each of the substituents is —C(═O)Me. In an embodiment of any of the embodiments described above, each of the substituents is oxetanyl.

In an embodiment, Re1 is azetidine substituted with 0, 1 or 2 substituents independently selected from —F and —OMe and -OEt.

In an embodiment, Re1 is pyrrolidine substituted with 0, 1 or 2 substituents independently selected from —F, —OMe, —OEt and —OCHF2.

In an embodiment, Re1 is piperidine substituted with 0, 1 or 2 instances of—F. In an embodiment, Re1 is unsubstituted hexahydro-1H-furo[3,4-c]pyrrole. In an embodiment, Re1 is unsubstituted 1, 4-oxazepane. In an embodiment, Re1 is unsubstituted 2-oxa-5-azabicyclo[2.2.1]heptane. In an embodiment, Re1 is unsubstituted 3-oxa-8-azabicyclo[3.2.1]octane. In an embodiment, Re1 is unsubstituted 8-oxa-3-azabicyclo[3.2.1]octane. In an embodiment, Re1 is unsubstituted 3-oxa-6-azabicyclo[3.1.1]heptane. In an embodiment, Re1 is unsubstituted 6-oxa-3-azabicyclo[3.1.1]heptane. In an embodiment, Re1 is unsubstituted 2-oxa-5-azabicyclo[2.2.2]octane. In an embodiment, Re1 is unsubstituted thiomorpholine.

In an embodiment, the attachment point for R is the nitrogen atom of the heterocycle.

In an embodiment, the R is selected from the group consisting of:

In an embodiment, the Rd is selected from the group consisting of:

In an embodiment, the R is selected from the group consisting of:

In an embodiment, Re1 is

In an embodiment, the 4-10 membered heterocycle of Re1 is substituted with 0, 1 or 2 substituents independently selected from fluoro and methyl.

In an embodiment, Re1 is selected from

In an embodiment, R is selected from

and each substituted with 0, 1 or 2 substituents independently selected from —F, -Me, —OMe and -OEt.

In an embodiment, the 4-10 membered heterocycle of Re1 is unsubstituted.

In an embodiment, Re1 is selected from,

and each unsubstituted.

In an embodiment, Re1 is

substituted with 0, 1 or 2 instances of -Me.

In an embodiment, Re1 is

substituted with 0, 1 or 2 substituents independently selected from —F and —OMe and -OEt.

In an embodiment, Re1 is

In an embodiment, Re1 is

In an embodiment, Re1 is

substituted with 0, 1 or 2 instances of —F.

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is selected from the group consisting of:

In an embodiment, Re1 is

In an embodiment, Re1 is selected from the group consisting of.

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted

In an embodiment, Re1 is unsubstituted.

As generally defined herein, Re2 is a 5-6 membered heteroaryl wherein the attachment point is a carbon atom group and wherein the heteroaryl is substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is a 5-6 membered heteroaryl group containing at least one nitrogen atom, wherein the attachment point for the heteroaryl group is a carbon atom group and wherein the heteroaryl is substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of pyrimidinyl, oxazolyl, 1,2,4-oxadiazolyl and 1,2,4-thiadiazolyl each substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of pyrimidinyl and 1,2,4-oxadiazolyl each substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of

In an embodiment Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

each substituted with 0, 1 or 2 substituents independently selected from halo, C1-C4 acyclic alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of

each substituted with 0, 1 or 2 substituents independently selected from halo, C1-C4 acyclic alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, the heteroaryl of Re2 is unsubstituted. In an embodiment, the heteroaryl of Re2 is substituted with 1 substituent as described above. In an embodiment, the heteroaryl of Re2 is substituted with 2 substituents as described above. In an embodiment of any of the embodiments of Re2 described above, each of the substituents is independently selected from halo, C1-C4 acyclic alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl. In an embodiment of any of the embodiments described above, each of the substituents is halo. In an embodiment of any of the embodiments described above, each of the substituents is C1-C4 acyclic alkyl. In an embodiment of any of the embodiments described above, each of the substituents is C1-C4 hydroxyalkyl. In an embodiment of any of the embodiments described above, each of the substituents is C1-C4 haloalkyl. In an embodiment of any of the embodiments described above, each of the substituents is C3-C6 heterocyclyl (e.g., containing 1 or 2 heteroatoms selected from N and O). In an embodiment of any of the embodiments described above, each of the substituents is C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl. In an embodiment of any of the embodiments described above, each of the substituents is independently selected from —F, -Me, -Et, -iPr, -tBu, —C(OH)(CH3)2, —CHF2, —CF2CH3, —CH(F)CH3, —CF3, oxetanyl, cyclopropyl, 1-Me-cyclopropyl and 2-F-cyclopropyl. In an embodiment of any of the embodiments described above, each of the substituents is —F. In an embodiment of any of the embodiments described above, each of the substituents is -Me. In an embodiment of any of the embodiments described above, each of the substituents is -Et. In an embodiment of any of the embodiments described above, each of the substituents is -iPr. In an embodiment of any of the embodiments described above, each of the substituents is -tBu. In an embodiment of any of the embodiments described above, each of the substituents is —C(OH)(CH3)2. In an embodiment of any of the embodiments described above, each of the substituents is oxetanyl. In an embodiment of any of the embodiments described above, each of the substituents is —CHF2. In an embodiment of any of the embodiments described above, each of the substituents is —CF2CH3. In an embodiment of any of the embodiments described above, each of the substituents is —CH(F)CH3. In an embodiment of any of the embodiments described above, each of the substituents is —CF3. In an embodiment of any of the embodiments described above, each of the substituents is cyclopropyl. In an embodiment of any of the embodiments described above, each of the substituents is 1-Me-cyclopropyl. In an embodiment of any of the embodiments described above, each of the substituents is 2-F-cyclopropyl.

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is a 6 membered heteroaryl group substituted with 0, 1 or 2 substituents independently selected from halo, acyclic C1-C4 alkyl, and C3-C6 cycloalkyl.

In an embodiment, Re2 is a 6 membered heteroaryl group substituted with 0, 1 or 2 substituents independently selected from —F, -Me, -Et, -iPr, and cyclopropyl.

In an embodiment, Re2 is unsubstituted pyrimidinyl or pyridazinyl.

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is a 5 membered heteroaryl group containing at least one nitrogen atom, wherein the attachment point for the heteroaryl group is a carbon atom group and wherein the heteroaryl is substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl and 1,2,4-thiadiazolyl each substituted with 0, 1 or 2 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is selected from the group consisting of

In an embodiment, Re2 is

In an embodiment, the 5 membered heteroaryl group of Re2 is substituted with 0 or 1 substituents independently selected from acyclic C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, the 5-membered heteroaryl group of Re2 is substituted with 0 or 1 substituents independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is selected from the group consisting of:

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment Re2

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

In an embodiment, Re2 is

As generally defined herein, Re3 is —NR5R6, wherein R5 and R6 are as defined in any of the embodiments described herein. In an embodiment, Re3 is selected from

In an embodiment, Re3 is

As generally defined herein, R is selected from the group consisting of H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy. In an embodiment, R is C1-C4 alkyl. In an embodiment, R is methyl.

As generally defined herein, each Rh is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each Rh is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Rh is selected from the group consisting of hydrogen, —F, and —C1. In an embodiment, Rh is selected from the group consisting of hydrogen and —F. In an embodiment, Rh is hydrogen.

As generally defined herein, each R, is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, Ri is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Ri is selected from the group consisting of hydrogen, —F, and —Cl. In an embodiment, Ri is selected from the group consisting of —F and —Cl. In an embodiment, Ri is —Cl. In an embodiment, Ri is —F.

As generally defined herein, each Rj is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each Rj is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Rj is selected from the group consisting of C1-C4 acyclic alkyl, C3-C4 cycloalkyl, C1-C4 alkenyl and C1-C4 haloalkyl. In an embodiment, Rj is selected from the group consisting of hydrogen, halo, C1-C4 acyclic alkyl, C3-C4 cycloalkyl, C1-C4 alkenyl and C1-C4 haloalkyl. In an embodiment, Rj is selected from the group consisting of hydrogen, halo, C3-C4 cycloalkyl and C1-C4 haloalkyl. In an embodiment, Rj is selected from the group consisting of hydrogen, —F, —Cl, -Me, -Et, cyclopropyl, cyclobutyl, prop-1-en-2-yl, —CHF2 and —CF3. In an embodiment, Rj is selected from the group consisting of —F, —Cl, cyclopropyl and —CF3. In an embodiment, Rj is selected from the group consisting of hydrogen, —F, —Cl and —CHF2. In an embodiment, Rj is selected from the group consisting of C3-C4 cycloalkyl and C1-C4 haloalkyl. In an embodiment, Rj is selected from the group consisting of -Me, -Et, cyclopropyl, cyclobutyl, prop-1-en-2-yl, —CHF2 and —CF3. In an embodiment, Rj is selected from the group consisting of cyclopropyl and —CF3. In an embodiment, Rj is cyclopropyl. In an embodiment, Rj is —CF3. In an embodiment, Rj is difluoromethyl.

As generally defined herein, each Rk is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each Rk is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Rk is selected from the group consisting of hydrogen, halo, C1-C4 acyclic alkyl, C3-C4 cycloalkyl, C1-C4 alkenyl and C1-C4 haloalkyl. In an embodiment, Rk is selected from the group consisting of hydrogen, halo, C3-C4 cycloalkyl and C1-C4 haloalkyl. In an embodiment, Rk is selected from the group consisting of hydrogen, —F, —Cl, -Me, -Et, cyclopropyl, cyclobutyl, prop-1-en-2-yl, —CHF2 and —CF3. In an embodiment, Rk is selected from the group consisting of —F, —Cl, cyclopropyl and —CF3. In an embodiment, Rk is selected from the group consisting of hydrogen, —F, —Cl and —CHF2. In an embodiment, Rk is selected from the group consisting of hydrogen and halo. In an embodiment, Rk is selected from the group consisting of hydrogen, —F and —Cl. In an embodiment, Rk is —F. In an embodiment, Rk is —Cl. In an embodiment, Rk is hydrogen.

As generally defined herein, each Rn is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each Rn is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Rn is selected from the group consisting of hydrogen, methyl and trifluoromethyl. In an embodiment, Rn is trifluoromethyl.

As generally defined herein, each Ro is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkenyl and C2-C3 alkynyl. In an embodiment, each Ro is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Ro is selected from the group consisting of hydrogen, methyl and trifluoromethyl. In an embodiment, Ro is methyl. In an embodiment, Ro is fluoro.

As generally defined herein, each Rp is independently selected from the group consisting of hydrogen, halo, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and C2-C3 alkynyl. In an embodiment, Rp is —NH2.

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, Ring A is selected from the group consisting of:

In an embodiment, the compound is of Formula I or Formula II:

In an embodiment, the compound is of Formula I. In an embodiment, the compound is of Formula II.

In an embodiment, the compound is of Formula III or Formula IV:

In an embodiment, the compound is of Formula III. In an embodiment, the compound is of Formula IV.

In an embodiment, the compound is of Formula V or Formula VI:

In an embodiment, the compound is of Formula V. In an embodiment, the compound is of Formula VI.

In an embodiment, the compound is of Formula VII, Formula VIII or Formula IX:

In an embodiment, the compound is of Formula VII. In an embodiment, the compound is of Formula VIII. In an embodiment, the compound is of Formula IX. In an embodiment, the compound is of Formula IXa:

or a salt thereof; and/or an isotopologue thereof, wherein R1, R2, Rf, Rn, Ro and Rp are as defined in any of the embodiments described herein.

Methods For Treatment of Cancer

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

In an aspect, provided is a compound of Formula (A), Formula (B) or Formula (C) 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.

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

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

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

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

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

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

Testing

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

The ability of compounds of Formula (A), Formula (B) and Formula (C), and pharmaceutically acceptable salts and/or isotopologues thereof, to inhibit activity of the GTP-bound form of KRAS G12C can be tested using methods such as the in vitro assay described in Examples 116 and 117 below. Example 116 describes determining, for various compounds, the half-maximal inhibition (IC50) of KRAS G12C loaded with GTP analogue GMPPNP from binding to cRaf, as the Ras-binding domain (RBD). Example 117 describes determining, for various compounds, the half-maximal inhibition (IC50) of KRAS G12C loaded with GTP analogue GMPPNP from binding to PI3Kα, as the Ras-binding domain (RBD). Example 120 describes testing compounds for the ability to inhibit cell viability in MCF10A G12C/A59G mutant, which abrogates GTPase activity, thus preventing hydrolysis of GTP to GDP.

Pharmaceutical Compositions

In general, the compounds of Formula (A), Formula (B) and Formula (C), and pharmaceutically acceptable salts and/or isotopologues thereof, of this disclosure (also may be referred to herein as “compounds” or “compounds of this disclosure”) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In some embodiments, a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; or about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of a compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

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

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

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

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

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

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.10% to 1% w/w of the formulation.

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

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

Combinations and Combination Therapies

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

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

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

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

In some embodiments, the compounds of the present disclosure are used in combination with a CDK 4/6 inhibitor. Examples of CDK 4/6 inhibitors suitable for the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4-ethylpiperazin-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) whereas 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 (pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

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

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

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

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

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

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

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

SELECTED EMBODIMENTS

each substituted with 0.1 or 2 substituents independently selected from —F, -Me, —OMe and -OEt.

substituted with 0, 1 or 2 instances of -Me.

substituted with 0, 1 or 2 substituents independently selected from —F and —OMe and -OEt.

substituted with 0, 1 or 2 instances of —F.

each substituted with 0, 1 or 2 substituents independently selected from halo, C1-C4 acyclic alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

each substituted with 0, 1 or 2 substituents independently selected from halo, C1-C4 acyclic alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 heterocyclyl and C3-C6 cycloalkyl optionally substituted with one or two instances of halo or methyl.

or a salt thereof, and/or an isotopologue thereof.

or a salt thereof, and/or an isotopologue thereof.

General Synthetic Methods

With the exception of compounds 56, 57 and 58 in Table 1, the compounds of the instant disclosure were prepared according to methods described in the Examples section or variations thereof that would be within the knowledge of one of skill in the art. Compounds 56, 57 and 58, marked in Table 1 with “*” can be prepared using methods adapted from those described in the Examples section, variations thereof, or synthetic methods known to persons of skill in the art.

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

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

EXAMPLES

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

The following abbreviations are used in this section:

FA
formic acid

g
grams

mg
milligrams

h
hours

mL
milliliters

NMR
Nuclear magnetic resonance

MHz
megahertz

spectrometry

Rt
Retention time

min
minutes

um
micrometers

mm
millimeters

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

SYNTHETIC EXAMPLES

General Schemes

General Scheme 1 (Method 1, Step 4) General Procedure for the Synthesis of Compounds of Formula (A) and Formula (B)

To a solution of NH piperazine intermediate A or B (1 eq) in dichloromethane was added substituted acrylic acid Intermediate X (2 eq), N,N-diisopropylethylamine (3 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.5 eq, 50% purity in ethyl acetate) at 0° C. and the mixture was stirred at 25° C. for 1 h to provide crude product of Formula (A) or Formula (B).

Intermediates

To a solution of 2,2-dimethylpropanenitrile (10 g, 120.29 mmol) in ethanol (100 mL) was added hydroxylamine;hydrochloride (12.54 g, 180.44 mmol) and potassium carbonate (33.25 g, 240.58 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was concentrated to dryness in vacuo. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording (Z)—N′-hydroxypivalimidamide (3.54 g, 25%) as a blue solid: 1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.91-8.76 (m, 1H), 5.27-5.13 (m, 2H), 1.08 (s, 9H).

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) affording (E)-ethyl 4-(((Z)-(amino(1-methylcyclopropyl)methylene)amino)oxy)-4-oxobut-2-enoate (1.85 g, 57.45%) as a white solid. LCMS Rt=0.630 min, m/z=240.1 [M+H]+.

The cyclization reaction was prepared in a similar fashion to Method #4, Step 4. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in petroleum ether) affording (E)-ethyl 3-(3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-yl)acrylate (1.2 g, 70.12%) as a yellow gum. LCMS Rt=0.820 min, m/z=222.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The reaction mixture was concentrated in vacuo affording (E)-3-(3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-yl)acrylic acid (800 mg, crude) as a white solid, used in next step without further purification. LCMS Rt=0.638 min, m/z=194.1 [M+H]+.

A mixture of (E)-4-ethoxy-4-oxo-but-2-enoic acid (13 g, 90.20 mmol), oxalyl dichloride (12.59 g, 99.22 mmol) and N,N-dimethylformaldehyde (659.27 mg, 9.02 mmol) in dichloromethane (80 mL) was degassed and purged with nitrogen (3 times), and then the mixture was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated in vacuo affording (E)-ethyl 4-chloro-4-oxobut-2-enoate (14 g, crude) as a yellow oil used in the next step without further purification.

The addition reaction was prepared in a similar fashion to Method #4, Step 2, the reaction mixture was concentrated in vacuo affording N-hydroxyoxetane-3-carboxamidine (1.26 g, crude) as a gray solid, used in next step without further purification. LCMS Rt=0.112 min, m/z=116.1 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3. The reaction mixture was concentrated in vacuo affording (E)-ethyl 4-(((Z)-(amino(oxetan-3-yl)methylene)amino)oxy)-4-oxobut-2-enoate (1.1 g, crude) as a white solid, used in next step without further purification. LCMS Rt=0.430 min, m/z=242.1 [M+H]+.

The cyclization reaction was prepared in a similar fashion to Method #4, Step 4. The reaction mixture was concentrated in vacuo affording ethyl (E)-3-[3-(oxetan-3-yl)-1,2,4-oxadiazol-5-yl]prop-2-enoate (860 mg, crude) as a brown oil, used in next step without further purification. LCMS Rt=0.671 min, m/z=224.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The reaction mixture was concentrated in vacuo affording (E)-3-[3-(oxetan-3-yl)-1,2,4-oxadiazol-5-yl]prop-2-enoic acid (570 mg, crude) as a yellow solid, used in next step without further purification. LCMS Rt=0.221 min, m/z=196.1 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3. The reaction mixture was concentrated in vacuo affording (E)-ethyl 4-(((E)-(1-amino-2,2-difluoropropylidene)amino)oxy)-4-oxobut-2-enoate (3.6 g, crude) as a brown oil, used in the next step without further purification. LCMS Rt=0.510 min, m/z=250.1 [M+H]+.

The cyclization reaction was prepared in a similar fashion to Method #4, Step 4. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 9% ethyl acetate in petroleum ether) affording ethyl (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoate (650 mg, 43.78%) as a white solid. LCMS Rt=0.633 min, m/z=232.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3.

The reaction mixture were concentrated in vacuo affording (E)-3-[3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl]prop-2-enoic acid (400 mg, crude) as a white solid used in the next step without further purification. LCMS Rt=0.545 min, m/z=204.0 [M+H]+.

To a solution of 3-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-4-methylcyclohexanone (15 g, 25.66 mmol) in N,N-dimethylformaldehyde (300 mL) was added cuprous iodide (14.66 g, 76.99 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (24.65 g, 128.32 mmol). The mixture was stirred at 90° C. for 2 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 3-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-methylcyclohexanone (12 g, 88.80%) as a yellow oil. LCMS Rt=0.875 min, m/z=526.2 [M+H]+.

To a solution of 3-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-methylcyclohexanone (12 g, 22.78 mmol) in tetrahydrofuran (600 mL) was added lithium hexamethyldisilazane (1 M, 34.18 mL) at −78° C. under nitrogen atmosphere for 1 h, then ethyl cyanoformate (2.7 g, 27.34 mmol) was added at −78° C. The resulting mixture was stirred at -78° C. for 0.5 h under nitrogen atmosphere. The reaction mixture was quenched with a saturated solution of ammonium chloride (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording ethyl 4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-methyl-2-oxo-cyclohexanecarboxylate (13.6 g, crude) as a yellow oil used in the next step without further purification. LCMS Rt=1.235 min, m/z=598.3 [M+H]+.

To a solution of ethyl 4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-methyl-2-oxocyclohexanecarboxylate (13 g, 21.72 mmol) in ethanol (1200 mL)/water (240 mL) was added sodium bicarbonate (45.61 g, 542.89 mmol) and 2-methylisothiourea;sulfuric acid (60.45 g, 217.15 mmol). The mixture was stirred at 50° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (4.7 g, 34.65%) as a yellow solid. LCMS Rt=1.046 min, m/z=624.2 [M+H]+.

To a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (1.5 g, 2.40 mmol) in dichloromethane (100 mL) was added triethylamine (970 mg, 9.60 mmol) and trifluoromethane anhydride (2.37 g, 8.40 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (30 mL) at 0° C. and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate (1.8 g, crude) as a yellow oil used in the next step without further purification. LCMS Rt=3.664 min, m/z=756.2 [M+H]+.

EXEMPLARY COMPOUNDS

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4.

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4.

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording (S)-diethyl (2-(4-(7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazin-1-yl)-2-oxoethyl)phosphonate (400 mg, 68%) as a brown solid. LCMS Rt=2.252 min, m/z=735.3 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4.

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4.

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3.

The cyclization reaction was prepared in a similar fashion to Method #4, Step 4.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3.

The amide coupling reaction was prepared in a similar fashion to Method #1, Step 4.

The addition reaction was prepared in a similar fashion to Method #4, Step 2. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording N,2-dihydroxy-2-methylpropanimidamide (2.2 g) as a white solid. LCMS Rt=0.351 min, m/z=118.1 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording (E)-ethyl 4-((2-hydroxy-2-methylpropanimidamido)oxy)-4-oxobut-2-enoate (2.2 g, 49.89%) as a white solid. LCMS Rt=0.552 min, m/z=244.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The crude product was concentrated in vacuo affording (E)-3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)acrylic acid (180 mg, 55.94%) as a white solid used in the next step without further purification. LCMS Rt=0.467 min, m/z=198.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The reaction mixture was quenched with hydrochloric acid (1M, 1 mL) and adjusted pH to 2, then extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording (E)-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)acrylic acid (500 mg, crude) as a yellow oil used in next step without any further purification. LCMS Rt=0.449 min, m/z=208.0 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #4, Step 3.

The reaction mixture was concentrated in vacuo affording (E)-ethyl 4-(((Z)-(1-amino-2-methylpropylidene)amino)oxy)-4-oxobut-2-enoate (15 g, crude), which was used in the next step without further purification. LCMS Rt=0.545 min, m/z=229.1 [M+H]+.

The cyclization reaction was prepared in a similar fashion to Method #4, Step 4. The reaction mixture was concentrated in vacuo affording (E)-ethyl 3-(3-isopropyl-1,2,4-oxadiazol-5-yl)acrylate (15 g, crude), which was used in the next step without further purification. LCMS Rt=0.740 min, m/z=211.1 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The reaction mixture was concentrated in vacuo affording (E)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)prop-2-enoic acid (2 g, crude), which was used in the next step without further purification. LCMS Rt=0.638 min, m/z=183.1 [M+H]+.

To a solution of 3-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-4-methylcyclohexanone (15 g, 25.66 mmol) in N,N-dimethylformamide (300 mL) was added cuprous iodide (14.66 g, 76.99 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (24.65 g, 128.32 mmol). The mixture was stirred at 90° C. for 2 h under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The remaining residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 3-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-methylcyclohexanone (12 g, 88.80%) as a yellow oil. LCMS Rt=0.875 min, m/z=527.2 [M+H]+.

To a solution of 3-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-methylcyclohexanone (12 g, 22.78 mmol) in tetrahydrofuran (600 mL) was added lithium hexamethyldisilazide (1 M, 34.18 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h, and ethyl cyanoformate (2.7 g, 27.34 mmol) was added. The resulting mixture was stirred at −78° C. for 0.5 h under a nitrogen atmosphere. The reaction mixture was quenched with a saturated solution of ammonium chloride (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording ethyl 4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-methyl-2-oxo-cyclohexanecarboxylate (13.6 g, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=1.235 min, m/z=599.3 [M+H]+.

To a solution of ethyl 4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-methyl-2-oxocyclohexanecarboxylate (13 g, 21.72 mmol) in a mixture of ethanol (1200 mL) and water (240 mL) was added sodium bicarbonate (45.61 g, 542.89 mmol) and S-methylisothiourea hemisulfate (60.45 g, 217.15 mmol). The mixture was stirred at 50° C. for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The remaining residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (4.7 g, 34.65%) as a yellow solid. LCMS Rt=1.046 min, m/z=625.2 [M+H]+.

To a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (1.5 g, 2.40 mmol) in dichloromethane (100 mL) was added triethylamine (970 mg, 9.60 mmol) and trifluoromethanesulfonic anhydride (2.37 g, 8.40 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (30 mL) at 0° C. and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate (1.8 g, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=3.664 min, m/z=757.2 [M+H]+.

To a solution of (2S)-tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2.5 g, 3.00 mmol) in dichloromethane (300 mL) was added meta-chloroperoxybenzoic acid (1.94 g, 9.01 mmol, 85% purity) at 0° C., and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated sodium sulfite (30 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) affording (2S)-tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.6 g, 61.63%) as a yellow oil. LCMS Rt=1.027 min, m/z=864.4 [M+H]+.

To a solution of (2S)-tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.6 g, 1.85 mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (442.23 mg, 2.78 mmol) in toluene (40 mL) was added sodium tert-butoxide (533.92 mg, 5.56 mmol) at −30° C., and the mixture was stirred for 10 min. The reaction mixture was quenched with saturated ammonium chloride (30 mL) at 0° C. and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The remaining residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording (2S)-tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.6 g, 91.61%) as a yellow solid. LCMS Rt=0.960 min, m/z=943.5 [M+H]+.

A mixture of tert-butyl 2-((E)-3-((2S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazin-1-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (40 mg, 49.27 umol) and trifluoroacetic acid (0.5 mL) in dichloromethane (1.5 mL) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated in vacuo affording 2-((2S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)-1-((E)-3-(azetidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile (40 mg, crude, trifluoroacetate salt) as a yellow oil, which was used in the next step without any further purification. LCMS Rt=0.455 min, m/z=712.4 [M+H]+.

The hydrolysis reaction was prepared in a similar fashion to Method #1, Step 3. The crude residue was diluted with a (5:1) mixture of petroleum ether and ethyl acetate (20 mL), and the resulting precipitate was filtered affording (E)-3-(2,6-dimethylpyrimidin-4-yl)prop-2-enoic acid (3 g, crude) as a yellow solid, which was used in the next step without further purification. LCMS Rt=0.349 min, m/z=179.1 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 10% ethyl acetate in petroleum ether) affording tert-butyl (S)-4-(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)-2-(cyanomethyl)piperazine-1-carboxylate (2.6 g, 98.61%) as a yellow oil. LCMS Rt=0.762 min, m/z=708.3 [M+H]+.

To a solution of tert-butyl (S)-4-(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)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 141.21 umol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo affording 2-((S)-4-(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)piperazin-2-yl)acetonitrile (100 mg, crude, trifluoroacetate salt) as a white solid, which was used in the next step without further purification. LCMS Rt=0.626 min, m/z=608.2 [M+H]+.

To a solution of (E)-4-bromobut-2-enoic acid (100 mg, 606.12 umol) in dichloromethane (50 mL) was added N,N-dimethylformamide (4.43 mg, 60.61 umol) and oxalyl dichloride (92.32 mg, 727.34 umol) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo affording (E)-4-bromobut-2-enoyl chloride (230 mg, crude) as a yellow oil, which was used in the next step without further purification.

To a solution of 2-((S)-4-(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)piperazin-2-yl)acetonitrile (100 mg, 164.46 umol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added sodium hydrogencarbonate (41.45 mg, 493.38 umol) and (E)-4-bromobut-2-enoyl chloride (90.50 mg, 493.38 umol). The mixture was stirred at 0° C. for 1 h affording a solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(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)piperazin-2-yl) in acetonitrile as a yellow liquid, which was used in the next step without further purification. LCMS Rt=0.730 min, m/z=754.1 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #21, Step 4. The reaction was concentrated in vacuo affording 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (619 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.640 min, m/z=738.2 [M+H]+.

The Suzuki coupling reaction was prepared in a similar fashion to Method #16, Step 7. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) affording tert-butyl (S)-2-(cyanomethyl)-4-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (3 g, 63.02%) as a brown gum. LCMS Rt=0.636 min, m/z=692.3 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The reaction was concentrated in vacuo affording 2-((S)-4-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (2 g, crude, trifluoroacetate salt) as a brown gum, which was used in the next step without further purification. LCMS Rt=0.520 min, m/z=592.2 [M+H]+.

The acylation reaction was prepared in a similar fashion to Method #21, Step 4. The resulting solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl) in acetonitrile (yellow liquid) was used in the next step without further purification. LCMS Rt=0.669 min, m/z=738.2 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (2.2 g, 92.09%) as a yellow oil. LCMS Rt=1.458 min, m/z=674.3 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The reaction mixture was concentrated in vacuo affording 2-((S)-4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (1 g, crude, trifluoroacetate salt) as a brown oil, which was used in the next step without further purification. LCMS Rt=0.579 min, m/z=574.3 [M+H]+.

The acylation reaction was prepared in a similar fashion to Method #21, Step 4. The resulting solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl) in acetonitrile (brown liquid) was used in the next step without any further purification. LCMS Rt=0.721 min, m/z=720.2 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) affording tert-butyl (S)-2-(cyanomethyl)-4-(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)piperazine-1-carboxylate (2.4 g, 96.45%) as a yellow oil. LCMS Rt=2.659 min, m/z=702.3 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The reaction mixture was concentrated in vacuo affording 2-((S)-4-(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)piperazin-2-yl)acetonitrile (400 mg, crude, trifluoroacetate acid) as a brown oil, which was used in the next step without further purification. LCMS Rt=0.661 min, m/z=602.3 [M+H]+.

The acylation reaction was prepared in a similar fashion to Method #21, Step 4. The resulting solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(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)piperazin-2-yl) in acetonitrile (brown liquid) was used in the next step without any further purification. LCMS Rt=0.771 min, m/z=748.2 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-90% ethyl acetate in petroleum ether) affording tert-butyl (S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.76 g, 62.99%) as a pale yellow solid. LCMS Rt=0.663 min, m/z=680.3 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The mixture was concentrated to dryness in vacuo affording 2-((S)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (300 mg, crude, trifluoroacetate acid) as a brown oil, which was used in the next step without any further purification. LCMS Rt=0.498 min, m/z=580.2 [M+H]+.

The acylation reaction was prepared in a similar fashion to Method #21, Step 4. The resulting solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(7-(3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl) in acetonitrile (brown liquid) was used in the next step without any further purification. LCMS Rt=0.651 min, m/z=726.2 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 mg, 30%) as a brown solid. LCMS Rt=0.865 min, m/z=854.4 [M+H]+.

To a solution of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (400 mg, 468.34 umol) in N,N-dimethylformaldehyde (5 mL) was added cesium fluoride (711.42 mg, 4.68 mmol), and the mixture was stirred at 25° C. for 1 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (S)-2-(cyanomethyl)-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)piperazine-1-carboxylate (300 mg, 81.71%) as a yellow gum. LCMS Rt=0.641 min, m/z=698.3 [M+H]+.

The deprotection of the Boc group was prepared in a similar fashion to Method #21, Step 2. The reaction mixture was concentrated in vacuo affording 2-((S)-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)piperazin-2-yl)acetonitrile (240 mg, crude, hydrochloride salt) as a yellow gum, which was used in the next step without any further purification. LCMS Rt=0.529 min, m/z=598.3 [M+H]+.

To a solution of 1-bromo-2,4-difluoro-3-methyl-benzene (20 g, 96.61 mmol) and furan (13.15 g, 193.22 mmol) in toluene (300 mL) was added n-butyllithium (2.5 M, 46.37 mL) at −20° C. The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride (900 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 4-fluoro-3-methyl-11-oxatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene (30 g, 58.75%) as a yellow oil. LCMS Rt=0.676 min, m/z=177.1 [M+H]+.

To a solution of 4-fluoro-3-methyl-11-oxatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene (30 g, 170.27 mmol) in ethanol (300 mL) was added hydrochloric acid (12 M, 170.27 mL). The mixture was stirred at 80° C. for 2 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording 7-fluoro-8-methyl-naphthalen-1-ol (16.2 g, 54.00%) as a red solid. LCMS Rt=0.732 min, m/z=177.1 [M+H]+.

To a mixture of 7-fluoro-8-methyl-naphthalen-1-ol (5 g, 28.38 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (22.01 g, 170.27 mmol) and trifluoromethanesulfonic anhydride (10.41 g, 36.89 mmol). The mixture was stirred at 0° C. for 0.5 h under a nitrogen atmosphere. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) affording (7-fluoro-8-methyl-1-naphthyl) trifluoromethanesulfonate (8 g, 91.45%) as a yellow oil. LCMS Rt=0.951 min, m/z=309.0 [M+H]+.

The Suzuki coupling reaction was prepared in a similar fashion to Method #16, Step 7. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoro-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (650 mg, 26.65%) as a black solid. LCMS Rt=0.805 min, m/z=688.3 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The reaction mixture was concentrated in vacuo affording 2-((S)-4-(8-fluoro-7-(7-fluoro-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (100 mg, crude, trifluoroacetate salt) as a brown oil, which was used in the next step without further purification. LCMS Rt=0.635 min, m/z=588.3 [M+H]+.

The amide coupling reaction was prepared in a similar fashion to Method #21, Step 4. The reaction was concentrated in vacuo affording 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(8-fluoro-7-(7-fluoro-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (125 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.766 min, m/z=736.2 [M+H]+.

The Suzuki reaction was prepared in a similar fashion to Method #16, Step 7. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording tert-butyl (S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (300 mg, 74.67%) as a yellow oil. LCMS Rt=0.798 min, m/z=708.2 [M+H]+.

The Boc deprotection reaction was prepared in a similar fashion to Method #21, Step 2. The reaction mixture was concentrated in vacuo affording 2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (254 mg, crude, trifluoroacetate acid) as a yellow oil, which was used in the next step without further purification. LCMS Rt=0.637 min, m/z=608.2 [M+H]+.

The acylation reaction was prepared in a similar fashion to Method #21, Step 4. The resulting solution of 2-((S)-1-((E)-4-bromobut-2-enoyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl) in acetonitrile (yellow liquid) was used in the next step without further purification.

BIOLOGICAL EXAMPLES

Example 116: Inhibition of KRASG12C and cRAF Binding

The AlphaScreen technology was used to determine IC50S for compound inhibition of KRAS G12C (present as the Cys-light (C51S, C80L and C118S), truncated version comprising amino acids 1-169) and cRAF interaction. Compounds were diluted in 100% DMSO and each compound concentration was spotted at 200 nl/well onto low volume, white 384 well plates. The KRAS G12C contained a biotin-AviTag and the cRaf, as Ras-binding domain (amino acids 50-131, RBD), was GST-tagged. KRAS G12C was preloaded with the GTP analogue Guanosine 5′-[β,γ-imido]triphosphate (GMPPNP). The KRAS G12C was diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100 and 10 μM GMPPNP and added at 10 ul/well to compound-spotted plates resulting in a DMSO concentration of 2%. Plates were incubated for 2 hours. A mixture of RBD and the AlphaScreen streptavidin donor and glutathione acceptor beads diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100 and 2% DMSO was then added at 10 ul/well and incubated for 60-90 minutes before the samples were read for emission at 570 nm after excitation of the donor beads at 680 nm. All incubations were performed at room temperature. The final top compound concentration was 50 μM with 1:3 titrations for 10-point dose response curves. Final assay conditions were 0.5 nM KRAS G12C, 0.75 nM RBD and 5 μg/ml each of AlphaScreen donor and acceptor beads. IC50S were determined using nonlinear regression fit of [inhibitor] vs. response (4 parameters).

A counter assay was also set up to rule out inhibitors of the AlphaScreen technology itself. Compound plates were incubated for 2 hours as above with buffer only. The AlphaScreen beads were added as above except biotin-AviTag-GST was substituted for the RBD. Samples were read and analyzed as above.

Results for compounds are shown in Table 1, Column 5.

Example 117: Inhibition of KRASG12C and PI3Ka Binding

The AlphaScreen technology was used to determine IC50S for compound inhibition of KRAS G12C (present as the Cys-light (C51S, C80L and C118S), truncated version comprising amino acids 1-169) and PI3Ka interaction. Compounds were diluted in 100% DMSO and each compound concentration was spotted at 200 nl/well onto low volume, white 384 well plates. The KRAS G12C contained a biotin-AviTag and the PI3Ka, as Ras-binding domain (amino acids 157-300, RBD), was His-tagged. KRAS G12C was preloaded with the GTP analogue Guanosine 5′-[β,γ-imido]triphosphate (GMPPNP). The KRAS G12C was diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100 and 10 μM GMPPNP and added at 10 ul/well to compound-spotted plates resulting in a DMSO concentration of 2%. Plates were incubated for 2 hours. A mixture of RBD and the AlphaScreen streptavidin donor and nickel chelate acceptor beads diluted in 25 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.01% TritonX-100 and 2% DMSO was then added at 10 ul/well and incubated for 60-90 minutes before the samples were read for emission at 570 nm after excitation of the donor beads at 680 nm. All incubations were performed at room temperature. The final top compound concentration was 50 μM with 1:3 titrations for 10-point dose response curves. Final assay conditions were 1.5 nM KRAS G12C, 100 nM RBD, 1.25 ug/ml of AlphaScreen donor beads and 10 μg/ml AlphaLISA acceptor beads. IC50s were determined using nonlinear regression fit of [inhibitor] vs. response (4 parameters).

A counter assay was also set up to rule out inhibitors of the AlphaScreen technology itself. Compound plates were incubated for 19-20 hours as above with buffer only. The AlphaScreen beads were added as above except an unrelated biotinylated His-tagged peptide was substituted for the RBD. Samples were read and analyzed as above.

Results for exemplary compounds are shown in Table 1, column 6.

Example 118: Determination of logD

Preparation of phosphate buffer saturated with 1-octanol: 10 mL of 100 mM phosphate buffer (pH 7.4) was added to 100 mL of 1-octanol. The mixture was shaken vigorously and left to stand at room temperature overnight.

Preparation of 1-octanol saturated with phosphate buffer: 10 mL of 1-octanol was added to 100 mL of 100 mM phosphate buffer (pH 7.4). The mixture was shaken vigorously and left to stand at room temperature overnight.

Procedure for measuring logD: 2 μL of a 10 mM DMSO stock solution of the test compound was aliquoted into 2 separate sample tubes. 149 μL of phosphate buffer saturated with 1-octanol was added into 1st sample tube. 149 μL of 1-octanol saturated with phosphate buffer was added into the 2nd sample tube. The sample tubes were mixed vigorously and shaken for 1 hour at a speed of 800 rpm at room temperature. The sample tubes were subjected to centrifugation at 4000 rpm for 5 minutes at room temperature. Samples of the supernatant were taken from both tubes, diluted with an appropriate LCMS buffer, and analyzed on an LCMS instrument. LogD was calculated according to the following equation.

The data for exemplary compounds is shown in Table 1, column 7.

Example 119: Determination of kinetic solubility (pH 7.4)

10 μL of a 10 mM DMSO stock solution of the test compound was aliquoted into the lower chamber of a Whatman Mini-UniPrep vial. 490 μL of a 50 mM phosphate buffer (pH 7.4) was added to the sample solution. The mixture was vortexed for at least 2 minutes. The vial was shaken on a Barnstead shaker at 800 rpm at room temperature for 2 hours. The vial was centrifuged at 4000 rpm for 20 minutes. The Mini-UniPrep vial was compressed to prepare a filtrate, which was injected into an HPLC-UV and LC-MS/MS system. Kinetic solubility was calculated by referencing sample peak areas to a standard calibration curve.

The data for exemplary compounds is shown in Table 1, column 8.

MCF10A (ATCC, cat. CRL-10317) cells are maintained in MEBM (Lonza, cat. CC-3151) with 1% horse serum (Sigma, cat. H1270), MEGM mammary epithelial cell growth medium SingleQuotsKit (Lonza, cat. CC-4146) and 25 ng/ml Cholera toxin (Sigma, cat. C8052). These cells are transduced with either KRAS G12C or G12C/A59G followed by puromycin selection to generate stably expressing cells. For the cell viability assay, 1000 cells of either MCF10A KRAS G12C or MCF10A G12C/A59G are plated in 384-well spheroid microplate (Corning, cat. 3830). The following day, cells are treated with compounds (10 uM top concentration, 3-fold dilution, and 11 doses). 10 uM Tremetinib (MCE, cat. HY-10999/CS-0060) is used as control. The Tecan: HP D300E is used to dispense the compounds. After five days of incubation, celltiter-glo luminescent assay kit (Promega, cat. G7573) is used according to manufacturer's protocol to measure cellular viability using a BioTek plate reader. The data is then imported to and processed in Dotmatics where EC50s were calculated using the Lavenberg-Marquardt 4 parameters fitting procedure, with difference gradients.

Example 121: Treatment of Human Patients

A human patient suffering from a cancer, (e.g., a KRAS mediated cancer, as disclosed herein) can be administered a therapeutically effective dose of a compound disclosed herein (e.g., a compound of Table 1). The treatment can slow down or halt the growth of a tumor, reduce a tumor volume or mass, or eradicate the tumor in the patient.

The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Exemplary compounds and experimental data

RBD
RBD
Log
pH

formate salt

* ++++ is less than 10 nM, +++ is 10 to less than 100 nM, ++ is 100 to less than 500 nM, + is greater or equal to 500 nM

The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.