Small molecule inhibitors of KRAS proteins

Abstract

Compounds of Formula (I) or their pharmaceutically acceptable salts can inhibit the G12C, G12D, G12V, and / or G13D mutants of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

Description

145021.608067 (002600.PC) SMALL MOLECULE INHIBITORS OF KRAS PROTEINS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 644,280, filed May 08, 2024, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to small molecule inhibitors of KRAS that inhibit, for example, the G12C mutant, G12D mutant, G12V mutant, G13D mutant, and the wild-type (WT) of Kirsten rat sarcoma (KRAS) protein and relates to a pharmaceutical composition comprising a compound of Formula (I) as well as methods of using such a compound for treatment of diseases, including cancers. BACKGROUND

[0003] RAS, which is a small monomeric GTP-binding protein having a molecular weight of about 21 kDa, acts as a molecular on / off switch. RAS can bind to GTP by binding to proteins of a guanine nucleotide exchange factor (GEF) (e.g., SOS1), which forces the release of a bound nucleotide, and releases GDP. When RAS binds to GTP, it becomes activated (turned on) and recruits and activates proteins necessary for the propagation of other receptors’ signals, such as c-Raf and PI 3-kinase. RAS also possesses enzymatic activity with which it cleaves the terminal phosphate of the GTP nucleotide and converts the nucleotide into GDP. The rate of conversion is usually slow, but can be dramatically sped up by a protein of the GTPase-activating protein (GAP) class, such as RasGAP. When GTP is converted into GDP, RAS is deactivated (turned off).

[0004] The commonly known members of the RAS subfamily include HRAS, KRAS, and NRAS. Of these, mutations of KRAS are observed in many malignant tumors: in 86% of pancreatic ductal adenocarcinoma (PDAC), in 41% of colorectal cancers (CRC), and in 32% of lung adenocarcinoma (LUAD; a subtype of non-small-cell lung cancer (NSCLC)). The mutations often occur in the glycine residue at position 12 of KRAS (“G12”); the mutation at G12 dominates 91% (PDAC), 68% (CRC) and 85% (LUAD) of the total KRAS mutations, respectively. The distributions of amino acid substitutions at G12 vary among each tissue type. The most prevalent mutation in LUAD is the mutation into cysteine (“G12C”) (46%), while the predominant mutation in PDAC (45%) and CRC (45%) is the145021.608067 (002600.PC) mutation into aspartic acid (“G12D”). The mutation at G12 into valine (”G12V”) is observed in a significant portion of G12 mutations in all of PDAC (35%), CRC (30%) and LUAD (23%). (Nature Reviews Drug Discovery, 19, 533-552, 2020).

[0005] Intense efforts in developing KRAS-G12C inhibitors are underway. Several covalent inhibitors which focus on the cysteine residue have been reported, and some of them have been subjected to clinical studies, such as AMG510 (NCT03600883), MRTX849 (NCT03785249) and JNJ-74699157 (NCT04006301). However, the KRAS-G12C mutation only accounts for a fraction of all KRAS mutations and is primarily found in LUAD. To effectively inhibit the other commonly-occurring KRAS mutated proteins, such as KRAS- G12D and KRAS-G12V, different approaches are needed as these mutants lack reactive cysteines in the active site (Nature Reviews Drug Discovery, 19, 533-552, 2020).

[0006] Studies have also indicated that gene amplification and high expression of WT KRAS in the absence of coding mutations can also occur in certain cancers. These amplifications were observed most frequently in esophageal, gastric and ovarian adenocarcinomas (Nature Medicine, 24, 968-977, 2018). Thus, effective inhibition of WT KRAS could provide a therapeutic benefit to patients suffering from such cancers. SUMMARY OF THE DISCLOSURE

[0007] The present disclosure provides small molecule inhibitors which modulate mutant and WT KRAS proteins and may be valuable pharmaceutically active compounds for the treatment of cancer. In some embodiments the disclosed compounds selectively inhibit the KRAS-G12C, KRAS-G12D and / or KRAS-G12V proteins. The compounds of Formula (I):and their pharmaceutically acceptable salts, can modulate the activity of KRAS and thereby affect the signaling pathway which regulates cell growth, differentiation, and proliferation associated with oncological disorders. In certain embodiments, the compounds of Formula145021.608067 (002600.PC) (I) can inhibit the KRAS-G12C, KRAS-G12D, KRAS-G12V, KRAS-G13D, and / or WT KRAS proteins. The disclosure furthermore provides processes for preparing compounds of Formula (I), methods for using such compounds to treat oncological disorders, and pharmaceutical compositions which comprise compounds of Formula (I). DETAILED DESCRIPTION OF THE INVENTION Compounds of the Disclosure

[0008] In one embodiment, the present disclosure provides a compound having structural Formula (I), or a pharmaceutically acceptable salt thereof, as shown above, wherein: each RXis independently selected from the group consisting of fluoro, cyano, hydroxy, oxo, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6alkoxy, C1-C6fluoroalkoxy, C1-C6cyanoalkyl, and C1-C6hydroxyalkyl;WAis selected from the group consisting of C(RW1)2 and S, wherein the two RW1substituents are independently methylene or ethylene, and wherein the two RW1substituents, together with the carbon atom to which they are attached, form a 3- to 5- membered saturated monocyclic ring;CYis:(i) a 9- to 10-membered fused bicyclic heteroaryl, wherein the 9- to 10-membered fused bicyclic heteroaryl contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or (ii) a 12- to 17-membered fused tricyclic heterocycloalkyl, where at least two of the rings of the 12- to 17-membered fused tricyclic heterocycloalkyl are aromatic, the third ring is partially unsaturated or aromatic, wherein the 12- to 17- membered fused tricyclic heterocycloalkyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein CYis unsubstituted or substituted by 1 to 3 RYsubstituents independentlyselected from the group consisting of halo, hydroxy, oxo, cyano, C1-C6alkyl,C3-C6cycloalkyl, C2-C6alkynyl, C2-C7alkenyl, C1-C6fluoroalkyl, C3-C6fluorocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6fluoroalkynyl, C2-C7fluoroalkenyl, C1-C3fluoroalkenylenyl, C1-C6alkylthio, C1-C6fluoroalkylthio, amino, C1-C6alkylamino, C1-C6dialkylamino, tri(C1-C6145021.608067 (002600.PC) alkyl)silyl, cyano, C1-C6cyanoalkyl, C1-C6fluorocyanoalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxycarbonyl, C1-C6acyl, and C1-C6alkylenyl,RZCis selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3alkyl, C1- C3fluoroalkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkenylenyl, C1-C3hydroxyfluoroalkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3cyanoalkyl, C3-C6cycloalkyl, C3-C6fluorocycloalkyl, C3-C6hydroxycycloalkyl, C3-C6hydroxyfluorocycloalkyl, C2-C4fluoroalkenyl, C1-C3alkylamino, C1-C3dialkylamino, methylene(C1-C3alkyl)amino, C1-C3alkylenedi(C1-C3alkyl)amino andmethylene(C1-C3alkyl)(C1-C3alkyl)carbamate; andsubscript n is 0, 1, 2, or 3;

[0009] In an embodiment, the 3- to 5-membered saturated monocyclic ring is a carbocyclic ring.

[0010] In an embodiment, each RXis independently selected from the group consisting of methyl and hydroxy.

[0013] In an embodiment,

[0014] In an embodiment, the two RW1substituents, together with the carbon atom towhich they are attached, form a 3-membered saturated monocyclic ring.145021.608067 (002600.PC)

[0016] In an embodiment, CYis a 9- to 10-membered fused bicyclic heteroaryl, wherein the 9- to 10-membered fused bicyclic heteroaryl contains two nitrogen heteroatoms.

[0017] In an embodiment, CYis a 12- to 14-membered fused tricyclic heteroaryl, wherein the 12- to 14-membered fused tricyclic heteroaryl contains two nitrogen heteroatoms.

[0018] In an embodiment, CYis substituted by 1 to 2 RYsubstituents independentlyselected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C2-C7alkenyl,C1-C6fluoroalkyl, and C3-C6fluorocycloalkyl.

[0019] In an embodiment, CYis substituted by 1 to 2 RYsubstituents independentlyselected from the group consisting of fluoro, chloro, ethyl, cyclopropyl, propenyl, trifluoromethyl, and fluorocyclopropyl.

[0020] In an embodiment, CYis selected from the group consisting of:subscript s is 0, 1, or 2.

[0021] In an embodiment, CYis selected from the group consisting of:145021.608067 (002600.PC).

[0022] In an embodiment, RZCis fluoro.

[0023] In an embodiment, RZCis fluoromethylenyl.

[0024] In an embodiment, the moietyselected from the group consisting of:

[0025] In one embodiment, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:145021.608067 (002600.PC)145021.608067 (002600.PC)

[0027] In an embodiment, the compound is:.

[0028] In an embodiment, the compound is:145021.608067 (002600.PC).

[0029] In an embodiment, the compound is:.

[0030] In an embodiment, the compound is:

[0031] In an embodiment, the compound is:.

[0032] In an embodiment, the compound is:145021.608067 (002600.PC) ..

[0034] In an embodiment, the compound is:.

[0036] In an embodiment, the compound is:145021.608067 (002600.PC).

[0037] In an embodiment, the compound is:.

[0038] In specific embodiments, the present disclosure provides a compound as described in any one of Examples 1-12 as set forth below, or a pharmaceutically acceptable salt thereof.

[0039] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined herein, including the pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. Definitions

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0041] As used throughout this disclosure, “compound(s) of Formula (I)”, “compound(s) disclosed herein”, “compound(s) described herein”, “compound(s) of the disclosure”, etc., are used interchangeably and are to be understood to include the disclosed compounds of Formula (I). The compounds of Formula (I) can form salts which are also within the scope of the present disclosure. Reference to a compound of the disclosure (or compound of Formula (I)) herein is understood to include reference to salts thereof, unless otherwise indicated.

[0042] “Acyl” refers to a moiety derived by the removal of one or more hydroxyl groups from an oxoacid. An acyl group contains a central carbon atom, a double-bonded oxygen145021.608067 (002600.PC) atom to the central carbon atom, and a single-bonded alkyl group to the central carbon atom.

[0043] “Amino” means an amine group that contains two substituents bonded to a nitrogen atom via two single covalent bonds. The bond to the parent group is through the nitrogen atom of the group.

[0044] “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched. Non-limiting examples include ethenyl, propenyl, and butenyl.

[0045] “Alkenylenyl” or “alkenylene” means a divalent group derived from an alkenyl. “Fluoroalkenylenyl” means an alkenylenyl that is mono-or multiple-fluoro-substituted.

[0046] “Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms. For instance, a C1-C6alkyl means an alkyl group having one (i.e., methyl) up to 6 carbon atoms (i.e., hexyl). In particular embodiments, linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3- 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

[0047] Alkylene,” means a divalent aliphatic hydrocarbon group radical. The aliphatic hydrocarbon group may be straight or branched. In contrast to alkylenyl, two single bonds exist and each single bond attaches to a different parent group. Non-limiting examples of an alkylene group include methylene (-CH2-) and ethylene (-CH2CH2-).

[0048] “Alkylenyl” means a divalent aliphatic hydrocarbon group radical. The aliphatic hydrocarbon group may be straight or branched. In contrast to alkenyl, the bond to the parent group is through a double bond. Non-limiting examples of an alkylenyl group include methylenyl (=CH2) and ethylenyl (=CHCH3).

[0049] "Alkylene alkylamino” means an alkylamino group linked to an alkylene group. The bond to the parent moiety is through a carbon atom of the alkylene group. For H example, methylene alkylamino has the structure of.

[0050] "Alkylene dialkylamino” means a dialkylamino group linked to an alkylene group. The bond to the parent moiety is through a carbon atom of the alkylene group. For example, methylene dialkylamino has the structure. In other words, the145021.608067 (002600.PC) carbamate group has alkyl groups, which can be the same or different as previously defined, attached to the nitrogen atom.

[0051] “Alkylenealkylalkylcarbamate” means a carbamate group (having two alkyl groups attached to the nitrogen atom) linked to an alkylene group. The bond to the parent moiety is through a carbon atom of the alkylene group. For example, methylene alkylalkylcarbamate has the structureother words, the carbamate group has alkylgroups, which can be the same or different, as previously defined, attached to the nitrogen atom.

[0052] “Alkylamino” means one or two alkyl groups linked to an amino group. The bond to the parent moiety is through a nitrogen atom of the amino component.

[0053] “Alkylthio” means an alkyl group linked to a sulfur. “Fluoroalkylthio” means an alkylthio that is mono-or multiple-fluoro-substituted.

[0054] “Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen. “Haloalkoxy” means an alkoxy that is mono-or multiple-halo- substituted. The halo groups on a multiple-halo-substituted alkoxy group can be the same or different.

[0055] “Alkoxycarbonyl” means an alkoxy group linked to a carbonyl group. The bond to the parent moiety is through a carbon atom of the carbonyl component.

[0056] “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched. Non-limiting examples include ethynyl, propynyl, and butynyl.

[0057] “Aryl” means a monocyclic, bicyclic, tricyclic, or tetracyclic carbocyclic aromatic ring or ring system containing 5-17 carbon atoms, wherein at least one of the rings is aromatic. Non-limiting examples include phenyl and naphthyl.

[0058] “Bicyclic ring system” refers to two joined rings. “Tricyclic ring system” refers to three joined rings. “Tetracyclic ring system” refers to four joined rings. The rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”, i.e., share only a single atom, or “bridged”, i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. Likewise the bicyclic or tricyclic rings may be aryl rings, heterocyclic rings, cycloalkyl rings, etc.

[0059] “Carbonyl” means a O=C- group. The bond to the parent group is through the carbon atom.145021.608067 (002600.PC)

[0060] “Cyano” means a N≡C- group. The bond to the parent group is through the carbon atom.

[0061] “Cyanoalkyl” means an -alkyl-CN group in which the alkyl is as previously defined. The bond to the parent moiety is through a carbon atom of the alkyl component. Non- limiting examples of suitable cyanoalkyl groups include cyanomethyl and 3-cyanopropyl. “Fluorocyanoalkyl” means a cyanoalkyl that is mono-or multiple-fluoro-substituted.

[0062] “Cycloalkyl” means a saturated cyclic hydrocarbon radical. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings, wherein cyclic systems having 2-3 rings can be fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. “Fluorocycloalkyl” means a saturated cyclic hydrocarbon radical that is mono- or multiple- fluoro-substituted, e.g., doubly fluoro-substituted cyclopentyl.

[0063] “Dialkylamino” means an alkylamino as previously defined, wherein the amino atom is substituted by two alkyl substituents, which substitutions can be the same or different, e.g., -N(CH3)2 or -N(CH3)(CH2CH3).

[0064] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1-difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included. “Fluoroalkenyl” includes mono- substituted as well as multiple fluoro-substituted alkenyl groups. “Fluoroalkynyl” includes mono-substituted as well as multiple fluoro-substituted alkynyl groups. “Fluoroalkoxy” includes mono-substituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined. “Hydroxyfluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted hydroxyalkyl groups. “Hydroxyfluorocycloalkyl” includes mono- substituted as well as multiple fluoro-substituted hydroxycycloalkyl groups.

[0065] “Halogen” or “halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0066] “Heteroaryl” refers to aromatic monocyclic, bicyclic and tricyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0067] “Heterocyclyl” or “heterocyclic ring” means a partially aromatic or non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17145021.608067 (002600.PC) ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphorus or sulfur, alone or in combination. The heterocyclyl or heterocyclic ring can be saturated or unsaturated. There are no adjacent oxygen and / or sulfur atoms present in the ring system. In some embodiments, heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa, phospha or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. For instance, in some embodiments, the heterocyclyl can contain N, S, S(O), S(O)2and / or O (which are referred to herein as “heteroatom groups”). Non-limiting examples of suitable monocyclic heterocyclyls include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, phosphorinane, phosphinane, 1- oxophosphinan-1-ium, pyrrolinyl, dihydropyranyl, and the like. The rings may be “fused,” i.e., share two adjacent atoms, or “spirocyclic,” i.e., share only a single atom, or “bridged,” i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. For example, “spirocyclic heterocyclyl” means a heterocyclyl having at least two rings sharing only a single atom.

[0068] “Heterocycloalkyl” means a saturated heterocyclyl or heterocyclic ring. The bond to the parent group is through a carbon atom. The rings may be “fused,” i.e., share two adjacent atoms, or “spirocyclic,” i.e., share only a single atom, or “bridged,” i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. For example, “spiroheterocycloalkyl” means a heterocycloalkyl having at least two rings sharing only a single atom. “Fused bicyclic heterocycloalkyl” means a heterocycloalkyl having at least two rings sharing two adjacent atoms. “Bridged bicyclic heterocycloalkyl” means a heterocycloalkyl having at least two rings sharing three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom.

[0069] “Hydroxy” means a HO- group in which the bond to the parent moiety is through the oxygen atom.

[0070] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. The bond to the parent moiety is through a carbon atom of the alkyl group. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. “Hydroxyfluoroalkyl” means a HO- fluoroalkyl- group in which fluoroalkyl is as previously defined. “Hydroxycycloalkyl”145021.608067 (002600.PC) means a HO-cycloalkyl- group in which cycloalkyl is as previously defined. “Hydroxyfluorocycloalkyl” means a HO-fluorocycloalkyl- group in which fluorocycloalkyl is as previously defined.

[0071] “Oxo” means an oxygen atom double bonded to the parent moiety.

[0072] “Trialkylsilyl” means a silicon radical having three alkyl groups covalently bonded to the silicon atom.

[0073] When any variable (e.g., Rx) occurs more than one time in any constituent or in Formula (I) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, e.g., Rx, are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heteroaryl ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0074] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0075] Unless expressly depicted or described otherwise, variables depicted in a structural formula with a “floating” bond, such as RX, are permitted on any available carbon atom in the ring to which the variable is attached. When a moiety is noted as being “optionally substituted” in Formula (I) or any embodiment thereof, it means that Formula (I) or the embodiment thereof encompasses compounds that contain the noted substituent (or substituents) on the moiety and also compounds that do not contain the noted substituent (or substituents) on the moiety.

[0076] The wavy line, as used herein, indicates a point of attachment to the compound, and when applicable, can be in either E or Z form. The cross line , as145021.608067 (002600.PC) used herein, indicates both the cis form and the trans form (and both the E form and the Z form) as well as mixtures of these forms in all ratios.

[0077] The compounds of Formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula (I) can all independently of one another have S configuration or R configuration. The compounds of Formula (I) include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism, the disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The present disclosure is meant to comprehend all such stereoisomeric forms of the compounds of Formula (I). Where a structural formula or chemical name specifies a particular configuration at a stereocenter, the enantiomer or stereoisomer of the compound resulting from that specified stereocenter is intended. Where a structural formula of the compounds of Formula (I) indicates a straight line at a chiral center, the structural formula includes both the S and R stereoisomers associated with the chiral center and mixtures thereof.

[0078] The compounds of Formula (I) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Vibrational circular dichroism (VCD) may also be used to determine the absolute stereochemistry. Alternatively, any stereoisomer or isomers of the compounds of Formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0079] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional145021.608067 (002600.PC) crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0080] The compounds of Formula (I) which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0081] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the compounds of Formula (I).

[0082] Some of the compounds of Formula (I) described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties. The individual atropisomers as well as mixtures thereof are encompassed with compounds of Formula (I) of the present disclosure. When resolved, individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.

[0083] In the compounds of Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formula (I) and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0084] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) is145021.608067 (002600.PC) acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can beformed include, for example, arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0085] When a compound of Formula (I) is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If a compound of Formula (I) simultaneously contains acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula (I) by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds of Formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0086] Furthermore, the compounds of Formula (I) may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds145021.608067 (002600.PC) of Formula (I) may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0087] Any pharmaceutically acceptable pro-drug modification of a compound of Formula (I) which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0088] The terms “therapeutically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for treatment” or “an effective dose” are intended to mean that amount of a compound of Formula (I) that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a compound of Formula (I) that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a compound of Formula (I) that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. Dosages of the compounds of Formula (I)

[0089] The dosage regimen utilizing a compound of Formula (I) is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an oncological condition, and a prophylactically effective amount, e.g., for prevention of an oncological condition.

[0090] While individual needs vary, determination of optimal ranges of effective amounts of the compounds of Formula (I) is within the skill of the art. For administration to a145021.608067 (002600.PC) human in, for example, the curative or prophylactic treatment of the conditions and disorders identified herein, the typical dosages of the compounds of Formula (I) can be about 0.05 mg / kg / day to about 50 mg / kg / day, or at least 0.05 mg / kg, or at least 0.08 mg / kg, or at least 0.1 mg / kg, or at least 0.2 mg / kg, or at least 0.3 mg / kg, or at least 0.4 mg / kg, or at least 0.5 mg / kg, and any amount therebetween, to about 50 mg / kg or less, or about 40 mg / kg or less, or about 30 mg / kg or less, or about 20 mg / kg or less, or about 10 mg / kg or less and any amount therebetween, which can be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, dosages of the compounds can be about 0.1 mg / kg / day to about 50 mg / kg / day, or about 0.05 mg / kg / day to about 10 mg / kg / day, or about 0.05 mg / kg / day to about 5 mg / kg / day, or about 0.05 mg / kg / day to about 3 mg / kg / day, or about 0.07 mg / kg / day to about 3 mg / kg / day, or about 0.09 mg / kg / day to about 3 mg / kg / day, or about 0.05 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 1 mg / kg / day to about 10 mg / kg / day, or about 1 mg / kg / day to about 5 mg / kg / day, or about 1 mg / kg / day to about 3 mg / kg / day, or about 3 mg / day to about 500 mg / day, or about 5 mg / day to about 250 mg / day, or about 10 mg / day to about 100 mg / day, or about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses. Pharmaceutical Compositions

[0091] The compounds of Formula (I) and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term “subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0092] The present disclosure therefore also provides the compounds of Formula (I) and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for modulating145021.608067 (002600.PC) the activity of mutant and / or WT KRAS proteins and in particular their use in the therapy and prophylaxis of the below-mentioned diseases or disorders as well as their use for preparing medicaments for these purposes. In certain embodiments, the compounds of Formula (I) and their pharmaceutically acceptable salts inhibit the KRAS-G12C, KRAS- G12D, KRAS-G12V, and / or KRAS-G13D proteins.

[0093] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0094] Thus, the present disclosure provides, for example, said compound and its pharmaceutically acceptable salts for use as pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the below-mentioned diseases or disorders, e.g., cancer, as well as their use for preparing medicaments for these purposes.

[0095] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion.

[0096] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0097] The amount of active compound of a compound described herein and / or its pharmaceutically acceptable salts in the pharmaceutical composition normally is from 0.01 to 200 mg, or from 0.1 to 200 mg, or from 1 to 200 mg, per dose, but depending on the type of the pharmaceutical composition, it can also be higher. In some embodiments, the amount of active compound of a compound of Formula (I) and / or its pharmaceutically acceptable salts in the pharmaceutical composition is from 0.01 to 10 mg per dose. The pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of at least one145021.608067 (002600.PC) compound of Formula (I) and / or its pharmaceutically acceptable salts. The preparation of the pharmaceutical compositions can be carried out in a manner known per se. For this purpose, one or more compounds of Formula (I) and / or their pharmaceutically acceptable salts, together with one or more solid or liquid pharmaceutical carrier substances and / or additives (or auxiliary substances) and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

[0098] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch, for example, maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example, of solutions for injection, or of emulsions or syrups are, for example, water, physiologically acceptable sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula (I) and their pharmaceutically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0099] Besides the active compounds and carriers, the pharmaceutical compositions can also contain customary additives, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents and / or antioxidants. Methods of Using the Compounds of Formula (I)

[0100] The present application provides a method of inhibiting RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Inhibition of RAS-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include (a) a decrease in GTPase activity of RAS; (b) a decrease in GTP bindingaffinity or an increase in GDP binding affinity; (c) an increase in Koffof GTP or a decrease145021.608067 (002600.PC)in Koffof GDP; (d) a decrease in the levels of signaling transduction moleculesdownstream in the RAS pathway, such as a decrease in pMEK, pERK, or pAKT levels; and / or (e) a decrease in binding of RAS complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.

[0101] The present application also provides methods of using the compounds of Formula (I) (or their pharmaceutically acceptable salts) or pharmaceutical compositions containing such compounds to treat disease conditions, including but not limited to, conditions implicated by mutant KRAS proteins and / or amplification or over expression of WT KRAS protein (e.g., cancer), and in some embodiments the KRAS-G12C, KRAS-G12D, KRAS- G12V, and / or KRAS-G13D mutants.

[0102] In some embodiments, a method for treatment of cancer is provided, the method comprising administering a therapeutically effective amount a compound of Formula (I) (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the cancer is mediated by a KRAS mutation, e.g., the KRAS-G12C, KRAS- G12D, KRAS-G12V, and / or KRAS-G13D mutations. In various embodiments, the cancer is pancreatic cancer, colorectal cancer or lung cancer. In some embodiments, the cancer is gall bladder cancer, thyroid cancer, or bile duct cancer.

[0103] In some embodiments the present disclosure provides a method of treating a disorder in a subject in need thereof, wherein said method comprises determining if the subject has a KRAS mutation (e.g., KRAS-G12C, KRAS-G12D, KRAS-G12V, and / or KRAS-G13D mutations) and if the subject is determined to have the KRAS mutation, then administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments the present disclosure provides a method of treating a disorder in a subject in need thereof, wherein said method comprises determining if the subject has amplified and / or over expression of WT KRAS protein and if the subject is determined to have such features, then administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0105] The disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, another embodiment of the145021.608067 (002600.PC) present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a compound of Formula (I).

[0106] KRAS mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and / or lymph nodes). Accordingly, certain embodiments are directed to administration of the compounds of Formula (I) (e.g., in the form of a pharmaceutical composition) to a subject in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In other embodiments, the compounds are useful for treatment of lymphomas such as Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In various embodiments, the compounds are useful for treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglubunemia.

[0107] Determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS-G12C, KRAS-G12D and / or KRAS-G12V mutations) or WT KRAS can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS mutant or WT KRAS protein. The sequence of wild-type human KRAS is known in the art.

[0108] Methods for detecting a mutation in a KRAS nucleotide sequence or a WT KRAS nucleotide sequence are also known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for KRAS mutations (e.g., the KRAS-G12C, KRAS- G12D, KRAS-G12V, and / or KRAS-G13D mutations) by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is145021.608067 (002600.PC) identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRAS gene.

[0109] Methods for detecting a mutation in a KRAS protein or a WT KRAS protein (e.g., the KRAS-G12C, KRAS-G12D, KRAS-G12V, KRAS-G13D mutations) are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant or WT KRAS protein using a binding agent (e.g., an antibody) specific for the mutant or WT protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0110] A number of tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS-G12C, KRAS-G12D, KRAS-G12V, and / or KRAS-G13D mutations) or amplified / overexpressed WT KRAS. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin- fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[0111] The present application also provides a method of treating a hyperproliferative disorder comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, said method relates to the treatment of a subject who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g., lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor,145021.608067 (002600.PC) gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer; multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer; small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0112] In some embodiments, the methods for treatment are directed to treating lung cancers, and the methods comprise administering a therapeutically effective amount of the compounds of Formula (I) (or pharmaceutical composition comprising such compounds) to a subject in need thereof. In certain embodiments, the lung cancer is a non-small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers which the compounds of Formula (I) may provide therapeutic benefit for include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[0113] The present disclosure also provides methods of modulating a mutant KRAS protein activity (e.g., activity resulting from the KRAS-G12C, KRAS-G12D, KRAS-G12V, and / or KRAS-G13D mutations) or a WT KRAS protein activity by contacting the protein with an145021.608067 (002600.PC) effective amount of a compound of Formula (I). Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides methods of inhibiting protein activity by contacting the mutant KRAS protein (e.g., KRAS-G12C, KRAS-G12D, KRAS-G12V, and / or KRAS-G13D mutants) or WT KRAS protein with an effective amount of a compound of Formula (I) in solution. In some embodiments, the present disclosure provides methods of inhibiting the mutant or WT KRAS protein activity by contacting a cell, tissue, or organ that expresses the protein of interest. In some embodiments, the disclosure provides methods of inhibiting protein activity in subjects including, but not limited to, rodents and mammals (e.g., humans) by administering into the subjects an effective amount of a compound of Formula (I). Combination Therapies

[0114] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula (I) (or a pharmaceutically acceptable salt thereof). An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula (I). The additional active agents also include free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including chemotherapeutic agents or therapeutic antibodies, may be used in any combination with the compound of Formula (I) in a single dosage formulation (e.g., a fixed dose drug combination), or in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents) to subjects. In addition, the compounds of Formula (I) (or pharmaceutically acceptable salts thereof) can be administered in combination with radiation therapy, hormone therapy, surgery or immunotherapy.

[0115] The present application also provides methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) with chemotherapeutic agents, immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents,145021.608067 (002600.PC) to provide a synergistic or additive therapeutic effect. In another embodiment, such therapy includes radiation treatment to provide a synergistic or additive therapeutic effect.

[0116] Examples of additional active agents (i.e., additional anti-cancer agents) include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents. Many anti- cancer agents can be classified within one or more of these groups. While certain anti- cancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It is to be understood that the classification herein of a particular agent into a particular group is not intended to be limiting. Many anti-cancer agents are presently known in the art and can be used in combination with the compounds of the present disclosure.

[0117] Further, an agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, suitable for use are one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor “c-met”.

[0118] In an embodiment, the additional anti-cancer agent is a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenesis agent (or angiogenesis inhibitor). In an embodiment, the additional anti-cancer agent is selected from the group consisting of a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an anti-metabolite, a platinum analog, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormonal agent, an anti-hormonal agent, an anti-estrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti-PD-L1 agent, a colony- stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti- CTLA4 agent, an anti-LAGl agent, an anti-LAG3 agent, an anti-ILT4 agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a BiTE, a signal transduction inhibitor, a growth factor inhibitor, a tyrosine kinase inhibitor, an EGFR inhibitor, a histone deacetylase (HDAC) inhibitor, a proteasome inhibitor, a cell-cycle inhibitor, an anti-angiogenesis agent,145021.608067 (002600.PC) a matrix-metalloproteinase (MMP) inhibitor, a hepatocyte growth factor inhibitor, a TOR inhibitor, a KDR inhibitor, a VEGF inhibitor, a HIF-1α inhibitor, a HIF-2α inhibitor, a fibroblast growth factor (FGF) inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, an AKT inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a HER-2 inhibitor, a BRAF-inhibitor, a gene expression modulator, an autophagy inhibitor, an apoptosis inducer, an antiproliferative agent, and a glycolysis inhibitor.

[0119] In one embodiment, the additional anti-cancer agent(s) is a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0120] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0121] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphaoramide, trietylenephosphoramide, and trimethylolomelamine; ambamustine; bendamustine; dacarbazine; etoglucid; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0122] Non-limiting examples of anti-metabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5-fluorouracil (5-FU), 6- azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone;145021.608067 (002600.PC) broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0123] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0124] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0125] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0126] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.

[0127] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.

[0128] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo- L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0129] In one embodiment, the additional anti-cancer agent(s) is a hormonal and / or anti- hormonal agent (i.e., hormone therapy). Non-limiting examples of hormonal and anti- hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4- hydroxy tamoxifen, aromatase inhibiting 4(5)-imidazoles, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; anti-adrenals such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin;145021.608067 (002600.PC) lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.

[0130] In one embodiment, the additional anti-cancer agent(s) is an immunotherapeutic agent (i.e., immunotherapy). Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0131] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa / interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon alfacon-1, peginterferon alfa-2a, peginterferon alfa-2b, and leukocyte alpha interferon; interferon beta such as interferon beta-1a, and interferon beta- 1b; interferon gamma such as natural interferon gamma-1a, and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.

[0132] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysates vaccine (Royal Newcastle Hospital).

[0133] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER- 2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), ipilimumab, quavonlimab, vibostolimab, favezelimab, lintuzumab, LYM-1 -iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, and trastuzumab.

[0134] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies such as ipilumumab and quavonlimab; anti-LAG1 agents; anti-LAG3 agents such as favezelimab, and anti-OX40 agents.145021.608067 (002600.PC)

[0135] Non-limiting examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, leridistim, mirimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.

[0136] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.

[0137] In one embodiment, the additional anti-cancer agent(s) is a targeted therapy agent (i.e., targeted therapy). Targeted therapy agents include, for example, monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapy agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell-cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF- inhibitors, BTK inhibitors (e.g., nemtabrutinib), gene expression modulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0138] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitory agents.

[0139] Non-limiting examples of EGFR inhibitory agents include small molecule antagonists of EGFR such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody-based EGFR inhibitory agents may include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res.1 : 1311-1318; Huang, S. M., et al., 1999, Cancer Res.15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res.59: 1236- 1243; monoclonal antibody Mab E7.6.3 (Yang, 1999 supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotide or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.145021.608067 (002600.PC)

[0140] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0141] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0142] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0143] In one embodiment, the additional anti-cancer agent(s) is an anti-angiogenic agent (or angiogenesis inhibitor) including, but not limited to, matrix-metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors such as everolimus and temsirolimus; PDGFR kinase inhibitory agents such as crenolanib; HIF-lα inhibitors such as PX 478; HIF-2α inhibitors such as belzutifan and the HIF-2α inhibitors described in WO 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitory agents such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitory agents; Tek antagonists (US 2003 / 0162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002 / 0042368); anti-eph receptor and / or anti- ephrin antibodies or antigen binding regions (US 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands.

[0144] Non-limiting examples of matrix-metalloproteinase (MMP) inhibitors include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96 / 33172, WO 96 / 27583, EP 1004578 , WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, EP 0931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999 / 007675 , EP 1786785, EP 1181017, US 2009 / 0012085 , US 5,863,949, US 5,861,510, and EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0145] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib,145021.608067 (002600.PC) pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™.

[0146] The additional anti-cancer agent(s) may also be another anti-angiogenic agent including, but not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors, (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany, BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IVAX, US), fibrinogen-E fragment, Flk-1 (ImClone Systems, US), forms of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM- 862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrabulin, OXI4503, PI 88, platelet factor 4, PPI 2458, ramucirumab, rBPI 21 and BPI-derived antiangiogenic (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG 292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitor, Tie-2 ligands (Regeneron, US), tissue factor pathway inhibitors (EntreMed, US), tumor necrosis factor-alpha inhibitors, tumstatin, TZ 93, urokinase plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.

[0147] In embodiments, the additional anti-cancer agent(s) is an additional active agent that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways or is a PD-1 and / or PD-L1 antagonist. In embodiments, the additional anti-cancer agent(s) is a RAF inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, AKT inhibitor, TOR inhibitor, MCL-1 inhibitor, BCL-2 inhibitor, SHP2 inhibitor, proteasome inhibitor, or immune therapy, including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, anti-LAG3, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0148] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.145021.608067 (002600.PC)

[0149] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0150] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017 / 068412.

[0151] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06 / 122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; and ZSTK474.

[0152] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt.2), 399-408); Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt.2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); l- H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Patent No.6,656,963; Sarkar and Li (2004) J Nutr.134(12 Suppl), 3493S-3498S); perifosine, Dasmahapatra et al. (2004) Clin. Cancer Res.10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); triciribine (Yang et al. (2004) Cancer Res.64, 4394-9); imidazooxazone compounds including trans-3-amino-1-methyl-3-[4-(3-phenyl- 5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (WO 2012 / 137870) ; afuresertib;; capivasertib; MK2206; patasertib, and those disclosed in WO 2011 / 082270 and WO 2012 / 177844.

[0153] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and Torin 1; TOR inhibitors in FKBP12 enhancer, rapamycins and derivatives thereof, including temsirolimus, everolimus, WO 9409010; rapalogs, e.g. as disclosed in WO 98 / 02441 and WO 01 / 14387, e.g. AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3- hydroxy(hydroxymethyl)methylpropanoate]-rapamycin ; 40-epi-(tetrazolyl)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05 / 005434; derivatives disclosed in US 5,258,389, WO 94 / 090101, WO 92 / 05179, US 5,118,677, US 5,118,678, US 5,100,883, US 5,151,413, US 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136,145021.608067 (002600.PC) WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05 / 016252).

[0154] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0155] Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019 / 167000 and WO 2020 / 022323.

[0156] Additional non-limiting examples of anti-cancer agents that are suitable for use include 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxins, antitumorigenic herbs, apaziquone, arglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestrabucil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell- cycle nonspecific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, dichloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), elfomithine, elsamitrucin, eniluracil, etanidazole, exisulind, ferruginol, folic acid replenisher such as frolinic acid, gacytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha fetoprotein, ibandronate, ibandronic acid, ICE chemotherapy regimen, imexon, iobenguane, IT-101 (CRLX101), laniquidar, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, lucanthone, masoprocol, melarsoprol, metoclopramide, miltefosine, miproxifene, mitoguazone, mitozolomide, mopidamol, motexafin gadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, nolatrexed, NSC 631570 octreotide (Ukrain), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronic acid, pentosan polysulfate sodium, phenamet, picibanil, pixantrone, platinum, podophyllinic acid, porfimer sodium, PSK (Polysaccharide-K), rabbit antithymocyte polyclonal antibody, rasburiembodiment, retinoic acid, rhenium Re 186 etidronate, romurtide, samarium (153 Sm) lexidronam, sizofiran, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethan, valspodar, verteporfin, zoledronic acid, and zosuquidar.145021.608067 (002600.PC)

[0157] The present disclosure further provides a method for using the compounds of Formula (I) or pharmaceutical compositions provided herein, in combination with radiation therapy to treat cancer. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of Formula (I) in this combination therapy can be determined as described herein.

[0158] Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachy therapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I -125, Y-90, Re-186, Re-188, Sm- 153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I -131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0159] The present disclosure also provides methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) with chemotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, therapeutic antibodies, targeted therapy agents, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[0160] The compounds of the disclosure can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered145021.608067 (002600.PC) with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound of Formula (I) and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Formula (I) and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Formula (I) can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula (I) and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0161] As one aspect of the present disclosure contemplates the treatment of the disease / conditions with a combination of pharmaceutically active compounds that may be administered separately, the disclosure further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula (I), and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[0162] The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, in therapy. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of Formula (I), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for the145021.608067 (002600.PC) compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer. The disclosure also provides the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer. Methods of Preparing the Compounds of the Disclosure

[0163] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. For instance, in some cases, the order of carrying out the steps of reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. These examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure. Any intermediates described below may be referred to herein by their number preceded by "Int-."

[0164] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: aq. = aqueous; atm = atmosphere; Bn = benzyl; BnOH = benzyl alcohol; BOP = benzotriazol-1-145021.608067 (002600.PC) yloxytris(dimethylamino)phosphonium hexafluorophosphate; B(pin) = (pinacolato)boron;; Bu = butyl; tBu = tert-butyl; tBuO = tert-butoxide; tBuOH = tert-butanol; cataCXium A Pd G2 = chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); cataCXium A Pd G3 = mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II); CSA = (1R)-(-)-camphor-10-sulfonic acid; DAST = (diethylamino)sulfur trifluoride; Davis reagent = 3-phenyl-2-(phenylsulfonyl)-1,2- oxaziridine; DCM = dichloromethane; DHP = 3,4-dihydro-2H-pyran; DIBAL = diisobutylaluminum hydride; DIPEA = DIEA = N,N-diisopropylethylamine; DMAP = 4- (dimethylamino)pyridine; DMF = N,N-dimethylformamide; DMPU = 1,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone; DMSO = dimethylsulfoxide; DMSO-d6= deuterated dimethylsulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; equiv, eq. = equivalent(s); Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; GDP = guanosine diphosphate; GNE = guanine nucleotide exchange; GTP = guanosine triphosphate; h = hour; HMPA = hexamethylphosphoramide; HPLC = high pressure liquid chromatography; Int = intermediate; i-Pr = iPr = isopropyl; KHMDS = potassium bis(trimethylsilyl)amide; min = minute; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; M = Molar; Martin's sulfurane = bis[α,α-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur = bis[(1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-yl)oxy]diphenyl-λ4-sulfane; mCPBA = 3- chlorobenzoperoxoic acid = m-chloroperoxybenzoic acid; Me = methyl; MeCN, ACN = acetonitrile; MeOH = methanol; MeTHF = 2-methyltetrahydrofuran; N = Normal; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMR = nuclear magnetic resonance; Pd(dppf)Cl2= [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pet. ether = petroleum ether; Ph = phenyl; pin = pinacolato; POCl3= phosphorus(V) oxide chloride; PPTS = pyridinium p-toluenesulfonate; r.t. = room temperature; sat. = saturated; SEM = (2- methoxyethyl)trimethylsilane; SEMCl = (2-(chloromethoxy)ethyl)trimethylsilane; SFC = supercritical fluid chromatography; SOS = Son of Sevenless; SPhos Pd G3 = (2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; TBAF = tetra-n-butylammonium fluoride; TBDPS = tert- butyldiphenylsilyl; TBDPSCl = tert-butylchlorodiphenylsilyl; tBu3P Pd G2 = chloro[(tri- tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); TEA = Et3N = triethylamine; Tf = trifluoromethanesulfonyl; TfO = trifluoromethanesulfonate; Tf2O = triflic anhydride = trifluoromethanesulfonic anhydride; TFA = trifluoroacetic acid; THF = tetrahydrofuran; THP = tetrahydropyran; TLC = thin layer chromatography; TMS = trimethylsilyl; TMSCN = Trimethylsilyl cyanide; TMP = 2,2,6,6-tetramethylpiperidine; TR-FRET = time-resolved145021.608067 (002600.PC) fluorescence resonance energy transfer; TsOH = p-toluenesulfonic acid = 4- methylbenzenesulfonic acid; Tween = polyoxyethylene (20) sorbitan monolaurate; VCD = vibrational circular dichroism; v, v / v = volume, volume to volume; w, w / w = weight, weight to weight, µm = micrometer. EXAMPLES Concentration refers to the removal of the volatile components at reduced pressure (e.g., by rotary evaporation) unless otherwise noted. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI) in positive ion detection mode and m / z refers to the [M+H]+ion unless otherwise noted.1H NMR spectra were recorded at 400-600 MHz at ambient temperature unless otherwise noted. Protons reported as 0.5 H are due to rotameric signals. RP-HPLC refers to reverse-phase HPLC on C18-functionalized preparative or semi-preparative columns with gradient elution using acetonitrile and water modified with trifluoroacetic acid or ammonium hydroxide as eluents and fractions were lyophilized or concentrated by rotary evaporation unless otherwise noted. Purification by column chromatography on silica gel was accomplished using a flash chromatography system (e.g., ISCO® or Biotage®) and commercial pre-packed silica gel columns with elution using the stated solvent systems. Compounds described herein were synthesized as the racemates unless otherwise noted in the experimental procedures and compound tables. Certain products / intermediates in the examples include indication of “Peak 1” and / or “Peak 2”, which refer to the order of elution of the indicated product / intermediate from the chromatography column (e.g., an SFC column) used to isolate the compound under the specified conditions. Thus, for example, Peak 1 refers to the first eluting compound, e.g., first eluting stereoisomer, under the specified conditions.

[0165] SFC and HPLC Columns used in the resolution of stereoisomers are summarized in the following table:145021.608067 (002600.PC)Intermediate Syntheses:

[0166] Intermediate 1: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-1)

[0167] Step A: 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-1A)

[0168] To a solution of 6-(trifluoromethyl)-1H-indazole (7.44 g, 40.0 mmol) in H2SO4(100 mL, conc. aq.) at 0 °C, was slowly added KNO3 (4.45 g, 44.0 mmol). The reaction mixture was warmed up to r.t. After stirring for 3 h at r.t., it was poured into crushed ice. The precipitated solid was collected by filtration and washed with water to afford 5-nitro-6- (trifluoromethyl)-1H-indazole (Int-1A). MS (ESI) [M+H]+: m / z 232.

[0169] Step B: 6-(trifluoromethyl)-1H-indazol-5-amine (Int-1B)

[0170] A mixture of 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-1A) (8.91 g, 38.5 mmol), iron (10.8 g, 193 mmol), and NH4Cl (10.3 g, 193 mmol) in EtOH (120 mL) and water (20 mL) was vigorously stirred at 70 °C for 1 h. The mixture was cooled to r.t. and diluted with EtOAc, filtered by glass fiber membrane filter, and washed with EtOAc. The filtrate was concentrated under reduced pressure and sat. aq. NaHCO3and EtOAc were added. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4,145021.608067 (002600.PC) filtered, and concentrated to give 6-(trifluoromethyl)-1H-indazol-5-amine (Int-1B). MS (ESI) [M+H]+: m / z 202.

[0171] Step C: 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-1C)

[0172] To a solution of 6-(trifluoromethyl)-1H-indazol-5-amine (Int-1B) (616 mg, 3.06 mmol) in THF (15 mL) was added 1,3-dimethylimidazolium chloride (40 mg, 0.30 mmol) and NCS (430 mg, 3.22 mmol). After stirred overnight at r.t., sat. aq. NaHCO3and EtOAc were added to the reaction mixture. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4-chloro-6- (trifluoromethyl)-1H-indazol-5-amine (Int-1C). MS (ESI) [M+H]+: m / z 236.

[0173] Step D: 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-1D)

[0174] To a solution of 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-1C) (634 mg, 2.69 mmol) in MeCN (20 mL) was added nitrosyl tetrafluoroborate (380 mg, 3.25 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min before a solution of KI (5.0 g, 30 mmol) in water (10 mL) was added with vigorous stirring. After stirring for 10 min, EtOAc and water were added and the layers were separated. The organic phase was washed with the mixture of sat. aq. NaHCO3and Na2S2O3solution, dried over Na2SO4, and concentrated to give 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-1D). MS (ESI) [M+H]+: m / z 347.

[0175] Step E: 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-1E)

[0176] A mixture of 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-1D) (920 mg, 2.66 mmol), (1R)-(-)-camphor-10-sulfonic acid (60 mg, 0.26 mmol), and 3,4-dihydro-2H- pyran (0.72 mL, 8.0 mmol) in toluene (20 mL) was stirred at 100 °C for 2.5 h. The reaction mixture was cooled to r.t., and sat. aq. NaHCO3 was added. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 1E). MS (ESI) [M+H]+: m / z 431.

[0177] Step F: 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol- 5-yl)cyclopropan-1-ol (Int-1F)

[0178] Potassium hydroxide (1.25 mL, 2.50 mmol, 2 N in H2O) was added to a solution of (4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-1E) (430 mg, 0.999 mmol), 2,2'-cyclopropylidenebis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)145021.608067 (002600.PC) (740 mg, 2.52 mmol), and chloro[(tri-tert-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (100 mg, 0.195 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at 50 °C for 3 h. The mixture was cooled to 0 °C, and MeOH (1 mL) and NaOH (5 mL, 2 N in H2O) were added. Hydrogen peroxide (1.2 mL, 30 wt% in H2O) was added slowly at 0 °C and stirred for 10 min. After 10 min, MeOH (2 mL) was added and stirred at 0 °C for 30 min. The reaction was quenched with H3PO4(10% aq.) and CHCl3and the layers were separated. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to afford 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-1F). MS (ESI) [M+H]+: m / z 361.

[0179] Step G: 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-1G)

[0180] Diethylaminosulfur trifluoride (0.035 mL, 0.27 mmol) was added to a solution of 1- (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)cyclopropan-1- ol (Int-1F) (43 mg, 0.12 mmol) in DCM (3 mL) at -78 °C. After stirring at -78 °C for 30 min, sat. aq. NaHCO3and EtOAc were added to the reaction mixture. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H- pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-1G). MS (ESI) [M+H]+: m / z 363.

[0181] Step H: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazol-4-yl)boronic acid (Int-1)

[0182] The mixture of 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-1G) (34 mg, 0.094 mmol), tetrahydroxydiboron (40 mg, 0.45 mmol), cataCXium A Pd G3 (6.0 mg, 0.009 mmol) and Et3N (0.080 mL, 0.57 mmol) in MeOH (1 mL) was stirred at r.t. for 60 h. EtOAc (30 mL), CHCl3(1 mL), and H3PO4(10% aq.) were added to the reaction mixture. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated unde reduced pressure. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-1). MS (ESI) [M+H]+: m / z 373.

[0183] Intermediate 2: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)boronic acid (Int-2)145021.608067 (002600.PC)

[0184] Step A: 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-2A)

[0185] To a solution of 4-chloro-2-fluorobenzaldehyde (58.0 g, 370 mmol) in conc. H2SO4 (500 mL) was added potassium nitrate (47.0 g, 470 mmol) at 0 °C. The reaction was warmed to r.t. and stirred for 1 h. The mixture was quenched with ice water (2 L), filtered, and the solid was washed with water (2 x 500 mL), dried in vacuo to give 4-chloro-2- fluoro-5-nitrobenzaldehyde (Int-2A).1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.47 (d, J=6.6 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H).

[0186] Step B: 6-chloro-5-nitro-1H-indazole (Int-2B)

[0187] To a solution of 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-2A) (67.0 g, 329 mmol) in DMF (1.00 L) were added hydrazine hydrate (161 mL, 2.82 mol) at 25 °C under N2atmosphere. The mixture was stirred at 100 °C for 15 h. The mixture was cooled and quenched with ice water (2 L). The mixture was filtered and the filtered cake was washed with water, dried in vacuo to give 6-chloro-5-nitro-1H-indazole (Int-2B).1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H). MS (ESI) [M+H]+: m / z 198.

[0188] Step C: 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-2C)145021.608067 (002600.PC)

[0189] To a solution of 6-chloro-5-nitro-1H-indazole (Int-2B) (92 g, 0.47 mol) in THF (1.0 L) were added 3,4-dihydro-2H-pyran (85 mL, 0.93 mol) and p-toluenesulfonic acid (8.0 g, 47 mmol) at 25 °C under N2atmosphere. The reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was cooled and evaporated under reduced pressure. The product was purified by flash silica gel chromatography (20 % EtOAc in petroleum ether) to give 6- chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-2C).1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 5.73 (dd, J=8.9, 2.5 Hz, 1H), 3.99-4.04 (m, 1H), 3.76-3.81 (m, 1H), 2.46-2.50 (m, 1H), 2.10-2.18 (m, 2H), 1.71-1.77 (m, 3H). MS (ESI) [M+H]+: m / z 282.

[0190] Step D: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int-2D)

[0191] To a solution of 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 2C) (38.6 g, 137 mmol) in EtOH (1.00 L) and water (200 mL) were added ammonium chloride (22.0 g, 411 mmol) and iron dust (38.3 g, 685 mmol) while stirring at 25 °C under N2 atmosphere. The reaction mixture was heated to 70 °C and stirred for 15 h. The reaction mixture was cooled, diluted with EtOAc (200 mL), filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (3 x 300 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by flash silica gel chromatography (15% EtOAc in petroleum ether) to give 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 2D). MS (ESI) [M+H]+: m / z 252.1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=0.8 Hz, 1H), 7.60 (s, 1H), 7.04 (s, 1H), 5.61 (dd, J=9.4, 2.7 Hz, 1H), 4.02-4.07 (m, 1H), 3.89-4.01 (m, 2H), 3.71-3.77 (m, 1H), 2.49-2.56 (m, 1H), 2.06-2.17 (m, 2H), 1.68-1.79 (m, 3H).

[0192] Step E: 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 2E)

[0193] To a solution of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 2D) (66.6 g, 265 mmol) in MeCN (660 mL) was added NBS (56.5 g, 318 mmol) at 20 °C under N2 atmosphere. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched with water (200 mL), diluted with EtOAc (200 mL), filtered, and concentrated. The residue was extracted with EtOAc (2 x 200 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by flash silica gel chromatography (10% EtOAc in petroleum ether) to give 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 2E).1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.59 (s, 1H), 5.61 (dd, J=9.0, 2.7 Hz, 1H),145021.608067 (002600.PC) 3.97-4.01 (m, 1H), 3.70-3.76 (m, 1H), 2.44-2.52 (m, 1H), 2.05-2.16 (m, 2H), 1.66-1.77 (m, 3H). MS (ESI) [M+H]+: m / z 330, 332.

[0194] Step F: 4-bromo-6-chloro-1H-indazol-5-amine (Int-2F)

[0195] To a solution of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- amine (Int-2E) (30 g, 90 mmol) was added 4 N HCl in MeOH (300 mL). The reaction was stirred at 50 °C for 2 h. The reaction mixture was cooled and evaporated under reduced pressure to give 4-bromo-6-chloro-1H-indazol-5-amine (Int-2F) isolated as an HCl salt. MS (ESI) [M+H]+: m / z 246, 248.

[0196] Step G: 4-bromo-6-chloro-5-iodo-1H-indazole (Int-2G)

[0197] To a solution of 4-bromo-6-chloro-1H-indazol-5-amine, HCl (Int-2F) (10.0 g, 35 mmol) in HCl (100 mL, 6 M aq.) was added a solution of sodium nitrite (2.90 g, 42 mmol) in water (20 mL) dropwise at -5 °C and stirred for 5 min. Then a solution of potassium iodide (23.0 g, 140 mmol) in water (100 mL) was added dropwise to the reaction mixture at -5 °C. The reaction mixture was stirred at 90 °C for 1 h. The reaction was cooled, quenched with ice water (150 mL) and sat. aq. Na2SO3 (100 mL), and then basified with sat. aq. NaHCO3(200 mL) to pH 8. The aqueous layer was extracted with EtOAc (2 x 200 mL), and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 4-bromo-6-chloro-5-iodo-1H-indazole (Int-2G).1H NMR (400 MHz, DMSO-d6) δ 13.62 (br s, 1H), 8.00 (s, 1H), 7.88 (d, J=0.8 Hz, 1H). MS (ESI) [M+H]+: m / z 357, 359.

[0198] Step H: 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 2H)

[0199] To a solution of 4-bromo-6-chloro-5-iodo-1H-indazole (Int-2G) (32.0 g, 90 mmol) in THF (300 mL) were added p-toluenesulfonic acid (1.50 g, 9.0 mmol) and 3,4-dihydro- 2H-pyran (16.0 mL, 180 mmol) at 20 °C under N2 atmosphere. The reaction mixture was stirred at 70 °C for 3 h. The mixture was cooled, evaporated under reduced pressure. The product was purified by flash silica gel chromatography (10% THF in petroleum ether) to give 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-2H). MS (ESI) [M+H]+: m / z 441, 443.1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.79 (d, J=0.7 Hz, 1H), 5.65 (dd, J=8.8, 2.7 Hz, 1H), 3.96-4.00 (m, 1H), 3.71-3.77 (m, 1H), 2.42-2.50 (m, 1H), 2.07-2.16 (m, 2H), 1.69-1.79 (m, 3H).

[0200] Step I: 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropan-1-ol (Int-2I)145021.608067 (002600.PC)

[0201] 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-2H) (0.202 g, 0.457 mmol) was added to a vial with a stir bar that was purged with N2. MeTHF (880 µL) was added to the vial via syringe and the reaction was cooled to 0 °C. Isopropylmagnesium chloride lithium chloride complex (0.343 mL, 0.686 mmol, 2 M in THF) was added dropwise via syringe. The reaction was stirred at 0 °C for 30 min. A separate flask was charged with 1-(phenylsulfonyl)cyclopropan-1-ol (80 mg, 0.39 mmol) and placed under N2. MeTHF (880 µL) was added and the solution was cooled to -78 °C. Methylmagnesium chloride (123 µL, 0.368 mmol, 3 M in THF) was added to the reaction followed by the contents of the first reaction flask containing, both dropwise via syringe. The reaction was allowed to warm to r.t. and stirred overnight. Sat. aq. Na2CO3(50 mL), H2O (500 mL), brine (25 mL), and EtOAc (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 150 mL) and the combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 to 40% EtOAc in hexanes) to provide 1-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-2I). MS (ESI): [M+H]+m / z 371.

[0202] Step J: 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (Int-2J)

[0203] Diethylaminosulfur trifluoride (90 µL, 0.68 mmol) was added to a solution of 1-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-2I) (112 mg, 0.300 mmol) in DCM (2.5 mL) at -78 °C. The mixture was stirred at -78 °C for 50 min. The mixture was quenched with sat. aq. NaHCO3and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatograpy (0 to 40% EtOAc in hexane) to afford 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (Int-2J). MS (ESI): [M+H]+m / z 373, 375.

[0204] Step K: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-2)

[0205] CataCXium A Pd G2 (24 mg, 0.036 mmol), hypodiboric acid (56.0 mg, 0.63 mmol), and Et3N (110 µL, 0.79 mmol) in MeOH (2.0 ml) were added to a vial containing 4-bromo- 6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-2J) (78 mg, 0.210 mmol). The mixture was evacuated and backfilled with N2(3x). The reaction was stirred at 50 °C for 2 h. The mixture was diluted with water, extracted with EtOAc (3x), and145021.608067 (002600.PC) the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (6-chloro-5-(1-fluorocyclopropyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-2), which was used directly in subsequent step(s) without further purification. MS (ESI): [M+H]+m / z 339.

[0206] Intermediate 3: : (6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-3)

[0207] Step A: 4-bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-3A)

[0208] To a solution of 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-2H) (2.0 g, 4.5 mmol) in MeTHF (20 mL) was added Pd(dppf)Cl2(0.66 g, 0.91 mmol), cyclopropylboronic acid (0.41 g, 4.8 mmol) and sodium carbonate (13.6 mL, 13.6 mmol, 1 M in H2O) at 25 °C under N2atmosphere. The reaction was stirred at 100 °C for 8 h. The mixture was cooled to r.t., diluted with H2O (20 mL), extracted with EtOAc (20 mL x3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by flash silica gel chromatography (0~7% petroleum ether / EtOAc) to give 4-bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (Int-3A). MS (ESI): [M+H]+m / z 355, 357.

[0209] Step C: (6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-3)

[0210] To a solution of 4-bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-3A) (2.0 g, 5.62 mmol) in MeOH (60 mL) was added TEA (3.14 mL, 22.5 mmol), tetrahydroxydiboron (0.756 g, 8.44 mmol) and chloro[(di(1-adamantyl)-N- butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.376 g, 0.562 mmol) at 20 °C under N2 atmosphere, the mixture was stirred at 30 °C for 2 h. The mixture was concentrated under reduced pressure and the residue purified by flash silica gel chromatography (0~15% petroleum ether / EE(EtOAc / EtOH=3:1)) to give (6-chloro-5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-3). MS (ESI): [M+H]+m / z 321.145021.608067 (002600.PC)

[0211] The compound in the table below was synthesized using a similar procedure as described in the synthesis of Int-3 by making the appropriate substitutions for starting material, intermediates, and / or reagents. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.

[0212] Intermediate 5: N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carboxamide (Int-5)

[0213] Step A: Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Int- 5A)

[0214] To a solution of ethyl 1H-pyrazole-4-carboxylate (13.8 g, 98.0 mmol) in DCM (100 mL) was added N,N-diisopropylethylamine (25.4 g, 196 mmol), and the mixture was stirred for 15 min under 0 °C, then (2-(chloromethoxy)ethyl)trimethylsilane (24.5 g, 147 mmol) was added slowly. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The material was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether gradient) to give ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Int-5A). MS (ESI) [M+H]+: m / z 271.145021.608067 (002600.PC)

[0215] Step B: N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxamide (Int-5)

[0216] To a mixture of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Int-5A) (20 g, 74 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.8 g, 111 mmol) in dry THF (350 mL) was added iPrMgBr (77 mL, 222 mmol, 2.9 M in MeTHF) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (3 x 300 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The material was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give N- methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int- 5). MS (ESI) [M+H]+: m / z 286.

[0217] Intermediate 6: (6-fluoro-5-methyl-1-((trifluoromethyl)sulfonyl)-1H- benzo[f]indazol-4-yl)boronic acid (Int-6)

[0218] Step A: 2-(2-bromo-4-fluorophenyl)-1,3-dioxolane (Int-6A)

[0219] To a solution of 2-bromo-4-fluorobenzaldehyde (4.38 g, 20.0 mmol) in toluene (50 mL) was added ethane-1,2-diol (3.34 mL, 59.9 mmol), trimethyl orthoformate (6.55 mL, 59.9 mmol) and 4-methylbenzenesulfonic acid (190 mg, 0.999 mmol), the reaction was stirred at 100 °C for 24 h. The mixture was cooled to r.t., basified with solid Na2CO3, stirred for 5 min, filtered, and concentrated under reduced pressure. The residue was purified by145021.608067 (002600.PC) flash silica gel chromatography (EtOAc / hexane) to give 2-(2-bromo-4-fluorophenyl)-1,3- dioxolane (Int-6A). MS (ESI) [M+H]+: m / z 247, 249.

[0220] Step B: 2-(2-bromo-4-fluoro-3-methylphenyl)-1,3-dioxolane (Int-6B)

[0221] To a solution of 2-(2-bromo-4-fluorophenyl)-1,3-dioxolane (Int-6A) (2.50 g, 10.1 mmol) and iodomethane (1.26 mL, 20.2 mmol) in THF (25 mL) was added dropwise (over 10 min) lithium diisopropylamide (13.0 mL, 13.9 mmol, 1.07 M in THF) at -40 °C under N2atmosphere. The mixture was stirred at -40 °C for 5 min. The mixture was quenched with 10% aq. H3PO4 and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(2-bromo-4-fluoro-3-methylphenyl)-1,3-dioxolane (Int-6B), which was used directly in the next step without further purification. MS (ESI) [M+H]+: m / z 261, 263.

[0222] Step C: 2-bromo-4-fluoro-3-methylbenzaldehyde (Int-6C)

[0223] To a solution of above 2-(2-bromo-4-fluoro-3-methylphenyl)-1,3-dioxolane (Int- 6B) (2.64 g, 10.1 mmol) in THF (25 mL) was added HCl (10 mL, aq.2 M), the reaction was stirred at r.t. for 2 h. The reaction was quenched with K2CO3 (aq., 2 M), and was extracted with EtOAc, washed with brine, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The solid was collected by filtration, and washed with a small amount of hexane to afford 2-bromo-4-fluoro-3-methylbenzaldehyde (Int-6C). MS (ESI) [M+H]+: m / z 217.219.

[0224] Step D: 5-((2-bromo-4-fluoro-3-methylphenyl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6D)

[0225] To a stirred solution of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-5) (4.20 g, 14.7 mmol) in THF (20 mL) was added lithium diisopropylamide (13.5 mL, 14.7 mmol, 1.09 M in THF) at -78 °C under N2 atmosphere, and the reaction was stirred at -78 °C for 20 min under N2. A solution of 2-bromo-4-fluoro- 3-methylbenzaldehyde (Int-6C) (2.13 g, 9.81 mmol) in THF (10 mL) was added dropwise to the above mixture. The reaction was stirred at -78 °C for another 1 h. The mixture was poured into HCl (aq., 2 M, 8 mL) and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc- hexane) to afford 5-((2-bromo-4-fluoro-3-methylphenyl)(hydroxy)methyl)-N-methoxy-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6D). MS (ESI) [M+H]+: m / z 502, 504.145021.608067 (002600.PC)

[0226] Step E: 5-(2-bromo-4-fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1H-pyrazole- 4-carboxamide (Int-6E)

[0227] To a stirred solution of 5-((2-bromo-4-fluoro-3-methylphenyl)(hydroxy)methyl)-N- methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int- 6D) (2.72 g, 5.41 mmol) in DCM (5.2 mL), and triethylsilane (13 mL, 81.4 mmol) was added TFA (6.21 mL), and the reaction was stirred at 50 °C for 24 h. The mixture was cooled to r.t., poured into a stirred solution of K2CO3(aq., 2 M, 40 mL), and extracted with EtOAc. The organic layers were washed with brine (120 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to afford 5-(2-bromo-4-fluoro-3-methylbenzyl)-N- methoxy-N-methyl-1H-pyrazole-4-carboxamide (Int-6E). MS (ESI) [M+H]+: m / z 356, 358.

[0228] Step F: Mixture of 3-(2-bromo-4-fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6F) and 5-(2-bromo-4-fluoro- 3-methylbenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- carboxamide (Int-6F)

[0229] To a solution of 5-(2-bromo-4-fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1H- pyrazole-4-carboxamide (Int-6E) (1.71 g, 4.80 mmol) in THF (40 mL) was added (1R)-(-)- camphor-10-sulfonic acid (0.112 g, 0.482 mmol) and 3,4-dihydropyran (0.610 mL, 6.70 mmol), and the mixture was stirred at 60 °C for 4 h. The mixture was cooled to r.t., basified with solid Na2CO3, stirred for 2 h, filtered, and concentrated. The residue was purified by flash silica gel chromatography (hexane-EtOAc) to give the mixture of 3-(2-bromo-4- fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- carboxamide (Int-6F) and 5-(2-bromo-4-fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6F). MS (ESI) [M+H]+: m / z 440, 442.

[0230] Step G: Mixture of 6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,9-dihydro- 4H-benzo[f]indazol-4-one and 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,9- dihydro- benzo[f]indazol-4-one (Int-6G)

[0231] a solution of the mixture of 3-(2-bromo-4-fluoro-3-methylbenzyl)-N-methoxy- N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6F) and 5-(2- bromo-4-fluoro-3-methylbenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-4-carboxamide (Int-6F) (2.10 g, 4.77 mmol) and hexamethylphosphoramide (1.00 mL, 5.75 mmol) in MeTHF (40 mL) was added dropwise n-butyllithium (4.50 mL, 7.2 mmol, 1.6 M in hexane) at -78 °C under N2 atmosphere. The reaction was stirred at -78145021.608067 (002600.PC) °C for 5 min. The reaction was quenched with HCl (aq., 2 M), diluted with THF and EtOAc, and the organic layer was separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford a mixture of 6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,9-dihydro-4H-benzo[f]indazol-4-one (Int-6G) and 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H- benzo[f]indazol-4-one (Int-6G), which was used without further purification. MS (ESI) [M+H]+: m / z 301.

[0232] Step H: 6-fluoro-5-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6H)

[0233] To a solution of the above mixture of 6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2- yl)-2,9-dihydro-4H-benzo[f]indazol-4-one (Int-6G) and 6-fluoro-5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6G) in DCM (40 mL) was added DIEA (4.15 mL, 23.8 mmol) at -78 °C, followed by triflic anhydride (2.40 mL, 14.3 mmol), and the reaction was stirred at -78 °C under N2 atmosphere for 10 min. Additional DIEA (2.07 mL, 11.9 mmol) and triflic anhydride (1.20 mL, 7.2 mmol) were added, and the mixture was stirred at -78 °C for 20 min. The reaction was quenched with H3PO4(aq, 10%), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to afford 6-fluoro-5-methyl-1- ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6H).1H-NMR (400 MHz, CDCl3) δ: 8.66 (s, 1H), 8.49 (s, 1H), 7.95 (dd, J = 9.1, 5.4 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 2.83 (d, J = 3.0 Hz, 3H).

[0234] Step I: (6-fluoro-5-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4- yl)boronic acid (Int-6)

[0235] To a solution of 6-fluoro-5-methyl-1-((trifluoromethyl)sulfonyl)-1H- benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6H) (596 mg, 1.24 mmol), hypodiboric acid (334 mg, 3.73 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino- 1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.090 g, 0.123 mmol) in MeOH (10 mL) was added TEA (0.864 mL, 6.21 mmol) at 25 °C, and the mixture was stirred at an ambient temperature for 20 min under N2atmosphere. The reaction was quenched with H3PO4 (aq, 10%), and extracted with CHCl3. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (hexane-EtOAc / EtOH(4 / 1)) to give (6-fluoro-5-methyl-145021.608067 (002600.PC) 1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)boronic acid (Int-6). MS (ESI) [M- Tf+H]+: m / z 244.

[0236] Intermediate 7: (6-chloro-5-ethyl-1-((trifluoromethyl)sulfonyl)-benzo[f]indazol-4-yl)boronic acid (Int-7) TsOH

[0237] Step A: 2-(2-bromo-4-chlorophenyl)-1,3-dioxolane (Int-7A)

[0238] To a solution of 2-bromo-4-chlorobenzaldehyde (4.38 g, 20.0 mmol) in toluene (50 mL) was added ethane-1,2-diol (3.34 mL, 59.9 mmol), trimethyl orthoformate (6.55 mL, 59.9 mmol), and 4-methylbenzenesulfonic acid (190 mg, 0.999 mmol). The reaction was stirred at 100 °C for 24 h. The mixture was cooled to r.t., basified with solid Na2CO3, stirred for 5 min, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to give 2-(2-bromo-4-chlorophenyl)-1,3-dioxolane (Int- 7A). MS (ESI) [M+H]+: m / z 263, 265.

[0239] Step B: 2-(2-bromo-4-chloro-3-ethylphenyl)-1,3-dioxolane (Int-7B)

[0240] To a solution of 2,2,6,6-tetramethylpiperidine (0.500 mL, 2.94 mmol) was added n- butyllithium (1.80 mL, 2.74 mmol, 1.52 M in hexane) at -78 °C. The mixture was stirred at -78 °C for 0.5 h, and a solution of 2-(2-bromo-4-chlorophenyl)-1,3-dioxolane (Int-7A) (527 mg, 2.00 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.314 ml, 2.60 mmol) in THF (5 mL) was added at -78 °C, followed by iodoethane (0.200 mL, 2.50 mmoL). The reaction was allowed to warm up to r.t. and stirred overnight. The mixture was145021.608067 (002600.PC) quenched with H3PO4 (aq, 10%), and extracted with EtOAc, and the organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to give 2-(2-bromo-4-chloro-3- ethylphenyl)-1,3-dioxolane (Int-7B). MS (ESI) [M+H]+: m / z 291.

[0241] Step C: 2-bromo-4-chloro-3-ethylbenzaldehyde (Int-7C)

[0242] To a solution of 2-(2-bromo-4-chloro-3-ethylphenyl)-1,3-dioxolane (Int-7B) (2.75 g, 9.43 mmol) in THF (25 mL) was added HCl (aq., 2 M, 10 mL), the reaction was stirred at 25 °C overnight. The reaction was quenched with K2CO3 (aq., 2 M), and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to give afford 2-bromo-4-chloro-3-ethylbenzaldehyde (Int-7C).1H NMR (400 MHz, CDCl3) δ 10.39 (d, J = 0.8 Hz, 1H), 7.71-7.68 (m, 1H), 7.44 (dd, J = 8.3, 0.8 Hz, 1H), 3.10 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H).

[0243] Step D: 5-((2-bromo-4-chloro-3-ethylphenyl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-7D)

[0244] To a stirred solution of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-5) (4.63 g, 16.2 mmol) in THF (30 mL) was added lithium diisopropylamide (15.0 mL, 14.7 mmol, 1.09 M in THF) at -78 °C under N2 atmosphere, and the reaction was stirred at -78 °C for 30 min under N2. A solution of 2-bromo-4-chloro- 3-ethylbenzaldehyde (Int-7C) (2.23 g, 9.01 mmol) in THF (10 mL) was added dropwise to the above mixture. The reaction was stirred at -78 °C for another 30 min. The mixture was quenched with HCl (aq., 2 M, 8 mL) and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate-hexane) to afford 5-((2-bromo-4-chloro-3-ethylphenyl)(hydroxy)methyl)-N- methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int- 7D). MS (ESI) [M+H]+: m / z 534.

[0245] Step E: 5-(2-bromo-4-chloro-3-ethylbenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-7E)

[0246] To a stirred solution of 5-((2-bromo-4-chloro-3-ethylphenyl)(hydroxy)methyl)-N- methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int- 7D) (4.05 g, 7.60 mmol) in DCM (7.3 mL), and triethylsilane (18.2 mL, 114 mmol) was added TFA (8.70 mL, 114 mmol), and the reaction was stirred at 50 °C for 24 h. The mixture was cooled to r.t., poured into a stirred solution of K2CO3 (aq.2 M, 40 mL), and145021.608067 (002600.PC) extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to afford 5-(2-bromo-4-chloro-3-ethylbenzyl)-N- methoxy-N-methyl-1H-pyrazole-4-carboxamide (Int-7E). MS (ESI) [M+H]+: m / z 386, 388.

[0247] Step F: 6-chloro-5-ethyl-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-7F)

[0248] To a solution of 5-(2-bromo-4-chloro-3-ethylbenzyl)-N-methoxy-N-methyl-1H- pyrazole-4-carboxamide (Int-7E) (0.300 mg, 0.776 mmol) and HMPA (0.160 mL, 0.920 mmol) in MeTHF (5 mL) was added lithium diisopropylamide (0.845 mL, 0.921 mmol, 1.09 M in THF) and n-butyllithium (1.70 mL, 2.70 mmol, 1.6 M in hexane) at -78 °C under N2atmosphere. The reaction was stirred at -78 °C for 10 min. The reaction was quenched with HCl (aq., 2 M), diluted with THF and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford 6-chloro-5-ethyl-1,9-dihydro-4H- benzo[f]indazol-4-one (Int-7F), which was used directly in the next step without further purification. MS (ESI) [M+H]+: m / z 247, 249.

[0249] Step G: 6-chloro-5-ethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-7G)

[0250] To a solution of 6-chloro-5-ethyl-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-7F) in DCM (7 mL) was added DIEA (1.60 mL, 9.19 mmol) at -78 °C, followed by triflic anhydride (1.55 mL, 9.21 mmol), and the reaction was stirred at -78 °C under N2atmosphere for 10 min. The reaction was quenched with H3PO4 (aq., 10%), and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc-hexane) to afford 6-chloro-5-ethyl-1- ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-7G).1H-NMR (400 MHz, CDCl3) δ: 8.71 (d, J = 0.8 Hz, 1H), 8.50 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 3.63 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H).

[0251] Step H: (6-chloro-5-ethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4- yl)boronic acid (Int-7)

[0252] To a solution of 6-chloro-5-ethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol- 4-yl trifluoromethanesulfonate (Int-7G) (204 mg, 0.399 mmol), hypodiboric acid (42 mg, 0.469 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl- 2-yl)palladium(II) dichloromethane adduct (0.029 g, 0.040 mmol) in MeOH (5 mL) was added TEA (0.200 mL, 1.44 mmol) at 25 °C, and the mixture was stirred at an ambient145021.608067 (002600.PC) temperature for 30 min under N2 atmosphere. The reaction mixture was quenched with H3PO4 (aq 10%), and extracted with CHCl3, and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (hexane-EtOAc / EtOH(4 / 1)) to give (6-chloro-5-ethyl-1- ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)boronic acid (Int-7). MS (ESI) [M+H]+: m / z 407.

[0253] The compound in the table below was synthesized using a similar procedure as described in the synthesis of Int-7 by making the appropriate substitutions for starting material, intermediates, and / or reagents. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.

[0254] Intermediate 9: (S,Z)- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Int-9)

[0255] Step A: Ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Int-9A)

[0256] A solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (1.0 g, 4.8 mmol) in DCM (15 mL) was bubbled with O3 at -78 °C until the145021.608067 (002600.PC) mixture turned blue. Dimethylsulfide (0.594 g, 9.56 mmol) was added to the mixture and the reaction was stirred at 25 °C for 16 h. The reaction mixture was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Int-9A). MS (ESI) [M+H]+: m / z 212.

[0257] Step B: Ethyl (S)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (Int-9B)

[0258] To a solution of fluoromethyl 2-pyridyl sulfone (684 mg, 3.91 mmol) in THF (10 mL) was added KHMDS (4.51 mL, 4.51 mmol, 1 M in THF) at -78 °C under N2. After 30 min, ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Int-9A) (750 mg, 3.55 mmol) in THF (8 mL) was added slowly at -78 °C and the mixture was stirred for 3 h. The reaction was warmed to r.t. and stirred for 1 h. The reaction was quenched with sat. aq. NH4Cl (1 mL) and HCl (2 mL, aq.3 M). The mixture was extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by flash silica gel chromatography (0 to 30% EtOAc in petroleum ether) to give ethyl (S)-2-(fluoromethylene)-5-oxotetrahydro-1H- pyrrolizine-7a(5H)-carboxylate (Int-9B). MS (ESI) [M+H]+: m / z 228.

[0259] Step C: (S)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Int- 9C)

[0260] To a solution of ethyl (S)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (Int-9B) (200 mg, 0.880 mmol) in THF (4 mL) at 0 °C was added diisobutylaluminium hydride (8.80 mL, 8.80 mmol, 1 M in toluene) at 0 °C and the mixture was stirred for 1 h. The reaction was warmed to rt and stirred for 0.5 h. The reaction mixture was quenched with solid Na2SO4·10H2O. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give (S)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (Int-9C). MS (ESI) [M+H]+: m / z 172.

[0261] Step D: (S,E)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2- (fluoromethylene)hexahydro-1H-pyrrolizine (Int-9D-1) & (S,Z)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-2-(fluoromethylene)hexahydro-1H-pyrrolizine (Int-9D-2)

[0262] To a mixture of (S)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (Int-9C) (120 mg, 0.701 mmol) in DCM (5 mL) was added DMAP (8.6 mg, 0.070 mmol), Et3N (0.195 mL, 1.40 mmol), and tert-butylchlorodiphenylsilane (289 mg,145021.608067 (002600.PC) 1.05 mmol) at 0 °C under N2, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (5 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give (S,E)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-2-(fluoromethylene)hexahydro-1H-pyrrolizine (Int-9D-1, the first peak eluting isomer, MS (ESI) [M+H]+: m / z 410) and (S,Z)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-2-(fluoromethylene)hexahydro-1H-pyrrolizine (Int-9D-2, the second peak eluting isomer, MS (ESI) [M+H]+: m / z 410).

[0263] Step E: -(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a -yl)methanol(Int-9)

[0264] To a mixture of (S,Z)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2- (fluoromethylene)hexahydro-1H-pyrrolizine (Int-9D-2) (91 mg, 0.22 mmol) in THF (1 mL) was added TBAF (0.44 mL, 0.44 mmol, 1 M in THF) at 25 °C under N2, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by preparative TLC (DCM / MeOH = 10:1) to give (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (Int-9). MS (ESI) [M+H]+: m / z 172.

[0265] Intermediate 10: (S)-4-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6- ol (Int-10)145021.608067 (002600.PC)

[0266] Step A: Methyl 2-chloro-3-fluoroisonicotinate (Int-10A)

[0267] Eight reactors were set up in parallel. To each reactor was charged MeOH (4.0 L) at 25 °C, 2-chloro-3-fluoroisonicotinic acid (400 g, 2.3 mol), and conc. H2SO4(45.0 g, 0.4 mol). The mixture was heated to 75 °C for 12 h. The contents of the eight reactors were combined and concentrated to remove MeOH. The pH of the resulting residue was adjusted to 7 using aq. Na2CO3and extracted with EtOAc (20 L × 2). The combined organics were dried with Na2SO4 and concentrated under reduced pressure to give methyl 2-chloro-3- fluoroisonicotinate (Int-10A), which was used directly in the next step without further purification.

[0268] Step B: (2-chloro-3-fluoropyridin-4-yl)methanol (Int-10B)145021.608067 (002600.PC)

[0269] Twelve reactors were set up in parallel. To each reactor was charged EtOH (2.3 L), methyl 2-chloro-3-fluoroisonicotinate (Int-10A) (235 g, 1.2 mol), and calcium chloride (206 g, 1.8 mol). The reactor was degassed and purged with N2times and cooled to 0~10 ℃. NaBH4 (93.0 g, 2.4 mol) was added at 0~10 ˚C and stirred for 1 h. The mixture was warmed to r.t. for 12 h. The contents of the twelve reactors were combined for workup. The reaction was slowly poured into ice water (5.0 V) under N2atmosphere, filtered, and the filter cake was washed with EtOAc (5.0 V). The filtrate was concentrated under reduced pressure to give (2-chloro-3-fluoropyridin-4-yl)methanol (Int-10B).1H NMR (400 MHz, CDCl3) δ 2.91 (s, 1H), 4.85 (s, 2H), 7.45 - 7.46 (t, J = 4.0 Hz, 1H), 8.17 - 8.18 (d, J = 4.0 Hz, 1H).

[0270] Step C: 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-10C)

[0271] Twelve reactors were set up in parallel. To each reactor was charged DCM (2.0 L) and (2-chloro-3-fluoropyridin-4-yl)methanol (Int-10B) (200 g, 1.2 mol). PBr3(402 g, 1.5 mol) was charged into the reactor vessel at 0 ˚C. The vessel was warmed to r.t. and stirred for 12 h. The contents of the twelve reactors were combined for workup and poured into 10% aq. NaHCO3(1.0 L) slowly. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (20 L) and the organic phase was separated. The aqueous solution was extracted with DCM (20 L × 2). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduce pressure to give 4- (bromomethyl)-2-chloro-3-fluoropyridine (Int-10C). MS (ESI) [M+H]+: m / z 224.

[0272] Step D: 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-10D)

[0273] Eight reactors were set up in parallel. To each reactor was charged MeCN (2.3 L), 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-10C) (230 g, 1.0 mol), TMSCN (1.01 kg, 10 mol), and lithium hydroxide (51.0 g, 1.2 mol). The mixture was stirred at 0 ˚C for 4 h and at r.t. for 8 h. The contents of the eight reactors were combined and concentrated to remove MeCN. The reaction was diluted with EtOAc (25 L) and H2O (10 L) and the organic phase was separated. The aqueous phase was extracted with EtOAc (10 L × 2). The combined organics were dried with Na2SO4, filtered, and concentrated to give 2-(2-chloro- 3-fluoropyridin-4-yl)acetonitrile (Int-10D). MS (ESI) [M+H]+: m / z 171.

[0274] Step E: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-10E)

[0275] Twelve reactors were set up in parallel. To each reactor was charged DMSO (1.7 L) and 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-10D) (170 g, 1.00 mol). The reactor was degassed and purged with N2three times. Potassium tert-butoxide (123 g, 1.1 mol) was added in batches at r.t. over 30 min. The mixture was stirred at r.t. for 30 min. After 30 min,145021.608067 (002600.PC) ethoxycarbonyl isothiocyanate (143 g, 1.1 mol) was added at r.t. The mixture was stirred at r.t. for 30 min. The reactor was warmed to 100 ˚C and stirred at 100 ˚C for 1 h. NaOH (1 L, 5 M in H2O) was added and the mixture was stirred at 100 ˚C for 10 h. The reaction was cooled and the contents of the 12 reactors were combined for workup. The reaction was poured into ice water (10 V) and stirred at 0 ˚C for 30 min. The resulting solid was filtered, washed with H2O (5.0 L), and dried in an oven at 50 ˚C for 12 h to obtain 2-amino-7- chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-10E). MS (ESI) [M+H]+: m / z 210.

[0276] Step F: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-10F)

[0277] Six reactors were set up in parallel. To each reactor was charged DMSO (2.1 L), 2- amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-10E) (70.0 g, 0.3 mol), and K2CO3(92.0 g, 0.6 mol). Hydrogen peroxide (615 g, 5.40 mol, 30% wt) was added slowly into the reactor in portions over 4 h. The mixture was stirred at 25 ˚C for 6 h. The contents of the six reactors were combined for workup. The reaction was poured into 10% aq. Na2SO3at 15-25 ˚C and the mixture was stirred at 0 ˚C for 0.5 h. The reaction mixture was filtered and the filter cake was washed with H2O (5.0 L). The resulting solid was dried in an oven at 50 ˚C for 12 h to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-10F). MS (ESI) [M+H]+: m / z 228.1H NMR (400 MHz, DMSO-d6) δ 7.19 - 7.20 (d, J = 4.0 Hz, 1 H), 8.10 - 8.11 (d, J = 4.0 Hz, 1H).

[0278] Step G: 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-10G)

[0279] Five reactors were set up in parallel. To each reactor was charged EtOH (0.5 L) and potassium hydroxide (52.0 g, 0.9 mol). The mixture was stirred at 25 ˚C for 0.5 h. Carbon disulfide (70.0 g, 0.9 mol) was added at 25 ˚C and the mixture was stirred at 25 ˚C for 0.5 h. H2O (0.5 L) was added followed by 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-10F) (70.0 g, 0.3 mol). The mixture was heated to 110 ˚C for 12 h. The contents of the five reactors were combined for workup. The reaction was concentrated to remove EtOH and the pH was adjusted to 3. The mixture was stirred at 0 ˚C for 1 h, filtered, and washed with H2O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ˚C for 8 h and dried in an oven at 40 ˚C for 12 h to give 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-ol (Int-10G). MS (ESI) [M+H]+: m / z 270.

[0280] Step H: 8-chloro-2-(methylthio) [2,3-d]pyrimidin-4-ol (Int-10H)

[0281] Two reactors were set up in parallel. To each reactor was charged EtOH (1.0 L), H2O (1.0 L), 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-10G) (135 g, 0.5 mol), and KOH (56.0 g, 1.0 mol). The mixture was stirred at 0 ˚C for 0.5 h.145021.608067 (002600.PC) Iodomethane (85.0 g, 0.6 mol) was added at 0 ˚C and stirred for 1.5 h. The contents of the two reactors were combined for workup. The reaction mixture was concentrated to remove EtOH and the pH was adjusted to 3. The mixture was stirred at 0 ˚C for 1 h, filtered, and washed with H2O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ˚C for 8 h and dried in an oven at 40 ˚C for 12 h to give 8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-10H), which may exist in a tautomeric form. MS (ESI) [M+H]+: m / z 284.1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 8.16 - 8.17 (d, J = 4.0 Hz, 1H), 8.44 - 8.45 (d, J = 4.0 Hz, 1H), 13.4 (s, 1H).

[0282] Step I: 4,8-dichloro-2-(methylthio) [2,3-d]pyrimidine (Int-10I)

[0283] Three reactors were set up in parallel. To each reactor was charged POCl3 (2.02 kg, 13 mol) and 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-10H) (55.0 g, 0.20 mol). The reaction mixture was stirred at 120 ˚C for 5 h. The contents of the three reactors were combined for workup. The reaction was concentrated, and the residue was triturated with EtOH (10 V) at 25 ˚C for 8 h. The resulting solid was dried in an oven at 40 ˚C for 12 h to give 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int-10I).1H NMR (400 MHz, DMSO-d6) δ 2.67 (s, 3H), 8.48 - 8.49 (d, J = 4.0 Hz, 1H), 8.65 - 8.66 (d, J = 4.0 Hz, 1H). MS (ESI) [M+H]+: m / z 302.

[0284] Step J: (S)-4-(8-chloro-2-(methylthio) [2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10J)

[0285] A mixture of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int-10I) (2 g, 6.6 mmol), (S)-6-methyl-1,4-oxazepan-6-ol, HCl (Int-12) (1.10 g, 6.60 mmol), and K2CO3(2.7 g, 20 mmol) in EtOH (30 mL) were heated at 80 °C for 2 h. The reaction mixture was cooled to r.t. and water was added. The solid obtained was filtered and dried under vacuum overnight to obtain (S)-4-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int- 10J). MS (ESI) [M+H]+: m / z 397.

[0286] Step K: (S)-4-(8-chloro-2-(methylsulfonyl)pyrido4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10K)

[0287] To a solution of (S)-4-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10J) (1.10 g, 2.77 mmol) in DCM (22 mL) was added mCPBA (1.43 g, 8.31 mmol). The reaction was stirred at r.t. for 3 h. The mixture was diluted with DCM, washed with sat. aq. NaHCO3solution, brine, and the organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under145021.608067 (002600.PC) reduced pressure to obtain (S)-4-(8-chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10K). MS (ESI) [M+H]+: m / z 429.

[0288] Step L: (S)-4-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido 4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10)

[0289] To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.640 g, 4.02 mmol) and sodium hydride (0.214 g, 5.36 mmol, 60 wt% in mineral oil) was added THF (7 mL) under nitrogen. The reaction was stirred for 1 h. To this reaction was added (S)-4-(8-chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6- methyl-1,4-oxazepan-6-ol (Int-10K) (1.15 g, 2.68 mmol) in THF (21 mL). The reaction was stirred at rt overnight. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography (0 to 100 % EtOAc in hexane) to obtain (S)-4-(8- chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int- 10). MS (ESI) [M+H]+: m / z 508.

[0290] Intermediate 11: 4-(benzyloxy)-8-chloro-2-(methylthio)-9H-

[0291] Step A: Methyl 2,6-dihydroxy-5-iodopyrimidine-4-carboxylate (Int-11A)

[0292] Periodic acid (9.04 g, 39.7 mmol) and iodine (23.5 g, 93 mmol) were added to a solution of methyl 2,6-dihydroxypyrimidine-4-carboxylate (37.5 g, 220 mmol) in MeOH (350 mL) at 25 °C. The mixture was heated to 70 °C and stirred for 16 h. The mixture was concentrated in vacuo and the residue was diluted with H2O. The resulting mixture was filtered and the filter cake was washed with H2O. The filter cake was dried via azeotropic145021.608067 (002600.PC) distillation using toluene to give methyl 2,6-dihydroxy-5-iodopyrimidine-4-carboxylate (Int-11A). MS (ESI) [M+H]+: m / z 297.

[0293] Step B: Methyl 2,6-dichloro-5-iodopyrimidine-4-carboxylate (Int-11B)

[0294] DIPEA (73.0 mL, 418 mmol) was added to a solution of methyl 2,6-dihydroxy-5- iodopyrimidine-4-carboxylate (Int-11A) (55 g, 186 mmol) in phosphoryl chloride (550 mL) at 25 °C. The mixture was heated to 110 °C for 6 h. The mixture was cooled to r.t. and was concentrated by distillation followed by azeotropic distillation using toluene. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 10 / 1) to give methyl 2,6-dichloro-5-iodopyrimidine-4-carboxylate (Int-11B).1H NMR (400MHz, CDCl3) δ 4.05 (s, 3H).

[0295] Step C: Methyl 6-(benzyloxy)-2-chloro-5-iodopyrimidine-4-carboxylate (Int-11C)

[0296] Cesium carbonate (63.7 g, 196 mmol) was added to a solution of methyl 2,6- dichloro-5-iodopyrimidine-4-carboxylate (Int-11B) (37.2 g, 112 mmol) and benzyl alcohol (10.88 g, 101 mmol) in MeCN (375 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give methyl 6-(benzyloxy)-2-chloro-5-iodopyrimidine-4-carboxylate (Int-11C). MS (ESI) [M+H]+: m / z 405.

[0297] Step D: Methyl 6-(benzyloxy)-5-iodo-2-(methylthio)pyrimidine-4-carboxylate (Int- 11D)

[0298] Sodium methanethiolate (8.45 g, 121 mmol) was added to a solution of methyl 6- (benzyloxy)-2-chloro-5-iodopyrimidine-4-carboxylate (Int-11C) (28.7 g, 70.9 mmol) in tert-butanol (450 mL) at 25 °C and the mixture was stirred for 16 h under N2atmosphere. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 6- (benzyloxy)-5-iodo-2-(methylthio)pyrimidine-4-carboxylic acid, which was used directly in the next step without further purification. MS (ESI) [M+H]+: m / z 403.

[0299] Potassium carbonate (49.0 g, 354 mmol) and iodomethane (17.72 mL, 283 mmol) was added to a solution of 6-(benzyloxy)-5-iodo-2-(methylthio)pyrimidine-4-carboxylic acid (28.5 g, 70.9 mmol) in DMF (300 mL) at 25 °C and the mixture was stirred for 16 h under N2 atmosphere. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel145021.608067 (002600.PC) chromatography (0 to 18% petroleum ether in THF) to afford methyl 6-(benzyloxy)-5-iodo- 2-(methylthio)pyrimidine-4-carboxylate (Int-11D). MS (ESI) [M+H]+: m / z 417.

[0300] Step E: Methyl 6-(benzyloxy)-5-(2-chloropyridin-4-yl)-2-(methylthio)pyrimidine- 4-carboxylate (Int-11E)

[0301] 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.28 g, 26.2 mmol), K2CO3(7.77 g, 56.2 mmol) and Pd(dppf)Cl2(2.74 g, 3.75 mmol) were added to a solution of methyl 6-(benzyloxy)-5-iodo-2-(methylthio)pyrimidine-4-carboxylate (Int-11D) (7.8 g, 18.74 mmol) in dioxane (100 mL) under N2 atmosphere and the mixture was stirred at 50 °C for 4 h. The mixture was diluted with H2O (40 mL) and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 5 / 1) to give methyl 6- (benzyloxy)-5-(2-chloropyridin-4-yl)-2-(methylthio)pyrimidine-4-carboxylate (Int-11E). MS (ESI) [M+H]+: m / z 402.

[0302] Step F: 4-(benzyloxy)-8-chloro-2-(methylthio)-d]pyrimidin-9-one (Int-11)

[0303] The reaction was set up using flow chemistry. Methyl 6-(benzyloxy)-5-(2- chloropyridin-4-yl)-2-(methylthio)pyrimidine-4-carboxylate (Int-11E) (5.6 g, 13.9 mmol) was dissolved in THF (120 mL) and charged into Reservoir 1 at 20 °C. Lithium diisopropylamide solution (20.9 mL, 41.8 mmol, 2 M in THF) and THF (120 mL) were charged into Reservoir 2 at 20 °C. The flow rates for Reservoir 1 and Reservoir 2 were adjusted to 12.0 mL / min with the total reaction residence time being 15 s. The mixture was quenched with aq. NH4Cl, the organic phase was collected, and the pumps and tubing were washed with THF. The mixture was diluted with additional sat. aq. NH4Cl (80 mL) and the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether / THF = 5 / 1) to give 4-(benzyloxy)-8-chloro-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9- one (Int-11). MS (ESI) [M+H]+: m / z 370.

[0304] Intermediate 12: (S)-6-methyl-1,4-oxazepan-6-ol (Int-12)145021.608067 (002600.PC)Step A Int-12AStep BInt-12

[0305] Step A: (S)-6-methyl-1,4-oxazepan-6-ol, acetyl-D-valinate salt (Int-12A)

[0306] A mixture of 6-methyl-1,4-oxazepan-6-ol (100 g, 0.762 mol) in MeCN (2.00 L) was stirred at 65 °C for 15 min. N-acetyl-D-valine (85.0 g, 0.534 mol) was added into the mixture at 65 °C, and the reaction was stirred for 2.5 h. The mixture was cooled to 50 °C and stirred for 0.5 h. The mixture was cooled to 40 °C and stirred for 15 min. The mixture was cooled to 25 °C and stirred for 1 h. The mixture was filtered and the filter cake was washed with MeCN. The filter cake was concentrated under reduced pressure to give (S)-6- methyl-1,4-oxazepan-6-ol, acetyl-D-valinate salt (Int-12A). MS (ESI) [M+H]+: m / z 132.

[0307] Step B: (S)-6-methyl-1,4-oxazepan-6-ol (Int-12)

[0308] To a solution of (S)-6-methyl-1,4-oxazepan-6-ol, acetyl-D-valinate salt (Int-12A) (33.7 g, 116 mmol) in water (33 mL) was added DOWEX 50WX8 (33 g) and the mixture was stirred at 20 °C for 1 h. The mixture was filtered, and the filter cake was washed with water (100 mL) and MeOH (100 mL) in turns. Then Dowex resin was collected and dissolved in 4 M NH3 / MeOH (200 mL). The mixture was stirred at 20 °C for 30 min, filtered, and washed with 4M NH3 / MeOH (150 mL). The combined filtrates were concentrated under reduced pressure to yield (S)-6-methyl-1,4-oxazepan-6-ol (Int-12). MS (ESI) [M+H]+: m / z 132.

[0309] Example 1: (6S)-4-(8-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-1)145021.608067 (002600.PC)

[0310] Step A: -4-(8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2- pyrido[4',3':4,5]thieno[2,3- 4-yl)-6-methyl-1,4-oxazepan-6-ol

[0311] To a solution of (S)-4-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Int-10J) (2.00 g, 5.04 mmol) in toluene (20 mL) was added (6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-3) (2.18 g, 6.80 mmol), K2CO3(12.6 mL, 25.2 mmol, 2 M in H2O) and SPhos Pd G3 (1.97 g, 2.52 mmol) at 25 °C. The reaction mixture was heated to 40 °C and stirred for 1 h under N2. The reaction mixture was cooled to r.t., diluted with H2O (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give (6S)-4-(8-(6-chloro-5- cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2- (methylthio)pyrido[4’,3’:4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 637.

[0312] Step B: (6S)-4-(8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-2-(methylsulfinyl)pyrido 4-yl)-6-methyl-1,4-oxazepan-6-ol

[0313] To a solution of (6S)-4-(8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol (20 mg, 0.031 mmol) in CHCl3 (0.5 mL) was added 3-phenyl-2- (phenylsulfonyl)-1,2-oxaziridine (9.6 mg, 0.037 mmol) at 0 °C, the reaction mixture was145021.608067 (002600.PC) stirred for 16 h under N2 atmosphere at 25 °C. The reaction mixture was quenched with Na2SO3 (2 mL), extracted with DCM (2 mL x3), the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The material was purified by preparative TLC (DCM / MeOH=10:1) to give (6S)-4-(8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6- methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 653.

[0314] Step C: (6S)-4-(8-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-1)

[0315] To ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methan-d2-ol (101 mg, 0.620 mmol) and (6S)-4-(8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol (135 mg, 0.207 mmol) was added THF (2.10 mL) and stirred at 60 °C for 18 h. The reaction was diluted with sat. aq. NH4Cl, then extracted with EtOAc (3x). The organic layers were washed with brine, then dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo.

[0316] The residue was suspended in DCM (2.1 mL), cooled to 0˚C, and TFA (796 µL, 10.3 mmol) was added. After 1.5 h of stirring at 0˚C, the mixture was concentrated under reduced pressure without submerging in hot water bath. The residue was suspended in MeCN, NH4OH solution (~30% in water) was added until pH ~ 7, and the solution was purified by reverse preparative HPLC (water:MeCN w / NH4OH modifier) to give (6S)-4-(8- (6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol (Ex-1).1H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H), 8.81 (d, J = 5.5 Hz, 1H), 7.92 – 7.76 (m, 2H), 7.61 (s, 1H), 5.22 (s, 1H), 4.05 – 3.99 (m, 1H), 3.95 – 3.85 (m, 5H), 3.58 – 3.38 (m, 2H), 3.09 – 2.96 (m, 2H), 2.15 – 1.99 (m, 2H), 1.99 – 1.89 (m, 2H), 1.86 – 1.69 (m, 3H), 1.23 (s, 1H), 1.00 (s, 3H), 0.52 (dt, J = 164.9, 9.3 Hz, 2H), 0.00 (s, 2H). MS (ESI) [M+H]+: m / z 668.

[0317] Example 2: (6S)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)-6-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-2)145021.608067 (002600.PC)

[0318] Step A: (6S)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 4-yl)-6-methyl-1,4-oxazepan-6-olmg, (1.18 mL, 2.36 mmol, 2 M aq. solution) were added to a mixture of (S)-4-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol (Int-10) (400 mg, 0.787 mmol) and (Z)-(5-(prop-1-en-1-yl)-1-(tetrahydro- 2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-4) (427 mg, 0.787 mmol) in toluene (10 mL) at 25 °C. The mixture was stirred at 50 °C for 3 h. The mixture was diluted with EtOAc (40 mL), washed with brine (3 x 8 mL), and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography (1 / 2 petroleum ether / THF) to give (6S)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl- 1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 782.

[0320] Step B: (6S)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)-6-(trifluoromethyl)- indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl- oxazepan-6-ol (Ex-2)

[0321] To a solution of (6S)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol145021.608067 (002600.PC) (150 mg, 0.199 mmol) in DCM (1.2 mL) was added TFA (500 µL), and the reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was partitioned between sat. aq. NaHCO3and CHCl3. The organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel chromatography (0% to 25% MeOH in CHCl3) to give (6S)-4-(2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-(5-((Z)-prop-1-en-1-yl)- 6-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl- 1,4-oxazepan-6-ol (Ex-2).1H NMR (500 MHz, CDCl3) δ 8.80-8.75 (m, 1H), 7.95-7.57 (m, 3H), 6.62 (d, J = 12.2 Hz, 2H), 5.56-5.46 (m, 1H), 5.26 (d, J = 53.4 Hz, 1H), 4.27-4.18 (m, 2H), 4.15-4.11 (m, 2H), 4.06-4.01 (m, 1H), 3.96 (td, J = 13.0, 2.7 Hz, 1H), 3.80 (dd, J = 12.5, 5.2 Hz, 1H), 3.75-3.70 (m, 1H), 3.63 (d, J = 15.0 Hz, 1H), 3.45-3.16 (m, 5H), 2.99- 2.96 (m, 1H), 2.20-2.03 (m, 3H), 1.96-1.84 (m, 3H), 1.37 (d, J = 5.5 Hz, 3H), 1.18-1.11 (m, 3H). MS (ESI) [M+H]+: m / z 698.

[0322] The examples in the table below were synthesized using a similar procedure as described in the synthesis of Ex-2 by making the appropriate substitutions for starting material, intermediates, and / or reagents. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.608067 (002600.PC)

[0323] Example 5: (6S)-4-(8-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2-(((S,Z)-2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a -yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6- 5)

[0324] Step A: (S)-4-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-6-methyl-1,4-oxazepan-6-ol

[0325] To a solution of 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-10H) (20 g, 71 mmol) in MeCN (300 mL) was added BOP (62.3 g, 141 mmol) at 25 °C, the mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. Then, (S)-6-methyl-1,4- oxazepan-6-ol (Int-12) (13.9 g, 106 mmol) and DIEA (61.6 mL, 352 mmol) were added at 25 °C, and the mixture was stirred at 80 °C for 2 h. The reaction was diluted with H2O (300 mL), extracted with DCM (100 mL x 3), and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by flash silica gel chromatography (0 to 70% Pet. ether / EtOAc) to give (S)-4-(8-chloro-2-145021.608067 (002600.PC) (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 397.

[0326] Step B: (S)-4-(8-chloro-2-(methylsulfonyl)pyrido4-yl)-6-methyl-1,4-oxazepan-6-ol

[0327] To a solution of (S)-4-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (20 g, 50 mmol) in DCM (300 mL) was added mCPBA (30.7 g, 151 mmol, 85% wt%) at 0 °C. The reaction was warmed to r.t. and stirred for 2 h. The mixture was diluted with sat. aq. NaHCO3 (30 mL) and sat. aq. Na2SO3 (60 mL) at 0 °C, then extracted with DCM (200 mL x 3), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give (S)-4-(8- chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol. MS (ESI) [M+H]+: m / z 429.

[0328] Step C: (S)-4-(8-chloro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin- 7a -yl)methoxy)pyrido 4-yl)-6-methyl-1,4-oxazepan-6-ol

[0329] To a solution of (S)-4-(8-chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (17.0 g, 39.6 mmol) and (S,Z)-(2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol hydrochloride (Int-9) (8.23 g, 39.6 mmol) in DMF (200 mL) was added NaH (9.51 g, 238 mmol, 60% in mineral oil) at 0 °C. Then the reaction was stirred at 25 °C for 10 min. The mixture was quenched with sat. aq. NH4Cl (200 mL), extracted with EtOAc, the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by flash silica gel chromatography (0-77% EtOAc / petroleum ether, basified with TEA) to give (S)-4-(8-chloro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 520.

[0330] Step D: (6S)-4-(8-(5-ethyl-6-fluoro-1-((trifluoromethyl)sulfonyl)-1H- benzo[f]indazol-4-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido 4-yl)-6-methyl-1,4-oxazepan-6-ol

[0331] To a - - tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol (9.5 g, 18.3 mmol) in toluene (100 mL) was added (5-ethyl-6-fluoro-1- ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)boronic acid (Int-8) (7.84 g, 20.1 mmol), SPhos Pd G3 (4.28 g, 5.48 mmol) and K2CO3 (46 mL, 92 mmol, 2 M in H2O) at 25145021.608067 (002600.PC) °C. The mixture was stirred at 60 °C for 2 h under N2 atmosphere. The reaction was diluted with H2O (80 mL), extracted with EtOAc (100 mL x 3), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by flash silica gel chromatography (0 to 45% THF / Petroleum ether, basified with TEA) to give (6S)-4-(8-(5-ethyl-6-fluoro-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol- 4-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 830.

[0332] Step E: (6S)-4-(8-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2-(((S,Z)-2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-5)

[0333] To a solution of (6S)-4-(8-(5-ethyl-6-fluoro-1-((trifluoromethyl)sulfonyl)-1H- benzo[f]indazol-4-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (9.5 g, 12 mmol) in DCM (5 mL) was added NH3 (100 mL, 700 mmol, 7 M in MeOH) at 25 °C. The mixture was stirred at 25 °C for 15 h. The reaction was evaporated under reduced pressure and the residue was purified by reverse preparative HPLC (Column D, 45-75% water:MeCN w / 0.04% NH4OH + 10 mM NH4HCO3 modifier) to give (6S)-4-(8-(5-ethyl-6- fluoro-1H-benzo[f]indazol-4-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6- ol (Ex-5).1H NMR (400 MHz, CD3OD) δ 8.79 (dd, J = 2.1, 5.7 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J = 6.0, 9.2 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 3.3 Hz, 1H), 7.33 (t, J = 9.4 Hz, 1H), 6.73 - 6.42 (m, 1H), 4.31 - 4.22 (m, 1H), 4.19 - 3.73 (m, 8H), 3.72 - 3.65 (m, 1H), 3.54 - 3.38 (m, 2H), 3.15 - 3.03 (m, 1H), 2.73 - 2.55 (m, 2H), 2.49 - 2.32 (m, 2H), 2.22 - 2.00 (m, 2H), 1.97 - 1.73 (m, 3H), 1.26 - 1.09 (m, 3H), 0.72 (dt, J = 3.5, 7.3 Hz, 3H). MS (ESI) [M+H]+: m / z 698.

[0334] Example 6: (6S)-4-(8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a -yl)methoxy)spiro[cyclopropane-1,9'-4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-6)145021.608067 (002600.PC)

[0335] Step A: 4-(benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2-(methylthio)-9H- pyrimidin-9-one

[0336] To a solution of 4- - - pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one (Int-11) (5.00 g, 13.5 mmol) in toluene (60 mL) was added K2CO3 (20.3 mL, 40.6 mmol, 2 M in H2O), cataCXiumA Pd G3 (4.52 g, 6.76 mmol) and (6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-3) (5.20 g, 16.2 mmol) at 25 °C, and the mixture was stirred at 50 °C for 16 h under N2 atmosphere. The mixture was diluted with H2O (50 mL), extracted with DCM (80 mL x 3), the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash silica gel chromatography (0-36% EtOAc / petroleum ether) to give 4-(benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2- d]pyrimidin-9-one. MS (ESI) [M+H]+: m / z 610.

[0337] Step B: 4-(benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-9-methyl-2-(methylthio)-9H- 9-ol

[0338] To a solution of 4-(benzyloxy)-8- pyran- 2-yl)-1H-indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-145021.608067 (002600.PC) one (4.70 g, 7.70 mmol) in THF (50 mL) was added methylmagnesium bromide (5.65 mL, 16.9 mmol, 3 M in THF) at -78 °C, the mixture was stirred at -78 °C for 40 min under N2 atmosphere. The mixture was quenched with sat. aq. NH4Cl (30 mL), extracted with EtOAc (30 mL x 3). The organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-45% EtOAc / petroleum ether gradient) to give 4-(benzyloxy)-8-(6- chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-9-methyl-2- (methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-ol. MS (ESI) [M+H]+: m / z 626.

[0339] Step C: 4-(benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-9-methylene-2-(methylthio)-9H-

[0340] To a solution of 4-(benzyloxy)-8-(6- pyran- 2-yl)-1H-indazol-4-yl)-9-methyl-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2- d]pyrimidin-9-ol (3.5 g, 5.59 mmol) in DCM (40 mL) was added Martin's Sulfurane (5.64 g, 8.38 mmol) at 25 °C, and the mixture was stirred at 25 °C for 20 min under N2 atmosphere. The mixture was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (0~17% THF / petroleum ether gradient) to give 4- (benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-9- methylene-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine. MS (ESI) [M+H]+: m / z 608.

[0341] Step D: 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2'-(methylthio)spiro[cyclopropane-1,9'-d]pyrimidine]

[0342] To a solution of trimethylsulfoxonium iodide (0.847 g, 3.85 mmol) in tBuOH (15 mL) was added potassium tert-butoxide (0.432 g, 3.85 mmol) at 25 °C under N2 atmosphere, the mixture was stirred at 25 °C for 1 h. To the mixture was added a solution of 4-(benzyloxy)-8-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-9- methylene-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine (1.8 g, 2.96 mmol) in tBuOH (15 mL) and the mixture was stirred at 60 °C for 1 h. The reaction was quenched with sat. aq. NH4Cl (20 mL) and was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The material was purified by flash silica gel chromatography (0-37% THF / petroleum ether) to give 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-145021.608067 (002600.PC) pyran-2-yl)-1H-indazol-4-yl)-2'-(methylthio)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 622.

[0343] Step E: 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2'-(methylsulfinyl)spiro[cyclopropane-1,9'-a - 5-cyclopropyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2'-(methylthio)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine] (1.00 g, 1.61 mmol) in DCM (15 mL) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (1.26 g, 4.82 mmol) at 25 °C under N2atmosphere and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (0~53% petroleum ether / EtOAc) to give 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(methylsulfinyl)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 638.

[0345] Step F: 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro- pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'-pyrido [1,2-

[0346] To a solution of 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl- pyran- 2-yl)-1H-indazol-4-yl)-2'-(methylsulfinyl)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine] (450 mg, 0.705 mmol) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (168 mg, 1.06 mmol) in THF (5 mL) was added LiHMDS (1.41 mL, 1.41 mmol, 1 M in THF) at 0 °C under N2atmosphere and the mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with sat. aq. NH4Cl (10 mL) and was extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (2 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~100% petroleum ether / EtOAc basified with TEA) to give 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 733.

[0347] Step G: 8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a -yl)methoxy)spiro[cyclopropane-1,9'-145021.608067 (002600.PC)

[0348] To a solution of 4'-(benzyloxy)-8'-(6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine] (100 mg, 0.136 mmol) in DCM (0.1 mL) was added TFA (2 mL, 26.0 mmol), the reaction was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give 8'-(6-chloro-5-cyclopropyl- 1H-indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-ol. MS (ESI) [M+H]+: m / z 559.

[0349] Step H: (6S)-4-(8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a -yl)methoxy)spiro[cyclopropane-1,9'-d] -4'-yl)-6-methyl-1,4-oxazepan-6-ola (6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-ol (76 mg, 0.136 mmol) in MeCN (1 mL) was added BOP (120 mg, 0.272 mmol) and the mixture was stirred at 25 °C for 0.5 h under N2atmosphere. (S)-6-methyl-1,4-oxazepan-6-ol (Int-12), HCl (45.6 mg, 0.272 mmol) was added to the mixture followed by and DIEA (0.142 mL, 0.816 mmol). The reaction was stirred at 50 °C for 16 h. The reaction was concentrated under reduced pressure. The material was purified by preparative HPLC (Column F, 38-100% water / MeCN w / 0.1% TFA modifier) to give racemic (6S)-4-(8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 672.

[0351] Step I: (6S)-4-(8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a -yl)methoxy)spiro[cyclopropane-1,9'-pyrido 4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-6)

[0352] - chloro-5-cyclopropyl-1H-indazol-4-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol (70 mg, 0.104 mmol) was separated by preparative SFC (Column A, 60% iPrOH in CO2w / 0.1% NH4OH) to give (6S)-4-(8'-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-6, the second eluting isomer from SFC).1H NMR (400MHz, CD3OD) δ 8.63 (d, J = 5.4 Hz, 1H),145021.608067 (002600.PC) 7.82 (s, 1H), 7.78 (d, J = 5.4 Hz, 1H), 7.43 (s, 1H), 5.66 - 5.45 (m, 1H), 4.65 - 4.56 (m, 1H), 4.52 - 4.45 (m, 1H), 4.22 (br d, J = 13.6 Hz, 1H), 4.11 (br d, J = 14.8 Hz, 1H), 4.03 (br dd, J = 3.7, 11.8 Hz, 1H), 3.89 - 3.79 (m, 4H), 3.72 (d, J = 12.5 Hz, 1H), 3.53 - 3.38 (m, 2H), 2.64 - 2.53 (m, 2H), 2.42 - 2.24 (m, 3H), 2.18 - 1.98 (m, 2H), 1.86 - 1.72 (m, 2H), 1.57 - 1.43 (m, 2H), 1.25 - 1.16 (m, 3H), 0.99 - 0.85 (m, 2H), 0.73 - 0.45 (m, 2H), 0.40 - 0.21 (m, 2H). MS (ESI) [M+H]+: m / z 672.

[0353] The examples in the table below were synthesized using a similar procedure as described in the synthesis of Ex-6 by making the appropriate substitutions for starting material, intermediates, and / or reagents. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.608067 (002600.PC)

[0354] Example 12: (6S)-4-(8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- 4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-12)145021.608067 (002600.PC)

[0355] Step A: 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-((trifluoromethyl)sulfonyl)-1H- benzo[f]indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one

[0356] In a round bottom flask, to a solution of 4-(benzyloxy)-8-chloro-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one (Int-11) (3.5 g, 9.46 mmol) and (5- ethyl-6-fluoro-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)boronic acid (Int-8) (3.69 g, 9.46 mmol) in toluene (70 mL) was added mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (3.45 g, 4.73 mmol) and 2 M aq. K2CO3 (23.7 mL, 47.3 mmol) at 20 °C. The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-145021.608067 (002600.PC) ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one. MS (ESI) [M+H]+: m / z 680.

[0357] Step B: 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2- (methylthio)-9H-pyrido 9-one

[0358] In a round a -8-(5-ethyl-6-fluoro-1- ((trifluoromethyl)sulfonyl)-1H-benzo[f]indazol-4-yl)-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one (3 g, 4.41 mmol) in DCM (50 mL) was added NH3 (100 mL, 7 M in MeOH) at 20 °C. The mixture was stirred at 30 °C for 48 h. The mixture was concentrated under reduced pressure. The material was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give 4-(benzyloxy)-8- (5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one. MS (ESI) [M+H]+: m / z 548.

[0359] Step C: 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one

[0360] In a round bottom flask, to a solution of 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1H- benzo[f]indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one (1.60 g, 2.92 mmol) in DCM (50 mL) was added 3,4-dihydropyran (0.801 mL, 8.77 mmol) and p-toluenesulfonic acid (0.167 g, 0.877 mmol) at 20 °C. The mixture was stirred at 20 °C for 48 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% ethyl acetate / petroleum ether) to give 4- (benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one. MS (ESI) [M+H]+: m / z 632.

[0361] Step D: 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-9-methyl-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2- d]pyrimidin-9-ol

[0362] In a round bottom flask, to a solution of 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-one (1.3 g, 2.058 mmol) in THF (15 mL) was added methylmagnesium bromide (1.51 mL, 4.53 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. The mixture was quenched with sat. NH4Cl (5 mL) and extracted with EtOAc (15 mL x 3). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% ethyl acetate / petroleum ether) to give 4-(benzyloxy)-8-(5-ethyl-145021.608067 (002600.PC) 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-9-methyl-2-(methylthio)- 9H-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-ol. MS (ESI) [M+H]+: m / z 648.

[0363] Step E: 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-9-methylene-2-(methylthio)-9H-pyrido[4',3':3,4]cyclopenta[1,2- d]pyrimidine

[0364] In a glovebox, bis[α,α-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur (934 mg, 1.39 mmol) was added to a solution of 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-9-methyl-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin-9-ol (600 mg, 0.926 mmol) in DCM (6 mL) was added at rt. The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% THF / petroleum ether) to give 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-9-methylene-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine. MS (ESI) [M+H]+: m / z 630.

[0365] Step F: 4'-(benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-2'-(methylthio)spiro[cyclopropane-1,9'-a iodide (273 mg, 1.239 mmol) in tBuOH (15 mL) was added potassium tert-butoxide (139 mg, 1.239 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. Then 4-(benzyloxy)-8-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-benzo[f]indazol-4-yl)-9-methylene-2-(methylthio)-9H- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine (600 mg, 0.953 mmol) in tBuOH (10 mL) and DCM (5 mL) was added to the above mixture. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with sat. aq. NH4Cl (15 mL) and extracted with EtOAc (15 mL x 3). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~30% THF / Pet.ether) to give 4'- (benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-2'- (methylthio)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 644.

[0367] Step G: 4'-(benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-2'-(methylsulfinyl)spiro[cyclopropane-1,9'-a - 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 1H-benzo[f]indazol-4-yl)-2'-(methylthio)spiro[cyclopropane-1,9'-145021.608067 (002600.PC) pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine] (400 mg, 0.621 mmol) in DCM (10 mL) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (487 mg, 1.864 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~30% THF / petroleum ether) to give 4'- (benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-2'- (methylsulfinyl)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 660.

[0369] Step H: 4'-(benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)spiro[cyclopropane-1,9'-

[0370] To a solution of 4'- - pyran-2-yl)- 1H-benzo[f]indazol-4-yl)-2'-(methylsulfinyl)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine] (100 mg, 0.152 mmol) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (36.2 mg, 0.227 mmol) in THF (2 mL) was added LiHMDS (0.303 mL, 0.303 mmol, 1 M in THF) at 0 °C under N2 atmosphere, and the mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with sat. NH4Cl (2 mL) and extracted with EtOAc (5 mL * 3). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prepative TLC (100% EtOAc) to give 4'-(benzyloxy)-8'-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidine]. MS (ESI) [M+H]+: m / z 755.

[0371] Step I: 8'-(5-ethyl-6-fluoro- benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a - methoxy)spiro[cyclopropane-1,9'- pyrido 4'-ol

[0372] a a of 4'-(benzyloxy)-8'-(5-ethyl-6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2- d]pyrimidine] (40 mg, 0.053 mmol) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo at 20 °C to give 8'-(5- ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]- 4'-ol. MS (ESI) [M+H]+: m / z 581.145021.608067 (002600.PC)

[0373] Step J: (6S)-4-(8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ola solution of 8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-ol (37 mg, 0.064 mmol) in MeCN (1 mL) was added BOP (42.3 mg, 0.096 mmol) and DIEA (0.089 mL, 0.510 mmol) at 20 °C, and the mixture was stirred at 20 °C for 1 h. Then (S)-6-methyl-1,4-oxazepan-6-ol (Int-12), HCl (32.0 mg, 0.191 mmol) was added to the mixture, and the resulting mixture was stirred at 50 °C for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC (Column E, 23 – 43% water / MeCN w / 0.2% formic acid) to give racemic (6S)-4-(8'-(5- ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'-pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]- 4'-yl)-6-methyl-1,4-oxazepan-6-ol. MS (ESI) [M+H]+: m / z 694.

[0375] Step K: (6S)-4-(8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-12)

[0376] The racemic mixture of (6S)-4-(8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol (20 mg, 0.029 mmol) was separated by preparative SFC (Column C, 60% EtOH in CO2 w / 0.1% NH4OH) to give (6S)-4-(8'-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)spiro[cyclopropane-1,9'- pyrido[4',3':3,4]cyclopenta[1,2-d]pyrimidin]-4'-yl)-6-methyl-1,4-oxazepan-6-ol (Ex-12, the second eluting isomer from SFC).1H NMR (400MHz, CD3OD) δ 8.69 (d, J = 5.4 Hz, 1H), 8.27 (s, 1H), 8.11 - 7.99 (m, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.30 (m, 1H), 5.37 - 5.21 (m, 1H), 4.27 - 4.17 (m, 2H), 4.13 - 4.06 (m, 2H), 3.98 - 3.86 (m, 2H), 3.80 - 3.71 (m, 2H), 3.48 (d, J = 12.8 Hz, 1H), 3.26 - 3.21 (m, 2H), 3.19 - 3.14 (m, 1H), 3.05 - 2.96 (m, 1H), 2.58 - 2.48 (m, 1H), 2.24 - 2.16 (m, 2H), 2.10 (br s, 1H), 1.98 (br s, 1H), 1.55 - 1.50 (m, 1H), 1.36 (dd, J = 2.2, 10.3 Hz, 3H), 1.28 (s, 3H), 1.03 - 0.98 (m, 1H), 0.92 (br s, 2H), 0.83 (t, J = 7.3 Hz, 3H), 0.50 - 0.40 (m, 1H). MS (ESI) [M+H]+: m / z 694. Assays145021.608067 (002600.PC)

[0377] Procedure for SOS-catalyzed nucleotide exchange assay for KRAS-WT, G12C / D / V, G13D, HRAS, and NRAS (Procedure A)

[0378] Recombinant KRAS-G12C protein used in this assay has an additional triple mutation (C51S / C80L / C118S). Whereas KRAS-WT, G12D / V, G13D, HRAS and NRAS are in context of their WT protein sequence background. Specifically, the SOS-catalyzed nucleotide exchange assay utilizes a preformed TR-FRET complex containing a specific biotinylated RAS protein (KRAS-WT, G12C / V / D, G13D, HRAS, NRAS; described above) with Bodipy-GDP, and Terbium-streptavidin. Compounds are preincubated with this complex for 60 minutes. Subsequently, recombinant human SOS protein and unlabeled GTP are added to initiate the exchange reaction. Small molecule inhibitors stabilize the Bodipy- GDP complex whereas the untreated protein rapidly exchanges Bodipy-GDP for unlabeled GTP resulting in reduced TR-FRET signal.

[0379] To assemble the preformed TR-FRET complexes, each biotinylated RAS protein is diluted to 2 µM in an EDTA Buffer (20 mM HEPES pH 7.5, 50 mM sodium chloride, 10 mM EDTA, and 0.01% Tween) and incubated at room temperature for one hour. This mixture is then further diluted to 90 nM in an Assay Buffer (20 mM HEPES pH 7.5, 150 mM sodium chloride, 10 mM magnesium chloride, and 0.005% Tween) containing 15 nM of Terbium- Streptavidin (Invitrogen, catalog# PV3577) and 900 nM of Bodipy-GDP (Invitrogen, catalog# G22360) and incubated at room temperature for six hours. It should be noted that this preformed TR-FRET complex for each of the RAS protein were made ahead of time, aliquoted and stored at -80oC until the day of the experiment.

[0380] Each test compound (10 mM stock in DMSO) is diluted in DMSO to make a final- 10-point, 3-fold dilution and is acoustically dispensed into a 384-well assay plate (Corning, catalog# 3820) using an Echo 550 (Labcyte). Each well of the assay plate receives 3 µL of a specific 3x RAS preformed TR-FRET complex and 3 µL of Assay Buffer and is incubated at room temperature for 60 minutes (preincubation time). Each well then receives 3 µL of 3x recombinant human SOS protein and GTP (Sigma, G8877) in Assay Buffer and is incubated at room temperature for 30 minutes (G13D), 60 minutes (KRAS WT / G12C / D, H / NRAS) or 90 minutes for G12V. The final reaction in each well of 9 μL consists of 3 mM GTP, specific Ras and SOS proteins in the following concentrations: KRAS-G12C / SOS = 3 nM / 40 nM, KRAS-WT and G12D / SOS = 1 nM / 40 nM, KRAS-G12V / SOS = 1.25 nM / 160 nM, KRAS-G13D / SOS = 1.25 nM / 0 nM, HRAS and NRAS = 1.25 nM / 40 nM.

[0381] The time-resolved fluorescence resonance energy transfer (TR-FRET) signal is measured on an Envision (PerkinElmer) plate reader: Excitation filter = 340 nm; emission1 =145021.608067 (002600.PC) 495 nm; emission2 = 520 nm; dichroic mirror = D400 / D505; delay time = 100 ms. The signal of each well is determined as the ratio of the emission at 520 nm to that at 495 nm. Percent effect of each well is determined after normalization to control wells containing DMSO (no effect) or a saturating concentration of inhibitor (max effect). The apparent effect as a function of compound concentration is fit to a four-parameter logistic equation.

[0382] Procedure for SOS-catalyzed nucleotide exchange assay for KRAS- G12C / D / V / WT (Procedure B)

[0383] Recombinant KRAS G12C (amino acids 1-169, SEQ ID NO:9), KRAS G12D (amino acids 1-169, SEQ ID NO:10), KRAS G12V (amino acids 1-169, SEQ ID NO:11), KRAS WT (amino acids 1-169, SEQ ID NO:12) and SOS1 (amino acids 564-1049, SEQ ID NO:13) proteins were expressed in E.coli and purified by affinity chromatography. To prepare each BODIPYTMFL GDP-bound KRAS protein, 50 μM KRAS proteins were incubated with 0.5 mM BODIPYTMFL GDP (Invitrogen, G22360) in a loading buffer (20 mM Tris-HCl pH 7.5, 50 mM NaCl, 1 mM DTT and 2.5 mM EDTA) for 1 hour on ice. After the incubation, MgCl2 was added to a final concentration of 10 mM, followed by an incubation at room temperature for 30 minutes. The mixtures were allowed to pass through a NAP-5 column to remove free nucleotides and purified BODIPYTMFL GDP-bound KRAS G12C, G12D, G12V and WT proteins were used for compound evaluation.

[0384] The inhibitory activity of compounds on recombinant KRAS is measured by the displacement of the bound BODIPYTMGDP. Specifically, 2.5 nM of each BODIPYTMFL GDP-bound KRAS complex was incubated with various concentrations of compound in a reaction buffer (20 mM Tris-HCl pH 7.5, 100 mM NaCl, 1 mM MgCl2, 2 mM DTT, 0.1% Tween 20) at 25°C for 1 hour. After the incubation, recombinant SOS1 and GMPPNP (Jena Bioscience GmbH, NU-401) were added and incubated at room temperature for 30 minutes to proceed SOS1-dependent GDP-GTP exchange reaction on KRAS. Displacement of BODIPYTMFL GDP by Guanosine-5'-[( β,γ )-imido]triphosphate, Tetralithium salt (GMPPNP) was measured by calculating the ratio of fluorescence intensities of BODIPYTMFL before and after the exchange reaction. Percent Inhibition was calculated by setting the fluorescence ratio from the reaction without test compound (DMSO control) and the fluorescence ratio from the reaction without SOS1 and GMPPNP as 0% and 100% inhibition, respectively. Dose response curves were analyzed using a 4-parameter logistic model to calculate IC50values.145021.608067 (002600.PC)

[0385] Procedure for cellular phospho-ERK assay in KRAS wild type and mutant (G12D , G12V) cell lines

[0386] MKN-1 cells (JCRB JCRB0252) containing amplified wild-type KRAS, were cultured in growth medium that contains RPMI 1640-GlutaMAX™-I (ThermoFisher Scientific 61870) containing 10% heat inactivated fetal bovine serum (ThermoFisher Scientific 10091148), 1 mM sodium pyruvate and 10 mM HEPES. AsPC-1 cells (ATCC® CRL-1682™), containing homozygous KRAS-G12D activating mutation, were cultured in T150 flask in growth medium (RPMI medium 1640-GlutaMAX™-I (ThermoFisher Scientific 61870) containing 10% fetal bovine serum (ThermoFisher Scientific 10091148)). SW620 cells (ATCC® CRL-227™), containing homozygous KRAS-G12V activating mutation, were cultured in growth medium that contains RPMI 1640-GlutaMAX™-I (ThermoFisher Scientific 61870) containing 10% heat inactivated fetal bovine serum (ThermoFisher Scientific 10091148).

[0387] Cells for the assay were harvested in growth medium after TrypLE (ThermoFisher scientific 12604021) digestion and were seeded in a 384-well collagen coated cell culture plate (Corning 356702) at a density of 10,000 -15,000 cells / 20 µL / well, and incubated at 37°C, 5% CO2overnight. The compound (with 10 mM stock concentration) dose-response titrations were prepared [30 µM final ERK detection assay concentration and 1:3 dilutions, 10-point dose response] and appropriate amounts (270 nL) of test compounds were dispensed in a 384-well intermediate plate using an Echo 550 liquid handler. 30 µL / well of RPMI medium 1640- GlutaMAX™-I was added to the intermediate plate and the contents of the intermediate plate (10 µL / well) were then transferred to the 384-well collagen coated cell culture plate, which was incubated at 37°C, 5% CO2for 2 hours. After removal of medium from the collagen coated cell culture plate, cells were lysed in lysis buffer from Alpha SureFire® Ultra™ Multiplex p- ERK and total ERK assay kit (PerkinElmer MPSU-PTERK) containing Halt™ Protease and Phosphatase inhibitor cocktail (ThermoFisher Scientific 78446) at room temperature with constant shaking at 300 rpm for 30 minutes. The cell lysates were then transferred to an OptiPlate-384 plate (PerkinElmer 6005620), and the phosphorylation of ERK (p-ERK) and total ERK levels were detected by Alpha SureFire® Ultra™ Multiplex p-EEK kit and total ERK assay kit (PerkinElmer MPSU-PTERK) following the manufacturer's protocol. Assay plates were read on a EnVision Multimode Plate Reader (PerkinElmer), and the ratio of p-ERK vs. total ERK in each well was used as the final readout. Dose response curves were analyzed using a 4-parameter logistic model to calculate IC50values using Spotfire software. The results of this assay are presented in the table below.145021.608067 (002600.PC)

[0388] For Example Nos.3 and 4 nucleotide exchange assays for KRAS G12D, WT, G12C, and G12V were performed according to Procedure B. All other compounds of the nucleotide exchange assays were tested according to Procedure A.

[0389] SEQUENCES (Procedure A)

[0390] SEQ ID NO: 1 – Recombinant Human KRAS G12C

[0391] GLNDIFEAQKIEWHETEYKLVVVGACGVGKSALTIQLIQNHFVDEYDPTIEDS YRKQVVIDGETSLLDILDTAGQEEYSAMRDQYMRTGEGFLLVFAINNTKSFEDIHHY REQIKRVKDSEDVPMVLVGNKSDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVD DAFYTLVREIRKHKEK

[0392] SEQ ID NO: 2 – Recombinant Human KRAS G12D

[0393] GLNDIFEAQKIEWHETEYKLVVVGADGVGKSALTIQLIQNHFVDEYDPTIEDS YRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHY REQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVD DAFYTLVREIRKHKEK

[0394] SEQ ID NO: 3 – Recombinant Human KRAS G12V145021.608067 (002600.PC)

[0395] GLNDIFEAQKIEWHETEYKLVVVGAVGVGKSALTIQLIQNHFVDEYDPTIEDS YRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHY REQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVD DAFYTLVREIRKHKEK

[0396] SEQ ID NO: 4 – Recombinant Human KRAS G13D

[0397] GLNDIFEAQKIEWHETEYKLVVVGAGDVGKSALTIQLIQNHFVDEYDPTIEDS YRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHY REQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVD DAFYTLVREIRKHKEK

[0398] SEQ ID NO: 5 – Recombinant Human HRAS

[0399] GGGGSHMTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVI DGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRV KDSDDVPMVLVGNKCDLAARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTL VREIRQH

[0400] SEQ ID NO: 6 – Recombinant Human NRAS

[0401] GGGGMTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDG ETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKD SDDVPMVLVGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVRE IRQYRMKKLN

[0402] SEQ ID NO: 7 – Recombinant Human SOS Protein

[0403] MGSSHHHHHHSGENLYFQGSSGLNDIFEAQKIEWHESSEEQMRLPSADVYRF AEPDSEENIIFEENMQPKAGIPIIKAGTVIKLIERLTYHMYADPNFVRTFLTTYRSFCKP QELLSLIIERFEIPEPEPTEADRIAIENGDQPLSAELKRFRKEYIQPVQLRVLNVCRHWV EHHFYDFERDAYLLQRMEEFIGTVRGKAMKKWVESITKIIQRKKIARDNGPGHNITF QSSPPTVEWHISRPGHIETFDLLTLHPIEIARQLTLLESDLYRAVQPSELVGSVWTKED KEINSPNLLKMIRHTTNLTLWFEKCIVETENLEERVAVVSRIIEILQVFQELNNFNGVL EVVSAMNSSPVYRLDHTFEQIPSRQKKILEEAHELSEDHYKKYLAKLRSINPPCVPFF GIYLTNILKTEEGNPEVLKRHGKELINFSKRRKVAEITGEIQQYQNQPYCLRVESDIKR FFENLNPMGNSMEKEFTDYLFNKSLEIEPRNPKPLPRFPKKYSYPLKSPGVRPSNPRP GT

[0404] SEQ ID NO: 8 – Recombinant Human KRAS WT

[0405] GGGGTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGE TCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDS145021.608067 (002600.PC) EDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREI RKHKEK

[0406] SEQUENCES (Procedure B)

[0407] SEQ ID NO: 9 – KRAS G12C (amino acids 1-169, N-terminal His-tag)

[0408] MASSHHHHHHSSENLYFQGMTEYKLVVVGACGVGKSALTIQLIQNHFVDEY DPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKS FEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSA KTRQGVDDAFYTLVREIRKHKEK

[0409] SEQ ID NO: 10 – KRAS G12D (amino acids 1-169, N-terminal His-tag)

[0410] MASSHHHHHHSSENLYFQGMTEYKLVVVGADGVGKSALTIQLIQNHFVDEY DPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKS FEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSA KTRQGVDDAFYTLVREIRKHKEK

[0411] SEQ ID NO: 11 – KRAS G12V (amino acids 1-169, N-terminal His-tag)

[0412] MGSSHHHHHHSSGLVPRGSHMASMTGGQQMGRGSENLYFQGMTEYKLVV VGAVGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSA MRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPS RTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEK

[0413] SEQ ID NO: 12 – KRAS WT (amino acids 1-169, N-terminal His-tag)

[0414] MASSHHHHHHSSENLYFQGMTEYKLVVVGAGGVGKSALTIQLIQNHFVDEY DPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKS FEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSA KTRQGVDDAFYTLVREIRKHKEK

[0415] SEQ ID NO: 13 – SOS1 (amino acids 564-1049, No tag)

[0416] GEEQMRLPSADVYRFAEPDSEENIIFEENMQPKAGIPIIKAGTVIKLIERLTYH MYADPNFVRTFLTTYRSFCKPQELLSLIIERFEIPEPEPTEADRIAIENGDQPLSAELKR FRKEYIQPVQLRVLNVCRHWVEHHFYDFERDAYLLQRMEEFIGTVRGKAMKKWVE SITKIIQRKKIARDNGPGHNITFQSSPPTVEWHISRPGHIETFDLLTLHPIEIARQLTLLES DLYRAVQPSELVGSVWTKEDKEINSPNLLKMIRHTTNLTLWFEKCIVETENLEERVA VVSRIIEILQVFQELNNFNGVLEVVSAMNSSPVYRLDHTFEQIPSRQKKILEEAHELSE DHYKKYLAKLRSINPPCVPFFGIYLTNILKTEEGNPEVLKRHGKELINFSKRRKVAEIT GEIQQYQNQPYCLRVESDIKRFFENLNPMGNSMEKEFTDYLFNKSLEIEPRNPKPLPR FPKKYSYPLKSPGVRPSNPRPGT

Claims

145021.608067 (002600.PC) We claim:

1. A compound of Formula (I)wherein: each RXis independently selected from the group consisting of fluoro, cyano, hydroxy, oxo, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6alkoxy, C1-C6fluoroalkoxy, C1-C6cyanoalkyl, and C1-C6hydroxyalkyl;WAis selected from the group consisting of C(RW1)2 and S, wherein the two RW1substituents are independently methylene or ethylene, and wherein the two RW1substituents, together with the carbon atom to which they are attached, form a 3- to 5- membered saturated monocyclic ring;CYis:(i) a 9- to 10-membered fused bicyclic heteroaryl, wherein the 9- to 10-membered fused bicyclic heteroaryl contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or (ii) a 12- to 17-membered fused tricyclic heterocycloalkyl, where at least two of the rings of the 12- to 17-membered fused tricyclic heterocycloalkyl are aromatic, the third ring is partially unsaturated or aromatic, wherein the 12- to 17-membered fused tricyclic heterocycloalkyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein CYis unsubstituted or substituted by 1 to 3 RYsubstituents independentlyselected from the group consisting of halo, hydroxy, oxo, cyano, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C2-C7alkenyl, C1-C6fluoroalkyl, C3-C6fluorocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6fluoroalkynyl, C2-C7fluoroalkenyl, C1-C3fluoroalkenylenyl, C1-C6alkylthio, C1-C6fluoroalkylthio,145021.608067 (002600.PC) amino, C1-C6alkylamino, C1-C6dialkylamino, tri(C1-C6alkyl)silyl, cyano, C1-C6cyanoalkyl, C1-C6fluorocyanoalkyl, C1-C3alkoxy C1-C3alkyl, C1-C6alkoxycarbonyl, C1-C6acyl, and C1-C6alkylenyl,RZC is selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkenylenyl, C1-C3hydroxyfluoroalkyl,C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3cyanoalkyl, C3-C6cycloalkyl, C3-C6fluorocycloalkyl, C3-C6hydroxycycloalkyl, C3-C6hydroxyfluorocycloalkyl, C2-C4fluoroalkenyl, C1-C3alkylamino, C1-C3dialkylamino, methylene(C1-C3alkyl)amino,C1-C3alkylenedi(C1-C3alkyl)amino and methylene(C1-C3alkyl)(C1-C3alkyl)carbamate; and subscript n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein each RXis independently selected from the group consisting of methyl and hydroxy.

3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereinWAis S.

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereinWAis C(RW1<sub>)2.

6. The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein thetwo RW1substituents, together with the carbon atom to which they are attached, form a 3-membered saturated monocyclic ring.145021.608067 (002600.PC) 7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the<img src='' class="img-anchor img-center" img-id="IMGF000097_0001" / >8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein CYis a 9- to 10-membered fused bicyclic heteroaryl, wherein the 9- to 10-membered fused bicyclic heteroaryl contains two nitrogen heteroatoms.

9. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein CYis a 12- to 14-membered fused tricyclic heteroaryl, wherein the 12- to 14-membered fused tricyclic heteroaryl contains two nitrogen heteroatoms.

10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein CYis substituted by 1 to 2 RYsubstituents independently selected from the group consisting ofhalo, C1-C6alkyl, C3-C6cycloalkyl, C2-C7alkenyl, C1-C6fluoroalkyl, and C3-C6fluorocycloalkyl.

11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, whereinCYis substituted by 1 to 2 RYsubstituents independently selected from the group consistingof fluoro, chloro, ethyl, cyclopropyl, propenyl, trifluoromethyl, and fluorocyclopropyl.

12. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein CYis selected from the group consisting of:145021.608067 (002600.PC)subscript s is 0, 1, or 2.

13. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein CYis selected from the group consisting of:<img src='' class="img-anchor img-center" img-id="IMGF000098_0002" / >.145021.608067 (002600.PC) 14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereinRZC< / sup>is fluoro.

15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereinRZCis fluoromethylenyl.

16. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the<img src='' class="img-anchor img-center" img-id="IMGF000099_0001" / >145021.608067 (002600.PC)or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:145021.608067 (002600.PC)<img src='' class="img-anchor img-center" img-id="IMGF000101_0001" / >.

19. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000101_0002" / >.

20. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000101_0003" / >.

21. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000101_0004" / >.145021.608067 (002600.PC) 22. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:<img src='' class="img-anchor img-center" img-id="IMGF000102_0001" / >.

23. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:<img src='' class="img-anchor img-center" img-id="IMGF000102_0002" / >.

24. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:<img src='' class="img-anchor img-center" img-id="IMGF000102_0003" / >.

25. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:145021.608067 (002600.PC)<img src='' class="img-anchor img-center" img-id="IMGF000103_0001" / >.

26. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000103_0002" / >.

27. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000103_0003" / >.

28. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:145021.608067 (002600.PC)<img src='' class="img-anchor img-center" img-id="IMGF000104_0001" / >.

29. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein the compound is:<img src='' class="img-anchor img-center" img-id="IMGF000104_0002" / >.

30. The compound of claim 1 selected from Examples 1-12 or the pharmaceutically acceptable salts thereof.

31. A pharmaceutical composition comprising the compound of any one of claims 1-30 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising the compound of any one of claims 1-30 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

33. A method of inhibiting KRAS-G12D protein comprising contacting KRAS-G12D protein with the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12D protein.

34. A method of inhibiting KRAS-G12C protein comprising contacting KRAS-G12C protein with the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12C protein.145021.608067 (002600.PC) 35. A method of inhibiting KRAS-G12V protein comprising contacting KRAS-G12V protein with the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12V protein.

36. A method of inhibiting KRAS-G13D protein comprising contacting KRAS-G13D protein with the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G13D protein.

37. A method of treating cancer comprising administering a therapeutically effective amount of the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

38. The method of claim 37, further comprising administering an additional active agent to the subject.

39. The compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, in therapy.

40. The compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for treating cancer.

41. The compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or use of the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

42. The compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer.145021.608067 (002600.PC) 43. The compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer, or use of the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer.

44. A pharmaceutical composition comprising the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, for treating cancer.

45. A pharmaceutical composition comprising the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of any one of claims 1-30, or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer.

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